Taketomo 2019

ACETILCISTEINA
Dosing: Pediatric
Acetaminophen poisoning: Infants, Children, and Adolescents: Only the 72-hour oral and 21-hour IV regimens are FDA
approved. Ideally, in patients with an acute acetaminophen ingestion, treatment should begin within 8 hours of
ingestion or as soon as possible after ingestion. In patients with a suspected acute ingestion where the time of ingestion
is unknown, the serum acetaminophen concentration is unobtainable or uninterpretable within 8 hours of ingestion, the
patient presents >8 hours after ingestion, or there is clinical evidence of toxicity, initiate treatment immediately and re-
evaluate the need for acetylcysteine upon receipt of the results (if applicable). In patients who present following
repeated supratherapeutic ingestions (RSTI) and treatment is deemed appropriate, acetylcysteine should be initiated
immediately. Regardless of the treatment regimen selected, serum acetaminophen concentrations, liver function, and
clinical status should be evaluated during and prior to the end of the treatment regimen to determine if treatment
discontinuation is appropriate. In patients who continue to experience symptoms of hepatotoxicity or elevated liver
function tests at the conclusion of a 72-hour oral or 21-hour IV regimen, extending the treatment course may be
appropriate; however, when and to which patients additional doses should be administered is unclear. Possible
candidates for extended therapy include patients with a suspected massive overdose, concomitant ingestion of other
substances, or patients with preexisting liver disease. In patients with persistently elevated acetaminophen
concentrations, persistently elevated liver function tests, or an elevated INR, additional acetylcysteine should be
administered. Typically, an additional "third dose" or "third bag" (IV: 100 mg/kg [maximum dose: 10 g/dose] infused
over 16 hours) is administered; however, this dose may be inadequate in some patients (Rumack 2012). Consultation
with a poison control center or clinical toxicologist is highly recommended to determine optimal patient care.
Oral: Effervescent tablet (Cetylev) or solution for oral administration (using injectable/nebulizer formulation): There is
no data for use of the OTC supplement tablets for acetaminophen poisoning. Dosing below is based on effervescent
tablet (Cetylev) or a solution for oral administration that is prepared from the solution for oral inhalation: 72-hour
regimen: Consists of 18 doses; total dose delivered: 1,330 mg/kg
Loading dose: 140 mg/kg; maximum dose: 15 g/dose

Maintenance dose: 70 mg/kg every 4 hours for 17 doses; maximum dose: 7.5 g/dose; repeat dose if emesis occurs
within 1 hour of administration; Note: Consultation with a poison control center or clinical toxicologist is highly
recommended when considering the discontinuation of oral acetylcysteine prior to the conclusion of a full 18-dose
course of therapy.
IV (Acetadote): 21-hour regimen: Consists of 3 doses; total dose delivered: 300 mg/kg
Loading dose: 150 mg/kg infused over 60 minutes; maximum dose: 15 g/dose
Second dose: 50 mg/kg infused over 4 hours; maximum dose: 5 g/dose
Third dose: 100 mg/kg infused over 16 hours; maximum dose: 10 g/dose
Respiratory conditions, adjuvant therapy: Note:Patients should receive an aerosolized bronchodilator 10 to 15 minutes
prior to acetylcysteine:
Nebulized inhalation:
Face mask, mouth piece, tracheostomy:
Infants: 1 to 2 mL of 20% solution (may be further diluted with sodium chloride or sterile water for inhalation) or 2 to 4
mL of 10% solution (undiluted); administer 3 to 4 times daily
Children: 3 to 5 mL of 20% solution (may be further diluted with sodium chloride or sterile water for inhalation) or 6 to
10 mL of 10% solution (undiluted); administer 3 to 4 times daily
Adolescents: 3 to 5 mL of 20% solution (may be further diluted with sodium chloride or sterile water for inhalation) or 6
to 10 mL of 10% solution (undiluted); administer 3 to 4 times daily; usual dosing range: 20% solution: 1 to 10 mL or 10%
solution: 2 to 20 mL every 2 to 6 hours
Tent, croupette: 10% or 20% solution: Dose must be individualized; dose is volume of solution necessary to maintain a
very heavy mist in tent or croupette; in some cases, may require up to 300 mL solution/treatment
Direct instillation: Children and Adolescents:
Endotracheal: 1 to 2 mL of 10% to 20% solution every 1 to 4 hours as needed
Percutaneous endotracheal catheter: 1 to 2 mL of 20% or 2 to 4 mL of 10% solution every 1 to 4 hours via syringe
attached to catheter
Diagnostic bronchogram: Children and Adolescents: Nebulization or endotracheal: 1 to 2 mL of 20% solution or 2 to 4 mL
of 10% solution administered 2 to 3 times prior to procedure
Distal intestinal obstruction syndrome (previously known as meconium ileus equivalent): Limited data available; dosing
regimens variable (polyethylene glycol has become more widely used for this indication):
Oral:
Children <10 years: 30 mL of 10% solution diluted in 30 mL juice or soda 3 times/day for 24 hours
Children 10 years and Adolescents: 60 mL of 10% solution diluted in 60 mL juice or soda 3 times/day for 24 hours
Note: Prior to treatment, administer a phosphosoda enema. A clear liquid diet should be used during the 24-hour
acetylcysteine treatment
Rectal enema: Children: Varying dosages; 100 to 300 mL of 4% to 6% solution 2 to 4 times daily; 50 mL of 20% solution 1
to 4 times daily and 5 to 30 mL of 10% to 20% solution 3 to 4 times daily have been used; rectal enemas appear to have
less favorable results than oral administration (Mascarenhas 2003). Note:Higher concentrations (10% to 20%) appear to
increase fluid in the bowel and lead to increased incidence of adverse effects (Perman 1975)
Dosing: Renal Impairment: Pediatric
There are no dosage adjustments provided in the manufacturer's labeling.
Dosing: Hepatic Impairment: Pediatric
Warnings/Precautions
Concerns related to adverse effects:
• Anaphylactoid reactions: Acute flushing and erythema have been reported; usually occurs within 30 to 60 minutes and
may resolve spontaneously. Serious anaphylactoid reactions (some fatal) have also been reported and are more
commonly associated with IV administration, but also occur with oral administration (Mroz 1997). When used for
acetaminophen overdose, the incidence is reduced when the initial intravenous loading dose is administered over 60
minutes. The acetylcysteine infusion may be interrupted until the treatment of allergic symptoms is initiated; the
infusion can then be carefully restarted. Treatment for anaphylactoid reactions should be immediately available.
Conversely, patients with high acetaminophen concentrations (>150 mg/L) may be at a reduced risk for anaphylactoid
reactions (Pakravan 2008; Sandilands 2009; Waring 2008).
• Disease-related concerns:
• Asthma/bronchospasm: Use caution in patients with asthma or history of bronchospasm; these patients may be at
increased risk of hypersensitivity reactions.
Other warnings/precautions:
• Acute acetaminophen overdose: Appropriate use: Acetylcysteine is indicated in patients with a serum acetaminophen
concentration that indicates they are at "possible" risk or greater for hepatotoxicity when plotted on the Rumack-
Matthew nomogram. There are several situations where the nomogram is of limited use. Serum acetaminophen
concentrations obtained <4 hours postingestion are not reliable, except to document the presence of acetaminophen
(Seifert 2015). Patients presenting late may have undetectable serum concentrations, despite having received a toxic
dose. The nomogram is less predictive of hepatic injury following an acute overdose with an extended release
acetaminophen product. The nomogram also does not take into account patients who may be at higher risk of
acetaminophen toxicity (eg, alcoholics, malnourished patients, concurrent use of CYP2E1 enzyme-inducing agents [eg,
isoniazid]). Nevertheless, acetylcysteine should be administered to any patient with signs of hepatotoxicity, even if the
serum acetaminophen concentration is low or undetectable. Patients who present >24 hours after an acute ingestion or
patients who present following an acute ingestion at an unknown time may be candidates for acetylcysteine therapy;
consultation with a poison control center or clinical toxicologist is highly recommended.
• Repeated supratherapeutic ingestion (RSTI) of acetaminophen: Appropriate use: The Rumack-Matthew nomogram is
not designed to be used following RSTIs. In general, an accurate past medical history, including a comprehensive
acetaminophen ingestion history, in conjunction with AST concentrations and serum acetaminophen concentrations,
may give the clinician insight as to the patient's risk of acetaminophen toxicity. Some experts recommend that
acetylcysteine be administered to any patient with "higher than expected" serum acetaminophen concentrations or
serum acetaminophen concentration >10 mcg/mL, even in the absence of hepatic injury; others recommend treatment
for patients with laboratory evidence and/or signs and symptoms of hepatotoxicity (Hendrickson 2006; Jones 2000).
Consultation with a poison control center or a clinical toxicologist is highly recommended.
Dosage form specific issues:
• Effervescent tablets (Cetylev): Contains sodium; consider acetylcysteine treatment as a source of sodium in patients
who may be sensitive to excess sodium intake (eg, heart failure, hypertension, renal impairment).
• Oral administration: Gastrointestinal hemorrhage: Oral administration of acetylcysteine may result in nausea and
vomiting, which may exacerbate vomiting associated with acetaminophen overdose. Therefore, patients at risk of
gastrointestinal hemorrhage (eg, esophageal varices, peptic ulcer) may experience an even higher risk of gastrointestinal
hemorrhage during therapy.
• Inhalation: Since increased bronchial secretions may develop after inhalation, percussion, postural drainage, and
suctioning should follow. If bronchospasm occurs, administer a bronchodilator; discontinue acetylcysteine if
bronchospasm progresses.
Preparation for Administration: Pediatric
Oral: Acetaminophen poisoning:
Effervescent tablets (Cetylev): Dissolve the effervescent tablets in the appropriate volume of water based upon patient
weight; use within 2 hours of preparation
1 to <20 kg: Prepare a 50 mg/mL solution by dissolving two 2.5 g tablets in 100 mL of water; determine volume for the
calculated dose and administer; discard any remaining solution
20 to <60 kg: Dissolve an appropriate number of tablets (2.5 or 5 g tablets in any combination) to deliver the calculated
dose in 150 mL of water
≥60 kg: Dissolve an appropriate number of tablets (2.5 or 5 g tablets in any combination) to deliver the calculated dose
in 300 mL of water
Solution for oral administration using the inhalation/injectable solution: Dilute the 20% solution 1:3 with a cola, orange
juice, or other soft drink to prepare a 5% solution. If being administered via a nasogastric tube or Miller-Abbott tube,
water may be used as the diluent. Use within 1 hour of preparation.
Parenteral: IV (Acetadote): Acetaminophen poisoning: Note:Volume of diluent based on weight; compatible diluents
include D5W, 1/2NS, SWFI:
Patient weight 5 to 20 kg: Dilute dose in the following volumes of compatible diluents:
Loading dose: 3 mL/kg
Second dose: 7 mL/kg
Third dose: 14 mL/kg
Patient weight 21 to 40 kg: Dilute dose in the following volumes of compatible diluents:
Loading dose: 100 mL
Second dose: 250 mL
Third dose: 500 mL
Patient weight: 41 to 100 kg: Dilute dose in the following volumes of compatible diluents. In patients requiring fluid
restriction, decrease diluent volume by 50%.
Loading dose: 200 mL
Second dose: 500 mL
Third dose: 1,000 mL
Undiluted injection, solution (Acetadote) is hyperosmolar (2,600 mOsmol/L); when the diluent volume is decreased for
patients <40 kg or requiring fluid restriction, the osmolarity of the solution may remain higher than desirable for
intravenous infusion. To ensure tolerance of the infusion, osmolarity should be adjusted to a physiologically safe level
(eg, ≥150 mOsmol/L in children).
Acetadote Concentration Osmolarity in 1/2 NS Osmolarity in D5W Osmolarity in Sterile Water for Injection
7 mg/mL 245 mOsmol/L 343 mOsmol/L 91 mOsmol/L
24 mg/mL 466 mOsmol/L 564 mOsmol/L 312 mOsmol/L
Solution for inhalation: The 20% solution may be diluted with sodium chloride or sterile water; the 10% solution may be
used undiluted.
Rectal: Dilute the inhalation solution in NS to the desired final concentration of 4 to 6%; may also be given undiluted
(Mascarenhas 2003; Perman 1975)
Administration: Pediatric
Oral: Differs based on use.
Acetaminophen poisoning:
Effervescent tablets (Cetylev): Use within 2 hours of preparation. If the patient vomits within 1 hour of administration,
repeat that dose. If the patient is persistently unable to retain the orally administered acetylcysteine, acetylcysteine may
be administered by nasoduodenal tube.
Solution for oral administration: Administer as a 5% solution (see Preparation for Administration); use within 1 hour of
preparation. If patient vomits within 1 hour of dose, readminister. Note: The unpleasant odor (sulfur-like) becomes less
noticeable as treatment progresses. It is helpful to put the acetylcysteine on ice, in a cup with a cover, and drink through
a straw; alternatively, administer via an NG tube.
Parenteral: Acetaminophen poisoning: IV (Acetadote):
Loading dose: Administer IV over 60 minutes
Second dose: Administer IV over 4 hours
Third dose: Administer IV over 16 hours
Note: If the commercial IV form is unavailable, the solution for inhalation has been used; each dose should be infused
through a 0.2 micron Millipore filter (in-line) over 60 minutes (Yip 1998); intravenous administration of the solution for
inhalation is not USP 797-compliant.
Inhalation solution: May be administered by nebulization either undiluted (both 10% and 20%) or diluted in NS.
Acetylcysteine solution for inhalation is incompatible with tetracyclines, erythromycin, amphotericin B, iodized oil,
chymotrypsin, trypsin, and hydrogen peroxide. Administer separately. Intermittent aerosol treatments are commonly
given when patient arises, before meals, and just before retiring at bedtime.
Rectal: Inhalation solution may be given undiluted (10% to 20%) or diluted to 4% to 6% solution and administer rectally
(Mascarenhas 2003; Perman 1975)
Monitoring Parameters
Acetaminophen poisoning: Monitor patient for the development of anaphylaxis or anaphylactoid reactions; monitor
serum acetaminophen concentrations, AST, ALT, bilirubin, PT, INR, serum creatinine, BUN, serum glucose, hemoglobin,
hematocrit, and electrolytes. Assess patient for nausea, vomiting, and skin rash following oral administration. Reassess
LFTs for possible hepatotoxicity every 4 to 6 hours. An early elevation in the INR may be related to acetylcysteine
therapy (Schmidt 2002).
Acute ingestion: Obtain the first acetaminophen concentration 4 hours postingestion (or as soon as possible thereafter);
plot on the Rumack-Matthew nomogram. In patients who have ingested an extended release formulation of
acetaminophen or have coingested an agent known to delay gastric emptying, obtain a repeat serum acetaminophen
measurement 4 to 6 hours following the first measurement if the original concentration (taken at 4 to 8 hours
postingestion) when plotted on the Rumack-Matthew nomogram indicated that treatment was not necessary.
Adverse Reactions
Intravenous:
Cardiovascular: Edema, flushing, tachycardia
Dermatologic: Rash, pruritus, urticaria
Gastrointestinal: Nausea, vomiting
Immunologic: Autoimmune disease
Respiratory: Pharyngitis, rhinorrhea, rhonchi, throat tightness
Miscellaneous: Anaphylactoid reaction
Rare but important or life-threatening: Anaphylaxis, angioedema, bronchospasm, chest tightness, cough, dizziness
(Sandilands 2008), dyspnea (Sandilands 2008), hypotension, respiratory distress, stridor, wheezing
Oral:
Cardiovascular: Chest tightness, hypotension (Bebarta 2010; Sandilands 2009)
Dermatologic: Rash (with or without fever), urticaria
Gastrointestinal: Gastrointestinal symptoms, nausea, vomiting
Hypersensitivity: Hypersensitivity reaction
Respiratory: Bronchitis, bronchospasm
Rare but important or life-threatening: Angioedema (Bebarta 2010), tachycardia (Bebarta 2010)
ACICLOVIR
Dosing: Pediatric
Note: Obese patients should be dosed using ideal body weight. Parenteral IV doses >15 mg/kg/dose or 500 mg/m2may
be associated with an increased risk of nephrotoxicity; close monitoring of renal function is recommended (Rao 2015).
CMV prophylaxis: Low-risk allogeneic hematopoietic stem cell transplant (HSCT) in seropositive recipient. Note: Begin at
engraftment and continue to day 100; requires close monitoring for CMV reactivation (due to weak activity); not for use
in patients at high risk for CMV disease (Tomblyn 2009):
Oral:
Infants, Children, and Adolescents <40 kg: 600 mg/m2/dose 4 times daily; maximum dose: 800 mg/dose
Children and Adolescents ≥40 kg: 800 mg 4 times daily
IV: Infants, Children, and Adolescents: 500 mg/m2/dose every 8 hours
Herpes zoster, acute retinal necrosis, treatment (HIV-exposed/-positive):
Initial treatment: IV: Note: Follow up IV therapy with oral acyclovir or valacyclovir maintenance therapy.
Infants: 10 to 15 mg/kg/dose every 8 hours for 10 to 14 days (DHHS [pediatric] 2013)
Children: 10 to 15 mg/kg/dose every 8 hours for 10 to 14 days (DHHS [pediatric] 2013)
Adolescents: 10 to 15 mg/kg/dose every 8 hours for 10 to 14 days (DHHS [adult] 2015)
Maintenance treatment; begin after 10- to 14-day course of IV acyclovir: Oral: Infants and Children: 20 mg/kg/dose 4
times daily for 4 to 6 weeks (DHHS [pediatric] 2013)
Herpes zoster (shingles), treatment:
Immunocompetent host:
Ambulatory therapy: Oral: Children ≥12 years and Adolescents: 800 mg every 4 hours (5 doses per day) for 5 to 7 days
(Red Book[AAP 2015])
Hospitalized patient: IV:
Infants: 10 mg/kg/dose every 8 hours for 7 to 10 days (Red Book [AAP 2015])
Children and Adolescents: 500 mg/m2/dose every 8 hours for 7 to 10 days; some experts recommend 10 mg/kg/dose
every 8 hours (Red Book[AAP 2015])
Immunocompromised host (non-HIV-exposed/-positive): IV: Infants, Children, and Adolescents: 10 mg/kg/dose every 8
hours for 7 to 10 days (Red Book [AAP 2015])
HIV-exposed/-positive:
Mild, uncomplicated disease and no or moderate immune suppression: Oral:
Infants and Children: 20 mg/kg/dose 4 times daily for 7 to 10 days; maximum dose: 800 mg/dose; consider longer course
if resolution of lesions is slow (DHHS [pediatric] 2013)
Adolescents: 800 mg 5 times daily for 7 to 10 days, longer if lesions resolve slowly (DHHS [adult] 2015)
Severe immune suppression or complicated disease; trigeminal nerve involvement, extensive multidermatomal zoster or
extensive cutaneous lesions or visceral involvement: IV:
Infants: 10 mg/kg/dose every 8 hours until resolution of cutaneous lesions and visceral disease clearly begins, then
convert to oral therapy to complete a 10- to 14-day total course of therapy (DHHS [pediatric] 2013)
Children: 10 mg/kg/dose or 500 mg/m2/dose every 8 hours until resolution of cutaneous lesions and visceral disease
clearly begins, then convert to oral therapy to complete a 10- to 14-day total course of therapy (DHHS [pediatric] 2013)
Adolescents: 10 to 15 mg/kg/dose every 8 hours until clinical improvement is evident, then convert to oral therapy to
complete a 10- to 14-day total course of therapy (DHHS [adult] 2015)
HSV neonatal infection, treatment and suppressive therapy in very young infants (independent of HIV status):
Treatment (disseminated, CNS, or skin, eye, or mouth disease): Infants 1 to 3 months: IV: 20 mg/kg/dose every 8 hours;
treatment duration: For cutaneous and mucous membrane infections (skin, eye, or mouth): 14 days; for CNS or
disseminated infection: 21 days (AAP [Kimberlin 2013]; Bradley 2015; CDC [Workowski 2015]; DHHS [pediatric]
2013; Red Book [AAP 2015])
Chronic suppressive therapy following any neonatal HSV infection:
AAP Recommendation (low dose, 6-month course): Infants: Oral: 300 mg/m2/dose every 8 hours for 6 months; begin
after completion of a 14- to 21-day-course of IV therapy dependent upon type of infection (AAP [Kimberlin 2013];
Kimberlin 2011; Red Book [AAP 2015])
Alternate dosing (high dose, 2-year course) in infants with disseminated or CNS infection (Tiffany 2005): Limited data
available: Infants and Children <3 years: Oral: Begin after completion of a 21-day course of IV therapy; dosing based on a
prospective trial of 16 consecutive neonates (GA: Premature: n=4; term= 12; age at treatment: Neonate: n=14; PNA >30
days: n=1) following disseminated or CNS infection; pharmacokinetic data were used to determine dosing regimen to
maintain serum acyclovir concentration above target of 2 to 3 mcg/mL; treatment was continued for 2 years in 14 of 16
patients; results showed normal neurodevelopmental outcomes in 69% and normal motor development in 70%; no
untoward effects were reported during the study duration.
Initial dosing: 400 mg twice daily; approximate dose: 1,200 to 1,600 mg/m2/dose twice daily
Maintenance dosing: Note: Approximate doses for patients born at term:
Infants 1 to <5 months: 400 mg twice daily
Infants 5 to <9 months: 600 mg twice daily
Infants and Children 9 to <15 months: 800 mg twice daily
Children 15 to 24 months: 1,000 mg twice daily
Note: In the trial, serum acyclovir concentrations were evaluated to assess adequacy of dosing to maintain serum
concentrations above the target of 2 to 3 mcg/mL. Samples were collected 1 hour after a witnessed dose; if the acyclovir
serum concentration approached or was below the target, the dose was increased to the next greater 200 mg
increment. Maximum dose: 1,200 mg. Serum concentrations were evaluated every 3 months; in order to limit the
phlebotomy losses, follow-up serum concentrations were not evaluated outside of routine monitoring.
HSV encephalitis, treatment:
Infants and Children 3 months to <12 years:
Non-HIV-exposed/-positive: IV: 10 to 15 mg/kg/dose every 8 hours for 14 to 21 days. Note: Due to increased risk of
neurotoxicity and nephrotoxicity, higher doses (20 mg/kg) are not recommended (Red Book [AAP 2015]).
HIV-exposed/-positive: IV: 10 mg/kg/dose every 8 hours for 21 days; higher doses (up to 20 mg/kg) may be necessary
(DHHS [pediatric] 2013)
Children ≥12 years and Adolescents (independent of HIV status): IV: 10 mg/kg/dose every 8 hours for 14 to 21 days (Red
Book [AAP 2015)]
HSV genital infection:
First infection, mild to moderate:
Non-HIV-exposed/-positive:
Children <12 years: Oral: 40 to 80 mg/kg/day divided in 3 to 4 doses per day for 5 to 10 days; maximum daily dose: 1,200
mg/day (Bradley 2015; Red Book [AAP 2015])
Children and Adolescents ≥12 years: Oral: 200 mg every 4 hours while awake (5 times daily) or 400 mg 3 times daily for 7
to 10 days; treatment can be extended beyond 10 days if healing is not complete (CDC [Workowski 2015]; Red
Book [AAP 2015])
Children: Oral: 20 mg/kg/dose 3 times daily for 7 to 10 days; maximum dose: 400 mg/dose (DHHS [pediatric] 2013)
Adolescents: Oral: 400 mg 3 times daily for 5 to 14 days (DHHS [adult] 2015)
First infection, severe (independent of HIV status): IV: Children and Adolescents ≥12 years: 5 mg/kg/dose every 8 hours
for 5 to 7 days or 5 to 10 mg/kg/dose every 8 hours for 2 to 7 days, followed with oral therapy to complete at least 10
days of therapy (CDC [Workowski 2015]; Red Book [AAP 2015])
Recurrent infection:
Children <12 years (independent of HIV status): Oral: 20 mg/kg/dose 3 times daily for 5 days; maximum dose: 400
mg/dose (Bradley 2015; DHHS [pediatric] 2013)
Children and Adolescents ≥12 years:
Non-HIV-exposed/-positive: Oral: 200 mg every 4 hours while awake (5 times daily) for 5 days, or 400 mg 3 times daily
for 5 days, or 800 mg twice daily for 5 days or 800 mg 3 times daily for 2 days (CDC [Workowski 2015]; Red Book [AAP
2015])
HIV-exposed/-positive: Adolescents: Oral: 400 mg 3 times daily for 5 to 14 days (DHHS [adult] 2015)
Suppression, chronic:
Children <12 years: Limited data available: Oral: 20 mg/kg/dose twice daily; maximum dose: 400 mg/dose (Bradley 2015)
Children and Adolescents ≥12 years: Oral: 400 mg twice daily; reassess therapy after 12 months (CDC [Workowski
2015]; Red Book [AAP 2015])
Infants and Children: Oral: 20 mg/kg/dose twice daily; maximum dose: 800 mg/dose (DHHS [pediatric] 2013)
Adolescents: Oral: 400 mg twice daily (DHHS [adult] 2015)
HSV gingivostomatitis:
Non-HIV-exposed/-positive: Primary infection:
AAP recommendations: Children and Adolescents: Oral: 20 mg/kg/dose 4 times daily for 5 to 7 days; usual maximum
dose: 200 mg/dose, others have reported higher (400 mg/dose) (Bradley 2015; Cernik 2008; Red Book [AAP 2015])
Alternate dosing: Infants ≥10 months, Children, and Adolescents: Oral: 15 mg/kg/dose five times daily for 7 days;
maximum dose: 200 mg/dose (Amir 1997; Balfour 1999); dosing based on a placebo controlled trial in children 1 to 6
years of age (n=72, treatment group: n=31); results showed when treatment started within 72 hours of symptom onset a
shorter duration of symptoms and viral shedding was observed (Amir 1997)
HIV-exposed/-positive (DHHS [pediatric] 2013):
Mild, symptomatic: Oral: Infants and Children: 20 mg/kg/dose 4 times daily for 7 to 10 days; maximum dose: 400
mg/dose
Moderate to severe, symptomatic: IV: Infants and Children: 5 to 10 mg/kg/dose every 8 hours; switch to oral therapy
once lesions begin to regress
HSV, herpes labialis (cold sore) (HIV-exposed/-positive): Treatment:
Infants and Children: Oral: 20 mg/kg/dose 4 times daily for 5 days; maximum dose: 400 mg/dose (DHHS [pediatric] 2013)
HSV, herpes labialis (cold sore) recurrent, chronic suppressive therapy: Immunocompetent Children and Adolescents:
Oral: 10 mg/kg/dose 3 times daily; maximum daily dose: 1,000 mg/day; reevaluate after 12 months (Red Book [AAP
2015])
HSV mucocutaneous infection:
Immunocompetent host: Infants, Children, and Adolescents:
Treatment (Bradley 2015):
IV: 5 mg/kg/dose every 8 hours
Oral: 20 mg/kg/dose 4 times daily for 5 to 7 days; maximum dose: 800 mg/dose
Suppression, chronic: Limited data available; no pediatric data; some experts recommend oral 20 mg/kg/dose 2 to 3
times daily for 6 to 12 months, then reevaluate need; maximum dose: 400 mg/dose (Bradley 2015)
Immunocompromised host:
Treatment:
IV:
Infants and Children: 10 mg/kg/dose every 8 hours for 7 to 14 days (Red Book [AAP 2015])
Adolescents: 5 to 10 mg/kg/dose every 8 hours; change to oral therapy after lesions begin to regress (DHHS [adult]
2015; Red Book [AAP 2015])
Oral: Children ≥2 years and Adolescents: 1,000 mg/day in 3 to 5 divided doses for 7 to 14 days; some suggest the
maximum daily dose should not exceed 80 mg/kg/day (Red Book2009; Red Book [AAP 2015])
Suppression, chronic (cutaneous, ocular) episodes:
Infants and Children (HIV-exposed/-positive): Oral: 20 mg/kg/dose twice daily; maximum dose: 800 mg/dose; reassess
after 12 months (DHHS [pediatric] 2013)
Children 12 years of age (non-HIV-exposed/-positive): Prevention of ocular episodes: Oral: 400 mg twice daily; reassess
at 12 months (Red Book [AAP 2015])
Adolescents (independent of HIV status): Oral: 400 mg twice daily; reassess at 12 months (DHHS [adult] 2015; Red
Book [AAP 2015])
HSV progressive or disseminated infection, treatment (immunocompromised host):
Non-HIV-exposed/-positive: Infants, Children, and Adolescents: IV: 10 mg/kg/dose every 8 hours for 7 to 14 days (Red
Book [AAP 2015])
HIV-exposed/-positive: Infants, Children, and Adolescents: IV: 10 mg/kg/dose every 8 hours for 21 days; higher doses (up
to 20 mg/kg/dose) may be used in children <12 years of age (DHHS [pediatric] 2013; Red Book[AAP 2015])
HSV, acute retinal necrosis, treatment (HIV-exposed/-positive): Children (DHHS [pediatric] 2013):
Initial treatment: IV: 10 to 15 mg/kg/dose every 8 hours for 10 to 14 days. Note: Follow up IV therapy with oral acyclovir
or valacyclovir maintenance therapy.
Maintenance treatment: Begin after 10- to 14-day course of IV acyclovir: Oral: 20 mg/kg/dose 4 times daily for 4 to 6
weeks
HSV prophylaxis; immunocompromised hosts, seropositive:
Hematopoietic stem cell transplant (HSCT) in seropositive recipient (Tomblyn 2009):
Prevention of early reactivation: Note: Begin at conditioning and continue until engraftment or resolution of mucositis;
whichever is longer (~30 days post-HSCT)
Infants, Children, and Adolescents <40 kg:
IV: 250 mg/m2/dose every 8 hours or125 mg/m2/dose every 6 hours; maximum daily dose: 80 mg/kg/day
Oral: 60 to 90 mg/kg/day in 2 to 3 divided doses; maximum dose: 800 mg/dose twice daily
Children and Adolescents ≥40 kg:
IV: 250 mg/m2/dose every 12 hours
Oral: 400 to 800 mg twice daily
Prevention of late reactivation: Note:Treatment during first year after HSCT.
Infants, Children, and Adolescents <40 kg: Oral: 60 to 90 mg/kg/day in 2 to 3 divided doses; maximum daily dose: 800
mg twice daily
Children and Adolescents ≥40 kg: Oral: 800 mg twice daily
Other immunocompromised hosts who are HSV seropositive:
IV: Infants, Children, and Adolescents: 5 mg/kg/dose every 8 hours during period of risk (Red Book [AAP 2015])
Oral: Children ≥2 years and Adolescents: 200 mg every 4 hours while awake (5 doses daily) or 200 mg every 8 hours;
administer during periods of risk (Red Book [AAP 2015])
Varicella (chickenpox) or Herpes zoster (shingles), prophylaxis
Hematopoietic stem cell transplant (HSCT):Prophylaxis of disease reactivation: Note:Continue therapy for 1 year after
HSCT (Tomblyn 2009):
Infants, Children, and Adolescents <40 kg: Oral: 60 to 80 mg/kg/day in 2 to 3 divided doses
Children and Adolescents ≥40 kg: Oral: 800 mg twice daily
HIV-exposed/-positive: Limited data available: Note:Consider use if >96 hours postexposure or if VZV-immune globulin is
not available; begin therapy 7 to 10 days after exposure; some experts begin therapy at first appearance of rash (DHHS
[pediatric] 2013).
Infants and Children: Oral: 20 mg/kg/dose 4 times daily for 7 days; maximum dose: 800 mg/dose (DHHS [pediatric] 2013)
Other immunocompromised hosts: Infants, Children, and Adolescents: Oral: 20 mg/kg/dose 4 times daily for 7 days;
maximum dose: 800 mg/dose. Note: Consider use if VZV-immune globulin or IVIG is not available; begin therapy 7 to 10
days after exposure (Red Book [AAP] 2015).
Varicella (chickenpox), treatment: Begin treatment within the first 24 hours of rash onset:
Immunocompetent host:
Ambulatory therapy: Oral: Children ≥2 years and Adolescents: 20 mg/kg/dose 4 times daily for 5 days; maximum daily
dose: 3,200 mg/day (Red Book [AAP 2015])
Hospitalized patient: IV: Infants, Children, and Adolescents: 10 mg/kg/dose or 500 mg/m2/dose every 8 hours for 7 to 14
days (Bradley 2015; Red Book [AAP 2015]); some experts recommend 15 to 20 mg/kg/dose for severe disseminated or
CNS infection (Bradley 2015)
Immunocompromised host (non-HIV-exposed/-positive): IV:
Infants: 10 mg/kg/dose every 8 hours for 7 to 10 days (Red Book [AAP 2015])
Children and Adolescents: 500 mg/m2/dose every 8 hours for 7 to 10 days; some experts recommend 10 mg/kg/dose
every 8 hours (Red Book [AAP 2015])
Mild, uncomplicated disease and no or moderate immune suppression: Oral:
Infants and Children: 20 mg/kg/dose 4 times daily for 7 to 10 days and until no new lesions for 48 hours; maximum dose:
800 mg/dose (DHHS [pediatric] 2013)
Adolescents: 800 mg 5 times daily for 5 to 7 days (DHHS [adult] 2015)
Severe, complicated disease or severe immune suppression: IV:
Infants: 10 mg/kg/dose every 8 hours for 7 to 10 days and until no new lesions for 48 hours (DHHS [pediatric] 2013)
Children: 10 mg/kg/dose or 500 mg/m2/dose every 8 hours for 7 to 10 days or until no new lesions for 48 hours (DHHS
[pediatric] 2013)
Adolescents: 10 to 15 mg/kg/dose every 8 hours for 7 to 10 days; may convert to oral therapy after defervescence and if
no evidence of visceral involvement is evident (DHHS [adult] 2015)
Monitor closely for neurotoxicity (Chowdhury 2016).
Infants, Children and Adolescents: IV:
CrCl >50 mL/minute/1.73 m2: No dosage adjustment necessary
CrCl 25 to 50 mL/minute/1.73 m2: Administer the usual recommended dose every 12 hours
CrCl 10 to <25 mL/minute/1.73 m2: Administer the usual recommended dose every 24 hours
CrCl <10 mL/minute/1.73 m2: Administer 50% of the usual recommended dose every 24 hours (eg, if the usual
recommended dose is 10 mg/kg/dose every 8 hours, then administer 5 mg/kg/dose every 24 hours)
Intermittent hemodialysis (IHD): Dialyzable (60% reduction following a 6-hour session): 5 mg/kg/dose every 24 hours;
administer after hemodialysis on dialysis days (Aronoff 2007)
Peritoneal dialysis (PD): 5 mg/kg/dose every 24 hours; no supplemental dose needed (Aronoff 2007)
Continuous renal replacement therapy (CRRT): 10 mg/kg/dose every 12 hours (Aronoff 2007)
• CNS effects: Neurotoxicity (eg, tremor/myoclonus, confusion, agitation, lethargy, hallucination, impaired
consciousness) has been reported; risk may be increased with higher doses and in patients with renal failure. Monitor
patients for signs/symptoms of neurotoxicity; ensure appropriate dosage reductions in patients with renal impairment
(Chowdhury 2016).
• Renal effects: Renal failure (sometimes fatal) has been reported. Dehydration, preexisting renal disease, and
nephrotoxic drugs increase risk; ensure patient is adequately hydrated during oral or IV therapy.
• Thrombotic microangiopathy: Has been reported in immunocompromised patients receiving acyclovir.
Disease-related concerns:
• Renal impairment: Use with caution; dosage adjustment recommended. Neurotoxicity may be more common in
patients with renal impairment (Chowdhury 2016).
• Varicella: Appropriate use: For maximum benefit, treatment should begin within 24 hours of appearance of rash; oral
route not recommended for routine use in otherwise healthy children with varicella but may be effective in patients at
increased risk of moderate-to-severe infection (>12 years of age, chronic cutaneous or pulmonary disorders, long-term
salicylate therapy, corticosteroid therapy).
Concurrent drug therapy issues:
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment,
additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed
information.
• Injection: Use IV preparation with caution in patients with underlying neurologic abnormalities, serious hepatic or
electrolyte abnormalities, or substantial hypoxia. Encephalopathic changes characterized by lethargy, obtundation,
confusion, hallucination, tremors, agitation, seizure, or coma have been observed in patients receiving IV acyclovir.
Parenteral: Reconstitute vial for injection to 50 mg/mL with SWFI; do not use bacteriostatic water containing benzyl
alcohol or parabens. For intravenous infusion, dilute in D5W, D5NS, D51/4NS, D51/2NS, LR, or NS to a final concentration ≤7
mg/mL. In fluid restricted patients, concentrations up to 10 mg/mL have been infused; concentrations >10 mg/mL
increase the risk of phlebitis.
Oral: May administer with or without food; shake suspension well before use. Maintain adequate hydration during
therapy.
Parenteral: Administer by slow IV infusion over at least 1 hour; rapid infusion is associated with nephrotoxicity due to
crystalluria and renal tubular damage and should be avoided. Maintain adequate hydration during therapy. Do not
administer IV push, IM, or SubQ.
Acyclovir IV is an irritant (depending on concentration); avoid extravasation. If extravasation occurs, stop infusion
immediately and disconnect (leave cannula/needle in place); gently aspirate extravasated solution (do NOT flush the
line); remove needle/cannula; elevate extremity. Apply dry warm compresses. Intradermal hyaluronidase may be
considered for refractory cases (Reynolds 2014).
Urinalysis, BUN, serum creatinine, urine output; liver enzymes, CBC; monitor for neurotoxicity and nephrotoxicity when
using high dose therapy; neutrophil count at least twice weekly in neonates receiving acyclovir 60 mg/kg/day IV
Drug Interactions
Mycophenolate: Acyclovir-Valacyclovir may increase the serum concentration of Mycophenolate. Mycophenolate may
increase the serum concentration of Acyclovir-Valacyclovir. Risk C: Monitor therapy
Zidovudine: Acyclovir-Valacyclovir may enhance the CNS depressant effect of Zidovudine. Risk C: Monitor therapy
Adverse Reactions
As reported with IV administration, unless otherwise noted.
Central nervous system: Headache (oral), malaise (oral)
Dermatologic: Pruritus, skin rash, urticaria
Gastrointestinal: Diarrhea (oral and IV), nausea (oral and IV), vomiting (oral and IV)
Hematologic & oncologic: Decrease in absolute neutrophil count (neonates), decreased hemoglobin (neonates),
thrombocytopenia (more common in neonates)
Hepatic: Increased serum bilirubin (neonates), increased serum transaminases
Local: Inflammation at injection site, injection site phlebitis
Renal: Increased blood urea nitrogen, increased serum creatinine
Rare but important or life-threatening (all routes): Abdominal pain, aggressive behavior, agitation, alopecia, anaphylaxis,
anemia, angioedema, anorexia, ataxia, coma, confusion, delirium, disseminated intravascular coagulation, dizziness,
drowsiness, dysarthria, encephalopathy, erythema multiforme, fatigue, fever, gastrointestinal distress, hallucination,
hematuria, hemolysis, hepatitis, hyperbilirubinemia, hypersensitivity angiitis, hypotension, impaired consciousness,
increased liver enzymes, jaundice, leukocytosis, leukopenia, lymphadenopathy, myalgia, neutropenia, neutrophilia,
obtundation, pain, paresthesia, peripheral edema, psychosis, renal failure syndrome, renal pain, seizure, skin
photosensitivity, Stevens-Johnson syndrome, thrombocythemia, toxic epidermal necrolysis, tremor, visual disturbance
ADENOSINA
Dosing: Pediatric
Paroxysmal supraventricular tachycardia: PALS Guidelines: Infants, Children and Adolescents: Rapid IV; IO: Initial: 0.1
mg/kg (maximum initial dose: 6 mg/dose); if not effective, increase to 0.2 mg/kg (maximum dose: 12 mg/dose) (PALS
[Klienman 2010])
Manufacturer's labeling: Rapid IV:
Infants, Children, and Adolescents <50 kg: Initial dose: 0.05 to 0.1 mg/kg via peripheral or central line; maximum initial
dose: 6 mg/dose; if not effective within 1 to 2 minutes, increase dose by 0.05 to 0.1 mg/kg increments every 1 to 2
minutes to a maximum single dose of 0.3 mg/kg or 12 mg, whichever is lower or until termination of PSVT
Children and Adolescents ≥50 kg: Initial: 6 mg via peripheral line, if not effective within 1 to 2 minutes, 12 mg may be
given; may repeat 12 mg bolus if needed. Note: In adults it has been suggested that the initial dose of adenosine should
be reduced to 3 mg if patient is currently receiving carbamazepine or dipyridamole, has a transplanted heart, or if
adenosine is administered via central line (ACLS 2010; Chang 2002).
NO
NO
Contraindications
Hypersensitivity to adenosine or any component of the formulation; second- or third-degree AV block, sick sinus
syndrome, or symptomatic bradycardia (except in patients with a functioning artificial pacemaker); known or suspected
bronchoconstrictive or bronchospastic lung disease (Adenoscan), asthma (ACLS [Neumar, 2010]; Adenoscan prescribing
information, 2014)
• Atrial fibrillation/flutter: There have been reports of atrial fibrillation/flutter when administered to patients with
paroxysmal supraventricular tachycardia (PSVT) and may be especially problematic in patients with PSVT and underlying
Wolff-Parkinson-White syndrome; has also been reported in patients with or without a history of atrial fibrillation
undergoing myocardial perfusion imaging with adenosine infusion.
• Cardiovascular events (Adenoscan): Cardiac arrest (fatal and nonfatal), myocardial infarction (MI), cerebrovascular
accident (hemorrhagic and ischemic), and sustained ventricular tachycardia (requiring resuscitation) have occurred
following Adenoscan use. Avoid use in patients with signs or symptoms of unstable angina, acute myocardial ischemia,
or cardiovascular instability due to possible increased risk of significant cardiovascular consequences. Appropriate
measures for resuscitation should be available during use.
• Conduction disturbances: Adenosine decreases conduction through the AV node and may produce first-, second-, or
third-degree heart block. Patients with preexisting SA nodal dysfunction may experience prolonged sinus pauses after
adenosine; use caution in patients with first-degree AV block or bundle branch block; use is contraindicated in patients
with high-grade AV block, sinus node dysfunction, or symptomatic bradycardia (unless a functional artificial pacemaker
is in place). Rare, prolonged episodes of asystole have been reported, with fatal outcomes in some cases. Discontinue
adenosine in any patient who develops persistent or symptomatic high-grade AV block.
• Hypersensitivity: Hypersensitivity reactions (including dyspnea, pharyngeal edema, erythema, flushing, rash, or chest
discomfort) have been reported following Adenoscan administration.
• Hypertension: Systolic and diastolic pressure increases have been observed with Adenoscan infusion. In most
instances, blood pressure increases resolved spontaneously within several minutes; occasionally, hypertension lasted for
several hours.
• Hypotension: May produce profound vasodilation with subsequent hypotension. When used as a bolus dose (PSVT),
effects are generally self-limiting (due to the short half-life of adenosine). However, when used as a continuous infusion
(pharmacologic stress testing), effects may be more pronounced and persistent, corresponding to continued exposure.
Use infusions with caution in patients with autonomic dysfunction, carotid stenosis (with cerebrovascular insufficiency),
hypovolemia, pericarditis, pleural effusion and/or stenotic valvular heart disease; discontinue infusion in patients who
develop persistent or symptomatic hypotension.
• Proarrhythmic effects: Monitor for proarrhythmic effects (eg, polymorphic ventricular tachycardia) during and shortly
after administration/termination of arrhythmia. The benign transient occurrence of atrial and ventricular ectopy is
common upon termination of arrhythmia.
• Seizures: Seizures (new-onset or recurrent) have been reported following Adenoscan administration; risk may be
increased with concurrent use of aminophylline. Use of any methylxanthine (eg aminophylline, caffeine, theophylline) is
not recommended in patients experiencing seizures associated with Adenoscan administration.
• Arrhythmia (wide-complex tachycardia): Avoid use in irregular or polymorphic wide-complex tachycardias; may cause
degeneration to ventricular fibrillation (ACLS 2010).
• Electrolyte imbalance: Correct electrolyte disturbances, especially hypokalemia or hypomagnesemia, prior to use and
throughout therapy.
• Heart transplant recipients: Use with extreme caution in heart transplant recipients; adenosine may cause prolonged
asystole; reduction of initial adenosine dose is recommended (ACLS 2010); considered by some to be contraindicated in
this setting (Delacrétaz 2006).
• Pulmonary artery hypertension: Acute vasodilator testing (not an approved use): Use with extreme caution in patients
with concomitant heart failure (LV systolic dysfunction with significantly elevated left heart filling pressures) or
pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis; significant decompensation has occurred with
other highly selective pulmonary vasodilators resulting in acute pulmonary edema.
• Respiratory disease: Avoid use in patients with bronchoconstriction or bronchospasm (eg, asthma); dyspnea,
bronchoconstriction, and respiratory compromise have occurred during use. Per the ACLS guidelines and the
manufacturer of Adenoscan, use considered contraindicated in patients with asthma. Use caution in patients with
obstructive lung disease not associated with bronchoconstriction (eg, emphysema, bronchitis). Immediately discontinue
therapy if severe respiratory difficulty is observed. Appropriate measures for resuscitation should be available during
use.
• Wolff-Parkinson-White (WPW) syndrome: Adenosine should not be used in patients with WPW syndrome and
preexcited atrial fibrillation/flutter since ventricular fibrillation may result (AHA/ACC/HRS [January 2014]).
information.
• Caffeine: Pharmacologic stress testing: Since caffeine antagonizes the activity of adenosine, withhold for 5 half-lives
prior to adenosine use; avoid dietary caffeine for at least 12 hours prior to pharmacologic stress testing (Henzlova 2006).
• Carbamazepine: Concomitant use potentiates the effects of adenosine; reduction of initial adenosine dose is
recommended when used for SVT (ACLS 2010).
• Dipyridamole: Concomitant use potentiates the effects of adenosine; reduction of initial adenosine dose is
recommended when used for SVT (ACLS 2010); withhold dipyridamole-containing medications for at least 24 hours prior
to pharmacologic stress testing (Henzlova 2006)
• Drugs which slow AV node conduction: Use with caution in patients receiving other drugs which slow AV node
conduction (eg, digoxin, verapamil).
• Theophylline (includes aminophylline): Pharmacologic stress testing: Since theophylline antagonizes the activity of
adenosine, withhold for 5 half-lives prior to adenosine use whenever possible.
Special populations:
• Elderly: Use with caution in the elderly; may be at increased risk of hemodynamic effects, bradycardia, and/or AV
block.
• Adenocard: Transient AV block is expected. When used in PSVT, at the time of conversion to normal sinus rhythm, a
variety of new rhythms may appear on the ECG. Administer as a rapid bolus, either directly into a vein or (if
administered into an IV line), as close to the patient as possible (followed by saline flush). Dose reduction recommended
when administered via central line (ACLS 2010).
• Appropriate use: ECG monitoring is required during use. Equipment for resuscitation and trained personnel
experienced in handling medical emergencies should always be immediately available. Adenosine does not convert atrial
fibrillation/flutter to normal sinus rhythm; however, may be used diagnostically in these settings if the underlying
rhythm is not apparent.
Parenteral: IV:
Doses ≥600 mcg: Give undiluted
Doses <600 mcg: Further dilution of dose may be necessary to ensure complete and accurate administration; dilution
with NS to a final concentration of 300 to 1,000 mcg/mL has been used; to prepare a 300 mcg/mL solution, add 3 mg of
adenosine (1 mL) to 9 mL of NS; to prepare a 1,000 mcg/mL, add 3 mg of adenosine (1 mL) to 2 mL of NS
Parenteral: Adenocard: For rapid bolus IV use, administer over 1 to 2 seconds at peripheral IV site closest to patient's
heart (IV administration into lower extremities may result in therapeutic failure or requirement of higher doses); follow
each bolus with NS flush (infants and children: 5 to 10 mL; adults: 20 mL); Note: The use of 2 syringes (one with
adenosine dose and the other with NS flush) connected to a T-connector or stopcock is recommended for IV and
intraosseous administration (PALS 2010). When administered peripherally IV in adults, the extremity is elevated for 10
to 20 seconds after the NS flush. Note: When administered via central line in adults, a reduced initial dose of 3 mg
recommended (ACLS 2010; Chang 2002); however, the FDA approved labeling for pediatric patients weighing <50 kg
states that doses listed may be administered either peripherally or centrally.
Drug Interactions
Digoxin: May enhance the adverse/toxic effect of Adenosine.Risk C: Monitor therapy
Theophylline Derivatives: May diminish the therapeutic effect of Adenosine. Risk D: Consider therapy modification
Adverse Reactions
Cardiovascular: Atrioventricular block, cardiac arrhythmia (transient and new arrhythmia after cardioversion; eg, atrial
fibrillation, atrial premature contractions, premature ventricular contractions), chest pain, chest pressure (and
discomfort), depression of ST segment on ECG, hypotension, palpitations
Central nervous system: Apprehension, dizziness, headache, nervousness, numbness, paresthesia
Dermatologic: Diaphoresis, facial flushing
Gastrointestinal: Gastrointestinal distress, Nausea
Neuromuscular & skeletal: Neck discomfort (includes throat, jaw), upper extremity discomfort
Respiratory: Dyspnea, hyperventilation
Rare but important or life-threatening: Atrial fibrillation, blurred vision, bradycardia, bronchospasm, cardiac arrest,
increased intracranial pressure, injection site reaction, myocardial infarction, respiratory arrest, torsades de pointes,
transient hypertension, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia
ADRENALINA
Dosing: Pediatric
Asystole or pulseless arrest (PALS [Kleinman 2010]): Infants, Children, and Adolescents:
IV, Intraosseous: 0.01 mg/kg (0.1 mL/kg of 0.1 mg/mLsolution) (maximum single dose: 1 mg); every 3 to 5 minutes until
return of spontaneous circulation
Endotracheal: 0.1 mg/kg (0.1 mL/kg of 1 mg/mLsolution) (maximum single dose: 2.5 mg) every 3 to 5 minutes until
return of spontaneous circulation or IV/intraosseous access established. Note: Recent clinical studies suggest that lower
epinephrine concentrations delivered by endotracheal administration may produce transient beta 2-adrenergic effects
which may be detrimental (eg, hypotension, lower coronary artery perfusion pressure). IV or intraosseous are the
preferred methods of administration.
Bradycardia (PALS [Kleinman 2010]): Infants, Children, and Adolescents:
IV, Intraosseous: 0.01 mg/kg (0.1 mL/kg of 0.1 mg/mLsolution) (maximum dose: 1 mg or 10 mL); may repeat every 3 to 5
minutes as needed
Endotracheal: 0.1 mg/kg (0.1 mL/kg of 1 mg/mLsolution) (maximum single dose: 2.5 mg); doses as high as 0.2 mg/kg
may be effective; may repeat every 3 to 5 minutes as needed until IV/intraosseous access established. Note: Recent
clinical studies suggest that lower epinephrine concentrations delivered by endotracheal administration may produce
transient beta 2-adrenergic effects which may be detrimental (eg, hypotension, lower coronary artery perfusion
pressure). IV or intraosseous are the preferred methods of administration.
Cardiac output increase or maintenance/post-resuscitation stabilization: Infants, Children, and Adolescents: Continuous
IV or intraosseous infusion: 0.05 to 1 mcg/kg/minute; doses <0.3 mcg/kg/minute generally produce beta-adrenergic
effects and higher doses (>0.3 mcg/kg/minute) generally produce alpha-adrenergic vasoconstriction; titrate dosage to
desired effect (ACCM [Davis 2017]; PALS [Kleinman 2010])
Hypersensitivity reaction/Anaphylaxis: Infants, Children, and Adolescents: Note: The preferred route of administration is
IM administration in the anterolateral aspect of the middle third of the thigh; SubQ administration results in slower
absorption and is less reliable (Campbell 2014; AAAAI [Lieberman 2015]; Simons 2011).
General dosing or health care settings: IM, SubQ: 0.01 mg/kg (0.01 mL/kg/dose of 1 mg/mL solution) not to exceed:
Prepubertal child: 0.3 mg/dose; adolescent: 0.5 mg/dose; administered every 5 to 15 minutes (Hegenbarth 2008; AAP
[Sicherer 2017]; Simons 2011; Simons 2015)
Manufacturer's labeling (eg, Adrenaclick, Auvi-Q, EpiPen Jr, EpiPen): IM, SubQ:
7.5 to <15 kg: 0.1 mg; if anaphylactic symptoms persist, dose may be repeated based on severity and response to initial
dose; more than 2 sequential doses should only be administered under direct medical supervision
15 to <30 kg: 0.15 mg; if anaphylactic symptoms persist, dose may be repeated based on severity and response to initial
dose; more than 2 sequential doses should only be administered under direct medical supervision
≥30 kg: 0.3 mg; if anaphylactic symptoms persist, dose may be repeated based on severity and response to initial dose;
more than 2 sequential doses should only be administered under direct medical supervision
Alternate dosing: AAP Recommendations (Sicherer 2017): Limited data available:
7.5 to <25 kg: 0.15 mg
≥25 kg: 0.3 mg
Refractory cases (unresponsive to IM doses): Continuous IV infusion: Prepared 1 mcg/mL solution: Initial:
0.1 mcg/kg/minute; titrate dose to response. Usual range: 0.1 to 1 mcg/kg/minute; maximum dose:
10 mcg/minute (Campbell 2014; Cheng 2011; AAAAI [Lieberman 2015]). Note: Suggested concentration of initial solution
is more dilute than those typically utilized in other clinical conditions; evaluate infusion concentration with continued
therapy and patient fluid status.
Hypotension/shock, fluid-resistant: Infants, Children, and Adolescents:
Continuous IV infusion: 0.1 to 1 mcg/kg/minute; rates >0.3 mcg/kg/minute associated with vasopressor activity; doses
up to 5 mcg/kg/minute may rarely be necessary; for fluid-resistant shock, may be combined with inotropic support
(ACCM [Davis 2017]; Hegenbarth 2008)
SubQ: 0.01 mg/kg (0.01 mL/kg of 1 mg/mL solution) (maximum single dose: 0.5 mg) every 20 minutes for 3 doses
(Hegenbarth 2008)
Contraindications
There are no absolute contraindications to the use of injectable epinephrine (including Adrenaclick, Auvi-Q, EpiPen,
EpiPen Jr, Symjepi, Allerject [Canadian product], and Twinject [Canadian product]) in a life-threatening situation. Some
products include the following contraindications: Hypersensitivity to sympathomimetic amines; general anesthesia with
halogenated hydrocarbons (eg, halothane) or cyclopropane; narrow angle glaucoma; nonanaphylactic shock; in
combination with local anesthesia of certain areas such as fingers, toes, and ears; use in situations where vasopressors
may be contraindicated (eg, thyrotoxicosis, diabetes, in obstetrics when maternal blood pressure is in excess of 130/80
mm Hg and in hypertension and other cardiovascular disorders).
Injectable solution (Adrenalin, Epinephrine injection, USP): There are no contraindications listed in the manufacturer's
labeling.
• Cardiac effects: May precipitate or aggravate angina pectoris or induce cardiac arrhythmias; use with caution
especially in patients with cardiac disease or those receiving drugs that sensitize the myocardium.
• Extravasation: IV administration: Vesicant; ensure proper needle or catheter placement prior to and during infusion.
Avoid extravasation.
• Pulmonary edema: Due to peripheral constriction and cardiac stimulation, pulmonary edema may occur.
• Renal effects: Due to renal blood vessel constriction, decreased urine output may occur.
• Cardiovascular disease: Use with caution in patients with cardiovascular diseases (eg, arrhythmias, cerebrovascular
disease, coronary artery disease, heart disease, hypertension).
• Diabetes: Use with caution in patients with diabetes mellitus; may transiently increase blood glucose levels.
• Hypovolemia: Correct blood volume depletion before administering any vasopressor.
• Parkinson disease: Use with caution in patients with Parkinson disease; psychomotor agitation or temporary
worsening of symptoms may occur.
• Pheochromocytoma: Use with caution in patients with pheochromocytoma.
• Thyroid disease: Use with caution in patients with thyroid disease.
information.
• Pediatric: Lacerations, bent needles, and embedded needles have been reported in young children who are
uncooperative during injection for hypersensitivity reaction. To minimize risk, hold the child's leg firmly in place and limit
movement prior to and during injection. Although the manufacturers of auto-injectors recommend varying lengths of
time for holding the device in the thigh (range: 2 to 10 seconds), longer times have occasionally resulted in injury. For all
devices, the needle should remain in the thigh for the least amount of time as possible (~3 seconds) (Brown 2016) (also
see Administration: IM).
• Accidental injection: Accidental injection into digits, hands, or feet may result in local reactions including injection-site
pallor, coldness, and hypoesthesia or injury resulting in bruising, bleeding, discoloration, erythema, or skeletal injury.
Patient should seek immediate medical attention if this occurs.
• IV administration: Rapid IV administration may cause death from cerebrovascular hemorrhage or cardiac arrhythmias.
However, rapid IV administration during pulseless arrest is necessary.
• Appropriate use: Hypersensitivity reactions: Do not inject into the buttock; may not effectively treat anaphylaxis and
has been associated with Clostridial infections (gas gangrene). Serious skin and soft tissue infections, including
necrotizing fasciitis and myonecrosis caused by Clostridia (gas gangrene), have been reported rarely at the injection site.
Cleansing skin with alcohol may reduce bacteria at the injection site, but alcohol cleansing does not
kill Clostridium spores. Preferred injection site is anterolateral aspect of the thigh. Do not administer repeated injections
at the same site (tissue necrosis may occur). Monitor for signs/symptoms of injection-site infection.

Endotracheal: May dilute in 1 to 5 mL NS based on patient size (Hegenbarth 2008).
Parenteral:
Direct IV or intraosseous administration: Dilute to a maximum concentration of 100 mcg/mL (0.1 mg/mL); if using 0.1
mg/mL concentration, no dilution is necessary
Continuous IV infusion: Concentration may vary by use.
Shock/hypotension; cardiac output maintenance/stabilization, postresuscitation: Dilute to a maximum concentration of
64 mcg/mL (Phillips 2011). ISMP and Vermont Oxford Network recommend a standard concentration of 10 mcg/mL for
neonates (ISMP 2011). Note: Although the manufacturer recommends dilution in dextrose containing solutions
(provides protection against significant loss of potency by oxidation) and does not recommend dilution in NS alone,
dilution in NS has been reported to be physically compatible (Trissel 2014).
Hypersensitivity/anaphylaxis (refractory): Prepare a 1 mcg/mL solution (eg, add 1 mg of the 1 mg/mL solution to 1000
mL of D5W or NS) (Campbell 2014)
Endotracheal:
Neonates: Use 0.1 mg/mL solution.
Infants, Children, and Adolescents: Use 1 mg/mLsolution; administer and flush with a minimum of 5 mL NS, followed by
5 manual ventilations.
Parenteral:
Direct IV or intraosseous administration: If using 0.1 mg/mL concentration, no dilution is necessary; the 1
mg/mL concentration must be further diluted.
Continuous IV infusion: When administering as a continuous infusion, central line administration is preferred. IV
infusions require an infusion pump. If central line not available, as a temporary measure, may administer peripherally
through a large vein. Avoid use of ankle veins (due to potential for gangrene), leg veins in those suffering from occlusive
vascular diseases (eg, diabetic endarteritis, Buerger disease, arteriosclerosis, atherosclerosis).
Vesicant; ensure proper needle or catheter placement prior to and during infusion; avoid extravasation. If extravasation
occurs, stop infusion immediately and disconnect (leave cannula/needle in place); gently aspirate extravasated solution
(do NOT flush the line); remove needle/cannula; elevate extremity. Initiate phentolamine (or alternative antidote) (see
Management of Drug Extravasations for more details). Apply dry warm compresses (Hurst 2004; Reynolds 2014).
IM (eg, Auvi-Q, EpiPen, EpiPen Jr): Intramuscularly into anterolateral aspect of the middle third of the thigh is preferred
in the setting of anaphylaxis (AAP [Sicherer 2017]); Kemp 2008; AAAAI [Lieberman 2015]). Administer through clothing if
necessary. Before administering to a child, immobilize leg to prevent laceration or other injury and consider restraining
children who are likely to move during administration. Although the manufacturers of auto-injectors recommend
varying lengths of time for holding the device in the thigh (range: 2 to 10 seconds), longer times have occasionally
resulted in injury. For all devices, the needle should remain in the thigh for the least amount of time as possible. With
nearly every device, the full dose is delivered within 3 seconds. For EpiPen, holding the device against the leg followed
by removing the cap and then compressing has been described for easier administration. Never reinsert needles (Baker
2011; Brown 2016; Kränke 2012; Lieberman 2011). Do not administer repeated injections at the same site. Do not inject
into the buttocks or into digits, hands, or feet. Some products are single-use products and a new device should be used
for each dose; consult product specific labeling. Note: In overweight or obese children, because skin surface to muscle
depth is greater in the upper half of the thigh, administration into the lower half of the thigh may be preferred. In very
obese children, injection into the calf will provide an even greater chance of intramuscular administration (Arkwright
2013).
SubQ: Use only 1 mg/mL solution. Although not preferred, if used for treatment of anaphylaxis, administer into the
anterolateral aspect of the middle third of the thigh (AAP [Sicherer 2017])
Drug Interactions
Alpha1-Blockers: May diminish the vasoconstricting effect of Alpha-/Beta-Agonists. Similarly, Alpha-/Beta-Agonists may
antagonize Alpha1-Blocker vasodilation. Risk C: Monitor therapy
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.Risk C:
Monitor therapy
Beta-Blockers (Beta1 Selective): May diminish the therapeutic effect of EPINEPHrine (Systemic). Risk C: Monitor therapy
Beta-Blockers (Nonselective): May enhance the hypertensive effect of EPINEPHrine (Systemic). Exceptions: Arotinolol;
Carvedilol; Labetalol. Risk C: Monitor therapy
Beta-Blockers (with Alpha-Blocking Properties): May diminish the therapeutic effect of EPINEPHrine (Systemic). Risk C:
Monitor therapy
Linezolid: May enhance the hypertensive effect of Sympathomimetics. Management: Reduce initial doses of
sympathomimetic agents, and closely monitor for enhanced pressor response, in patients receiving linezolid. Specific
dose adjustment recommendations are not presently available. Risk D: Consider therapy modification
Serotonin/Norepinephrine Reuptake Inhibitors: May enhance the tachycardic effect of Alpha-/Beta-Agonists.
Spironolactone: May diminish the vasoconstricting effect of Alpha-/Beta-Agonists. Risk C: Monitor therapy
Adverse Reactions
Cardiovascular: Angina pectoris, cardiac arrhythmia, cardiomyopathy (stress), cerebrovascular accident, chest pain,
hypertension, increased cardiac work, ischemic heart disease, limb ischemia, localized blanching, myocardial infarction,
palpitations, peripheral vasoconstriction, supraventricular tachycardia, tachyarrhythmia, tachycardia, vasoconstriction,
ventricular arrhythmia, ventricular ectopy, ventricular fibrillation
Central nervous system: Anxiety, apprehension, cerebral hemorrhage, disorientation, dizziness, drowsiness,
exacerbation of Parkinson disease, headache, memory impairment, panic, paresthesia, psychomotor agitation,
restlessness, tingling sensation
Dermatologic: Diaphoresis, gangrene of skin or other tissue (at injection site), pallor, piloerection
Endocrine & metabolic: Hyperglycemia, hypoglycemia, hypokalemia, insulin resistance, lactic acidosis
Local: Tissue necrosis at injection site
Neuromuscular & skeletal: Asthenia, tremor
Renal: Renal insufficiency
Respiratory: Dyspnea, pulmonary edema, rales
ALBUMINA
Dosing: Pediatric
Note: Albumin 5% should be used in hypovolemic or intravascularly depleted patients; albumin 25% should be used in
patients with fluid or sodium restrictions (eg, patients with hypoproteinemia and generalized edema, or nephrotic
syndrome). Dose depends on condition of patient:
Ascites with hypoalbuminemia: Limited data available: Infants, Children, and Adolescents: 25% albumin: IV: 1 g/kg/dose
over 2 to 3 hours; may repeat up to 3 times per day until albumin is >2.5 g/dL; maximum dose: 25 g/dose (Giefer 2011,
Sabri 2003)
Hypovolemia, plasma volume expansion, including hypovolemic shock (SCCM [Dellinger 2013]): Infants, Children, and
Adolescents: 5% albumin: IV: 0.5 to 1 g/kg/dose (10 to 20 mL/kg/dose) over 5 to 10 minutes. Usual adult dose: 12.5 to
25 g/dose (250 to 500 mL/dose). May repeat after 30 minutes if response is not adequate (Kleigman 2007).
Large volume paracentesis: Limited data available: Infants, Children, and Adolescents: 5% or 25% albumin: IV: 0.5 to 1
g/kg over 1 to 2 hours after paracentesis (Giefer 2011, Kramer 2001)
Nephrotic syndrome edema, refractory: Infants, Children, and Adolescents: 25% albumin: IV: 0.5 to 1 g/kg/dose over 30
to 60 minutes followed by diuretic therapy (Gipson 2009; Kliegman 2011; Robinson 2003)
NO
NO
Contraindications
Hypersensitivity to albumin or any component of the formulation; severe anemia, heart failure; patients at risk of
volume overload (eg, patients with renal insufficiency, severe anemia, stabilized chronic anemia, or heart failure);
dilution with sterile water for injection (may cause hemolysis or acute renal failure)
• Hypersensitivity: Severe allergic or anaphylactic reaction may occur. Discontinue immediately and manage
appropriately if allergic or anaphylactic reactions are suspected.
• Coagulation abnormality: Large replacement volumes may result in coagulation abnormality. Monitor and replete with
blood constituents if indicated.
• Electrolyte imbalance: Large replacement volumes may result in electrolyte imbalance. Monitor electrolytes and
replace or maintain as indicated.
• Hemodynamic effects: Cardiac or respiratory failure, renal failure, or increasing intracranial pressure can occur; closely
monitor hemodynamic parameters in all patients.
• Hypervolemia/hemodilution: Use with caution in conditions where hypervolemia and its consequences or
hemodilution may increase the risk of adverse effects (eg, heart failure, pulmonary edema, hypertension, hemorrhagic
diathesis, esophageal varices). Adjust rate of administration per hemodynamic status and solution concentration;
monitor closely with rapid infusions. Avoid rapid infusions in patients with a history of cardiovascular disease (may cause
circulatory overload and pulmonary edema). Discontinue at the first signs of cardiovascular overload (eg, headache,
dyspnea, jugular venous distention, rales, abnormal elevations in systemic or central venous blood pressure). All patients
should be observed for signs of hypervolemia, such as pulmonary edema. Monitor blood pressure.
• Critical illness: In patients with increased microvascular permeability (eg, sepsis, trauma, burn), the translocation of
fluid from the interstitial compartment to the intravascular compartment may decrease due to increased albumin in the
interstitial space. Furthermore, in extreme microvascular permeability states, administration of albumin (or other
colloids) may increase the net flux of fluid into the interstitial space reducing intravascular volume and precipitating
edematous states (eg, pulmonary edema) (Roberts, 1998).
• Hepatic impairment: Use with caution in patients with hepatic impairment; protein load may exacerbate or precipitate
encephalopathy.
• Renal impairment: Use with caution in patients with renal impairment; protein load may precipitate azotemia. Patients
with chronic renal insufficiency receiving albumin solution may be at risk for accumulation of aluminum and potential
toxicities (eg, hypercalcemia, vitamin D refractory osteodystrophy, anemia, severe progressive encephalopathy).
• Sodium restricted patients: Use with caution in those patients for whom sodium restriction is necessary. Albumin 5%
and 25% solutions contain 130 to 160 mEq/L sodium and are considered isotonic with plasma.
• Aluminum: The parenteral product may contain aluminum (Kelly, 1989); toxic aluminum concentrations may be seen
with high doses, prolonged use, or renal dysfunction. Premature neonates are at higher risk due to immature renal
function and aluminum intake from other parenteral sources. Parenteral aluminum exposure of >4 to 5 mcg/kg/day is
associated with CNS and bone toxicity; tissue loading may occur at lower doses (Federal Register 2002). See
manufacturer's labeling.
• Dilution: Do not dilute 5% albumin with sterile water for injection (may result in hemolysis and/or renal failure).
• Human plasma: Product of human plasma; may potentially contain infectious agents which could transmit disease.
Screening of donors, as well as testing and/or inactivation or removal of certain viruses, reduces the risk. Infections
thought to be transmitted by this product should be reported to the manufacturer.
Warnings: Additional Pediatric Considerations
In neonates, use the 25% concentration with extreme caution due to risk of intraventricular hemorrhage (from rapid
expansion of the intravascular volume); infuse slowly.
Due to the occasional shortage of 5% human albumin, 5% solutions may at times be prepared by diluting 25% human
albumin with NS or with D5W (if sodium load is a concern); however, do not use sterile water to dilute albumin solutions,
as this may result in hypotonic-associated hemolysis which can be fatal.
Parenteral: IV: If 5% human albumin is unavailable, it may be prepared by diluting 25% human albumin with NS or D5W
(if sodium load is a concern). Do not use sterile water to dilute albumin solutions, as this has been associated with
hypotonic-associated hemolysis.
Parenteral: IV: Too rapid infusion may result in vascular overload. Rate of infusion dependent upon use. In emergencies,
may administer as rapidly as necessary to improve clinical condition. After initial volume replacement:
5%: Do not exceed 2 to 4 mL/minute in patients with normal plasma volume; 5 to 10 mL/minute in patients with
hypoproteinemia
25%: Do not exceed 1 mL/minute in patients with normal plasma volume; 2 to 3 mL/minute in patients with
hypoproteinemia
Product-specific details:
Observe for signs of hypervolemia, pulmonary edema, cardiac failure, vital signs, fluid status, Hgb, Hct, urine specific
gravity
AMIKACINA
Dosing: Pediatric
Note: Individualization is critical because of the low therapeutic index. Dosage should be based on an estimate of ideal
body weight. In morbidly obese children and adolescents, dosage requirement may best be estimated using a
dosing weight of IBW + 0.4 (TBW - IBW). Initial dosing recommendation presented; dosage should be
individualized based upon serum concentration monitoring. Initial and periodic plasma drug concentrations (eg,
peak and trough with conventional dosing, post dose level at a prespecified time with extended-interval dosing)
should be determined, particularly in critically ill patients with serious infections or in disease states known to
significantly alter aminoglycoside pharmacokinetics (eg, cystic fibrosis, burns, or major surgery).
General dosing, severe, susceptible infections: Infants, Children, and Adolescents:
IM, IV: 15 to 22.5 mg/kg/day divided every 8 hours or 15 to 20 mg/kg/dose every 24 hours (Red Book [AAP
2015]);
CNS infections:
Meningitis (Tunkel 2004):
Infants and Children: IV: 20 to 30 mg/kg/daydivided every 8 hours
Adolescents: IV: 15 mg/kg/day divided every 8 hours
VP-shunt infection, ventriculitis: Limited data available: Intraventricular/intrathecal (use a preservative-

free preparation): Infants, Children, and Adolescents: 5 to 50 mg/day; usual dose: 30 mg/day
Cystic fibrosis, pulmonary infection: Infants, Children, and Adolescents:
Traditional dosing: IV, IM: 10 mg/kg/dose every 8 hours (Wallace 1993)
Extended-interval dosing: IV: 30 mg/kg/dose every 24 hours (Flume 2009); Note: The CF Foundation
recommends extended-interval dosing as preferred over traditional dosing.
Endocarditis, treatment: Children and Adolescents: IV: 15 mg/kg/day divided every 8 to 12 hours; use in
combination with other antibiotics dependent upon organism and source of infection (ie, valve-type) (AHA
[Baltimore 2015])
Intra-abdominal infection, complicated: Infants, Children, and Adolescents: IV: 15 to 22.5 mg/kg/day divided
every 8 to 24 hours (Solomkin 2010)
Mycobacterium, avium complex infection (MAC), treatment: HIV-exposed/-positive:
Infants and Children: IV: 15 to 30 mg/kg/daydivided every 12 to 24 hours as part of a multiple drug
regimen; maximum daily dose: 1,500 mg/day (HHS [OI pediatric 2013])
Adolescents: IV: 10 to 15 mg/kg/dose every 24 hours as part of a multiple drug regimen; maximum daily
dose: 1,500 mg/day (HHS [OI adult 2016]; HHS [OI pediatric 2013])
Tuberculosis, drug-resistant:
Infants, Children, and Adolescents ≤14 years:
Once-daily regimen: IM, IV: 15 to 20 mg/kg/dose once daily as part of a multiple drug regimen
(ATS/CDC/IDSA [Nahid 2016]); current guidelines do not provide a maximum daily dose;
for HIV-exposed/-positive pediatric patients, a maximum daily dose of 1,000 mg/dayhas
been suggested for similar mg/kg doses (HHS [OI pediatric 2013])
Twice-weekly regimen: IM, IV: 25 to 30 mg/kg/dose administered twice weekly as part of a

multiple drug regimen; dosing based on experience in adult patients and pediatric
pharmacokinetic considerations (ATS/CDC/IDSA [Nahid 2016]); current guidelines do
not provide a maximum daily dose; for HIV-exposed/-positive pediatric patients, a
maximum daily dose of 1,000 mg/dayhas been suggested for similar mg/kg doses (HHS
[OI pediatric 2013])
HIV-exposed/-positive: IM, IV: 15 to 30 mg/kg/dose once daily as part of a multiple drug regimen;
maximum daily dose: 1,000 mg/day (HHS [OI pediatric 2013])
Adolescents ≥15 years: Independent of HIV status:
Once-daily regimen: IM, IV: 15 mg/kg/dose once daily as part of a multiple drug regimen
(ATS/CDC/IDSA [Nahid 2016]; HHS [OI adult 2016]); current guidelines do not provide a
maximum daily dose; for HIV-exposed/-positive pediatric patients, a maximum daily dose of
1,000 mg/day has been suggested for similar mg/kg doses (HHS [OI pediatric 2013])
Three-times-weekly regimen: IM, IV: 25 mg/kg/dose 3 times weekly (ATS/CDC/IDSA [Nahid 2016];
HHS [OI adult 2016]). Current guidelines do not provide a maximum dose; for HIV-exposed/-
positive pediatric patients, a maximum daily dose of 1,000 mg/day has been suggested for
similar mg/kg doses (HHS [OI pediatric 2013]).
Peritonitis (CAPD): Infants, Children, and Adolescents: Intraperitoneal: Continuous: Loading dose: 25 mg per liter
of dialysate; maintenance dose: 12 mg per liter (Warady 2012)
Dosing: Renal Impairment: Pediatri
by serum concentrations
Peritoneal dialĺlysis (PD): 5 mg/kg/dose; redose as indicated by serum concentrations9
Continuous renal replacement therapy (CRRT): 7.5 mg/kg/dose every 12 hours, monitor serum
concentrations
Contraindications
Hypersensitivity to amikacin, other aminoglycosides, or any component of the formulation
• Hypersensitivity: Cross-sensitivity to other aminoglycosides may occur.
• Nephrotoxicity: [US Boxed Warning]: May cause nephrotoxicity; usual risk factors include preexisting renal
impairment, concomitant nephrotoxic medications, advanced age and dehydration. Discontinue treatment
if signs of nephrotoxicity occur; renal damage is usually reversible.
• Neuromuscular blockade and respiratory paralysis: [US Boxed Warning]: May cause neuromuscular blockade
and respiratory paralysis; especially when given soon after anesthesia or muscle relaxants.
• Neurotoxicity: [US Boxed Warning]: May cause neurotoxicity; usual risk factors include preexisting renal
impairment, concomitant neuro-/nephrotoxic medications, advanced age and dehydration. Ototoxicity is
proportional to the amount of drug given and the duration of treatment. Tinnitus or vertigo may be
indications of vestibular injury and impending bilateral irreversible damage. Discontinue treatment if signs
of ototoxicity occur.
• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated
diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic
treatment.
• Hearing impairment: Use with caution in patients with preexisting vertigo, tinnitus, or hearing loss.
• Hypocalcemia: Use with caution in patients with hypocalcemia.
• Neuromuscular disorders: Use with caution in patients with neuromuscular disorders, including myasthenia
gravis or parkinsonism.
• Renal impairment: Use with caution in patients with preexisting renal insufficiency; dosage modification
required.
additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more
detailed information.
• Neurotoxic and/or nephrotoxic drugs: [US Boxed Warning]: Avoid concomitant or sequential use of other
neurotoxic and/or nephrotoxic drugs (eg, bacitracin, cisplatin, amphotericin B, paromomycin, polymyxin
B, colistin, vancomycin, other aminoglycosides).
• Potent diuretics: [US Boxed Warning]: Avoid concomitant use with potent diuretics (eg, ethacrynic acid,
furosemide) since diuretics themselves may cause ototoxicity and may enhance aminoglycoside toxicity.
• Sulfites: May contain sulfites which may cause allergic-type reactions (including anaphylaxis) as well as life-
threatening or less severe asthmatic episodes in certain individuals.
• Surgical irrigation: Irreversible deafness, renal failure, and death due to neuromuscular blockade have been
reported following use of aminoglycosides as surgical irrigation; rapid systemic absorption occurs with
topical application (except to the urinary bladder).
Use with caution in pediatric patients on extracorporeal membrane oxygenation (ECMO); pharmacokinetics of
aminoglycosides may be altered; dosage adjustment and close monitoring necessary.
Parenteral: IV intermittent infusion: Dilute in a compatible solution (eg, NS, D5W) to a final concentration of 0.25 to 5
mg/mL per the manufacturer; concentrations as high as 10 mg/mL have been reported (Murray 2014).
Parenteral: Administer around-the-clock to promote less variation in peak and trough serum levels.
IM: Administer undiluted into a large muscle mass. Slower absorption and lower peak concentrations, probably due to
poor circulation in the atrophic muscle, may occur following IM injection; in paralyzed patients, suggest IV route
Intermittent IV infusion: Infuse over 30 to 60 minutes; in infants infusion over 1 to 2 hours is recommended by the
manufacturer.
Some penicillins (eg, carbenicillin, ticarcillin, and piperacillin) have been shown to inactivate aminoglycosides in vitro.
This has been observed to a greater extent with tobramycin and gentamicin, while amikacin has shown greater
stability against inactivation. Concurrent use of these agents may pose a risk of reduced antibacterial efficacy in
vivo, particularly in the setting of profound renal impairment; however, definitive clinical evidence is lacking. If
combination penicillin/aminoglycoside therapy is desired in a patient with renal dysfunction, separation of doses
(if feasible), and routine monitoring of aminoglycoside levels, CBC, and clinical response should be considered.
Preparation for Administration: Adult
For intravenous administration, dilute in a compatible solution (eg, NS, D5W) to a final concentration of 0.25 to 5
mg/mL.
Administration: Adult
IM: Administer IM injection in large muscle mass.
IV: Infuse over 30 to 60 minutes.
Some penicillins (eg, carbenicillin, ticarcillin, and piperacillin) have been shown to inactivate in vitro. This has been
observed to a greater extent with tobramycin and gentamicin, while amikacin has shown greater stability against
inactivation. Concurrent use of these agents may pose a risk of reduced antibacterial efficacy in vivo, particularly
in the setting of profound renal impairment. However, definitive clinical evidence is lacking. If combination
penicillin/aminoglycoside therapy is desired in a patient with renal dysfunction, separation of doses (if feasible),
and routine monitoring of aminoglycoside levels, CBC, and clinical response should be considered.
Intrathecal/Intraventricular (off-label route): Reconstitute with preservative-free diluent (NS) only to a final volume of 3
mL (Corpus 2004; Preston 1993). When administered through a ventricular drain, clamp drain for 15 to 60
minutes before opening the drain to allow amikacin solution to equilibrate in the CSF (IDSA [Tunkel 2017).
Inhalation (off-label route): Nebulization: Use with standard jet nebulizer connected to an air compressor or ultrasonic
nebulizer; administer with mouthpiece or face mask (Le 2010)
Urinalysis, urine output, BUN, serum creatinine, peak and trough serum amikacin concentrations; be alert to ototoxicity
With conventional dosing, typically obtain serum concentration after the third dose; exceptions for earlier monitoring
may include neonates or patients with rapidly changing renal function. With extended-interval dosing, usually
obtain serum concentration after first, second, or third dose.
Not all infants and children who receive aminoglycosides require monitoring of serum aminoglycoside concentrations.
Indications for use of aminoglycoside serum concentration monitoring include:
• Treatment course >5 days
• Patients with decreased or changing renal function
• Patients with poor therapeutic response
• Neonates and Infants <3 months of age
• Atypical body constituency (obesity, expanded extracellular fluid volume)
• Clinical need for higher doses or shorter intervals (eg, cystic fibrosis, burns, endocarditis, meningitis, critically ill
patients, relatively resistant organisms)
• Patients on hemodialysis or chronic ambulatory peritoneal dialysis
• Signs of nephrotoxicity or ototoxicity
• Concomitant use of other nephrotoxic agents
Reference Range
Therapeutic levels:
Peak:
Life-threatening infections: 25 to 40 mcg/mL
Serious infections: 20 to 25 mcg/mL
Urinary tract infections: 15 to 20 mcg/mL
Trough: <8 mcg/mL; the American Thoracic Society (ATS) recommends trough levels of <4 to 5 mcg/mL for patients with
hospital-acquired pneumonia
Timing of serum samples: Draw peak 30 minutes after completion of 30-minute infusion or at 1 hour following initiation
of infusion or IM injection; draw trough within 30 minutes prior to next dose; aminoglycoside levels measured
from blood taken from Silastic central catheters can sometimes give falsely elevated readings
Drug Interactions
Amphotericin B: May enhance the nephrotoxic effect of Aminoglycosides. Risk C: Monitor therapy
Cephalosporins (2nd Generation): May enhance the nephrotoxic effect of Aminoglycosides. Risk C: Monitor therapy
Cephalosporins (3rd Generation): May enhance the nephrotoxic effect of Aminoglycosides. Risk C: Monitor therapy
Cephalosporins (4th Generation): May enhance the nephrotoxic effect of Aminoglycosides. Risk C: Monitor therapy
Cephalothin: May enhance the nephrotoxic effect of Aminoglycosides. Risk C: Monitor therapy
Cephradine: May enhance the nephrotoxic effect of Aminoglycosides. Risk C: Monitor therapy
Colistimethate: Aminoglycosides may enhance the nephrotoxic effect of Colistimethate. Aminoglycosides may enhance
the neuromuscular-blocking effect of Colistimethate. Risk D: Consider therapy modification
CycloSPORINE (Systemic): Aminoglycosides may enhance the nephrotoxic effect of CycloSPORINE (Systemic).Risk C:
Monitor therapy
Loop Diuretics: May enhance the adverse/toxic effect of Aminoglycosides. Specifically, nephrotoxicity and
ototoxicity. Risk C: Monitor therapy
Mannitol (Systemic): May enhance the nephrotoxic effect of Aminoglycosides. Risk X: Avoid combination
Neuromuscular-Blocking Agents: Aminoglycosides may enhance the respiratory depressant effect of Neuromuscular-
Blocking Agents. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May decrease the excretion of Aminoglycosides. Data only in premature
infants. Risk C: Monitor therapy
Penicillins: May decrease the serum concentration of Aminoglycosides. Primarily associated with extended spectrum
penicillins, and patients with renal dysfunction. Exceptions: Amoxicillin; Ampicillin; Bacampicillin; Cloxacillin;
Dicloxacillin; Nafcillin; Oxacillin; Penicillin G (Parenteral/Aqueous); Penicillin G Benzathine; Penicillin G Procaine;
Penicillin V Benzathine; Penicillin V Potassium. Risk D: Consider therapy modification
Vancomycin: May enhance the nephrotoxic effect of Aminoglycosides. Risk C: Monitor therapy
Pharmacodynamics/Kinetics (Adult data unless noted)
Absorption:
IM: Rapid
Oral: Poorly absorbed
Distribution: Vd: 0.25 L/kg (Vozeh 1988); primarily into extracellular fluid (highly hydrophilic); poor penetration into the
blood-brain barrier even when meninges are inflamed; Vd is increased in neonates and patients with edema,
ascites, fluid overload; Vd is decreased in patients with dehydration
Relative diffusion of antimicrobial agents from blood into CSF: Good only with inflammation (exceeds usual MICs)
CSF:blood level ratio: Infants: Normal meninges: 10% to 20%; Inflamed meninges: up to 50%
Protein-binding: 0% to 11%
Half-life elimination (renal function and age dependent):
Infants: Low birth weight (1 to 3 days): 7 to 9 hours; Full-term >7 days: 4 to 5 hours (Howard 1975)
Children: 1.6 to 2.5 hours
Adolescents: 1.5 ± 1 hour
Adults: Normal renal function: ~2 hours; Anuria/end-stage renal disease: 17 to 150 hours (Aronoff 2007)
Time to peak, serum: IM: 60 minutes; IV: Within 30 minutes following a 30-minute infusion
Excretion: Urine (94% to 98% unchanged)
Pharmacodynamics/Kinetics: Additional Considerations
Renal function impairment: Clearance is decreased in renal impairment.
Adverse Reactions
Central nervous system: Neurotoxicity
Genitourinary: Nephrotoxicity
Otic: Auditory ototoxicity, vestibular ototoxicity
Rare but important or life-threatening: Dyspnea, eosinophilia, hypersensitivity reaction
AMPICILINA
Dosing: Pediatric
General dosing, susceptible infection (Bradley 2019; Red Book [AAP 2018]): Infants, Children, and Adolescents:
Mild to moderate infection:
Oral: 50 to 100 mg/kg/day divided every 6 hours; maximum daily dose: 2,000 mg/day.
IM, IV: 50 to 200 mg/kg/day divided every 6 hours; maximum daily dose: 8 g/day.
Severe infection (eg, meningitis, endocarditis): IM, IV: 300 to 400 mg/kg/day divided every 4 to 6 hours; maximum
daily dose: 12 g/day.
Community-acquired pneumonia (CAP) (IDSA/PIDS [Bradley 2011]): Infants >3 months, Children, and
Adolescents: Note: May consider addition of vancomycin or clindamycin to empiric therapy if community-
acquired MRSA suspected. In children ≥5 years, a macrolide antibiotic should be added if atypical pneumonia
cannot be ruled out.
Empiric treatment or S. pneumoniae (MICs for penicillin ≤2 mcg/mL) or H. influenzae (beta-lactamase negative) in
fully immunized patients: IV: 150 to 200 mg/kg/day divided every 6 hours.
Group A Streptococcus: IV: 200 mg/kg/day divided every 6 hours.
S. pneumoniae (MICs for penicillin ≥4 mcg/mL): IV: 300 to 400 mg/kg/day divided every 6 hours.
Endocarditis:
Treatment: Children and Adolescents: IV: 200 to 300 mg/kg/day divided every 4 to 6 hours; maximum daily dose:
12 g/day; use in combination with other antibiotics for at least 4 weeks; some organisms may require
longer duration (AHA [Baltimore 2015]).
Prophylaxis: Note: AHA guidelines (Baltimore 2015) limit the use of prophylactic antibiotics to patients at the
highest risk for infective endocarditis (IE) or adverse outcomes (eg, prosthetic heart valves, patients with
previous IE, unrepaired cyanotic congenital heart disease, repaired congenital heart disease with prosthetic
material or device during first 6 months after procedure, repaired congenital heart disease with residual
defects at the site or adjacent to site of prosthetic patch or device, and heart transplant recipients with
cardiac valvulopathy):
Dental or oral procedures or respiratory tract procedures (eg, tonsillectomy, adenoidectomy):Infants,

Children, and Adolescents: IV, IM: 50 mg/kg within 30 to 60 minutes before procedure; maximum
dose: 2,000 mg/dose. Intramuscular (IM) injections should be avoided in patients who are receiving
anticoagulant therapy. In these circumstances, orally administered regimens should be used
whenever possible. Intravenously (IV) administered antibiotics should be used for patients who are
unable to tolerate or absorb oral medications (Wilson 2007).
Intra-abdominal infection, complicated: Infants, Children, and Adolescents: IV: 200 mg/kg/day divided every 6 hours;
maximum single dose: 2,000 mg; maximize doses if undrained abdominal abscesses (IDSA [Solomkin 2010]).
Meningitis (including health care-associated meningitis and ventriculitis): Infants, Children, and Adolescents: IV: 300 to
400 mg/kg/day divided every 4 to 6 hours; maximum daily dose: 12 g/day (Bradley 2019; IDSA [Tunkel 2004];
IDSA [Tunkel 2017]; Red Book [AAP 2018]).
Peritonitis (CAPD) Limited data available: Infants, Children, and Adolescents: Intraperitoneal: 125 mg per liter of
dialysate for 2 weeks (ISPD [Warady 2012]).
Surgical prophylaxis: Infants, Children, and Adolescents: IV: 50 mg/kg within 60 minutes prior to surgical incision; may
repeat in 2 hours if lengthy procedure or excessive blood loss; maximum dose: 2,000 mg/dose (ASHP/IDSA
[Bratzler 2013]; Red Book [AAP 2018]).

Infants, Children, and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling; however,
the following adjustments have been recommended (Aronoff 2007). Note: Renally adjusted dose
recommendations are based on IM, IV doses of 100 to 200 mg/kg/day divided every 6 hours: IM, IV:
GFR 30 to 50 mL/minute/1.73 m2: 35 to 50 mg/kg/dose every 6 hours
GFR 10 to 29 mL/minute/1.73 m2: 35 to 50 mg/kg/dose every 8 to 12 hours
GFR <10 mL/minute/1.73 m2: 35 to 50 mg/kg/dose every 12 hours
Intermittent hemodialysis: 35 to 50 mg/kg/dose every 12 hours
Peritoneal dialysis (PD): 35 to 50 mg/kg/dose every 12 hours
Continuous renal replacement therapy (CRRT): 35 to 50 mg/kg/dose every 6 hours
NO
Contraindications
Hypersensitivity (eg, anaphylaxis) to ampicillin, any component of the formulation, or other penicillins; infections caused
by penicillinase-producing organisms
• Hypersensitivity/anaphylactoid reactions: Serious and occasionally severe or fatal hypersensitivity

(anaphylactoid) reactions have been reported in patients on penicillin therapy, especially with a history of
beta-lactam hypersensitivity or a history of sensitivity to multiple allergens. Serious anaphylactoid reactions
require emergency treatment and airway management. Appropriate treatments must be readily available.
• Rash: Appearance of a rash should be carefully evaluated to differentiate a nonallergic ampicillin rash from a
hypersensitivity reaction; rash occurs in 5% to 10% of children and is a generalized dull red, maculopapular
rash, generally appearing 3 to 14 days after the start of therapy. It normally begins on the trunk and
spreads over most of the body. It may be most intense at pressure areas, elbows, and knees.
• Superinfection: Prolonged use may result in fungal or bacterial superinfection,

including Clostridioides(formerly Clostridium) difficile-associated diarrhea (CDAD) and pseudomembranous
colitis; CDAD has been observed >2 months postantibiotic treatment.
• Infectious mononucleosis: A high percentage of patients with infectious mononucleosis have developed rash
during therapy; ampicillin-class antibiotics not recommended in these patients. Rash (generalized
maculopapular and pruritic) usually appears 7 to 10 days after initiation and usually resolves within a week
of discontinuation. It is not known whether these patients are truly allergic to ampicillin
• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment recommended.
Ampicillin has been shown to prolong the bleeding time in neonates in 2 prospective studies. The first study found a
prolonged bleeding time by an average of 60 seconds longer than baseline in neonates (n=15; GA: 33 to 41 weeks;
weight: 1,760 to 3,835 g) after receiving the third and fourth doses of ampicillin (50 to 100 mg/kg/dose every 12 hours)
(Sheffield 2010). The second study evaluated the effect on bleeding time in very low birth weight patients (n=20; GA: 23
to 33 weeks; weight: 400 to 1,410 g); results showed that patients receiving ampicillin for ≥10 days had a prolonged
bleeding time compared to baseline; on average bleeding time was 2 minutes longer (p=0.001) (Sheffield 2011). The
clinical significance of ampicillin's effect on bleeding time is unknown, but probably depends on the patient's clinical
status and risk of hemorrhage.
Oral: Reconstitute powder for oral suspension with appropriate amount of water as specified on the bottle. Shake
vigorously until suspended.
Parenteral:
IM: Reconstitute vial with SWFI to a final concentration of 125 to 250 mg/mL (see manufacturer's labeling for
specific details).
IV:
IV push: Reconstitute vial with SWFI (see manufacturer's labeling for specific details).
Intermittent IV infusion: Concentration should not exceed 30 mg/mL due to concentration-dependent

stability restrictions.
Oral: Administer around-the-clock to promote less variation in peak and trough serum levels. Administer on an empty
stomach (ie, 1 hour prior to or 2 hours after meals) to increase total absorption; shake suspension well before
using
Parenteral:
IM: Inject deep IM into a large muscle mass
IV:
IV push: Doses ≤500 mg should be administered over 3 to 5 minutes; doses >500 mg should be
administered over 10 to 15 minutes; rapid administration has been associated with seizures.
Intermittent IV infusion: Infuse over 10 to 15 minutes
Some penicillins (eg, carbenicillin, ticarcillin, and piperacillin) have been shown to inactivate aminoglycosides in vitro.
This has been observed to a greater extent with tobramycin and gentamicin, while amikacin has shown greater
stability against inactivation. Concurrent use of these agents may pose a risk of reduced antibacterial efficacy in
vivo, particularly in the setting of profound renal impairment; however, definitive clinical evidence is lacking. If
combination penicillin/aminoglycoside therapy is desired in a patient with renal dysfunction, separation of doses
(if feasible), and routine monitoring of aminoglycoside levels, CBC, and clinical response should be considered.
Dietary Considerations
Take on an empty stomach 30 minutes before or 2 hours after meals. Some products may contain sodium.
With prolonged therapy, monitor renal, hepatic, and hematologic function periodically; observe for change in bowel
frequency; observe for signs of anaphylaxis with first dose
Drug Interactions
Allopurinol: May enhance the potential for allergic or hypersensitivity reactions to Ampicillin. Risk C: Monitor therapy
Atenolol: Ampicillin may decrease the bioavailability of Atenolol. Risk C: Monitor therapy
Chloroquine: May decrease the serum concentration of Ampicillin. Management: Chloroquine prescribing information
recommends separating administration of ampicillin and chloroquine by at least 2 hours to minimize any potential
negative impact of chloroquine on ampicillin bioavailability. Risk D: Consider therapy modification
Methotrexate: Penicillins may increase the serum concentration of Methotrexate. Risk C: Monitor therapy
Probenecid: May increase the serum concentration of Penicillins. Management: Avoid the routine use of penicillins and
probenecid, but this combination may be used advantageously in select cases with careful monitoring. Monitor
for toxic effects of penicillins if probenecid is initiated or the dose is increased. Risk D: Consider therapy
modification
Tetracyclines: May diminish the therapeutic effect of Penicillins. Risk D: Consider therapy modification
Vitamin K Antagonists (eg, warfarin): Penicillins may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C:
Monitor therapy
Food Interactions
Food decreases ampicillin absorption rate; may decrease ampicillin serum concentration. Management: Take at equal
intervals around-the-clock, preferably on an empty stomach (30 minutes before or 2 hours after meals). Maintain
adequate hydration, unless instructed to restrict fluid intake.
Adverse Reactions
Central nervous system: Brain disease (penicillin-induced), glossalgia, seizure, sore mouth
Dermatologic: Erythema multiforme, exfoliative dermatitis, skin rash, urticaria

Note: Appearance of a rash should be carefully evaluated to differentiate (if possible) nonallergic ampicillin rash
from hypersensitivity reaction. Incidence is higher in patients with viral infection, Salmonella infection,
lymphocytic leukemia, or patients that have hyperuricemia.
Gastrointestinal: Diarrhea, enterocolitis, glossitis, melanoglossia, nausea, oral candidiasis, pseudomembranous colitis,
stomatitis, vomiting
Hematologic & oncologic: Agranulocytosis, anemia, eosinophilia, hemolytic anemia, immune thrombocytopenia,
leukopenia
Hepatic: Increased serum AST
Hypersensitivity: Anaphylaxis
Immunologic: Serum sickness-like reaction
Renal: Interstitial nephritis (rare)
Respiratory: Stridor
Miscellaneous: Fever
Rare but important or life-threatening: Dysgeusia (Syed 2016)
ATROPINA
Dosing: Neonatal
Bradycardia: Note: Neonatal resuscitation guidelines do not include atropine for the treatment of bradycardia
(Kattwinkel 2010).
IV, Intraosseous: 0.02 mg/kg/dose; may repeat once in 3 to 5 minutes; reserve use for patients unresponsive to
improved oxygenation/ventilation and epinephrine (Eichenwald 2017); use of a minimum dose of 0.1 mg in
patients <5 kg will result in dosages >0.02 mg/kg; in some cases toxicity and even death have been
reported (Barrington 2011; Gillick 1974; Kumar 2015; Rizzi 2004).
Endotracheal: 0.04 to 0.06 mg/kg/dose; immediately follow with 1 mL of NS; may repeat once if needed
(Eichenwald 2017)
Intubation, premedication (preferred vagolytic): IV, IM: 0.02 mg/kg/dose; a minimum dose of 0.1 mg/dose is not
recommended (AAP [Kumar 2010]; Barrington 2011; Eichenwald 2017).
Organophosphate or carbamate insecticide or nerve agent poisoning: Note: If exposure is known or suspected,
antidotal therapy should be given as soon as symptoms appear; do not wait for confirmation. The dose of
atropine required varies considerably with the severity of poisoning. The total amount of atropine used for
carbamate poisoning is usually less than with organophosphate insecticide or nerve agent poisoning. Severely
poisoned patients may exhibit significant tolerance to atropine; ≥2 times the suggested doses may be needed.
Titrate to pulmonary status (decreased bronchial secretions); consider administration of atropine via continuous
IV infusion in patients requiring large doses of atropine. Once patient is stable for a period of time, the
dose/dosing frequency may be decreased. Pralidoxime is a component of the management of organophosphate
insecticide and nerve agent toxicity; refer to pralidoxime for the specific route and dose.
IV, IM, Intraosseous: Initial: 0.05 to 0.1 mg/kg; repeat every 5 to 15 minutes as needed, doubling the dose if
previous dose did not induce atropinization (AAP [Roberts 2012]; Roberts 2013; Rotenberg 2003). Maintain
atropinization by administering repeat doses as needed for ≥2 to 12 hours based on recurrence of
symptoms (Roberts 2013).
Continuous IV infusion: Following atropinization, administer 10% to 20% of the total loading dose required to
induce atropinization as a continuous IV infusion per hour; adjust as needed to maintain adequate
atropinization without atropine toxicity (Eddleston 2004; Roberts 2007).
IM (AtroPen): 0.25 mg (yellow pen):
Mild symptoms (≥2 mild symptoms): Administer one 0.25 mg (yellow pen) dose as soon as an exposure is
known or strongly suspected. If severe symptoms develop after the first dose, 2 additional doses
should be repeated in rapid succession 10 minutes after the first dose; do not administer more than
3 doses. If profound anticholinergic effects occur in the absence of excessive bronchial secretions,
further doses of atropine should be withheld. Mild symptoms of insecticide or nerve agent
poisoning, as provided by manufacturer in the AtroPen product labeling to guide therapy, include:
Blurred vision, bradycardia, breathing difficulties, chest tightness, coughing, drooling, miosis,
muscular twitching, nausea, runny nose, salivation increased, stomach cramps, tachycardia, teary
eyes, tremor, vomiting, or wheezing.
Severe symptoms (≥1 severe symptom):Immediately administer three 0.25 mg (yellow pen) doses. Severe
symptoms of insecticide or nerve agent poisoning, as provided by manufacturer in the AtroPen
product labeling to guide therapy, include: Breathing difficulties (severe), confused/strange
behavior, defecation (involuntary), muscular twitching/generalized weakness (severe), respiratory
secretions (severe), seizure, unconsciousness, urination (involuntary); Note:Neonates and infants
may become drowsy or unconscious with muscle floppiness as opposed to muscle twitching.
Endotracheal: Increase the dose by 2 to 3 times the usual IV dose. Mix with 3 to 5 mL of normal saline and
administer. Flush with 3 to 5 mL of NS and follow with 5 assisted manual ventilations (Rotenberg 2003)
Dosing: Pediatric
Bradycardia: Infants, Children, and Adolescents:
IV, Intraosseous: 0.02 mg/kg/dose; minimum dose: 0.1 mg/dose, maximum dose: 0.5 mg/dose; may repeat once
in 5 minutes; reserve use for those patients unresponsive to improved oxygenation and epinephrine (PALS
[de Caen 2015]; PALS [Kleinman 2010]); some have suggested the minimum dose should not be used in
patients <5 kg (Barrington 2011; Prakash 2017).
Endotracheal: 0.04 to 0.06 mg/kg/dose; may repeat once if needed (PALS [de Caen 2015]; PALS [Kleinman 2010])
Inhibit salivation and secretions (preoperative/intraoperative):
Infants and Children <12 years: IM, IV, SubQ: 0.02 mg/kg/dose; maximum dose: 0.5 mg/dose; administer first
dose 30 to 60 minutes preoperatively and then repeat every 4 to 6 hours as needed; maximum total dose:
1 mg/procedure.
Children ≥12 years and Adolescents: IM, IV, SubQ: 0.02 mg/kg/dose; maximum dose: 1 mg/dose; administer first
dose 30 to 60 minutes preoperatively and then repeat every 4 to 6 hours as needed; maximum total dose:
2 mg/procedure.
Intubation; emergent (premedication): Note: Routine use not recommended for preintubation in infants and children;
atropine may be considered in situations with a high-risk of bradycardia (eg, succinylcholine use) (PALS [de Caen
2015]) or septic shock (Brierley 2009). Infants and Children: IV: 0.02 mg/kg/dose with no minimum dose;
maximum dose: 0.5 mg/dose (PALS [de Caen 2015]).
Muscarine-containing mushroom poisoning: Limited data available: Infants, Children, and Adolescents: IV: 0.02
mg/kg/dose; minimum dose: 0.1 mg. Titrate and repeat as needed (Goldfrank 2015)
Organophosphate or carbamate insecticide or nerve agent poisoning: Note: If exposure is known or suspected,
antidotal therapy should be given as soon as symptoms appear; do not wait for confirmation. The dose of
atropine required varies considerably with the severity of poisoning. The total amount of atropine used for
carbamate poisoning is usually less than with organophosphate insecticide or nerve agent poisoning. Severely
poisoned patients may exhibit significant tolerance to atropine; ≥2 times the suggested doses may be needed.
Titrate to pulmonary status (decreased bronchial secretions); consider administration of atropine via
continuous IV infusion in patients requiring large doses of atropine. Once patient is stable for a period of time,
the dose/dosing frequency may be decreased. Pralidoxime is a component of the management of
organophosphate insecticide and nerve agent toxicity; refer to pralidoxime for the specific route and dose.
IV, IM, Intraosseous:
Infants and Children: Initial: 0.05 to 0.1 mg/kg; repeat every 5 to 10 minutes as needed, doubling the dose
if previous dose does not induce atropinization (AAP [Roberts 2012]; Hegenbarth 2008; Roberts
2013; Rotenberg 2003). Maintain atropinization by administering repeat doses as needed for ≥2 to
12 hours based on recurrence of symptoms (Roberts 2013).
Adolescents: Initial: 1 to 3 mg/dose; repeat every 3 to 5 minutes as needed, doubling the dose if previous
dose does not induce atropinization. Maintain atropinization by administering repeat doses as
needed for ≥2 to 12 hours based on recurrence of symptoms (Roberts 2013).
Continuous IV infusion: Infants, Children, and Adolescents: Following atropinization, administer 10% to 20% of the
total loading dose required to induce atropinization as a continuous IV infusion per hour; adjust as needed
to maintain adequate atropinization without atropine toxicity (Eddleston 2004; Roberts 2007; Roberts
2013).
Endotracheal: Infants, Children, and Adolescents: Increase the dose by 2 to 3 times the usual IV dose. Mix with 3
to 5 mL of normal saline and administer. Flush with 3 to 5 mL of NS and follow with 5 assisted manual
ventilations (Rotenberg 2003).

Contraindications
There are no contraindications listed in the manufacturer’s labeling.
• Anaphylaxis: May occur.
• Hyperthermia: In the presence of a high environmental temperature, heat prostration can occur.
• Psychosis: Can occur in sensitive individuals or following use of excessive doses.
• Arrhythmias: Avoid relying on atropine for effective treatment of type II second-degree or third-degree AV block
(with or without a new wide QRS complex). Asystole or bradycardic PEA: Although no evidence exists for
significant detrimental effects, routine use is unlikely to have a therapeutic benefit and is no longer
recommended (ACLS 2010).
• Autonomic neuropathy: Use with caution in patients with autonomic neuropathy.
• Cardiovascular disease: Use with caution in patients with myocardial ischemia, heart failure, tachyarrhythmias
(including sinus tachycardia), and/or hypertension; treatment-related blood pressure increases and
tachycardia may lead to ischemia, precipitate an MI, or increase arrhythmogenic potential.
• Gastrointestinal disease: Use may convert partial organic pyloric stenosis into complete obstruction. Avoid use
in patients with paralytic ileus, intestinal atony of the elderly or debilitated patient, severe ulcerative colitis,
and toxic megacolon complicating ulcerative colitis.
• Glaucoma: Use may precipitate acute glaucoma.
• Hepatic impairment: Use with caution in patients with hepatic impairment; effects of atropine may be
prolonged in severe hepatic impairment.
• Hiatal hernia: Use with caution in patients with hiatal hernia associated with reflux esophagitis.
• Hyperthyroidism: Use with caution in patients with hyperthyroidism.
• Myasthenia gravis: Use with extreme caution when used to treat side effects of acetylcholinesterase inhibition
or avoid; may precipitate a myasthenic crisis.
• Renal impairment: Use with caution in patients with renal impairment; effects of atropine may be prolonged in
severe renal impairment.
• Respiratory impairment: Use may cause thickening of bronchial secretions and formation of viscid plugs in
patients with chronic lung disease.
• Urinary retention: Use may lead to complete urinary retention in patients with prostatic hypertrophy. Avoid use
if possible in patients with obstructive uropathy or in other conditions resulting in urinary retention
• Pediatric: Children may be more sensitive to the anticholinergic effects of atropine. Use with caution in children
with spastic paralysis.
• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol and/or sodium
benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl
alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in
neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations,
CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse
(AAP ["Inactive" 1997]; CDC 1982); some data suggest that benzoate displaces bilirubin from protein
binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol and/or benzyl alcohol
derivative with caution in neonates. See manufacturer's labeling.
• Appropriate use: Anticholinesterase poisoning: Atropine reverses the muscarinic but not the nicotinic effects
associated with anticholinesterase toxicity. Clinical symptoms consistent with highly-suspected
organophosphate or carbamate insecticides or nerve agent poisoning should be treated with antidote
immediately; administration should not be delayed for confirmatory laboratory tests. Signs of
atropinization include flushing, mydriasis, tachycardia, and dryness of the mouth or nose. Monitor effects
closely when administering subsequent injections as necessary. The presence of these effects is not
indicative of the success of therapy; inappropriate use of mydriasis as an indicator of successful treatment
has resulted in atropine toxicity. Reversal of bronchial secretions is the preferred indicator of success.
Adjunct treatment with a cholinesterase reactivator (eg, pralidoxime) may be required in patients with
toxicity secondary to organophosphorus insecticides or nerve agents. Treatment should always include
proper evacuation and decontamination procedures; medical personnel should protect themselves from
inadvertent contamination. Antidotal administration is intended only for initial management; definitive and
more extensive medical care is required following administration. Individuals should not rely solely on
antidote for treatment, as other supportive measures (eg, artificial respiration) may still be required.
Parenteral: Mass chemical terrorism: Preparation of bulk atropine solution: Add atropine sulfate powder to 100 mL NS
in polyvinyl chloride bags to yield a final concentration of 1 mg/mL (Dix 2003).
Endotracheal: Administer and flush with 1 to 5 mL NS or SWFI based on patient size, followed by 5 manual ventilations.
Absorption may be greater with sterile water. Stop compressions (if using for cardiac arrest), spray the drug
quickly down the tube. Follow immediately with several quick insufflations and continue chest compressions.
Parenteral:
IV: Administer undiluted by rapid IV injection; slow injection may result in paradoxical bradycardia
Heart rate, blood pressure, pulse, mental status; intravenous administration requires a cardiac monitor
Organophosphate or carbamate insecticide or nerve agent poisoning: Heart rate, blood pressure, respiratory status,
oxygenation secretions. Maintain atropinization with repeated dosing as indicated by clinical status. Crackles in lung
bases, or continuation of cholinergic signs, may be signs of inadequate dosing. Pulmonary improvement may not parallel
other signs of atropinization. Monitor for signs and symptoms of atropine toxicity (eg, fever, muscle fasciculations,
delirium); if toxicity occurs, discontinue atropine and monitor closely.
Consult individual institutional policies and procedures.
Drug Interactions
Acetylcholinesterase Inhibitors: May diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents
may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Risk C: Monitor therapy
Anticholinergic Agents: May enhance the adverse/toxic effect of other Anticholinergic Agents. Risk C: Monitor therapy
Gastrointestinal Agents (Prokinetic): Anticholinergic Agents may diminish the therapeutic effect of Gastrointestinal
Agents (Prokinetic). Risk C: Monitor therapy
Glucagon: Anticholinergic Agents may enhance the adverse/toxic effect of Glucagon. Specifically, the risk of
gastrointestinal adverse effects may be increased. Risk C: Monitor therapy
Nitroglycerin: Anticholinergic Agents may decrease the absorption of Nitroglycerin. Specifically, anticholinergic agents
may decrease the dissolution of sublingual nitroglycerin tablets, possibly impairing or slowing nitroglycerin
absorption. Risk C: Monitor therapy
Opioid Agonists: Anticholinergic Agents may enhance the adverse/toxic effect of Opioid Agonists. Specifically, the risk for
constipation and urinary retention may be increased with this combination. Risk C: Monitor therapy
Potassium Chloride: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Chloride. Management:
Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of
potassium chloride. Risk X: Avoid combination
Secretin: Anticholinergic Agents may diminish the therapeutic effect of Secretin. Management: Avoid concomitant use of
anticholinergic agents and secretin. Discontinue anticholinergic agents at least 5 half-lives prior to administration
of secretin. Risk D: Consider therapy modification
Thiazide and Thiazide-Like Diuretics: Anticholinergic Agents may increase the serum concentration of Thiazide and
Thiazide-Like Diuretics. Risk C: Monitor therapy
Onset of action:
Inhibition of salivation: IM: Within 30 minutes; maximum effect: 30 to 60 minutes (Mirakhur 1980; Volz-Zang
1995)
Increased heart rate:
IM: Within 15 to 30 minutes (Kentala 1990; Volz-Zang 1995); maximum effect: 45 to 60 minutes (Mirakhur
1980; Volz-Zang 1995)
IV: Immediate; maximum effect: 0.7 to 4 minutes (Lonnerholm 1975; Santini 1999)
Duration: Inhibition of salivation: IM: ≤4 hours (Mirakhur 1980; Volz-Zang 1995)
Absorption: Rapid and well absorbed from all dosage forms
Distribution: Widely throughout the body; crosses blood-brain barrier
Protein binding: 14% to 44%
Metabolism: Hepatic via enzymatic hydrolysis
Half-life elimination: Children <2 years: 6.9 ± 3 hours; Children >2 years: 2.5 ± 1.2 hours; Adults: 3 ± 0.9 hours; Elderly 65
to 75 years of age: 10 ± 7.3 hours
Time to peak: IM: 30 minutes; IM autoinjector: 3 minutes
Excretion: Urine (13% to 50% as unchanged drug and metabolites)
Adverse Reactions
Severity and frequency of adverse reactions are dose related.
Cardiovascular: Asystole, atrial arrhythmia, atrial fibrillation, atrioventricular dissociation (transient), bigeminy,
bradycardia, chest pain, decreased blood pressure, ECG changes (prolonged P wave, shortened PR segment, R on
T phenomenon, shortened RT duration, prolonged QT interval, widening of QRS Complex, flattened T wave,
repolarization abnormalities, ST segment elevation, retrograde conduction), ectopic beats (atrial), extrasystoles
(nodal, ventricular, superventricular), flushing, increased blood pressure, left heart failure, myocardial infarction,
nodal arrhythmia (no P wave on ECG), palpitations, sinus tachycardia, supraventricular tachycardia (including
junctional tachycardia), tachycardia, trigeminy, ventricular arrhythmia (including flutter), ventricular fibrillation,
ventricular flutter, ventricular premature contractions, ventricular tachycardia, weak pulse (or impalpable
peripheral pulses)
Central nervous system: Abnormal electroencephalogram (runs of alpha waves, increase in photic stimulation, and signs
of drowsiness), agitation (children), amnesia, anxiety, ataxia, behavioral changes, coma, confusion, decreased
deep tendon reflex, delirium, dizziness, drowsiness, dysarthria, dysmetria, emotional disturbance, excitement,
feeling hot, hallucination (visual or aural), headache, hyperpyrexia, hyperreflexia, hypertonia, insomnia,
intoxicated feeling, irritability (children), lack of concentration, lethargy (children), mania, myoclonus, neurologic
abnormality, nocturnal enuresis, opisthotonus, paranoia, positive Babinski sign, restlessness, seizure (generally
tonic-clonic), stupor, vertigo
Dermatologic: Anhidrosis, cold skin, dermatitis, dry and hot skin, erythematous rash, hyperhidrosis, macular eruption,
maculopapular rash, papular rash, scarlatiniform rash, skin rash
Endocrine & metabolic: Dehydration, hyperglycemia, hypoglycemia, hypokalemia, hyponatremia, increased thirst, loss of
libido
Gastrointestinal: Abdominal and bladder distension, abdominal pain, constipation, delayed gastric emptying, diminished
bowel sounds, dry mucous membranes, dysphagia, malabsorption, nausea, oral lesion, paralytic ileus, salivation,
vomiting, xerostomia
Genitourinary: Difficulty in micturition, impotence, urinary hesitancy, urinary retention, urinary urgency
Hematologic & oncologic: Abnormal erythrocytes (increased), decreased hemoglobin, increased hemoglobin,
leukocytosis, petechiae
Local: Injection site reaction
Neuromuscular & skeletal: Laryngospasm, muscle twitching, weakness
Ophthalmic: Abnormal eye movements (cyclophoria and heterophoria), angle-closure glaucoma (acute), blepharitis,
blindness, blurred vision, conjunctivitis, crusted of eyelid, cycloplegia, decreased accommodation, decreased
visual acuity, dry eye syndrome, eye irritation, keratoconjunctivitis sicca, lacrimation, mydriasis, photophobia,
strabismus
Renal: Increased blood urea nitrogen
Respiratory: Bradypnea, changes in respiration (labored respiration), cyanosis, dyspnea, laryngitis, pulmonary edema,
respiratory failure, stridor (inspiratory), tachypnea
Miscellaneous: Failure to thrive, fever (secondary to decreased sweat gland activity), swelling (children)
AZITROMICINA
Dosing: Neonatal
Note: With oral therapy, monitor for infantile hypertrophic pyloric stenosis (IHPS).
General dosing, susceptible infection (Red Book [AAP 2012]):
Oral: 10 to 20 mg/kg once daily
IV: 10 mg/kg once daily
Chlamydial conjunctivitis or chlamydial pneumonia: Limited data available: Oral: 20 mg/kg once daily for 3 days (CDC
[Workowski 2015]; Hammerschlag 1998)
Pertussis, treatment and postexposure prophylaxis: Oral, IV: 10 mg/kg once daily for 5 days (Red Book [AAP 2012])
Dosing: Pediatric
General dosing, susceptible infection (Red Book [AAP] 2012): Infants, Children, and Adolescents:
Mild to moderate infection: Oral: 5 to 12 mg/kg/dose; typically administered as 10 to 12 mg/kg/dose on day 1

followed by 5 to 6 mg/kg once daily for remainder of treatment duration; usual maximum dose for the total
course: 1,500 to 2,000 mg
Serious infection: IV: 10 mg/kg once daily; maximum dose: 500 mg/dose
Babesiosis: Infants, Children, and Adolescents: Oral: 10 mg/kg once on day 1 (maximum dose: 500 mg/dose), then 5
mg/kg once daily on days 2 to 10 (maximum dose: 250 mg/dose) in combination with atovaquone; longer
duration of therapy may be necessary in some cases; in immunocompromised patients, higher doses (eg, adults:
600 to 1,000 mg daily) may be required (Red Book [AAP] 2012; IDSA [Wormser 2006])
Bartonellosis: Oral:
Cat scratch disease (B. henselae) with extensive lymphadenopathy (IDSA [Stevens] 2014): Non-HIV-exposed/-
positive:
Infants, Children, and Adolescents ≤45 kg: 10 mg/kg once on day 1 (maximum dose: 500 mg/dose),
followed by 5 mg/kg once daily on days 2 to 5 (maximum dose: 250 mg/dose)
Children and Adolescents >45 kg: 500 mg as a single dose on day 1, then 250 mg once daily for 4 additional
days
Cutaneous bacillary angiomatosis (B. henselae or B. quintana): HIV- exposed/-positive: Infants, Children, and
Adolescents: 5 to 12 mg/kg once daily; maximum dose: 600 mg/dose; usual treatment duration: 3 months
(CDC 2009)
Chancroid (CDC 2010; Red Book [AAP] 2012): Oral:
<45 kg: 20 mg/kg as a single dose; maximum dose: 1,000 mg/dose
≥45 kg: 1,000 mg as a single dose
Chlamydial infections:
Cervicitis, urethritis (C. trachomatis): Children and Adolescents ≥45 kg: Oral: 1,000 mg as a single dose (CDC
2010; Red Book [AAP] 2012)
Conjunctivitis: Infants: Oral, IV: 20 mg/kg once daily for 3 days (Red Book [AAP] 2012)
Pneumonia, community-acquired (Bradley 2011): Infants >3 months, Children, and Adolescents:
Mild infection or step-down therapy: Oral: 10 mg/kg once on day 1 (maximum dose: 500 mg/dose)
followed by 5 mg/kg once daily on days 2 to 5 (maximum dose: 250 mg/dose)
Severe infection: IV: 10 mg/ kg once daily for at least 2 days, then transition to oral route with a single daily
dose of 5 mg/kg to complete course of therapy; maximum dose: 500 mg/dose
Cystic fibrosis; improve lung function, reduce exacerbation frequency: Limited data available; dosing regimen variable
(Mogayzel 2013; Saiman 2003; Saiman 2010): Children ≥6 years and Adolescents: Oral:
18 to 35.9 kg: 250 mg three times weekly (Monday, Wednesday, Friday)
≥36 kg: 500 mg three times weekly (Monday, Wednesday, Friday)
Diarrhea, infectious:
Campylobacter: Infants, Children, and Adolescents: Oral: 10 mg/kg once daily for 3 days; maximum dose: 500
mg/dose (Red Book [AAP] 2012)
Shigellosis: Infants, Children, and Adolescents: Oral:
AAP Recommendation: 12 mg/kg once on day 1 (maximum dose: 500 mg/dose), followed by 6 mg/kg once
daily on days 2 to 5 (maximum dose: 250 mg/dose) (Red Book [AAP] 2012)
Alternate dosing: 10 mg/kg once daily for 3 days (Dupont 2009; Mackell 2005); WHO Guidelines
recommend up to 20 mg/kg/dose and in some cases, a wider range of duration of therapy (eg, 1 to 5
days) (WHO 2005)
Endocarditis; prophylaxis: Infants, Children, and Adolescents: Oral: 15 mg/kg/dose 30 to 60 minutes before procedure;
maximum dose: 500 mg/dose (Wilson 2007)
Gonococcal infection; uncomplicated (cervicitis, urethritis, anorectal): Oral:
Children <45 kg: 20 mg/kg as a single dose; maximum dose: 1,000 mg/dose (Red Book [AAP] 2012)
Children > 8 years and ≥45 kg and Adolescents: 1,000 mg as a single dose (CDC 2012; Red Book [AAP] 2012)
Group A streptococcal infection; treatment of streptococcal tonsillopharyngitis:
Manufacturer's labeling and AHA recommendations: Infants, Children, and Adolescents: Oral: 12 mg/kg/dose
once daily for 5 days; maximum dose: 500 mg/dose (AHA [Gerber 2009])
Alternate dosing:
IDSA recommendations: Note: Recommended as an alternative agent for group A streptococcal pharyngitis
in penicillin-allergic patients. Infants, Children, and Adolescents: Oral: 12 mg/kg (maximum: 500
mg/dose) on day 1 followed by 6 mg/kg/dose (maximum: 250 mg/dose) once daily on days 2 through
5 (IDSA [Shulman 2012]).
Three-day regimen: Limited data available: Children and Adolescents: Oral: 20 mg/kg/dose once daily for 3
days; maximum dose: 1,000 mg/dose (Cohen 2004; O'Doherty 1996)
Meningococcal disease, chemoprophylaxis of high-risk contacts: Infants, Children, and Adolescents: Oral: 10 mg/kg as a
single dose; maximum dose: 500 mg/dose; Note: Not routinely recommended; may consider if fluoroquinolone
resistance detected (Red Book [AAP] 2012)
Mycobacterium avium complex (MAC) infection (HIV-exposed/-positive):
Infants and Children (DHHS [pediatric] 2013): Oral:
Treatment: 10 to 12 mg/kg once daily in combination with ethambutol, with or without rifabutin; maximum
dose: 500 mg/dose; treatment duration at least 12 months; dependent upon clinical response
Primary prevention of first episode: Preferred: 20 mg/kg once weekly (maximum dose: 1,200
mg/dose) or alternatively, 5 mg/kg once daily (maximum dose: 250 mg/dose)
Secondary prevention of recurring episodes: 5 mg/kg once daily in combination with ethambutol, with or
without rifabutin; maximum dose: 250 mg/dose
Adolescents (DHHS [adult] 2013): Oral:
Treatment: 500 to 600 mg daily in combination with ethambutol
Primary prophylaxis: 1,200 mg once weekly oralternatively, 600 mg twice weekly
Secondary prophylaxis: 500 to 600 mg daily in combination with ethambutol
Otitis media, acute (AOM): Infants ≥6 months, Children, and Adolescents: Oral: Note: Due to increased S
pneumoniaand H. influenzae resistance, azithromycin is not routinely recommended as a treatment option (AAP
[Lieberthal 2013])
Single-dose regimen: 30 mg/kg as a single dose; maximum dose: 1,500 mg/dose; if patient vomits within 30
minutes of dose, repeat dosing has been administered although limited data available on safety
Three-day regimen: 10 mg/kg once daily for 3 days; maximum dose: 500 mg/dose
Five-day regimen: 10 mg/kg once on day 1 (maximum dose: 500 mg/dose), followed by 5 mg/kg (maximum dose:
250 mg/dose) once daily on days 2 to 5
Peritonitis (peritoneal dialysis), prophylaxis for patients receiving peritoneal dialysis who require dental
procedures: Infants, Children, and Adolescents: Oral: 15 mg/kg administered 30 to 60 minutes before dental
procedure; maximum dose: 500 mg/dose (Warady [ISPD 2012])
Pertussis (CDC 2005; Red Book [AAP] 2012): Oral, IV:
Infants 1 to 5 months: 10 mg/kg/dose once daily for 5 days
Infants ≥6 months, Children, and Adolescents: 10 mg/kg once on day 1 (maximum dose: 500 mg/dose), followed
by 5 mg/kg once daily on days 2 to 5 (maximum dose: 250 mg/dose)
Pneumonia, community-acquired (excluding mycobacterial [mycoplasma pneumoniae] and chlamydial infections):

Oral:
Immediate release: Infants >3 months, Children, and Adolescents: 10 mg/kg once on day 1 (maximum dose:
500 mg/dose), followed by 5 mg/kg (maximum dose: 250 mg/dose) once daily on days 2 to 5
(Bradley 2011)
Extended-release oral suspension (Zmax): Infants ≥6 months, Children, and Adolescents: 60 mg/kg as a
single dose; maximum dose: 2,000 mg/dose
IV: Infants >3 months, Children, and Adolescents: 10 mg/kg once daily for at least 2 days, follow IV therapy by the
oral route with a single daily dose of 5 mg/kg to complete a 5-day course of therapy; maximum dose: 500
mg/dose (Bradley 2011)
Pneumonia, community acquired; mycoplasma pneumoniae, or chlamydial infection (Bradley 2011): Infants >3
months, Children, and Adolescents:
Mild infection or step-down therapy: Oral: 10 mg/kg once on day 1 (maximum dose: 500 mg/dose) followed by
5 mg/kg once daily on days 2 to 5 (maximum dose: 250 mg/dose)
Severe infection: IV: 10 mg/kg once daily for at least 2 days (maximum dose: 500 mg/dose), then transition to oral
route with a single daily dose of 5 mg/kg to complete course of therapy (maximum dose: 250 mg/dose)
Rhinosinusitis, bacterial: Oral: Infants ≥6 months, Children, and Adolescents: 10 mg/kg once daily for 3 days; maximum
dose: 500 mg/dose; Note: Although FDA approved, macrolides are not recommended for empiric therapy due to
high rates of resistance (Chow 2012).
Sexual victimization, prophylaxis: Oral: Note: Use in combination with cefixime or ceftriaxone and completion of
hepatitis B virus immunization; also consider prophylaxis for trichomoniasis and bacterial vaginosis (CDC
2010; Red Book [AAP] 2012).
Children <45 kg: 20 mg/kg as a single dose
Children ≥45 kg and Adolescents: 1,000 mg as a single dose
Toxoplasma gondii, encephalitis (HIV-exposed/-positive); treatment and prevention: Oral: Adolescents: 900 to 1,200
mg once daily in combination with pyrimethamine/leucovorin; treatment duration: 6 weeks or longer if extensive
disease or incomplete response at 6 weeks (DHHS [adult] 2013)
Infants ≥6 months, Children, and Adolescents:
Use with caution in patients with GFR <10 mL/minute (AUC increased by 35% compared to patients with normal
renal function); however, no dosage adjustment is provided in the manufacturer's labeling.
No supplemental dose or dosage adjustment necessary, including patients on intermittent hemodialysis,

peritoneal dialysis, or continuous renal replacement therapy (eg, CVVHD) (Aronoff 2007; Heintz 2009).

Azithromycin is predominantly hepatically eliminated; however, there is no dosage adjustment provided in the
manufacturer's labeling. Use with caution due to potential for hepatotoxicity (rare); discontinue immediately for signs or
symptoms of hepatitis.
Contraindications
Hypersensitivity to azithromycin, erythromycin, other macrolide (eg, azalide or ketolide) antibiotics, or any component
of the formulation; history of cholestatic jaundice/hepatic dysfunction associated with prior azithromycin use
Note: The manufacturer does not list concurrent use of pimozide as a contraindication; however, azithromycin is listed
as a contraindication in the manufacturer's labeling for pimozide.
• Hypersensitivity reactions: Allergic reactions (eg, angioedema, anaphylaxis, Stevens-Johnson syndrome, toxic
epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms [DRESS]) have been
reported (rare), including fatalities; reappearance of allergic reaction may occur shortly after
discontinuation of symptomatic treatment without further azithromycin exposure.
• Altered cardiac conduction: Macrolides (especially erythromycin) have been associated with rare QTc
prolongation and ventricular arrhythmias, including torsades de pointes; consider avoiding use in patients
with prolonged QT interval, congenital long QT syndrome, history of torsades de pointes,
bradyarrhythmias, uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia,
uncompensated heart failure, or concurrent use of Class IA (eg, quinidine, procainamide) or Class III (eg,
amiodarone, dofetilide, sotalol) antiarrhythmic agents or other drugs known to prolong the QT interval.
• Cardiac risk: A retrospective cohort study done in Tennessee Medicaid patients demonstrated an increased
cardiac risk with azithromycin relative to amoxicillin or ciprofloxacin, and similar risk compared to
levofloxacin; notably, increased cardiac mortality (an estimated 47 additional deaths per 1 million 5-day
courses of treatment compared to amoxicillin) was associated with higher baseline cardiovascular risk (Ray
2012); however, these data may not be generalizable to the population as a whole (Ray 1989). In another
retrospective population study of US veterans, azithromycin was shown to significantly increase the risk of
mortality and arrhythmia on days 1 to 5, but not on days 6 to 10 after dispensing the prescription (Rao
2014). In contrast, 2 additional large retrospective cohort studies did notdemonstrate an increased risk of
cardiovascular events, including all-cause mortality or cardiovascular death (Svanstrom 2013, Mortensen
2014). The implications of these data have yet to be determined.
diarrhea (CDAD); CDAD has been observed >2 months postantibiotic treatment.
• Gonorrhea/syphilis: May mask or delay symptoms of incubating gonorrhea or syphilis, so appropriate culture
and susceptibility tests should be performed prior to initiating a treatment regimen.
• Hepatic impairment: Use with caution in patients with preexisting liver disease; hepatocellular and/or
cholestatic hepatitis (with or without jaundice), hepatic necrosis, failure, and death have occurred.
Discontinue immediately if symptoms of hepatitis occur (malaise, nausea, vomiting, abdominal colic, fever).
• Myasthenia gravis: Use with caution in patients with myasthenia gravis; exacerbation and new onset of
symptoms have occurred.
• Renal impairment: Use with caution in patients with severe renal impairment (GFR <10 mL/minute); increased
gastrointestinal adverse effects may occur.
• Infants: Use of azithromycin in neonates and infants (treatment up to 42 days of life) has been associated with
infantile hypertrophic pyloric stenosis (IHPS); observe for non-bilious vomiting or irritability with feeding
(Eberly 2015).
• Oral suspensions: Immediate release and extended release suspensions are not interchangeable.
Oral:
Immediate release oral suspension: Reconstitute powder for oral suspension with appropriate amount of water as
specified on the bottle. Shake vigorously until suspended.
Oral suspension 1,000 mg packet for a single dose: Prepare by mixing contents of 1 packet with approximately 60
mL of water.
Extended release oral suspension: Prepare 2,000 mg azithromycin suspension by reconstituting with 60 mL of
water to a final concentration of 27 mg/mL
Parenteral: Prepare initial solution by adding 4.8 mL of SWFI to the 500 mg vial resulting in a concentration of 100
mg/mL. Use of a standard syringe is recommended due to the vacuum in the vial (which may draw additional
solution through an automated syringe).
The initial solution should be further diluted to a concentration of 1 mg/mL to 2 mg/mL in NS, D5W, or LR.
Oral:
Immediate release: May administer without regard to food; do not administer with antacids that contain
aluminum or magnesium.
Oral suspension, multiple doses: Shake well before use.
Oral suspension 1,000 mg packet for a single dose: Administer the entire contents immediately after mixing; add
an additional 60 mL of water, mix, and drink. Do not use to administer any other dose except 1,000 mg or
2,000 mg.
Extended release oral suspension: Shake suspension well before use; administer on an empty stomach 1 hour
before or 2 hours after a meal; must be administered within 12 hours of reconstitution. May be
administered without regard to antacids containing aluminum or magnesium.
Parenteral: Do not give IM or by direct IV injection.Administer IV infusion at a final concentration of 1 mg/mL over 3
hours; for a 2 mg/mL concentration, infuse over 1 hour; do not infuse over a period of less than 60 minutes.
Some products may contain sodium and/or sucrose.
Oral suspension, immediate release, may be administered with or without food.
Oral suspension, extended release, should be taken on an empty stomach (at least 1 hour before or 2 hours following a
meal).
Tablet may be administered with food to decrease GI effects.
Liver function tests, WBC with differential; number and type of stools/day for diarrhea; monitor patients receiving
azithromycin and drugs known to interact with erythromycin (ie, theophylline, digoxin, anticoagulants, triazolam) since
there are still very few studies examining drug-drug interactions with azithromycin. When used as part of alternative
treatment for gonococcal infection, test-of-cure 7 days after dose (CDC, 2012).
Drug Interactions
AtorvaSTATin: Azithromycin (Systemic) may enhance the myopathic (rhabdomyolysis) effect of AtorvaSTATin.Risk C:
Monitor therapy
BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Risk C:
Monitor therapy
Cardiac Glycosides: Macrolide Antibiotics may increase the serum concentration of Cardiac Glycosides. Risk C: Monitor
therapy
Chloroquine: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of
Chloroquine. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents
are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk.Risk C:
Monitor therapy
Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution
into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with
impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal
and hepatic function, reduce colchicine dose as directed. See full monograph for details. Risk D: Consider therapy
modification
CycloSPORINE (Systemic): Azithromycin (Systemic) may increase the serum concentration of CycloSPORINE
(Systemic). Risk C: Monitor therapy
Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Risk C: Monitor
therapy
Haloperidol: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of
Haloperidol. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents
are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk.Risk C:
Monitor therapy
Ivermectin (Systemic): Azithromycin (Systemic) may increase the serum concentration of Ivermectin (Systemic). Risk C:
Monitor therapy
Ondansetron: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of
Ondansetron. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these
agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk.Risk C:
Monitor therapy
Tacrolimus (Systemic): Azithromycin (Systemic) may increase the serum concentration of Tacrolimus (Systemic). Risk C:
Monitor therapy
Tacrolimus (Topical): Macrolide Antibiotics may increase the serum concentration of Tacrolimus (Topical). Risk C:
Monitor therapy
Vitamin K Antagonists (eg, warfarin): Macrolide Antibiotics may increase the serum concentration of Vitamin K
Antagonists. Risk C: Monitor therapy
Food Interactions
Rate and extent of GI absorption may be altered depending upon the formulation. Azithromycin suspension, not tablet
form, has significantly increased absorption (46%) with food. Management: Immediate release suspension and tablet
may be taken without regard to food; extended release suspension should be taken on an empty stomach (at least 1
hour before or 2 hours following a meal).
Absorption: Oral: Rapid from the GI tract
Distribution: Extensive tissue; distributes well into skin, lungs, sputum, tonsils, and cervix; penetration into CSF is poor;
Vd: 31 to 33 L/kg
Protein binding (concentration dependent and dependent on alpha1-acid glycoprotein concentrations): Oral, IV: 7% to
51%
Metabolism: Hepatic to inactive metabolites
Bioavailability: Oral: Tablet, immediate release oral suspension: 34% to 52%; extended release oral suspension: 28% to
43%; variable effect with food (increased with immediate or delayed release oral suspension, unchanged with
tablet)
Half-life elimination: Terminal: Oral, IV:

Infants and Children 4 months to 15 years: 54.5 hours
Adults: Immediate release: 68 to 72 hours; Extended release: 59 hours
Time to peak, serum: Oral: Immediate release: ~2 to 3 hours; Extended release: 3 to 5 hours
Excretion: Oral, IV: Biliary (major route 50%, unchanged); urine (6% to 14% unchanged)
Renal function impairment: Cmax and AUC increased 61% and 35%, respectively, in subjects with severe renal
impairment.
Geriatric: In elderly women, a higher Cmax was observed but there was no change in drug accumulation.
Adverse Reactions
Cardiovascular: Chest pain, palpitations
Central nervous system: Dizziness, drowsiness, fatigue, headache, vertigo
Dermatologic: Dermatitis (children), pruritus, skin photosensitivity, skin rash (single-dose regimens tend to be associated
with increased incidence)
Endocrine & metabolic: Decreased serum bicarbonate (adults), decreased serum glucose (adults), increased gamma-
glutamyl transferase, increased lactate dehydrogenase, increased serum potassium
Gastrointestinal: Abdominal pain (single-dose regimens tend to be associated with increased incidence), anorexia,
diarrhea (more common with single-dose regimens), dysgeusia, dyspepsia, flatulence, gastritis, loose stools
(single-dose regimens tend to be associated with increased incidence), melena (adults, multiple-dose regimens),
mucositis, nausea (more common with single-dose regimens), oral candidiasis, vomiting (children: Single-dose
regimens tend to be associated with increased incidence; adults: More common with single 2 g dose)
Genitourinary: Genital candidiasis (adults, multiple-dose regimens), vaginitis
Hematologic & oncologic: Change in neutrophil count (children), decreased hematocrit (adults), decreased hemoglobin
(adults), decrease in absolute neutrophil count (children: 500 to 1,500 cells/mm3), eosinophilia, increased
neutrophils (adults), lymphocytopenia, thrombocythemia (adults)
Hepatic: Cholestatic jaundice, increased serum ALT, increased serum AST, increased serum bilirubin
Local (adults with IV administration): Local inflammation, pain at injection site
Neuromuscular & skeletal: Increased creatine phosphokinase
Renal: Increased blood urea nitrogen, increased serum creatinine, nephritis (adults, multiple-dose regimens)
Respiratory: Bronchospasm
Miscellaneous: Fever (children)
Rare but important or life-threatening: Abnormal stools, acute generalized exanthematous pustulosis, acute renal
failure, ageusia, aggressive behavior, agitation, alteration in sodium, altered sense of smell, altered serum
glucose, anaphylaxis, anemia, angioedema, anosmia, anxiety, arthralgia, asthma, basophilia, bronchitis, cardiac
arrhythmia, Clostridium difficileassociated diarrhea, conjunctivitis (children), constipation, convulsions, cough,
deafness, decreased serum potassium (children), decreased serum sodium, diaphoresis, DRESS syndrome,
dyspnea, dysuria, eczema, edema, emotional lability, enteritis, erythema multiforme, exacerbation of myasthenia
gravis, facial edema, flu-like symptoms (children), fungal dermatitis (children), fungal infection (children),
gastrointestinal disease, hearing loss, hepatic failure, hepatic insufficiency, hepatic necrosis, hepatitis,
hepatotoxicity (idiosyncratic) (Chalasani 2014), hostility, hyperactivity, hyperkinesia, hypersensitivity reaction,
hypotension, increased monocytes, increased serum alkaline phosphatase, increased serum bicarbonate,
increased serum phosphate, interstitial nephritis, insomnia, irritability, jaundice, Lambert-Eaton syndrome,
leukopenia, maculopapular rash, malaise, nervousness, neutropenia, otitis media, pain, pancreatitis, paresthesia,
pharyngitis, pleural effusion, prolonged Q-T interval on ECG, pseudomembranous colitis, pyloric stenosis, pyloric
stenosis (infantile hypertrophic), rhinitis, seizure, Stevens-Johnson syndrome, syncope, thrombocytopenia,
tinnitus, tongue discoloration, toxic epidermal necrolysis, urticaria, ventricular tachycardia, vesiculobullous
dermatitis, weakness
BACLOFENO
Dosing: Pediatric
Spasticity:
Oral: Note: Dose-related side effects (eg, sedation) may be minimized by slow titration; lower initial doses than
described below (2.5 to 10 mg daily) may be used with subsequent titration to 8 hourly doses. There is
limited published data in infants and children; the following is a compilation of small prospective studies
(Milla 1977; Scheinberg 2006) and one large retrospective analysis of baclofen use in children (Lubsch
2006). Efficacy results variable (AAN [Delgado 2010]):
Infants ≥4 months and Children <2 years: Limited data available: 10 to 20 mg daily divided every 8 hours;
begin at low end of range and titrate dose to patient response, titration intervals of every 3 days to
weekly have been used in pediatric patients ≥2 years (Millia 1997; Scheinberg 2006). Maximum daily
dose: 40 mg/day (Lubsch 2006). Note: To minimize dose-related side effects (eg, sedation), lower
initial doses (eg, 2.5 mg once daily) and slower titration may be considered (eg, weekly) and has
been reported in pediatric patients >2 years (Scheinberg 2006).
Children 2 to 7 years: Limited data available: 20 to 40 mg daily divided every 8 hours; begin at low end of
range (or even lower [2.5 to 10 mg daily] and titrate dose to patient response; titration intervals of
every 3 days to weekly have been used in pediatric patients. Maximum daily dose: 60
mg/day (Lubsch 2006; Millia 1997; Scheinberg 2006)
Children ≥8 years and Adolescents: Limited data available in children <12 years: 30 to 40 mg daily divided
every 8 hours; begin at low end of range (or even lower [10 mg to 15 mg daily in 3 divided doses])
and titrate dose to patient response, titration intervals of every 3 days to weekly have been used
(Millia 1997; Scheinberg 2006); some patients ≥12 years may require every 6 hour dosing; usual
maximum daily dose range: 60 to 80 mg/day(Lubsch 2006; Millia 1977). Note: Higher maximum daily
doses (up to 200 mg/day) have been described in some patients in a retrospective review, usually
the higher doses were needed over time (Lubsch 2006).
Intrathecal: Note: Dosage adjustments may be required often during the first few months of therapy to adjust for
life style changes due to alleviation of spasticity. Maintain lowest dose that produces adequate response.
Most patients require gradual increases over time to maintain optimal response. Sudden large
requirements for a dose increase may indicate a catheter complication (eg, kink, dislodgement). Titrate
dose to allow sufficient muscle tone and occasional spasms to optimize activities of daily living, support
circulation, and possibly prevent DVT formation. Use extreme caution when filling the pump; follow
manufacturer instructions carefully. With chronic therapy, 5% to 10% of patients will become refractory to
dose adjustments; may consider a drug holiday (hospitalized patients only) with a gradual withdrawal over
2 to 4 weeks and use of alternative spasticity management methods. Following the drug holiday intrathecal
baclofen may be resumed at the initial continuous infusion dose. Limited data available in children <4 years
old, dosing for this age group based on expert consensus recommendations (Berweck 2014).
Screening dose:
Children <4 years: Limited data available: Initial: 25 mcg; if response is inadequate, double the initial dose
and administer 24 hours after the first dose (Berweck 2014)
Children ≥4 years and Adolescents: Initial: 50 mcg (1 mL) for 1 dose; following initial administration,
observe patient for 4 to 8 hours. A positive response consists of a significant decrease in muscle tone
and/or frequency and/or severity of spasms. If response is inadequate, may give 75 mcg as a second
screening dose 24 hours after the first screening dose; observe patient for 4 to 8 hours. If response is
still inadequate, may repeat a final screening dose of 100 mcg given 24 hours after the second
screening dose. Patients not responding to screening dose of 100 mcg should not be considered for
chronic infusion/implanted pump. Note: A 25 mcg initial screening dose may be considered in very
small pediatric patients.
Dose titration following pump implant: Children and Adolescents: After positive response to screening dose, a
maintenance intrathecal infusion can be administered via an implanted intrathecal pump.
Initial total daily dose via pump: Children and Adolescents: Double the screening dose that gave a positive
response and administer over 24 hours, unless efficacy of the bolus dose was maintained for >8
hours, then infuse a dose equivalent to the screening dose over 24 hours. Do not increase dose in
first 24 hours (to allow steady state to be achieved); thereafter, increase daily dose slowly by 5% to
15% once every 24 hours until satisfactory response is achieved; usual range: 50 to 100 mcg daily
(Berweck 2014).
Titration to maintenance dose: Children ≥4 years and Adolescents: Daily dose may be increased 5% to 20%
(maximum increase: 20%); may also be decreased 10% to 20% for adverse effects.
Some experts have suggested the following titration parameters: Children and Adolescents (Berweck
2014):
Inpatient titration: May adjust by 10% to 20% of dose (usual dose change is 50 mcg);
maximum increment change: 100 mcg
Outpatient titration: May adjust by 10% of daily dose (usual dose change is 25 mcg)
Usual maintenance dose: Children and Adolescents: 100 to 2,000 mcg daily (Berweck 2014); the manufacturer
provides the following:
Children 4 to 12 years: 24 to 1,199 mcg daily (average: 274 mcg/day)
Children ≥12 years and Adolescents: 90 to 703 mcg daily; daily doses have ranged from 22 mcg to 1,400
mcg; experience with doses >1,000 mcg daily is limited
Oral: There are no dosage adjustments provided in the manufacturer's labeling; however, baclofen is primarily
renally eliminated; use with caution; dosage reduction may be necessary.
Intrathecal: Children and Adolescents: There are no dosage adjustments provided in the manufacturer’s labeling;
however, baclofen is primarily renally eliminated; use with caution; dosage reduction may be necessary.
Oral, Intrathecal: There are no dosage adjustments provided in the manufacturer's labeling.
Contraindications
Hypersensitivity to baclofen or any component of the formulation
Intrathecal formulation: IV, IM, SubQ, or epidural administration
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be
cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).
• Intrathecal mass: Cases (most from pharmacy compounded preparations) of intrathecal mass formation at the
implanted catheter tip have been reported; patients may experience worsening or return of spasticity,
pain, inadequate response to dose adjustments, and/or neurological deficit/dysfunction. Neurosurgical
evaluation and/or an appropriate imaging study should be considered if a mass is suspected.
• Urinary retention: May cause acute urinary retention (may be related to underlying disease); use with caution in
patients with urinary obstruction.
• Autonomic dysreflexia: Use intrathecal baclofen with caution in patients with a history of autonomic dysreflexia;
presence of nociceptive stimuli or abrupt baclofen withdrawal may cause an autonomic dysreflexic
episode.
• Gastrointestinal disorders: Use with caution in patients with peptic ulcer disease, decreased GI motility, and/or
gastrointestinal obstructive disorders.
• Psychiatric disease: Use with caution in patients with psychotic disorders, schizophrenia, or confusional states;
may cause exacerbation of condition.
• Renal impairment: Use with caution in patients with renal impairment; baclofen is eliminated primarily
unchanged via the kidneys. Multiple cases describing neurotoxicity due to oral baclofen accumulation in
adult patients with varying levels of renal impairment have been reported in the literature. In patients with
renal impairment, initiation of oral baclofen at lower doses and/or extended intervals has been suggested
(Aisen 1994; Chen 1997; Chou 2006; El-Husseini 2011; Peces 1998; Su 2009; Vlavonu 2014).
• Respiratory disease: Use with caution in patients with respiratory disease.
• Seizure disorder: Use with caution in patients with a history of seizure disorder; monitor regularly for loss of
seizure control. Seizures have been reported with withdrawal from intrathecal baclofen as well as in
patients maintained on therapeutic doses of intrathecal baclofen.
• Elderly: Use with caution in elderly patients; may be more sensitive to adverse CNS effects, especially at higher
doses.
• Pediatric: Intrathecal: Children should be of sufficient body mass to accommodate the implantable pump for
chronic infusion.
• Abrupt withdrawal: [US Boxed Warning]: Abrupt withdrawal of intrathecal baclofen, regardless of the cause,
has resulted in sequelae (hyperpyrexia, altered mental status, exaggerated rebound spasticity, and
muscle rigidity, which, in rare cases, has advanced to rhabdomyolysis), multiple organ-system failure,
and death. Prevention of abrupt discontinuation requires careful attention to programming and
monitoring of infusion system, refill scheduling and procedures, and pump alarms. Advise patients and
caregivers of the importance of keeping scheduled refill visits and educate them on the early symptoms
of baclofen withdrawal. Give special attention to patients at apparent risk (eg, spinal cord injuries at T-6
or above, communication difficulties, history of withdrawal symptoms from oral or intrathecal baclofen).
Consult the technical manual of the implantable infusion system for additional postimplant clinician and
patient information. In most cases, symptoms of withdrawal (eg, return of baseline spasticity, hypotension,
paresthesia, pruritus) appear within hours to a few days following interruption of therapy. Priapism may
develop or recur if treatment with intrathecal baclofen is interrupted. Clinically, the advanced intrathecal
baclofen withdrawal syndrome may resemble autonomic dysreflexia, infection (sepsis), malignant
hyperthermia, neuroleptic-malignant syndrome, or other conditions associated with a hypermetabolic
state or widespread rhabdomyolysis. Suggested treatment for intrathecal baclofen withdrawal is
restoration of intrathecal baclofen at or near the same dosage as before therapy was interrupted. Abrupt
withdrawal of oral therapy has been associated with hallucinations and seizures; gradual dose reductions
(over ~1 to 2 weeks) are recommended in the absence of severe adverse reactions.
• Appropriate use: Intrathecal: For use only in an FDA-approved implantable pump for intrathecal baclofen
administration; health care providers should be experienced with chronic intrathecal infusion therapy and
resuscitative equipment should be readily available. Ensure patient is infection-free and then evaluate
patient's response to bolus intrathecal injection (screening phase) prior to implanting pump. Monitor
closely during the initial phase of pump use and when adjusting the dosing rate and/or the concentration in
the reservoir. Educate patients and caregivers on proper home care of the pump and insertion site. Use
extreme caution when filling an implantable pump; pumps should only be refilled through the reservoir
refill septum. Inadvertent injection into the subcutaneous tissue can occur if the reservoir refill septum is
not properly accessed. Some pumps are equipped with a catheter access port that allows direct access to
the intrathecal catheter; direct injection into this catheter access port or inadvertent injection into the
subcutaneous tissue may cause a life-threatening overdose. Except in overdose related emergencies,
intrathecal baclofen should be reduced slowly if discontinuation is necessary.
• Appropriate use: Oral: Efficacy of oral baclofen has not been established in patients with stroke, Parkinson
disease, or cerebral palsy; therefore, use is not recommended. Not indicated for spasticity associated with
rheumatic disorders. Use with caution when spasticity is utilized to sustain upright posture and balance in
locomotion, or when spasticity is necessary to obtain increased function.
• Overdose: Intrathecal use: Monitor closely for signs and symptoms of overdose which may appear suddenly or
insidiously, especially during the initial screening and dose-titration phase of treatment, and during
reintroduction of therapy after a period of interruption. Signs/symptoms of overdose may include
drowsiness, dizziness, somnolence, hypothermia, respiratory depression, seizures, rostral progression of
hypotonia and loss of consciousness progressing to coma. If overdose is suspected, patient should be
evaluated immediately in a hospital setting and the pump reservoir emptied.
Parenteral: Intrathecal: For screening dosages, dilute with preservative-free sodium chloride to a final concentration of
50 mcg/mL. For maintenance infusions, concentrations of 500 to 2,000 mcg/mL may be used; if preparing a
concentration that is not commercially available, preservative-free sodium chloride must be used.
Oral: Administer with food or milk
Parenteral: Intrathecal: Screening dosage: Administer as a bolus injection by barbotage into the subarachnoid space over
at least 1 minute, followed by maintenance infusion via implantable infusion pump; do not abruptly discontinue
intrathecal baclofen administration. Do not administer intrathecal formulation IV, IM, SubQ, or epidurally.
Muscle rigidity, spasticity (decrease in number and severity of spasms), modified Ashworth score. Regular
electroencephalogram (EEG) in patients with epilepsy (loss of seizure control has been reported).
Drug Interactions: Metabolism/Transport Effects
None known.
Drug Interactions
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Minocycline: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination
OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid
concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents
should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and
duration of each drug. Risk D: Consider therapy modification
Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin
Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Risk C: Monitor therapy
Onset of action: Intrathecal bolus: 30 minutes to 1 hour; Continuous infusion: 6 to 8 hours after infusion initiation
Peak effect: Intrathecal bolus: 4 hours (effects may last 4 to 8 hours); Continuous infusion: 24 to 48 hours
Absorption (dose dependent): Oral: Rapid; absorption from the GI tract is thought to be dose dependent; in pediatric
patients (age range: 2 to 17 years) with cerebral palsy, absorption from GI tract highly variable and delayed
(reported time lag: 0.59 ± 0.28 hours) (He 2014)
Bioavailability: Oral: 74% (Agarwal 2015)
Protein binding: 30%
Volume of distribution: Pediatric patients (age range: 2 to 17 years: Oral: Highly variable: 1.16 L/kg with 43.5%
interindividual variability (He 2014)
Metabolism: Hepatic (15% of dose) (He 2014)
Half-life elimination:
Oral:
Pediatric patients with cerebral palsy (age range: 2 to 17 years): 4.5 hours (He 2014)
Adults: 3.75 ± 0.96 hours (Brunton 2011)
Intrathecal: CSF elimination half-life: 1.51 hours over the first 4 hours
Time to peak, serum: Oral: 1 hour (0.5 to 4 hours) (Brunton 2011)
Excretion: Urine (>70% as unchanged drug) and feces (Brunton 2011)
Adverse Reactions
Cardiovascular: Hypotension, peripheral edema
Central nervous system: Abnormality in thinking, agitation, chills, coma, confusion, depression, dizziness, drowsiness,
headache, hypertonia, hypotonia, insomnia, pain, paresthesia, seizure, speech disturbance
Dermatologic: Pruritus, urticaria
Gastrointestinal: Constipation, diarrhea, nausea, sialorrhea, vomiting, xerostomia
Genitourinary: Difficulty in micturition, impotence, urinary frequency, urinary incontinence, urinary retention
Neuromuscular & skeletal: Asthenia, back pain, tremor
Ophthalmic: Amblyopia
Respiratory: Dyspnea, hypoventilation, pneumonia
Miscellaneous: Accidental injury
Rare but important or life-threatening: Abdominal pain, accommodation disturbance, akathisia, albuminuria, alopecia,
amnesia, ankle edema, anorexia, anxiety, apnea, ataxia, blurred vision, bradycardia, carcinoma, chest pain,
contact dermatitis, decreased libido, deep vein thrombophlebitis, dehydration, dermal ulcer, diaphoresis,
diplopia, dysarthria, dysautonomia, dysgeusia, dysphagia, dystonia, dysuria, epilepsy, erectile dysfunction,
euphoria, excitement, facial edema, fecal incontinence, fever, gastrointestinal hemorrhage, hallucination,
hematuria, hyperglycemia, hyperhidrosis, hypertension, hyperventilation, hypothermia, hysteria, inhibited
ejaculation, intestinal obstruction, leukocytosis, loss of postural reflex, malaise, miosis, muscle rigidity, myalgia,
mydriasis, nasal congestion, nephrolithiasis, nocturia, nystagmus disorder, occult blood in stools, oliguria,
opisthotonus, orgasm disturbance, pallor, palpitations, paranoid ideation, personality disorder, petechial rash,
priapism, pulmonary embolism, scoliosis, scoliosis progression, sedated state, sexual disorder, skin rash, slurred
speech, strabismus, suicidal ideation, syncope, taste disorder, tinnitus, tongue irritation, vaginitis, vasodilatation,
weight gain, weight loss
BROMURO DE IPRATROPIO
Dosing: Neonatal
Bronchopulmonary dysplasia/Respiratory distress syndrome (RDS), ventilated patients: Very limited data available;
optimal dose not established.
Nebulization:
Weight-based dosing: 25 mcg/kg/dose 3 times daily. Dosing based on a placebo controlled, comparative
trial in 17 preterm infants (ipratropium group, n=5; EGA 25 to 29 weeks; PNA 19 to 103 days) with
BPD and reported a significant decrease in respiratory resistance (Wilkie 1987).
Fixed dosing: Some centers have used 175 mcg/dose 3 times daily administered through the ventilator
circuit; dosing based on a dose range study of 10 preterm infants with BPD (EGA 24 to 28 weeks, PNA
18 to 34 days) which showed significant reduction in respiratory resistance; additional benefit
observed when administered after albuterol (Brundage 1990).
Inhalation, MDI: 4 puffs/dose every 6 to 8 hours delivered as either a single dose or 2 puffs every 20 minutes for 2
inhalations. In a randomized, placebo-controlled trial in preterm neonates (n=10, PNA: 1 week; EGA: 26 to
34 weeks) with RDS which evaluated a single 72 mcg dose (4 puffs [18 mcg/puff product used; not currently
available in the US]) and reported beneficial effects on blood gases and ventilator efficiency. In another
trial, which was a crossover, randomized, controlled, double-blind trial of preterm neonates (n=21, PNA: 20
± 9 days; EGA: 27.3 ± 1.6 weeks) with RDS, a significant reduction in respiratory resistance was reported in
38% of patients after a total dose of 80 mcg (40 mcg every 20 minutes for 2 doses [20 mcg/puff product
used; not currently available in the US]); higher doses (120 mcg [6 puffs]) were not shown to have
additional benefit (Fayon 2007; Lee 1994).
Dosing: Pediatric
Asthma, acute exacerbation: Limited data available (GINA 2018; NAEPP 2007): Note: For moderate to severe
exacerbations, ipratropium may be considered if poor response to initial short-acting beta-2 agonist (SABA)
therapy during initial management in an acute care setting (eg, emergency department). Ipratropium has not
been shown to provide further benefit (eg, after first 24 hours) once the patient is hospitalized (GINA 2018;
Vézina 2014):
Children:
Nebulization: 0.25 to 0.5 mg (250 to 500 mcg) every 20 minutes for 1 hour (ie, 3 doses), then as needed; in
trials, the usual reported dose is 0.25 mg (250 mcg) and reported interval range is every 1 to 8 hours
typically with an increasing dosing interval as patient improves; some trials continued combination
SABA/ipratropium therapy for duration of hospitalization (up to 49 hours) although trials have not
demonstrated additional benefit with extended use (Vézina 2014)
Metered-dose inhaler: 4 to 8 puffs every 20 minutes as needed for up to 3 hours
Adolescents:
Nebulization: 0.5 mg (500 mcg) every 20 minutes for 3 doses, then as needed
Metered-dose inhaler: 8 puffs every 20 minutes as needed for up to 3 hours
Asthma, maintenance (nonacute): Limited data available: Note: Evidence is lacking that ipratropium provides added
benefit to beta-2 agonists in long-term control asthma therapy (GINA 2018; NAEPP 2007):
Children <12 years:
Nebulization: 0.25 to 0.5 mg (250 to 500 mcg) every 6 to 8 hours
Metered-dose inhaler: 1 to 2 inhalations every 6 hours; not to exceed 12 inhalations/day
Children ≥12 years and Adolescents:
Nebulization: 0.25 to 0.5 mg (250 to 500 mcg) every 6 hours
Metered-dose inhaler: 2 to 3 inhalations every 6 hours; maximum daily dose: 12 inhalations/day

Bronchospasm associated with chronic pulmonary conditions: Children ≥12 years and Adolescents: Nebulization: 0.5
mg (500 mcg, one unit-dose vial) 3 to 4 times daily with doses 6 to 8 hours apart
Bronchospasm, wheezing: Limited data available; efficacy results variable: Infants: Nebulization: 0.125 to 0.25 mg (125
to 250 mcg) every 4 hours has been found helpful in some infants with chronic or recurrent wheezing, and some
patients with bronchiolitis; however, most bronchiolitis data suggests ipratropium is not effective (Hodges 1981;
Prendiville 1987; Schuh 1992; Stokes 1983; Wang 1992).
There are no dosage adjustments provided in the manufacturer's labeling (not studied); however, dosage adjustment
unlikely necessary due to low systemic absorption.
There are no dosage adjustments provided in the manufacturer's labeling (not studied); however, dosage adjustment
unlikely necessary due to low systemic absorption.
Contraindications
Hypersensitivity to ipratropium, atropine (and its derivatives), or any component of the formulation
• Bronchospasm: Paradoxical bronchospasm that may be life-threatening and may occur with use of inhaled
bronchodilating agents; this should be distinguished from inadequate response. If paradoxical
bronchospasm occurs, discontinue ipratropium and institute alternative therapy.
• CNS effects: May cause dizziness and blurred vision; patients must be cautioned about performing tasks which
require mental alertness (eg, operating machinery or driving).
• Hypersensitivity reactions: Hypersensitivity reactions (urticaria, angioedema, rash, bronchospasm,

oropharyngeal edema), including anaphylaxis, have been reported. Discontinue therapy immediately if
patient develops an allergic reaction.
• Glaucoma: Use with caution in patients with narrow-angle glaucoma; may increase intraocular pressure.
• Prostatic hyperplasia/bladder neck obstruction: Use with caution in patients with prostatic hyperplasia or
bladder neck obstruction; may cause urinary retention.
additional monitoring, and/or selection of alternative therapy. Consult drug interactions for more detailed
information.
• Appropriate use: Not indicated for the initial treatment of acute episodes of bronchospasm where rescue
therapy is required for rapid response. Only use in acute exacerbations of asthma in conjunction with
short-acting beta-adrenergic agonists for acute episodes (NAEPP 2007).
Inhalation:
Nebulization: May be administered with or without dilution in NS; use of a nebulizer with a mouth piece, rather than a
face mask, may be preferred to prevent contact with eyes
Oral Inhalation (metered-dose inhaler): Atrovent HFA: Prior to initial use, prime inhaler by releasing 2 test sprays into
the air. If the inhaler has not been used for >3 days, reprime. Avoid spraying into the eyes. Use spacer device in
children <8 years; use spacer device and face mask for children ≤4 years.
Drug Interactions
Anticholinergic Agents: Ipratropium (Oral Inhalation) may enhance the anticholinergic effect of Anticholinergic
Agents. Risk X: Avoid combination
Glucagon: Anticholinergic Agents may enhance the adverse/toxic effect of Glucagon. Specifically, the risk of
gastrointestinal adverse effects may be increased. Risk C: Monitor therapy
Opioid Agonists: Anticholinergic Agents may enhance the adverse/toxic effect of Opioid Agonists. Specifically, the risk for
constipation and urinary retention may be increased with this combination. Risk C: Monitor therapy
Potassium Citrate: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Citrate. Risk X: Avoid
combination

Onset of action: Bronchodilation: Within 15 minutes
Peak effect: 1 to 2 hours
Duration: Metered-dose inhaler: 2 to 4 hours; Nebulization solution: 4 to 5 hours, up to 7 to 8 hours in some patients
Absorption: Not readily absorbed into the systemic circulation from the surface of the lung or from the GI tract; ~7%
absorbed after nebulization of a 2 mg dose
Distribution: 15% of dose reaches lower airways
Protein Binding: ≤9%
Metabolism: Partially metabolized to inactive ester hydrolysis products
Half-life elimination: 2 hours
Excretion: Urine (50%)
Adverse Reactions
Central nervous system: Dizziness, headache
Gastrointestinal: Dysgeusia, dyspepsia, nausea, xerostomia
Genitourinary: Urinary tract infection
Neuromuscular & skeletal: Back pain
Respiratory: Bronchitis, cough, dyspnea, exacerbation of chronic obstructive pulmonary disease, flu-like symptoms,
rhinitis, sinusitis, upper respiratory tract infection
Rare but important or life-threatening: Accommodation disturbance, acute eye pain, anaphylaxis, angioedema,
bronchospasm, corneal edema, glaucoma, hypersensitivity reaction, hypotension, increased intraocular pressure,
laryngospasm, palpitations, stomatitis, tachycardia, urinary retention
CEFAZOLINA
Dosing: Neonatal
General dosing, susceptible infection: IM, IV:
Weight-directed dosing (Bradley 2019):
Body Weight Postnatal Age Dose

≤2 kg ≤7 days 50 mg/kg/day divided every 12 hours
8 to 28 days 75 mg/kg/day divided every 8 hours
29 to 60 days 100 to 150 mg/kg/day divided every 6 to 8 hours
≤7 days 100 mg/kg/day divided every 12 hours
>2 kg 8 to 28 days 150 mg/kg/day divided every 8 hours
29 to 60 days 100 to 150 mg/kg/day divided every 6 to 8 hours
Surgical prophylaxis: PNA >72 hours: IV: 30 mg/kg; administer within 60 minutes before procedure (Red Book [AAP
2018])
Dosing: Pediatric
General dosing, susceptible infection (Bradley 2019; Red Book [AAP 2018]): Infants, Children, and Adolescents: IM, IV:
Mild to moderate infections: 25 to 100 mg/kg/day divided every 8 hours; maximum daily dose: 6 g/day
Severe infections (eg, bone/joint infections): 100 to 150 mg/kg/day divided every 6 to 8 hours; maximum daily
dose: 12 g/day
Endocarditis, bacterial:
Prophylaxis for dental and upper respiratory procedures: Infants, Children, and Adolescents: IM, IV: 50 mg/kg 30
to 60 minutes before procedure; maximum dose: 1,000 mg/dose (AHA [Wilson 2007]). Note: AHA
guidelines (Baltimore 2015) limit the use of prophylactic antibiotics to patients at the highest risk for
infective endocarditis (IE) or adverse outcomes (eg, prosthetic heart valves, patients with previous IE,
unrepaired cyanotic congenital heart disease, repaired congenital heart disease with prosthetic material or
device during first 6 months after procedure, repaired congenital heart disease with residual defects at the
site or adjacent to site of prosthetic patch or device, and heart transplant recipients with cardiac
valvulopathy).
Treatment: Children and Adolescents: IV: 100 mg/kg/day in divided doses every 8 hours; usual adult dose: 2,000
mg/dose; maximum daily dose: 12 g/day; treat for at least 4 weeks; longer durations may be necessary;
may use with or without gentamicin (AHA [Baltimore 2015])
Peritonitis (peritoneal dialysis) (ISPD [Warady 2012]): Limited data available: Infants, Children, and Adolescents:
Prophylaxis:
Touch contamination of PD line: Intraperitoneal: 125 mg per liter
Invasive dental procedures: IV: 25 mg/kg administered 30 to 60 minutes before procedure; maximum dose:
1,000 mg/dose
Gastrointestinal or genitourinary procedures: IV: 25 mg/kg administered 60 minutes before procedure;

maximum dose: 2,000 mg/dose
Treatment: Intraperitoneal:
Intermittent: 20 mg/kg every 24 hours in the long dwell
Continuous: Loading dose: 500 mg per liter of dialysate; maintenance: 125 mg per liter of dialysate
Pneumonia, community-acquired pneumonia (CAP), S. aureus, methicillin susceptible: Infants >3 months, Children,
and Adolescents: IV: 50 mg/kg/dose every 8 hours (Bradley 2011); usual maximum dose for severe infections:
12 g/day (Red Book [AAP 2018])
Skin and soft tissue infections, S. aureus, methicillin susceptible (mild to moderate): (IDSA [Stevens 2014]): Infants,
Children, and Adolescents:
S. aureus, methicillin susceptible skin and soft tissue infections including pyomyositis: IV: 50 mg/kg/day divided
every 8 hours; maximum dose: 1,000 mg/dose; higher doses may be required in severe cases; duration of
therapy at least 5 days, but longer may be necessary in some cases, eg, febrile and neutropenic patients: 7
to 14 days; pyomyositis: 14 to 21 days
S. aureus, methicillin susceptible necrotizing infection of skin, fascia, or muscle: IV: 100 mg/kg/day divided every 8
hours; maximum dose: 1,000 mg/dose; continue therapy until surgical debridement no longer necessary,
clinical improvement and afebrile for 48 to 72 hours
Streptococcal, nonpurulent skin infection (cellulitis): IV: 100 mg/kg/day divided every 8 hours; maximum dose:
1,000 mg/dose; duration of therapy at least 5 days, but longer may be necessary in some cases
Surgical prophylaxis: Infants, Children, and Adolescents: IV: 30 mg/kg within 60 minutes prior to procedure, may repeat
in 4 hours for prolonged procedure or excessive blood loss (eg, >1,500 mL in adults); maximum dose dependent
upon patient weight: Weight <120 kg: 2,000 mg/dose; weight ≥120 kg: 3,000 mg/dose (ASHP/IDSA [Bratzler
2013]; Red Book [AAP 2018])
IM, IV:
Infants >1 month, Children, and Adolescents: After initial loading dose is administered, modify dose based on the
degree of renal impairment:
CrCl >70 mL/minute: No dosage adjustment required
CrCl 40 to 70 mL/minute: Administer 60% of the usual daily dose divided every 12 hours
CrCl 20 to 40 mL/minute: Administer 25% of the usual daily dose divided every 12 hours
CrCl 5 to 20 mL/minute: Administer 10% of the usual daily dose given every 24 hours
Hemodialysis: 25 mg/kg/dose every 24 hours (Aronoff 2007)
Peritoneal dialysis: 25 mg/kg/dose every 24 hours (Aronoff 2007)
Continuous renal replacement therapy: 25 mg/kg/dose every 8 hours (Aronoff 2007)

Contraindications
Hypersensitivity to cefazolin, other cephalosporin antibiotics, penicillins, other beta-lactams, or any component of the
formulation.
• Elevated INR: May be associated with increased INR, especially in nutritionally-deficient patients, prolonged
treatment, hepatic or renal disease.
• Hypersensitivity reactions: Hypersensitivity reactions, including anaphylaxis, may occur. If an allergic reaction
occurs, discontinue treatment and institute appropriate supportive measures.
• Penicillin allergy: Use with caution in patients with a history of penicillin allergy.
treatment.
• Gastrointestinal disease: Use with caution in patients with a history of gastrointestinal disease, particularly
colitis.
• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment required.
• Seizure disorders: Use with caution in patients with a history of seizure disorder; high levels, particularly in the
presence of renal impairment, may increase risk of seizures.
Parenteral:
IM: Dilute 500 mg vial with 2 mL SWFI and 1 g vial with 2.5 mL SWFI resulting in a concentration of 225 mg/mL and 330
mg/mL, respectively.
IV Push: Reconstitute appropriate vial size and further dilute to a maximum concentration: 100 mg/mL (Klaus 1989); in
fluid-restricted patients, a concentration of 138 mg/mL using SWFI results in a maximum recommended
osmolality for peripheral infusion (Robinson 1987).
Intermittent IV infusion: Further dilute dose with a compatible solution (eg, D5W, NS) to a final concentration of ≤20
mg/mL per the manufacturer. A stability study utilizing a concentration of 40 mg/mL has been shown to be stable
when diluted with D5W or NS and stored in PVC minibags under refrigeration for 30 days (Donnelly 2011).
Parenteral:
IM: Deep IM injection into a large muscle mass.
IV: May be administered IVP over 3 to 5 minutes or IV intermittent infusion over 10 to 60 minutes.
Some products may contain sodium.
Renal function periodically when used in combination with other nephrotoxic drugs, hepatic function tests, and CBC;
prothrombin time in patients at risk; number and type of stools/day for diarrhea; monitor for signs of anaphylaxis during
first dose
Drug Interactions
Monitor therapy
Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Management: Avoid cholera
vaccine in patients receiving systemic antibiotics, and within 14 days following the use of oral or parenteral
antibiotics. Risk X: Avoid combination
Fosphenytoin: CeFAZolin may decrease the protein binding of Fosphenytoin. Risk C: Monitor therapy
Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Risk C: Monitor
therapy
Phenytoin: CeFAZolin may decrease the protein binding of Phenytoin. Risk C: Monitor therapy
Probenecid: May increase the serum concentration of Cephalosporins. Risk C: Monitor therapy
RifAMPin: CeFAZolin may enhance the adverse/toxic effect of RifAMPin. Specifically, the risk for bleeding may be
increased. Management: Avoid concomitant use of rifampin with cefazolin when possible. If combined, closely
monitor prothrombin time or other coagulation tests and administer vitamin K as needed. Risk D: Consider
therapy modification
Vitamin K Antagonists (eg, warfarin): Cephalosporins may enhance the anticoagulant effect of Vitamin K
Test Interactions
Positive direct and indirect Coombs', false-positive urinary glucose test using cupric sulfate (Benedict's solution, Clinitest,
Fehling's solution), false-positive serum or urine creatinine with Jaffé reaction.
Some penicillin derivatives may accelerate the degradation of aminoglycosides in vitro, leading to a potential
underestimation of aminoglycoside serum concentration.
Distribution: Widely into most body tissues and fluids including gallbladder, liver, kidneys, bone, sputum, bile, pleural,
and synovial; CSF penetration is poor
Protein binding: 80% (Marshall 1999)
Half-life elimination: IM or IV: Neonates: 3 to 5 hours; Adults: 1.8 hours (IV); ~2 hours (IM) (prolonged with renal
impairment)
Time to peak, serum: IM: 0.5 to 2 hours; IV: Within 5 minutes
Excretion: Urine (70% to 80% as unchanged drug)
Adverse Reactions
Cardiovascular: Localized phlebitis
Central nervous system: Seizure
Dermatologic: Pruritus, skin rash, Stevens-Johnson syndrome
Gastrointestinal: Abdominal cramps, anorexia, diarrhea, nausea, oral candidiasis, pseudomembranous colitis, vomiting
Genitourinary: Vaginitis
Hepatic: Hepatitis, increased serum transaminases
Hematologic: Eosinophilia, leukopenia, neutropenia, thrombocythemia, thrombocytopenia
Local: Pain at injection site
Renal: Increased blood urea nitrogen, increased serum creatinine, renal failure
CEFEPIME
Dosing: Neonatal
General dosing, susceptible infection:
Mild to moderate infection (Bradley 2016; Red Book[AAP 2015]): IM, IV: 30 mg/kg/dose every 12 hours
Severe infection (eg, meningitis, Pseudomonas) (Bradley 2016): Note: Pharmacokinetic studies suggest that every
12-hour dosing provides adequate concentrations for severe infections (including meningitis and
pseudomonal infections) during the neonatal period (Lima-Rogel 2008)
Body weight <1 kg:
PNA 0 to 14 days: IM, IV: 50 mg/kg/dose every 12 hours
PNA ≥15 days: IM, IV: 50 mg/kg/dose every 8 hours
Body weight 1 to 2 kg:
PNA 0 to 7 days: IM, IV: 50 mg/kg/dose every 12 hours
PNA ≥8 days: IM, IV: 50 mg/kg/dose every 8 hours
Body weight >2 kg: IM, IV: 50 mg/kg/dose every 8 hours
Dosing: Pediatric
General dosing, susceptible infection (Red Book [AAP 2015]): Infants, Children, and Adolescents: IM, IV:
Mild to moderate infection: 50 mg/kg/dose every 12 hours; maximum dose: 2,000 mg/dose
Severe infection: 50 mg/kg/dose every 8 to 12 hours; maximum dose: 2,000 mg/dose
Cystic fibrosis, acute pulmonary exacerbation: Infants, Children, and Adolescents: IV: 50 mg/kg/dose every 8
hours; maximum dose: 2,000 mg/dose; patients with more resistant pseudomonal isolates (MIC ≥16 mg/L)
may require 50 mg/kg/dose every 6 hours (Zobell 2013)
Endocarditis, prosthetic valve, treatment within 1 year of replacement: Children and Adolescents: IV: 50
mg/kg/dose every 8 to 12 hours in combination with vancomycin and rifampin for 6 weeks plus gentamicin
for the first 2 weeks; maximum dose: 2,000 mg/dose (AHA [Baltimore 2015])
Febrile neutropenia, empiric therapy: Infants, Children, and Adolescents: IV: 50 mg/kg/dose every 8 hours;
maximum dose: 2,000 mg/dose (Red Book [AAP 2015]); duration of therapy dependent upon febrile
neutropenia risk-status; in high-risk patients, may discontinue empiric antibiotics if all of the following
criteria met: Negative blood cultures at 48 hours; afebrile for at least 24 hours, and evidence of marrow
recovery. In low-risk patients, may discontinue empiric antibiotics after 72 hours duration in patients with a
negative blood culture and who have been afebrile for 24 hours regardless of marrow recovery status;
follow-up closely (Lehrnbecher 2017).
Intra-abdominal infection, complicated: Infants, Children, and Adolescents: IV: 50 mg/kg/dose every 12 hours in
combination with metronidazole; maximum dose: 2,000 mg/dose. Note: IDSA guidelines recommend
duration of 4 to 7 days (provided source controlled) (IDSA [Solomkin 2010]).
Meningitis: Infants, Children, and Adolescents: IV: 50 mg/kg/dose every 8 hours; maximum dose: 2,000 mg/dose
(Tunkel 2004)
Peritonitis (peritoneal dialysis) (ISPD [Warady 2012]): Infants, Children, and Adolescents: Intraperitoneal:
Intermittent: 15 mg/kg/dose every 24 hours into the long dwell
Continuous: Loading dose: 500 mg per liter of dialysate; maintenance dose: 125 mg per liter
Pneumonia, moderate to severe: Infants ≥2 months, Children, and Adolescents:
Due to P. aeruginosa: IV: 50 mg/kg/dose every 8 hours for 10 days; maximum dose: 2,000 mg/dose
Not due to P. aeruginosa: IV: 50 mg/kg/dose every 12 hours for 10 days; maximum dose: 2,000 mg/dose
Skin and skin structure infections, uncomplicated:Infants ≥2 months, Children, and Adolescents: IV: 50
mg/kg/dose every 12 hours for 10 days; maximum dose: 2,000 mg/dose
Urinary tract infection, complicated and uncomplicated: Infants ≥2 months, Children, and Adolescents:
Mild to moderate infection: IM, IV: 50 mg/kg/dose every 12 hours for 7 to 10 days; maximum dose: 1,000
mg/dose. Note: IM may only be considered for mild to moderate infections due to E. coli.
Severe infection: IV: 50 mg/kg/dose every 12 hours for 10 days; maximum dose: 2,000 mg/dose
Manufacturer's labeling: Infants ≥2 months, Children, and Adolescents: There are no dosage adjustments
provided in the manufacturer's labeling; however, similar dosage adjustments to adults would be
anticipated based on comparable pharmacokinetics between children and adults.
Alternative dosing recommendations (Aronoff 2007): Infants, Children, and Adolescents: Note: Renally
adjusted dose recommendations are based on doses of 50 mg/kg/dose every 8 to 12 hours.
GFR >50 mL/minute/1.73 m2: No adjustment needed
GFR 10 to 50 mL/minute/1.73 m2: 50 mg/kg/dose every 24 hours
GFR <10 mL/minute/1.73 m2: 50 mg/kg/dose every 48 hours
Intermittent hemodialysis: 50 mg/kg/dose every 24 hours
Peritoneal dialysis (PD): 50 mg/kg/dose every 24 hours
Continuous renal replacement therapy (CRRT): 50 mg/kg/dose every 12 hours

No dosage adjustments necessary.
Contraindications
Hypersensitivity to cefepime, other cephalosporins, penicillins, other beta-lactam antibiotics, or any component of the
formulation
• Elevated INR: May be associated with increased INR, especially in nutritionally-deficient patients, prolonged
treatment, hepatic or renal disease.
• Hypersensitivity: May occur; use caution in patients with a history of penicillin sensitivity; cross-hypersensitivity
may occur. If a hypersensitivity reaction occurs, discontinue therapy and institute supportive measures.
• Neurotoxicity: Severe neurological reactions (some fatal) have been reported, including encephalopathy,
aphasia, myoclonus, seizures, and nonconvulsive status epilepticus. Risk may be increased in the presence
of renal impairment; ensure dose adjusted for renal function and discontinue therapy if patient develops
neurotoxicity; effects are often reversible upon discontinuation of cefepime.
treatment.
• Renal impairment: Use with caution in patients with renal impairment (CrCl ≤60 mL/minute); dosage
adjustments recommended. May increase risk of encephalopathy, myoclonus, and seizures.
• Elderly: Serious adverse reactions have occurred in elderly patients with renal insufficiency given unadjusted
doses of cefepime, including life-threatening or fatal occurrences of encephalopathy, myoclonus, and
seizures.

The manufacturer does not recommend the use of cefepime in pediatric patients for the treatment of serious infections
due to Haemophilus influenzae type b, for suspected meningitis, or for meningeal seeding from a distant infection site.
However, limited data suggest that cefepime may be a valuable alternative for treating bacterial meningitis in children in
conjunction with other agents like vancomycin in areas with a high incidence of cephalosporin nonsusceptible
pneumococci (Haase 2004).
Parenteral:
IV: Reconstitute 500 mg vial with 5 mL and 1 or 2 g vial with 10 mL of a compatible diluent (resulting concentration of
100 mg/mL for 500 mg and 1 g vial and 160 mg/mL for 2 g vial); further dilute in D5W, NS, D10W, D5NS, or D5LR;
final concentration should not exceed 40 mg/mL.
IM: Reconstitute 500 mg or 1 g vial with 1.3 mL or 2.4 mL, respectively, of SWFI, NS, D5W, lidocaine 0.5% or 1%, or
bacteriostatic water for injection to a final concentration of 280 mg/mL
Parenteral:
IV: Administer as an intermittent IV infusion over 30 minutes; in adult clinical trials, cefepime has been administered by
direct IV injection over 3 to 5 minutes at final concentrations of 40 mg/mL (Garrelts 1999) and 100 mg/mL
(Jaruratanasirikul 2002; Lipman 1999) for severe infections
IM: Administer by deep IM injection into large muscle mass
Preparation for Administration: Adult
IV: Reconstitute 500 mg vial with 5 mL and 1 or 2 g vial with 10 mL of a compatible diluent (resulting concentration of
100 mg/mL for 500 mg and 1 g vial and 160 mg/mL for 2 g vial) and further dilute in a compatible IV infusion fluid.
IM: Reconstitute 500 mg or 1 g vial with 1.3 mL or 2.4 mL, respectively, of SWFI, NS, D5W, lidocaine 0.5% or 1%, or
bacteriostatic water for injection; resulting concentration is 280 mg/mL.
Administration: Adult
IM: Inject deep IM into large muscle mass.
IV: Administer as an intermittent infusion over 30 minutes.
Off-label:
Direct IV: Inject direct IV over 5 minutes (Garrelts 1999)
Extended infusion: In certain patients where extended infusions may be appropriate, doses are usually
infused over 3 to 4 hours (Bauer 2013; Nicasio 2010).
With prolonged therapy, monitor renal and hepatic function periodically; number and type of stools/day for diarrhea;
CBC with differential. Observe for signs and symptoms of anaphylaxis during first dose.
Drug Interactions
Aminoglycosides: Cephalosporins (4th Generation) may enhance the nephrotoxic effect of Aminoglycosides.Risk C:
Monitor therapy
Test Interactions
Positive direct Coombs', false-positive urinary glucose test using cupric sulfate (Benedict's solution, Clinitest®, Fehling's
solution), false-positive serum or urine creatinine with Jaffé reaction, false-positive urinary proteins and steroids
Absorption: IM: Rapid and complete
Distribution: Vd:
Neonates (Capparelli 2005):
PMA <30 weeks: 0.51 L/kg
PMA >30 weeks: 0.39 L/kg
Infants and Children 2 months to 11 years: 0.3 L/kg
Adults: 18 L, 0.26 L/kg; penetrates into inflammatory fluid at concentrations ~80% of serum concentrations and
into bronchial mucosa at concentrations ~60% of plasma concentrations; crosses the blood-brain barrier
Protein binding, plasma: ~20%
Metabolism: Minimally hepatic
Neonates: 4 to 5 hours (Lima-Rogel 2008)
Children 2 months to 6 years: 1.77 to 1.96 hours
Adults: 2 hours
Hemodialysis: 13.5 hours

Continuous peritoneal dialysis: 19 hours
Time to peak: IM: 1 to 2 hours; IV: 0.5 hours
Excretion: Urine (85% as unchanged drug)
Renal function impairment: Total body clearance is decreased proportionally with creatinine clearance.
Adverse Reactions
Cardiovascular: Localized phlebitis
Central nervous system: Headache
Dermatologic: Pruritus, skin rash
Endocrine & metabolic: Hypophosphatemia
Gastrointestinal: Diarrhea, nausea, vomiting
Hematologic & oncologic: Eosinophilia, positive direct Coombs test (without hemolysis)
Hepatic: Abnormal partial thromboplastin time, abnormal prothrombin time, increased serum ALT, increased serum AST
Hypersensitivity: Hypersensitivity (in patients with a history of penicillin allergy)
Rare but important or life-threatening: Agranulocytosis, anaphylactic shock, anaphylaxis, anemia, aphasia, brain
disease, Clostridium difficile associated diarrhea, colitis, coma, confusion, decreased hematocrit, erythema,
hallucination, hypercalcemia, hyperkalemia, hyperphosphatemia, hypocalcemia, increased blood urea nitrogen,
increased serum alkaline phosphatase, increased serum bilirubin, increased serum creatinine, leukopenia, local
inflammation, local pain, neurotoxicity, neutropenia, oral candidiasis, pseudomembranous colitis, seizure, status
epilepticus (nonconvulsive), stupor, thrombocytopenia, vaginitis
CEFOTAXIMA
Dosing: Neonatal
General dosing, susceptible infection: IM, IV:
Gestational age-directed dosing (Red Book [AAP 2018]):
Gestational Age PostnatalAge Dose

<14 days 50 mg/kg/dose every 12 hours
<32 weeks
14 to 28 days 50 mg/kg/dose every 8 hours
Gestational Age PostnatalAge Dose
≤7 days 50 mg/kg/dose every 12 hours
≥32 weeks
Weight-directed dosing (Bradley 2018):
Body Postnatal
Dose
Weight Age
<1 kg 15 to 28 days 50 mg/kg/dose every 8 hours
1 to 2 kg 8 to 28 days 50 mg/kg/dose every 8 hours
>2 kg 8 to 28 days 50 mg/kg/dose every 8 hours
Gonococcal infections, disseminated (including sepsis, arthritis, and meningitis)/scalp abscess: IM, IV: 25 mg/kg/dose
every 12 hours for 7 days; therapy should be extended to 10 to 14 days if meningitis is documented (CDC
[Workowski 2015])
Meningitis (IDSA [Tunkel 2004]): IV: Note: Treat for a minimum of 21 days; use smaller doses and longer intervals for
neonates <2 kg.
PNA ≤7 days and ≥2 kg: 100 to 150 mg/kg/day divided every 8 to 12 hours
PNA >7 days and ≥2 kg: 150 to 200 mg/kg/day divided every 6 to 8 hours
Dosing: Pediatric
General dosing, susceptible infection: Infants, Children, and Adolescents: IM, IV: 150 to 180 mg/kg/day in divided doses
every 8 hours; maximum daily dose: 8 g/day; higher doses necessary for treatment of meningitis (Bradley
2018; Red Book [AAP 2018])
Acute bacterial rhinosinusitis, severe infection requiring hospitalization: Children and Adolescents: IV: 100 to 200
mg/kg/day divided every 6 hours for 10 to 14 days; maximum dose: 2,000 mg (IDSA [Chow 2012])
Endocarditis, treatment: Children and Adolescents: IV: 200 mg/kg/day in divided doses every 6 hours; maximum daily
dose: 12 g/day; treat for at least 4. to 6 weeks; longer durations may be necessary; may use in combination with
gentamicin for some organisms (AHA [Baltimore 2015])
Enteric bacterial infections, empiric treatment (HIV-exposed/-positive): Adolescents: IV: 1,000 mg every 8 hours (HHS
[OI adult 2018])
Gonorrhea, disseminated infections (including arthritis and arthritis-dermatitis syndrome) (as an alternative to
ceftriaxone) (CDC [Workowski 2015]): Adolescents: IV: 1,000 mg every 8 hours in combination with azithromycin
for a total duration of at least 7 days.
Intra-abdominal infection, complicated: Infants, Children, and Adolescents: IV: 150 to 200 mg/kg/day divided every 6 to
8 hours; maximum dose: 2,000 mg; use in combination with metronidazole (IDSA [Solomkin 2010])
Lyme disease, cardiac or CNS manifestations or recurrent arthritis: Infants, Children, and Adolescents: IV: 150 to 200
mg/kg/day in divided doses every 6 to 8 hours for 14 to 28 days; maximum daily dose: 6 g/day (AAN [Halperin
2007]; IDSA [Wormser 2006])
Meningitis: Infants, Children, and Adolescents: IV: 225 to 300 mg/kg/day divided every 6 to 8 hours; maximum dose:
2,000 mg/dose; use in combination with vancomycin for empiric coverage (IDSA [Tunkel 2004]; IDSA [Tunkel
2017]); some experts recommend 300 mg/kg/day divided every 4 to 6 hours with a maximum daily dose of
12 g/day (Red Book [AAP 2018])
Peritonitis (peritoneal dialysis) (ISPD [Warady 2012]): Infants, Children, and Adolescents: Intraperitoneal:
Intermittent: 30 mg/kg/dose every 24 hours in the long dwell
Continuous: Loading dose: 500 mg per liter of dialysate; maintenance dose: 250 mg per liter; Note: 125 mg/liter
has also been recommended as a maintenance dose (Aronoff 2007)
Pneumonia:
Bacterial pneumonia (HIV-exposed/-positive): Infants, Children, and Adolescents: IV: 150 to 200
mg/kg/day divided every 6 to 8 hours; maximum dose: 2,000 mg/dose (HHS [OI adult 2018]; HHS [OI
pediatric 2016])
Community-acquired pneumonia (CAP): Infants >3 months, Children, and Adolescents: IV: 50 mg/kg/dose every 8
hours; maximum dose: 2,000 mg; Note: May consider addition of vancomycin or clindamycin to empiric
therapy if community-acquired MRSA suspected. In children ≥5 years, a macrolide antibiotic should be
added if atypical pneumonia cannot be ruled out (IDSA/PIDS [Bradley 2011]).
Salmonellosis (HIV-exposed/-positive): Adolescents: IV: 1,000 mg every 8 hours (HHS [OI adult 2018])
Skin and soft tissue infections, necrotizing: Infants, Children, and Adolescents: IV: 50 mg/kg/dose every 6 hours in
combination with metronidazole or clindamycin; maximum dose: 2,000 mg/dose. Continue until further
debridement is not necessary, patient has clinically improved, and patient is afebrile for 48 to 72 hours (IDSA
[Stevens 2014]).
Surgical prophylaxis: Children and Adolescents: IV: 50 mg/kg within 60 minutes prior to the procedure; may repeat in 3
hours if procedure is lengthy or if there is excessive blood loss; maximum dose: 1,000 mg; a larger maximum dose
(2,000 mg) is recommended for obese patients (ASHP/IDSA [Bratzler 2013])
Urinary tract infection: Infants and Children 2 to 24 months: IM, IV: 150 mg/kg/day divided every 6 to 8 hours (AAP
2011)

Infants, Children, and Adolescents: The following adjustments have been recommended (Aronoff
2007). Note: Renally adjusted dose recommendations are based on doses of 100 to 200 mg/kg/day divided
every 8 hours.
GFR 30 to 50 mL/minute/1.73 m2: 35 to 70 mg/kg/dose every 8 to 12 hours
GFR 10 to 29 mL/minute/1.73 m2: 35 to 70 mg/kg/dose every 12 hours
GFR <10 mL/minute/1.73 m2: 35 to 70 mg/kg/dose every 24 hours
Intermittent hemodialysis: 35 to 70 mg/kg/dose every 24 hours
Contraindications
Hypersensitivity to cefotaxime, any component of the formulation, or other cephalosporins
• Arrhythmia: A potentially life-threatening arrhythmia has been reported in patients who received a rapid (<1
minute) bolus injection via central venous catheter.
• Granulocytopenia: Granulocytopenia and more rarely agranulocytosis may develop during prolonged treatment
(>10 days).
• Penicillin allergy: Use with caution in patients with a history of penicillin allergy, especially IgE-mediated
reactions (eg, anaphylaxis, angioedema, urticaria).
treatment.
• Tissue inflammation: Minimize tissue inflammation by changing infusion sites when needed.
• Colitis: Use with caution in patients with a history of colitis.
• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment may be required.
Parenteral:
IM: Reconstitute powder for injection with SWFI to a final concentration between 230 to 330 mg/mL (see
manufacturer's labeling for specific details). Shake to dissolve.
IV:
IV Push: Reconstitute vials with at least 10 mL SWFI to a maximum concentration of 200 mg/mL.
Intermittent infusion: Reconstitute powder for injection with SWFI, resultant concentration dependent upon
product (single dose vials or Pharmacy Bulk vial; see manufacturer's labeling for specific details). Dilute
dose to a final concentration of 10 to 40 mg/mL with NS, D5W, D10W, D5NS, D51/2NS, D51/4NS, or LR; some
centers have used concentrations up to 60 mg/mL.
Parenteral:
IM: Administer by deep IM injection into a large muscle mass such as the upper outer quadrant of the gluteus maximus.
Doses of 2,000 mg should be divided and administered at two different sites.
IV:
IV Push: May be administered over 3 to 5 minutes; avoid rapid injection (<1 minute) due to association with
arrhythmias
Intermittent infusion: Infuse over 15 to 30 minutes.
Some products may contain sodium.
Observe for signs and symptoms of anaphylaxis during first dose; monitor infusion site for extravasation; with prolonged
therapy, monitor renal, hepatic, and hematologic function periodically; number and type of stools/day for diarrhea
None known.
Drug Interactions
Aminoglycosides: Cephalosporins (3rd Generation) may enhance the nephrotoxic effect of Aminoglycosides.Risk C:
Monitor therapy
Monitor therapy
therapy
Probenecid: May increase the serum concentration of Cefotaxime. Management: Avoid cefotaxime doses greater than 6
g/day with concurrent probenecid. Any patients receiving this combination should be monitored closely for
evidence of cefotaxime toxicity. Risk D: Consider therapy modification
Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a
strain is affected. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in
patients being treated with systemic antibacterial agents. Use of this vaccine should be postponed until at least 3
days after cessation of antibacterial agents. Risk D: Consider therapy modification
Test Interactions
Positive direct Coombs', false-positive urinary glucose test using cupric sulfate (Benedict's solution, Clinitest®, Fehling's
solution), false-positive serum or urine creatinine with Jaffé reaction
Distribution: Widely to body tissues and fluids including aqueous humor, ascitic and prostatic fluids, bone; penetrates
CSF best when meninges are inflamed
Metabolism: Partially hepatic to active metabolite, desacetylcefotaxime
Cefotaxime: Infants ≤1500 g: 4.6 hours; Infants >1500 g: 3.4 hours; Children: 1.5 hours; Adults: 1 to 1.5 hours;
prolonged with renal and/or hepatic impairment
Desacetylcefotaxime: 1.3 to 1.9 hours; prolonged with renal impairment (Ings 1982)
Time to peak, serum: IM: Within 30 minutes

Excretion: Urine (~60% as unchanged drug and metabolites)
Adverse Reactions
Gastrointestinal: Colitis, diarrhea, nausea, vomiting
Hematologic & oncologic: Eosinophilia
Local: Induration at injection site (IM), inflammation at injection site (IV), pain at injection site (IM), tenderness at
injection site (IM)
Rare but important or life-threatening: Acute generalized exanthematous pustulosis, acute renal failure, agranulocytosis,
anaphylaxis, bone marrow failure, brain disease, candidiasis, cardiac arrhythmia (after rapid IV injection via
central catheter), cholestasis, Clostridium difficile associated diarrhea, erythema multiforme, granulocytopenia,
hemolytic anemia, hepatitis, increased blood urea nitrogen, increased gamma-glutamyl transferase, increased
lactate dehydrogenase, increased serum alkaline phosphatase, increased serum ALT, increased serum AST,
increased serum bilirubin, increased serum creatinine, injection site phlebitis, interstitial nephritis, jaundice,
leukopenia, neutropenia, pancytopenia, positive direct Coombs test, pseudomembranous colitis, Stevens-Johnson
syndrome, thrombocytopenia, toxic epidermal necrolysis, vaginitis
CEFTAZIDIMA
Dosing: Pediatric
General dosing, susceptible infection (Red Book [AAP 2015]): IM, IV: Infants, Children, and Adolescents:
Mild to moderate infections: 90 to 150 mg/kg/day divided every 8 hours; maximum daily dose: 3,000 mg/day
Severe infections: 200 mg/kg/day divided every 8 hours; maximum daily dose: 6 g/day; higher doses (300 mg/kg/day)
have been recommended for cystic fibrosis patients
Cystic fibrosis, lung infection caused by Pseudomonas spp: Infants, Children, and Adolescents: IV: 150 to 200 mg/kg/day
divided every 6 to 8 hours (Bradley 2017); maximum daily dose: 6 g/day; higher doses have been used: 200 to 400
mg/kg/day divided every 6 to 8 hours; maximum daily dose: 12 g/day (Zobell 2013)
Endocarditis, treatment: Children and Adolescents: IV: 100 to 150 mg/kg/day divided every 8 hours; maximum daily
dose: 4,000 mg/day; use in combination with gentamicin or vancomycin and gentamicin (plus rifampin if prosthetic
material is present) depending on the cause of infection (AHA [Baltimore 2015])
Intra-abdominal infections, complicated: Infants, Children, and Adolescents: IV: 50 mg/kg/dose every 8 hours in
combination with metronidazole; maximum daily dose: 6 g/day (Solomkin 2010)
Meningitis: Infants, Children, and Adolescents: IV: 150 mg/kg/day divided every 8 hours; maximum daily dose:
6 g/day (Tunkel 2004)
Peritonitis (peritoneal dialysis): Infants, Children, and Adolescents: Intraperitoneal:
Intermittent: 20 mg/kg/dose every 24 hours in the long dwell (ISPD [Warady 2012]); in adults, intermittent: 1,000 to
1,500 mg every 24 hours per exchange in the long dwell (≥6 hours) (Li 2010)
Continuous: Loading dose: 500 mg per liter of dialysate; maintenance dose: 125 mg per liter (ISPD [Warady 2012])
Urinary tract infection: Infants and Children 2 to 24 months: IV: 100 to 150 mg/kg/day divided every 8 hours (AAP 2011)
Infants, Children, and Adolescents: The manufacturer recommends decreasing dosing frequency based on the calculated
BSA-adjusted creatinine clearance. The following guidelines have been used by some clinicians (Aronoff
2007): Note:Renally adjusted dose recommendations are based on a usual dose of 25 to 50 mg/kg/dose every 8 hours:
GFR >50 mL/minute/1.73 m2: No adjustment required
Hemodialysis: Dialyzable (50% to 100%): 50 mg/kg/dose every 48 hours, give after dialysis on dialysis days
Peritoneal dialysis: 50 mg/kg/dose every 48 hours
Continuous renal replacement therapy (CRRT): 50 mg/kg/dose every 12 hours
Infants, Children and Adolescents: No adjustment required.
• Elevated INR: May be associated with increased INR, especially in nutritionally-deficient patients, prolonged treatment,
hepatic or renal disease. Monitor INR during treatment if patient is at risk; administer vitamin K as clinically indicated.
• Hypersensitivity: Hypersensitivity and anaphylaxis have been reported in patients receiving beta-lactam drugs. Use
caution in patients with a history of hypersensitivity to penicillins or other beta-lactams; use is contraindicated in
patients with cephalosporin allergy (according to the manufacturer). If severe hypersensitivity occurs, discontinue
immediately and institute supportive emergency measures.
• Neurotoxicity: High ceftazidime levels in patients with renal insufficiency can lead to seizures, nonconvulsive status
epilepticus, encephalopathy, coma, asterixis, myoclonia, and neuromuscular excitability. Adjust dosage based on renal
function.
• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea
(CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.
• Gastrointestinal disease: Use with caution in patients with a history of GI disease, especially colitis.
• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment recommended.
Note: Any carbon dioxide bubbles that may be present in the withdrawn solution should be expelled prior to injection.
IM: Reconstitute the 500 mg vials with 1.5 mL or the 1,000 mg vials with 3 mL of either SWFI, bacteriostatic water for
injection, or lidocaine (0.5% or 1%) to a final concentration of 280 mg/mL
IV:
IV Push: Reconstitute vial using SWFI to a concentration of 100 to 170 mg/mL; see manufacturer's labeling for specific
details.
Intermittent IV infusion: Further dilute with a compatible solution (eg, D5W, NS) to a final concentration ≤40 mg/mL. In
fluid-restricted patients, a concentration of 125 mg/mL using SWFI results in a maximum recommended osmolality for
peripheral infusion (Robinson 1987).
Parenteral: Inadvertent intra-arterial administration may result in distal necrosis.
IM: Deep IM injection into a large muscle mass such as the upper outer quadrant of the gluteus maximus or lateral part
of the thigh.
IV:
IV Push: Administer over 3 to 5 minutes
Intermittent IV infusion: Administer over 15 to 30 minutes
Renal function periodically when used in combination with aminoglycosides; with prolonged therapy also monitor
hepatic and hematologic function periodically; number and type of stools/day for diarrhea. Observe for signs and
symptoms of anaphylaxis during first dose. Monitor prothrombin time in patients at risk for increased INR (nutritionally
deficient patients, prolonged treatment, hepatic or renal disease)
Drug Interactions
Aminoglycosides: Cephalosporins (3rd Generation) may enhance the nephrotoxic effect of Aminoglycosides. Risk C:
Monitor therapy
Monitor therapy
Chloramphenicol (Systemic): May diminish the therapeutic effect of CefTAZidime. Management: Consider using a
different combination of antimicrobials, especially if bactericidal activity is desired. If these agents are combined,
monitor for reduced antimicrobial effectiveness and/or therapeutic failure. Risk D: Consider therapy modification
therapy
Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using
an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently
using an antibiotic.Risk D: Consider therapy modification
strain is affected. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in patients
being treated with systemic antibacterial agents. Use of this vaccine should be postponed until at least 3 days after
cessation of antibacterial agents. Risk D: Consider therapy modification
Adverse Reactions
Endocrine & metabolic: Increased gamma-glutamyl transferase, increased lactate dehydrogenase
Gastrointestinal: Diarrhea
Hematologic & oncologic: Agranulocytosis, eosinophilia, leukopenia, lymphocytosis, neutropenia, positive direct Coombs
test (without hemolysis), thrombocythemia, thrombocytopenia
Hepatic: Increased serum alkaline phosphatase, increased serum ALT, increased serum AST
Hypersensitivity: Hypersensitivity reactions
Local: Inflammation at injection site, injection site phlebitis
Renal: Increased blood urea nitrogen, increased serum creatinine
Rare but important or life-threatening: Abdominal pain, anaphylaxis (severe in rare instances, including cardiopulmonary
arrest), angioedema, candidiasis, Clostridium difficileassociated diarrhea, dizziness, erythema multiforme, headache,
hemolytic anemia, hyperbilirubinemia, jaundice, nausea, pain at injection site, paresthesia, renal insufficiency, Stevens-
Johnson syndrome, toxic epidermal necrolysis, urticaria, vaginitis, vomiting
CEFTRIAXONA
Dosing: Neonatal
Note: Use cefotaxime in place of ceftriaxone if hyperbilirubinemia is present or if patient is receiving calcium-containing
intravenous solutions.
General dosing, susceptible infection (Red Book [AAP 2018]): IM, IV: 50 mg/kg/dose every 24 hours
Gonococcal infections (CDC [Workowski 2015]): Note: Administer cautiously to hyperbilirubinemic neonates, especially
those born premature; alternative agent may be necessary.
Prophylaxis, asymptomatic neonates born to mothers with gonococcal infection: IM, IV: 25 to 50 mg/kg as a single
dose; maximum dose: 125 mg/dose
Treatment:
Disseminated infection (including sepsis, arthritis, and meningitis)/Scalp abscess: IM, IV: 25 to 50
mg/kg/dose every 24 hours for 7 days, up to 10 to 14 days if meningitis is documented
Ophthalmia neonatorum: IM, IV: 25 to 50 mg/kg as a single dose; maximum dose: 125 mg/dose; Note: May
also be used for prophylaxis if erythromycin ointment is not available.
Meningitis, non-gonococcal: Limited data available, dose not established: Note: In neonates, current IDSA guidelines
suggest cefotaxime as the preferred nonpseudomonal third-generation cephalosporin; no ceftriaxone dosing is
provided in the guidelines (IDSA [Tunkel 2004]). Dosing based on an open-label prospective trial of 71 patients
(age range: PNA 14 days to 15 years) which included 26 patients diagnosed with meningitis and a pharmacokinetic
analysis of 20 neonates and infants (n=12 neonates; including six with PNA <14 days) with sepsis or meningitis;
both trials reported adequate CSF penetration and favorable response (Martin 1984; Yogev 1986). IV:
PNA <14 days: 50 mg/kg/dose once daily
PNA ≥14 days: 100 mg/kg for one dose, followed by 80 to 100 mg/kg/dose once daily
Dosing: Pediatric
General dosing, susceptible infection (Red Book [AAP 2018]): Infants, Children, and Adolescents: IM, IV:
Mild to moderate infection: 50 to 75 mg/kg/dose once daily; maximum daily dose: 1,000 mg/day
Severe infection (eg, meningitis, penicillin-resistant pneumococcal pneumonia): 100 mg/kg/daydivided every 12
to 24 hours; maximum daily dose: 4,000 mg/day
Chancroid: Infants, Children, and Adolescents: IM: 50 mg/kg as a single dose; maximum dose: 250 mg/dose (Red
Book [AAP 2018])
Endocarditis, bacterial (non-gonococcal):
Prophylaxis for dental and upper respiratory procedures (patients allergic to penicillins and/or unable to take
oral): Infants, Children, and Adolescents: IM, IV: 50 mg/kg 30 to 60 minutes prior to procedure; maximum
dose: 1,000 mg/dose (Red Book [AAP 2018]; Wilson 2007). Note: AHA guidelines (Baltimore 2015) limit the
use of prophylactic antibiotics to patients at the highest risk for infective endocarditis (IE) or adverse
outcomes (eg, prosthetic heart valves, patients with previous IE, unrepaired cyanotic congenital heart
disease, repaired congenital heart disease with prosthetic material or device during first 6 months after
procedure, repaired congenital heart disease with residual defects at the site or adjacent to site of
prosthetic patch or device, and heart transplant recipients with cardiac valvulopathy).
Treatment: Children and Adolescents: IV: 100 mg/kg/day divided every 12 hours or 80 mg/kg/dose every 24
hours; maximum daily dose: 4,000 mg/day, daily doses over 2,000 mg should be divided into 2 doses; treat
for at least 4 weeks; longer durations may be necessary; may use in combination with other antibiotics
based on organism (AHA [Baltimore 2015])
Enteric infection, bacteria, empiric therapy pending diagnostic studies (HIV-exposed/-positive): Adolescents: IV: 1,000
mg every 24 hours (HHS [OI adult 2018])
Gonococcal infections, treatment:
Bacteremia (CDC [Workowski 2015]):
Infants and Children weighing ≤45 kg: IM, IV: 50 mg/kg/dose once daily for 7 days; maximum dose: 1,000
mg/dose
Children weighing >45 kg and Adolescents: IM, IV: 1,000 mg once daily for 7 days
Epididymitis, acute: Adolescents: IM: 250 mg in a single dose in combination with oral doxycycline (CDC
[Workowski 2015])
Uncomplicated cervicitis, pharyngitis, proctitis, urethritis, and vulvovaginitis (CDC [Workowski 2015]):
Infants and Children weighing ≤45 kg: IM, IV: 25 to 50 mg/kg as a single dose; maximum dose: 125 mg/dose
Children weighing >45 kg and Adolescents: IM: 250 mg as a single dose in combination with single oral dose
of azithromycin
Disseminated infection (arthritis or arthritis-dermatitis syndrome) (CDC [Workowski 2015]):
Infants and Children: IM, IV: 50 mg/kg/dose once daily for 7 days; maximum dose: 1,000 mg/dose
Adolescents: IM, IV: 1,000 mg once daily for 7 days; use in combination with a single oral dose of
azithromycin
Conjunctivitis: Adolescents: IM: 1,000 mg in a single dose in combination with a single oral dose of azithromycin
(CDC [Workowski 2015])
Meningitis:
Infants and Children weighing <45 kg: IV, IM: 50 mg/kg/day divided every 12 to 24 hours for 10 to 14 days;
maximum daily dose: 2,000 mg/day(Red Book [AAP 2018])
Children weighing ≥45 kg and Adolescents: IV: 1,000 to 2,000 mg every 12 to 24 hours for 10 to 14 days;
use in combination with a single dose of oral azithromycin (CDC [Workowski 2015]; Red Book [AAP
2018])
Endocarditis:
Infants and Children weighing <45 kg: IV, IM: 50 mg/kg/day divided every 12 to 24 hours for at least 28
days; maximum daily dose: 2,000 mg/day (Red Book [AAP 2018])
Children weighing ≥45 kg and Adolescents: IV: 1,000 to 2,000 mg every 12 to 24 hours for at least 28 days;
use in combination with a single dose of oral azithromycin (CDC [Workowski 2015]; Red Book [AAP
2018])
Intra-abdominal infection, complicated: Infants, Children, and Adolescents: IV: 50 to 75 mg/kg/day divided every 12 to
24 hours; maximum daily dose: 2,000 mg/day(IDSA [Solomkin 2010])
Lyme disease, neurologic involvement, persistent/recurrent arthritis, heart block, or carditis: Infants, Children, and
Adolescents: IV: 50 to 75 mg/kg/dose once daily; maximum dose: 2,000 mg/dose; duration dependent on
symptoms and response (AAN [Halperin 2007]; IDSA [Wormser 2006])
Meningitis: Note: Per the manufacturer's labeling, doses may be administered IM.
Acute bacterial meningitis: Infants, Children, and Adolescents: IV: 80 to 100 mg/kg/day divided every 12 to 24
hours; maximum daily dose: 4,000 mg/day (IDSA [Tunkel 2004])
Health care-associated meningitis/ventriculitis: Infants, Children, and Adolescents: IV: 100 mg/kg/daydivided
every 12 to 24 hours; maximum daily dose: 4,000 mg/day (IDSA [Tunkel 2017])
Meningococcal infection, chemoprophylaxis for high-risk contacts (close exposure to patients with invasive
meningococcal disease) (Red Book [AAP 2018]):
Infants, Children, and Adolescents <15 years: IM: 125 mg in a single dose
Adolescents ≥15 years: IM: 250 mg in a single dose
Otitis media, acute (AAP [Lieberthal 2013]; Red Book [AAP 2018]): Infants, Children, and Adolescents:
Acute bacterial: IM, IV: 50 mg/kg/dose once daily for 1 or 3 days; maximum dose: 1,000 mg/dose
Persistent or relapsing: IM, IV: 50 mg/kg/dose once daily for 3 days; maximum dose: 1,000 mg/dose
Peritonitis (peritoneal dialysis), prophylaxis for patients receiving peritoneal dialysis who require dental
procedures: Infants, Children, and Adolescents: IM, IV: 50 mg/kg administered 30 to 60 minutes before dental
procedure; maximum dose: 1,000 mg/dose (ISPD [Warady 2012])
Pneumonia, community-acquired (CAP) (IDSA/PIDS [Bradley 2011]): Infants >3 months, Children, and Adolescents: IV:
50 to 100 mg/kg/day divided every 12 to 24 hours; usual maximum daily dose: 2,000 mg/day; higher maximum
daily doses as high as 4,000 mg/dayhave been recommended for HIV-exposed/-positive patients (HHS [OI
pediatric 2018]). Note: May consider addition of vancomycin or clindamycin to empiric therapy if community-
acquired MRSA suspected. Use the higher end of the range for penicillin-resistant S. pneumoniae; in children ≥5
years, a macrolide antibiotic should be added if atypical pneumonia cannot be ruled out; preferred in patients not
fully immunized for H. influenzae type b and S. pneumoniae, or significant local resistance to penicillin in invasive
pneumococcal strains.
Prophylaxis against sexually transmitted diseases following sexual assault (CDC [Workowski 2015]): Adolescents: IM:
250 mg as a single dose in combination with a single dose of oral azithromycin and oral metronidazole (or oral
tinidazole)
Rhinosinusitis, acute bacterial:

Ambulatory patients: Children and Adolescents: IM, IV: 50 mg/kg as a single dose; usual maximum dose: 2,000
mg/dose; use for patients who are unable to tolerate oral medication, or unlikely to be adherent to the
initial doses of antibiotic (AAP [Wald 2013])
Severe infection requiring hospitalization: Infants, Children, and Adolescents: IV: 50 mg/kg/daydivided every 12
hours for 10 to 14 days; maximum daily dose: 2,000 mg/day (IDSA [Chow 2012])
Salmonellosis: Note: Salmonella in healthy patients typically does not require antibiotic treatment as it generally
resolves in 5 to 7 days (CDC 2015).
Infants <6 months of age or Infants, Children, and Adolescents who have severe infection, prostheses, valvular
heart disease, severe atherosclerosis, malignancy, or uremia: Non-typhi species diarrhea: IM, IV: 100
mg/kg/day divided every 12 to 24 hours for 14 days; or longer if relapsing. Note: Not recommended for
routine use (Guerrant 2001).
HIV-exposed/-positive: Adolescents: IV: 1,000 mg every 24 hours; duration dependent upon CD4 counts and
presence of bacteremia (HHS [OI adult 2018])
If CD4 count ≥200 cells/mm3: 7 to 14 days; if bacteremia present: At least 14 days; longer durations if
bacteremia or if infection is complicated
If CD4 count <200 cells/mm3: 2 to 6 weeks
Shigellosis: Infants, Children, and Adolescents: IM, IV: 50 to 100 mg/kg/dose once daily; maximum daily dose: 4,000
mg/day; usual duration 5 days; may shorten duration to 2 days if clinical response good and no extraintestinal
involvement (Red Book [AAP 2018]; WHO 2005)
Skin/skin structure infections: Infants, Children, and Adolescents: IM, IV: 50 to 75 mg/kg/day in 1 to 2 divided doses;
maximum daily dose: 2,000 mg/day
S. pneumoniae infection, invasive (Red Book [AAP 2018]): Infants, Children, and Adolescents: IV:
CNS infection: 100 mg/kg/day divided every 12 to 24 hours; maximum dose: 2,000 mg/dose; maximum daily dose:
4,000 mg/day
Non-CNS infection: 50 to 75 mg/kg/day divided every 12 to 24 hours; maximum dose: 2,000 mg/dose; maximum
daily dose: 4,000 mg/day
Surgical prophylaxis: Children and Adolescents: IV: 50 to 75 mg/kg within 60 minutes prior to the procedure; maximum
dose: 2,000 mg/dose (ASHP/IDSA [Bratzler 2013])
Syphilis: Note: Not considered first-line therapy and use should be reserved for special circumstances with close
monitoring and follow-up:
Congenital syphilis, treatment (CDC [Workowski 2015]): Note: There is insufficient data regarding the use of
ceftriaxone for treatment of congenital syphilis (penicillin is recommended); use should be reserved for
situations of penicillin shortage.
Infants ≥30 days: IM, IV: 75 mg/kg/dose once daily for 10 to 14 days
Children: IM, IV: 100 mg/kg/dose once daily for 10 to 14 days
Postexposure prophylaxis (HIV-exposed/-positive): Adolescents: IM, IV: 1,000 mg once daily for 10 to 14 days
(HHS [OI adult 2018])
Treatment:
Early syphilis (independent of HIV status): Adolescents: IM, IV: 1,000 to 2,000 mg once daily for 10 to 14
days; optimal dose and duration have not been defined (CDC [Workowski 2015]; HHS [OI adult
2018])
Neurosyphillis, otic, ocular disease (HIV-exposed/-positive; penicillin-allergic): Adolescents: IM, IV: 2,000
mg once daily for 10 to 14 days (CDC [Workowski 2015). Note: Penicillin desensitization is the
preferred approach; use should be reserved when desensitization is not feasible (HHS [OI adult
2018]).
Typhoid fever: Infants, Children, and Adolescents: IV: 80 mg/kg/dose once daily for 14 days (Stephens
2002). Note: Ceftriaxone is reserved for patients who have failed oral therapy or who have severe disease,
intestinal complications, or obtundation and cannot take oral medications.
Urinary tract infections: Infants, Children, and Adolescents: IM, IV: 50 mg/kg/dose once daily; usual maximum dose:
2,000 mg/dose (AAP 2016; Bradley 2018)
No dosage adjustment is generally necessary in renal impairment; Note: If concurrent renal and hepatic dysfunction, a
reduced maximum daily dose should be considered; in adults a maximum daily dose ≤2,000 mg/day is suggested.
Not dialyzable; no supplemental dose is necessary following hemodialysis or peritoneal dialysis; patients with
concomitant hepatic dysfunction must be monitored closely for safety and efficacy.
No adjustment is generally necessary in hepatic impairment; Note: If concurrent renal and hepatic dysfunction, a
reduced maximum daily dose should be considered; in adults a maximum daily dose ≤2,000 mg/day is suggested.
Contraindications
Hypersensitivity to ceftriaxone, any component of the formulation, or other cephalosporins; do not use in
hyperbilirubinemic neonates, particularly those who are premature since ceftriaxone is reported to displace bilirubin
from albumin binding sites; concomitant use with intravenous calcium-containing solutions/products in neonates (≤28
days); IV use of ceftriaxone solutions containing lidocaine.

• Hypersensitivity: Serious and sometimes fatal hypersensitivity has been reported. Use caution in patients with a
history of any allergy (particularly drugs), penicillin allergy or beta-lactam sensitivity. If severe
hypersensitivity occurs, discontinue immediately and institute supportive emergency measures.
• Elevated INR: May be associated with increased INR (rarely), especially in nutritionally-deficient patients,
prolonged treatment, hepatic or renal disease. Monitor INR during treatment if patient has impaired
synthesis or low stores of vitamin K; supplementation may be needed if clinically indicated.
• Hemolytic anemia: Severe cases (including some fatalities) of immune-related hemolytic anemia have been
reported in patients receiving cephalosporins, including ceftriaxone.
• Pancreatitis: Secondary to biliary obstruction, pancreatitis has been reported rarely. Most patients had biliary
stasis or sludge risk factors (eg, preceding major surgery, sever illness, TPN).
treatment.
• Gallbladder pseudolithiasis: Abnormal gallbladder sonograms have been reported, possibly due to ceftriaxone-
calcium precipitates; probability is greatest in pediatric patients. Discontinue in patients who develop signs
and symptoms and/or sonographic evidence of gallbladder disease.
• Gastrointestinal disease: Use with caution in patients with a history of GI disease, especially colitis.
• Renal/hepatic impairment (concurrent) Use with caution in patients with concurrent hepatic dysfunction and
significant renal disease; dosage should not exceed 2 g/day.
• Neonates: Use extreme caution in neonates due to risk of hyperbilirubinemia, particularly in premature infants
(contraindicated in hyperbilirubinemic neonates and neonates <41 weeks postmenstrual age). Fatal
precipitation reactions in neonates due to coadministration of calcium-containing solutions have been
reported; concurrent use in neonates is contraindicated.
• Precipitation: Ceftriaxone may complex with calcium causing precipitation. Fatal lung and kidney damage
associated with calcium-ceftriaxone precipitates has been observed in premature and term neonates. Due
to reports of precipitation reaction in neonates, do not reconstitute, admix, or coadminister with calcium-
containing solutions (eg, LR, Hartmann’s solution, parenteral nutrition), even via separate infusion
lines/sites or at different times in any neonate. Ceftriaxone should not be diluted or administered
simultaneously with any calcium-containing solution via a Y-site in any patient. However, ceftriaxone and
calcium-containing solutions may be administered sequentially of one another for use in patients other
than neonates if infusion lines are thoroughly flushed (with a compatible fluid) between infusions.
Parenteral: Do not reconstitute with calcium-containing solutions.
IM: Vials should be reconstituted with appropriate volume of diluent (including D5W, NS, SWFI, bacteriostatic water, or
1% lidocaine) to make a final concentration of 250 mg/mL or 350 mg/mL; more dilute concentrations (100
mg/mL) can be used if needed; see manufacturer's labeling for specific detail.
IV: Reconstitute powder for injection to a concentration of ~100 mg/mL with an appropriate IV diluent (including SWFI,
D5W, D10W, NS); see manufacturer's labeling for specific details. Further dilute dose in compatible solution (eg,
D5W or NS) to a final concentration not to exceed 40 mg/mL.
Parenteral: Do not coadminister with calcium-containing solutions.
IM: Administer IM injections deep into a large muscle mass
Intermittent IV infusion:
Neonates: Administer over 60 minutes to decrease risk of bilirubin encephalopathy
Infants, Children, and Adolescents: Administer over 30 minutes; shorter infusion times (15 minutes) have been
reported (Yogev 1986)
IV Push: Administration over 2 to 4 minutes has been reported in pediatric patients >11 years and adults primarily in the
outpatient setting (Baumgartner 1983; Garrelts 1988; Poole 1999) and over 5 minutes in pediatric patients ages
newborn to 15 years with meningitis (Grubbauer 1990; Martin 1984). Rapid IVP injection over 5 minutes of a
2,000 mg dose resulted in tachycardia, restlessness, diaphoresis, and palpitations in an adult patient (Lossos
1994). IV push administration in young infants may also have been a contributing factor in risk of cardiopulmonary
events occurring from interactions between ceftriaxone and calcium (Bradley 2009).
CBC with differential, platelet count, PT, renal and hepatic function tests periodically; number and type of stools/day for
diarrhea; observe for signs and symptoms of anaphylaxis
Drug Interactions
Aminoglycosides: Cephalosporins (3rd Generation) may enhance the nephrotoxic effect of Aminoglycosides.Risk C:
Monitor therapy
Monitor therapy
Calcium Salts (Intravenous): May enhance the adverse/toxic effect of CefTRIAXone. Ceftriaxone binds to calcium forming
an insoluble precipitate. Management: Use of ceftriaxone is contraindicated in neonates (28 days of age or
younger) who require (or are expected to require) treatment with IV calcium-containing solutions. In older
patients, flush lines with compatible fluid between administration. Risk D: Consider therapy modification
therapy
Ringer's Injection (Lactated): May enhance the adverse/toxic effect of CefTRIAXone. Ceftriaxone binds to calcium in the
Lactated Ringer's forming an insoluble precipitate. Management: Use of ceftriaxone is contraindicated in
neonates (28 days of age or younger) who require (or are expected to require) treatment with IV calcium-
containing solutions (ie, LR). In older patients, flush lines with compatible fluid between administration. Risk D:
Consider therapy modification
strain is affected. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in
patients being treated with systemic antibacterial agents. Use of this vaccine should be postponed until at least 3
days after cessation of antibacterial agents. Risk D: Consider therapy modification
Test Interactions
Positive direct Coombs', false-positive urinary glucose test using nonenzymatic methods, false-positive galactosemia
tests.
Absorption: IM: Well absorbed
Distribution: Widely throughout the body including gallbladder, lungs, bone, bile, CSF (higher concentrations achieved
when meninges are inflamed); Vd:
Neonates: 0.34 to 0.55 L/kg (Richards 1984)
Infants and Children: 0.32 to 0.4 L/kg (Richards 1984)
Adults: ~6 to 14 L
Neonates (Martin 1984): 1 to 4 days: 16 hours; 9 to 30 days: 9 hours
Infants and Children: 4 to 6.6 hours (Richards 1984)
Adults: Normal renal and hepatic function: ~5 to 9 hours
Adults: Renal impairment (mild-to-severe): ~12 to 16 hours
Time to peak, serum: IM: 2 to 3 hours
Excretion: Urine (33% to 67% as unchanged drug); feces (as inactive drug)
Adverse Reactions
Dermatologic: Skin rash, skin tightness (IM)
Gastrointestinal: Diarrhea
Hematologic & oncologic: Eosinophilia, leukopenia, thrombocythemia
Hepatic: Increased serum transaminases
Local: Induration at injection site (incidence higher with IM), pain at injection site, tenderness at injection site, warm
sensation at injection site (IM)
Renal: Increased blood urea nitrogen
Rare but important or life-threatening: Abdominal pain, acute generalized exanthematous pustulosis, acute renal failure
(post-renal), agranulocytosis, allergic dermatitis, anaphylactoid reaction, anaphylaxis, anemia, basophilia, blood
coagulation disorder, bronchospasm, candidiasis, casts in urine, choledocholithiasis, cholelithiasis, clostridium
difficile associated diarrhea, colitis, decreased prothrombin time, dysgeusia, dyspepsia, edema, epistaxis,
erythema multiforme, fever, flushing, gallbladder sludge, glossitis, glycosuria, granulocytopenia, headache,
hematuria, hemolytic anemia, hypersensitivity pneumonitis, increased monocytes, increased serum alkaline
phosphatase, increased serum bilirubin, increased serum creatinine, jaundice, kernicterus, leukocytosis,
lymphocytopenia, lymphocytosis, nephrolithiasis, neutropenia, oliguria, palpitations, pancreatitis, phlebitis,
prolonged prothrombin time, pseudomembranous colitis, seizure, serum sickness, Stevens-Johnson syndrome,
stomatitis, thrombocytopenia, toxic epidermal necrolysis, ureteral obstruction, urogenital fungal infection,
urolithiasis, vaginitis
CIPROFLOXACINO
Dosing: Neonatal
Note: In pediatric patients, ciprofloxacin is not routinely first-line therapy, but after assessment of risks and benefits, can
be considered a reasonable alternative for some situations (Bradley 2011b). Note: Oral liquid products are available in
two concentrations (ie, 50 mg/mL and 100 mg/mL); precautions should be taken to verify product selection and avoid
confusion between the different concentrations.
Anthrax:
Cutaneous, without systemic involvement: AAP recommendations (Bradley 2014): Duration: 7 to 10 days for
naturally acquired infection, up to 60 days for biological weapon-related event
Preterm neonates (32 to 37 weeks): Oral, immediate release: 10 mg/kg/dose every 12 hours
Term neonates: Oral, immediate release: 15 mg/kg/dose every 12 hours
Inhalational (postexposure prophylaxis):
Oral, immediate release:
Manufacturer's labeling: 15 mg/kg/dose every 12 hours for 60 days
AAP recommendation (Bradley 2014):
Preterm neonates (32 to 37 weeks): 10 mg/kg/dose every 12 hours
Term infants (>37 weeks): 15 mg/kg/dose every 12 hours
IV: 10 mg/kg/dose every 12 hours for 60 days
Systemic (including meningitis): AAP recommendations (Bradley 2014):
Initial treatment as part of combination therapy: Continue until clinical criteria for stability are met.
Preterm neonates (32 to 37 weeks): IV: 10 mg/kg/dose every 12 hours
Term neonates (>37 weeks): IV: 15 mg/kg/dose every 12 hours
Oral step-down to complete a 60 day total course:
Preterm neonates (32 to 37 weeks): Oral, immediate release: 10 mg/kg/dose every 12 hours
Term neonates (>37 weeks): Oral, immediate release: 15 mg/kg/dose every 12 hours
Plague:
Oral, immediate release: 15 mg/kg/dose every 8 to 12 hours for 10 to 21 days
IV: 10 mg/kg/dose every 8 to 12 hours for 10 to 21 days
Severe infection (eg, sepsis); usually multidrug resistant:Limited data available: IV: 10 mg/kg/dose every 12 hours
(Kaguelidou 2011). A study of 20 neonates (28 to 36 weeks) showed this dose produced serum concentrations
sufficient to treat common gram-negative pathogens. A higher daily dose divided into shorter intervals may be
required to achieve serum concentrations sufficient to treat Staphylococcus aurousor Pseudomonas
aeruginosa (Aggarwal 2004). Reported range: 10 to 60 mg/kg/day (Krcméry 1999; Schaad 1995; van den Oever
1998).
Dosing: Pediatric
Note: In pediatric patients, ciprofloxacin is not routinely first-line therapy, but after assessment of risks and benefits, can
be considered a reasonable alternative for some situations [eg, anthrax, resistance (cystic fibrosis)] or in situations
where the only alternative is parenteral therapy and ciprofloxacin offers an oral therapy option (Bradley 2011b).
Oral liquid products are available in two concentrations (ie, 50 mg/mL and 100 mg/mL); precautions should be
taken to verify product selection and avoid confusion between the different concentrations. Extended release
tablets and immediate release formulations are not interchangeable.
General dosing, susceptible infection (Red Book [AAP 2015]): Infants, Children, and Adolescents:
Mild to moderate infections: Oral, immediate release: 10 mg/kg/dose twice daily; maximum dose: 500
mg/dose
Severe infections:
Oral, immediate release: 15 to 20 mg/kg/dose twice daily; maximum dose: 750 mg/dose
IV: 10 mg/kg/dose every 8 to 12 hours; maximum dose: 400 mg/dose
Anthrax: Infants, Children, and Adolescents:
Cutaneous, without systemic involvement: AAP recommendations: Oral, immediate release: 15 mg/kg/dose
every 12 hours; maximum dose: 500 mg/dose. Duration: 7 to 10 days for naturally acquired
infection, up to 60 days for biological weapon-related event (AAP [Bradley 2014])
Inhalational (postexposure prophylaxis):
Oral, immediate release: 15 mg/kg/dose every 12 hours for 60 days; maximum dose: 500 mg/dose
IV: 10 mg/kg/dose every 12 hours for 60 days; maximum dose: 400 mg/dose; may substitute oral
antibiotics for IV antibiotics as soon as clinical condition improves
Systemic (including meningitis): AAP recommendations (Bradley 2014):
Initial treatment as part of combination therapy: IV: 10 mg/kg/dose every 8 hours; maximum dose:
400 mg/dose; continue until clinical criteria for stability are met
Oral step-down to complete a 60 day total course: Oral, immediate release: 15 mg/kg/dose twice
daily
Campylobacteriosis, HIV-exposed/-infected (HHS [adult] 2015): Duration of therapy: 7 to 10 days for

gastroenteritis, at least 14 days for bacteremia, 2 to 6 weeks for recurrent bacteremic disease
Oral, immediate release: Adolescents: 500 to 750 mg every 12 hours
IV: Adolescents: 400 mg every 12 hours
Catheter (peritoneal dialysis); exit-site or tunnel infection: Infant, Children, and Adolescents: Oral, immediate
release: 10 to 15 mg/kg/dose once daily; maximum dose: 500 mg/dose (Warady [ISPD 2012])
Chancroid: Adolescents: Oral, immediate release: 500 mg twice daily for 3 days (Red Book [AAP 2015])
Cystic fibrosis: Limited data available: Children and Adolescents:
Oral, immediate release: 20 mg/kg/dose every 12 hours; maximum dose: 1,000 mg/dose (Stockmann 2012)
IV: 10 mg/kg/dose every 8 hours; maximum dose: 400 mg/dose (Stockmann 2012)
Endocarditis, culture negative, empiric therapy: AHA guidelines (Baltimore 2015): Administer in combination
with other antibiotics: Children and Adolescents:
Oral, immediate release: 10 to 15 mg/kg/dose twice daily for 4 to 6 weeks; maximum dose: 750 mg/dose
IV: 10 to 15 mg/kg/dose twice daily for 4 to 6 weeks; maximum dose: 400 mg/dose
Infectious diarrhea: Limited data available:
Cholera: Infants, Children, and Adolescents: Oral, immediate release: 15 mg/kg/dose twice daily for 3 days;
maximum dose: 500 mg/dose (Red Book [AAP 2015]; WHO 2012). Alternately, 20 mg/kg/dose as a
single dose has been used (Red Book [AAP 2015]).
Shigellosis dysentery:
Non-HIV-exposed/-infected: Infants, Children, and Adolescents: Oral, immediate release: 15

mg/kg/dose twice daily for 3 days; maximum dose: 500 mg/dose (WHO 2005)
HIV-exposed-infected (HHS [adult] 2015): Adolescents: Duration of therapy: 7 to 10 days for

gastroenteritis, at least 14 days for bacteremia, up to 6 weeks for recurrent infection
Intra-abdominal infection, complicated: Infants, Children, and Adolescents: IV: 10 to 15 mg/kg/dose every 12
hours; maximum dose: 400 mg/dose (IDSA [Solomkin 2010])
Meningococcal invasive disease prophylaxis, high-risk contacts: Infants, Children, and Adolescents: Oral:
Immediate release: 20 mg/kg as a single dose, maximum dose 500 mg/dose (Red Book [AAP 2015])
Mycobacterium avium Complex, severe or disseminated disease, HIV-exposed/-infected (HHS [pediatric] 2013):
Infants and Children: Oral, immediate release: 10 to 15 mg/kg/dose twice daily in addition to other
antibiotics; maximum dose: 750 mg/dose
Plague:
Manufacturer's labeling: Infants, Children, and Adolescents:
Oral, immediate release: 15 mg/kg/dose every 8 to 12 hours for 10 to 21 days; maximum dose: 500
mg/dose
IV: 10 mg/kg/dose every 8 to 12 hours for 10 to 21 days; maximum dose: 400 mg/dose
Alternate dosing (CDC [plague] 2015): Children and Adolescents:
Treatment:
Initial treatment: IV: 15 mg/kg/dose every 12 hours; maximum dose: 400 mg/dose; continue
until 2 days after fever subsides, then may change to oral therapy
Oral step-down to complete a 10 to 14 day course: Oral, immediate release: 20 mg/kg/dose

twice daily; maximum dose: 500 mg/dose
Postexposure prophylaxis: Oral, immediate release: 20 mg/kg twice daily for 7 days; maximum dose:
500 mg/dose.
Pneumonia, community acquired (Haemophilus influenza): Infants >3 months and Children: IV: 15 mg/kg/dose
every 12 hours (IDSA/PIDS [Bradley 2011a])
Salmonellosis, HIV-exposed/-infected (HHS [adult] 2015): Duration of therapy: At least 7 to 14 days if CD4 > 200
cells/mm2, 2 to 6 weeks if CD4 <200 cells/mm2
Surgical prophylaxis: Children and Adolescents: IV: 10 mg/kg within 120 minutes prior to surgical incision;
maximum dose: 400 mg/dose (ASHP [Bratzler 2013])
Tularemia, mild disease: Limited data available: Infants, Children, and Adolescents:
Treatment or contained casualty situation: IV: 15 mg/kg/dose twice daily for at least 10 days; maximum
dose: 400 mg/dose (Dennis 2001; WHO 2007)
Prophylaxis, mass casualty situation: Oral, immediate release: 15 mg/kg/dose twice daily for 14 days;
maximum dose: 500 mg/dose (Dennis 2001)
Urinary tract infection:
Cystitis, acute uncomplicated: Adolescents ≥ 18 years: Oral, extended release: 500 mg every 24 hours for 3
days
Complicated (including pyelonephritis):
Oral, immediate release: Children and Adolescents: 10 to 20 mg/kg/dose every 12 hours for 10 to 21
days; maximum dose: 750 mg/dose
Oral, extended release: Adolescents ≥18 years: 1,000 mg every 24 hours for 7 to 14 days
IV: Children and Adolescents: 6 to 10 mg/kg/dose every 8 hours for 10 to 21 days; maximum dose:
400 mg/dose
Infants, Children, and Adolescents:
IV and Oral, immediate release: There are no dosage adjustments provided in the manufacturer's labeling;
however, the following guidelines have been used by some clinicians (Aronoff 2007):
GFR ≥30 mL/minute/1.73 m2: No dosage adjustment necessary
GFR 10 to 29 mL/minute/1.73m2: 10 to 15 mg/kg/dose every 18 hours
GFR <10 mL/minute/1.73m2: 10 to 15 mg/kg/dose every 24 hours
Hemodialysis/peritoneal dialysis (PD) (after dialysis on dialysis days): Minimally dialyzable (<10%): 10
to 15 mg/kg/dose every 24 hours
CRRT: 10 to 15 mg/kg/dose every 12 hours
Oral, extended release: Adolescents ≥18 years:
CrCl ≥30 mL/minute: No dosage adjustment necessary
CrCl <30 mL/minute: 500 mg every 24 hours
Hemodialysis/peritoneal dialysis (PD) (administer after dialysis on dialysis days): 500 mg every 24
hours
There are no dosage adjustments provided in manufacturer's labeling; use with caution in severe impairment.
Contraindications
Hypersensitivity to ciprofloxacin, any component of the formulation, or other quinolones; concurrent administration of
tizanidine
Canadian labeling: Additional contraindications (not in the US labeling): Concurrent administration of agomelatine
• Altered cardiac conduction: Fluoroquinolones may prolong QTc interval; avoid use in patients with a history of or
at risk for QTc prolongation, torsades de pointes, uncorrected electrolyte disorders (hypokalemia or
hypomagnesemia), cardiac disease (heart failure, myocardial infarction, bradycardia) or concurrent
administration of other medications known to prolong the QT interval (including Class Ia and Class III
antiarrhythmics, cisapride, erythromycin, antipsychotics, and tricyclic antidepressants).
• Aortic aneurysm and dissection: Fluoroquinolones have been associated with aortic aneurysm ruptures or
dissection within 2 months following use, particularly in elderly patients. Fluoroquinolones should not be
used in patients with a known history of aortic aneurysm or those at increased risk, including patients with
peripheral atherosclerotic vascular diseases, hypertension, genetic disorders involving blood vessel changes
(eg, Marfan syndrome, Ehlers-Danlos syndrome), and elderly patients, unless no other treatment options
are available. Longer treatment duration (eg, >14 days) may increase risk (Lee 2018).
• Crystalluria: Rarely, crystalluria has occurred; urine alkalinity may increase the risk. Ensure adequate hydration
during therapy.
• Glucose regulation: Fluoroquinolones have been associated with disturbances in glucose regulation, including
hyperglycemia and hypoglycemia. These events have occurred most often in patients receiving
concomitant oral hypoglycemic agents or insulin. Severe cases of hypoglycemia, including coma and death,
have been reported. Diabetic patients should be monitored closely for signs/symptoms of disordered
glucose regulation. Discontinue if a hypoglycemic reaction occurs and immediately initiate appropriate
therapy.
• Hepatotoxicity: Hepatocellular, cholestatic, or mixed liver injury has been reported, including hepatic necrosis,
life-threatening hepatic events, and fatalities. Acute liver injury can be rapid onset (range: 1 to 39 days) and
is often associated with hypersensitivity. The pattern of injury can be hepatocellular, cholestatic, or mixed.
Most fatalities occurred in patients >55 years of age. Discontinue immediately if signs/symptoms of
hepatitis (abdominal tenderness, dark urine, jaundice, pruritus) occur. Additionally, temporary increases in
transaminases or alkaline phosphatase, or cholestatic jaundice may occur (highest risk in patients with
previous liver damage).
• Hypersensitivity reactions: Severe hypersensitivity reactions, including anaphylaxis, have occurred with
fluoroquinolone therapy. The spectrum of these reactions can vary widely; reactions may present as typical
allergic symptoms (eg, itching, urticaria, rash, edema) after a single dose, or may manifest as severe
idiosyncratic dermatologic (eg, Stevens-Johnson, toxic epidermal necrolysis), vascular (eg, vasculitis),
pulmonary (eg, pneumonitis), renal (eg, nephritis), hepatic (eg, hepatitis, jaundice, hepatic failure or
necrosis), and/or hematologic (eg, anemia, cytopenias) events, usually after multiple doses. Prompt
discontinuation of drug should occur if skin rash or other symptoms arise.
• Photosensitivity/phototoxicity: Avoid excessive sunlight and take precautions to limit exposure (eg, loose fitting
clothing, sunscreen); may cause moderate-to-severe phototoxicity reactions which may appear as
exaggerated sunburn reactions. Discontinue use if phototoxicity occurs.
• Serious adverse reactions: [US Boxed Warning]: Fluoroquinolones are associated with disabling and
potentially irreversible serious adverse reactions that may occur together, including tendinitis and
tendon rupture, peripheral neuropathy, and CNS effects. Discontinue ciprofloxacin immediately and
avoid use of fluoroquinolones in patients who experience any of these serious adverse reactions. Patients
of any age or without preexisting risk factors have experienced these reactions; may occur within hours to
weeks after initiation.
- CNS effects: Fluoroquinolones have been associated with an increased risk of CNS effects, including
seizures, increased intracranial pressure (including pseudotumor cerebri), dizziness, and tremors.
Status epilepticus cases have been reported. Use with caution in patients with a history of seizures,
with known or suspected CNS disorder (severe cerebral arteriosclerosis, previous history of
convulsion, reduced cerebral blood flow, altered brain structure, or stroke), or with other risk factors
that may predispose to seizures or lower the seizure threshold (eg, certain drug therapy, renal
dysfunction). Discontinue if seizures occur and institute appropriate therapy.
- Peripheral neuropathy: Fluoroquinolones have been associated with an increased risk of peripheral
neuropathy; may occur soon after initiation of therapy and may be irreversible; discontinue
immediately if symptoms of sensory or sensorimotor neuropathy occur. Avoid use in patients who
have previously experienced peripheral neuropathy.
- Psychiatric reactions: Fluoroquinolones have been associated with an increased risk of psychiatric
reactions, including toxic psychosis, hallucinations, or paranoia; may also cause nervousness,
agitation, delirium, attention disturbances, insomnia, anxiety, nightmares, memory impairment,
confusion, depression, and suicidal thoughts or actions. Use with caution in patients with a history of
or risk factor for mental illness. Reactions may appear following the first dose; discontinue if reaction
occurs and institute appropriate therapy.
- Tendinitis/tendon rupture: Fluoroquinolones have been associated with an increased risk of tendonitis
and tendon rupture in all ages; risk may be increased with concurrent corticosteroids, solid organ
transplant recipients, and in patients >60 years of age, but has also occurred in patients without
these risk factors. Rupture of the Achilles tendon has been reported most frequently; but other
tendon sites (eg, rotator cuff, biceps, hand) have also been reported. Inflammation and rupture may
occur bilaterally. Cases have been reported within hours or days of initiation, and up to several
months after discontinuation of therapy. Strenuous physical activity, renal failure, and previous
tendon disorders may be independent risk factor for tendon rupture. Discontinue at first sign of
tendon pain, swelling, inflammation or rupture. Avoid use in patients with a history of tendon
disorders or who have experienced tendinitis or tendon rupture.
treatment.
• Myasthenia gravis: [US Boxed Warning]: May exacerbate muscle weakness related to myasthenia gravis; avoid
use in patients with a known history of myasthenia gravis. Cases of severe exacerbations, including the
need for ventilatory support and deaths have been reported.
• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment required. May
increase risk of tendon rupture.
• Rheumatoid arthritis: Use with caution in patients with rheumatoid arthritis; may increase risk of tendon
rupture.
• Syphilis: Since ciprofloxacin is ineffective in the treatment of syphilis and may mask symptoms, all patients
should be tested for syphilis at the time of gonorrheal diagnosis and 3 months later.

• Elderly: Adverse effects (eg, tendon rupture, QT changes) may be increased in elderly patients.
• Pediatric: Adverse effects, including those related to joints and/or surrounding tissues, are increased in pediatric
patients and therefore, ciprofloxacin should not be considered as drug of choice in children (exception is
anthrax treatment).
• Appropriate use: [US Boxed Warning]: Reserve use of ciprofloxacin for treatment of acute bacterial sinusitis,
acute bacterial exacerbation of chronic bronchitis, or acute uncomplicated cystitis for patients who have
no alternative treatment options because of the risk of disabling and potentially serious adverse
reactions (eg, tendinitis and tendon rupture, peripheral neuropathy, CNS effects).
Increased osteochondrosis in immature rats and dogs was observed with ciprofloxacin and fluoroquinolones have
caused arthropathy with erosions of the cartilage in weight-bearing joints of immature animals. In an international
safety data analysis of ciprofloxacin in approximately 700 pediatric patients (1 to 17 years), the follow-up arthropathy
rate at 6 weeks and cumulative arthropathy rate at 1 year were higher in ciprofloxacin treatment group than
comparative controls (6 weeks: 9.3% vs 6%; 1 year: 13.7% to 9.5%). In pediatric patients, fluoroquinolones are not
routinely first-line therapy, but after assessment of risks and benefits, can be considered a reasonable alternative for
situations where no safe and effective substitute is available (eg, resistance [anthrax, common CF pathogens, multidrug
resistant tuberculosis]) or in situations where the only alternative is parenteral therapy and ciprofloxacin offers an oral
therapy option (Bradley 2011b).
Oral: Reconstitute powder for oral suspension with appropriate amount of water as specified on the bottle. Shake
Parenteral: May be diluted with NS, D5W, SWFI, D10W, D51/4NS, D51/2NS, LR to a final concentration not to exceed 2
mg/mL
Oral: May administer with food to minimize GI upset; divalent and trivalent cations [dairy foods (milk, yogurt) and
mineral supplements (eg, iron, zinc, calcium) or calcium-fortified juices] decrease ciprofloxacin absorption; usual
dietary calcium intake (including meals which include dairy products) has not been shown to interfere with
ciprofloxacin absorption (per manufacturer). Administer immediate release ciprofloxacin and Cipro XR at least 2
hours before or 6 hours after any of these products.
Oral suspension: Shake vigorously prior to each dose. Should not be administered through feeding tubes
(suspension is oil-based and adheres to the feeding tube). Patients should avoid chewing on the
microcapsules.
Tablets:
Immediate release: Administering 2 hours after meals is preferable.
Extended release: Do not crush, split, or chew. May be administered with meals containing dairy products
(calcium content <800 mg), but not with dairy products alone.
Nasogastric/orogastric tube: Crush immediate release tablet and mix with water. Flush feeding tube before and after
administration. Hold tube feedings at least 1 hour before and 2 hours after administration.
Parenteral: Administer by slow IV infusion over 60 minutes to reduce the risk of venous irritation (burning, pain,
erythema, and swelling)
Food: May be taken with meals that contain dairy products (eg, milk, yogurt) or calcium-fortified juices, but not with
these products alone; separate administration of Cipro XR and calcium >800 mg by at least 2 hours.
Caffeine: Patients consuming regular large quantities of caffeinated beverages may need to restrict caffeine intake if
excessive cardiac or CNS stimulation occurs.
Monitor renal, hepatic, and hematopoietic function periodically; monitor number and type of stools/day for diarrhea
Reference Range
Therapeutic: 2.6 to 3 mcg/mL
Drug Interactions
Antacids: May decrease the absorption of Quinolones. Of concern only with oral administration of quinolones.
Management: Avoid concurrent administration of quinolones and antacids to minimize the impact of this
interaction. Recommendations for optimal dose separation vary by specific quinolone. Exceptions: Sodium
Bicarbonate. Risk D: Consider therapy modification
Monitor therapy
Blood Glucose Lowering Agents: Quinolones may enhance the hypoglycemic effect of Blood Glucose Lowering Agents.
Quinolones may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is
being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Risk C: Monitor therapy
Caffeine: Ciprofloxacin (Systemic) may increase the serum concentration of Caffeine. Risk C: Monitor therapy
Calcium Salts: May decrease the absorption of Quinolones. Of concern only with oral administration of both
agents.Exceptions: Calcium Chloride. Risk D: Consider therapy modification
CarBAMazepine: Ciprofloxacin (Systemic) may increase the serum concentration of CarBAMazepine. Risk C: Monitor
therapy
Corticosteroids (Systemic): May enhance the adverse/toxic effect of Quinolones. Specifically, the risk of tendonitis and
tendon rupture may be increased. Risk C: Monitor therapy
Fosphenytoin: May enhance the QTc-prolonging effect of Ciprofloxacin (Systemic). Ciprofloxacin (Systemic) may diminish
the therapeutic effect of Fosphenytoin. Ciprofloxacin (Systemic) may decrease the serum concentration of
Fosphenytoin. Risk C: Monitor therapy
Haloperidol: QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of
Haloperidol. Risk C: Monitor therapy
Iron Salts: May decrease the serum concentration of Quinolones. Management: Give oral quinolones at least several
hours before (4 h for moxi- and sparfloxacin, 2 h for others) or after (8 h for moxi-, 6 h for cipro/dela-, 4 h for
lome-, 3 h for gemi-, and 2 h for levo-, nor-, oflox-, pefloxacin, or nalidixic acid) oral iron salts Exceptions: Ferric
Carboxymaltose; Ferric Gluconate; Ferric Hydroxide Polymaltose Complex; Ferric Pyrophosphate Citrate;
Ferumoxytol; Iron Dextran Complex; Iron Isomaltoside; Iron Sucrose. Risk D: Consider therapy modification
therapy
Magnesium Salts: May decrease the serum concentration of Quinolones. Management: Administer oral quinolones
several hours before (4 h for moxi/pe/spar-, 2 h for others) or after (8 h for moxi-, 6 h for cipro/dela-, 4 h for
lome/pe-, 3 h for gemi-, and 2 h for levo-, nor-, or ofloxacin or nalidixic acid) oral magnesium salts. Risk D:
Methotrexate: Ciprofloxacin (Systemic) may increase the serum concentration of Methotrexate. Risk C: Monitor therapy
Multivitamins/Minerals (with ADEK, Folate, Iron): May decrease the serum concentration of Quinolones. Specifically,
polyvalent cations in multivitamin products may decrease the absorption of orally administered quinolone
antibiotics. Management: Interactions can be minimized by administering the oral quinolone at least 2 hours
before, or 6 hours after, the dose of a multivitamin that contains polyvalent cations (i.e., calcium, iron,
magnesium, selenium, zinc). Risk D: Consider therapy modification
Multivitamins/Minerals (with AE, No Iron): May decrease the serum concentration of Quinolones. Specifically, minerals
in the multivitamin/mineral product may impair absorption of quinolone antibiotics. Management: Interactions
can be minimized by administering the oral quinolone at least 2 hours before, or 6 hours after, the dose of a
multivitamin that contains polyvalent cations (i.e., calcium, iron, magnesium, selenium, zinc). Risk D: Consider
Mycophenolate: Quinolones may decrease the serum concentration of Mycophenolate. Specifically, quinolones may
decrease concentrations of the active metabolite of mycophenolate. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May enhance the neuroexcitatory and/or seizure-potentiating effect of
Quinolones. Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Quinolones.Risk C:
Monitor therapy
Phenytoin: Ciprofloxacin (Systemic) may diminish the therapeutic effect of Phenytoin. Ciprofloxacin (Systemic) may
decrease the serum concentration of Phenytoin. Risk C: Monitor therapy
Probenecid: May decrease the excretion of Quinolones. Specifically, probenecid may decreased the renal excretion of
quinolone antibiotics. Probenecid may increase the serum concentration of Quinolones. Risk C: Monitor therapy
QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-
prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and
ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc
prolongation may be at even higher risk.Risk C: Monitor therapy
Spironolactone: May enhance the arrhythmogenic effect of Ciprofloxacin (Systemic). Risk C: Monitor therapy
Thyroid Products: Ciprofloxacin (Systemic) may decrease the serum concentration of Thyroid Products. Risk C: Monitor
therapy
Vitamin K Antagonists (eg, warfarin): Quinolones may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C:
Monitor therapy
Zinc Salts: May decrease the serum concentration of Quinolones. Management: Give oral quinolones at least several
hours before (4 h for moxi- and sparfloxacin, 2 h for others) or after (8 h for moxi-, 6 h for cipro/dela-, 4 h for
lome-, 3 h for gemi-, and 2 h for levo-, nor-, pe- or ofloxacin or nalidixic acid) oral zinc salts. Exceptions: Zinc
Chloride. Risk D: Consider therapy modification
Food Interactions
Food decreases rate, but not extent, of absorption. Ciprofloxacin may increase serum caffeine levels if taken
concurrently. Rarely, crystalluria may occur. Enteral feedings may decrease plasma concentrations of ciprofloxacin
probably by >30% inhibition of absorption. Management: May administer with most foods to minimize GI upset. If
unable to avoid the following foods, administer ciprofloxacin at least 2 hours before or 6 hours after dairy products or
calcium-fortified juices alone or in a meal containing >800 mg calcium. Restrict caffeine intake if excessive cardiac or CNS
stimulation occurs. Ensure adequate hydration during therapy. Ciprofloxacin should not be administered with enteral
feedings. The feeding would need to be discontinued for 1 to 2 hours prior to and after ciprofloxacin administration.
Nasogastric administration produces a greater loss of ciprofloxacin bioavailability than does nasoduodenal
administration.
Test Interactions
Some quinolones may produce a false-positive urine screening result for opioids using commercially-available
immunoassay kits. This has been demonstrated most consistently for levofloxacin and ofloxacin, but other quinolones
have shown cross-reactivity in certain assay kits. Confirmation of positive opioid screens by more specific methods
should be considered.

Absorption: Oral: Well-absorbed; 500 mg orally every 12 hours produces an equivalent AUC to that produced by 400 mg
IV over 60 minutes every 12 hours
Distribution: Vd: 2.1 to 2.7 L/kg; tissue concentrations often exceed serum concentrations especially in kidneys,
gallbladder, liver, lungs, gynecological tissue, and prostatic tissue; CSF concentrations: 10% of serum
concentrations (noninflamed meninges), 14% to 37% (inflamed meninges)
Metabolism: Partially hepatic; forms 4 metabolites (limited activity)
Bioavailability: Oral: 50% to 85%; younger CF patients have a lower bioavailability of 68% vs CF patients >13 years of age
with bioavailability of 95%
Half-life elimination: Children: 4 to 5 hours; Adults: Normal renal function: 4 to 6 hours
Time to peak: Oral:
Immediate release tablet: 0.5 to 2 hours
Extended release tablet: Cipro XR: 1 to 2.5 hours
Excretion: Urine (35% to 70% as unchanged drug); feces (15% to 35%; <1% as unchanged drug)
Clearance: After IV: CF children: 0.84 L/hour/kg; Adults: 0.5 to 0.6 L/hour/kg
Renal function impairment: The half-life is prolonged.
Geriatric: Cmax increased 16% to 40%, AUC increased approximately 20% to 30%, and half-life increased approximately
20%.
Adverse Reactions
Central nervous system: Headache (IV administration), neurological signs and symptoms (children; includes dizziness,
insomnia, nervousness, somnolence), restlessness (IV administration)
Dermatologic: Skin rash (more common in children)
Gastrointestinal: Abdominal pain (more common in children), diarrhea (more common in children), dyspepsia (more
common in children), nausea, vomiting (more common in children)
Hepatic: Increased serum ALT, increased serum AST (adults)
Local: Injection site reaction (IV administration)
Respiratory: Rhinitis (children)

Miscellaneous: Fever (more common in children)
Rare but important or life-threatening: Abnormal gait, acute generalized exanthematous pustulosis, acute gout attack,
acute renal failure, ageusia, agitation, agranulocytosis, albuminuria, anaphylactic shock, anaphylaxis, anemia,
angina pectoris, angioedema, anorexia, anosmia, anxiety, arthralgia, ataxia, atrial flutter, bone marrow depression
(life-threatening), bronchospasm, candidiasis, candiduria, cardiorespiratory arrest, casts in urine, cerebral
thrombosis, chills, cholestatic jaundice, chromatopsia, Clostridium difficile-associated diarrhea, confusion,
constipation, crystalluria (particularly in alkaline urine), decreased hematocrit, decreased hemoglobin, decreased
prothrombin time, delirium, depersonalization, depression (including self-injurious behavior), dizziness,
drowsiness, dyspepsia (adults), dysphagia, dysphasia, dyspnea, edema, eosinophilia, erythema multiforme,
erythema nodosum, exacerbation of myasthenia gravis, exfoliative dermatitis, fixed drug eruption, flatulence,
gastrointestinal hemorrhage, hallucination, headache (oral), hematuria, hemolytic anemia, hepatic failure, hepatic
necrosis, hepatotoxicity (idiosyncratic) (Chalasani, 2014), hyperesthesia, hyperglycemia, hyperpigmentation,
hypersensitivity reaction, hypertension, hypertonia, hypoglycemia, hypotension, increased blood urea nitrogen,
increased creatine phosphokinase, increased INR (in patients treated with vitamin K antagonists), increased
intracranial pressure, increased lactate dehydrogenase, increased serum alkaline phosphatase, increased serum
bilirubin, increased serum cholesterol, increased serum creatinine, increased serum glucose, increased serum
lipase, increased serum triglycerides, increased uric acid, insomnia, interstitial nephritis, intestinal perforation,
irritability, jaundice, laryngeal edema, lethargy, lymphadenopathy, malaise, manic behavior, mastalgia,
methemoglobinemia, migraine, myalgia, myocardial infarction, myoclonus, nephritis, nephrolithiasis, nightmares,
nystagmus, orthostatic hypotension, palpitations, pancreatitis, pancytopenia (life-threatening), paranoia,
paresthesia, peripheral neuropathy, petechia, phobia, phototoxicity, pneumonitis, polyneuropathy, prolonged
prothrombin time (in patients treated with vitamin K antagonists), pseudotumor cerebri, pulmonary edema,
rupture of tendon, seizure (including grand mal), serum sickness-like reaction, skin photosensitivity, status
epilepticus, Stevens-Johnson syndrome, suicidal ideation, suicidal tendencies, syncope, tachycardia, tendonitis,
thrombocythemia, thrombocytopenia, thrombophlebitis, tinnitus, torsades de pointes, toxic epidermal necrolysis,
toxic psychosis, tremor, twitching, unresponsive to stimuli, urethral bleeding, vaginitis, vasculitis, ventricular
arrhythmia, ventricular ectopy, visual disturbance, vulvovaginal candidiasis, weakness
CLINDAMICINA
No adjustment required. Not dialyzable (0% to 5%).
No adjustment required. Use caution with severe hepatic impairment.
Contraindications
Hypersensitivity to clindamycin, lincomycin, or any component of the formulation.
Canadian labeling: Additional contraindications (not in US labeling): Oral clindamycin: Infants <30 days of age.
• Colitis: [US Boxed Warning]: Can cause severe and possibly fatal colitis. Should be reserved for serious infections
where less toxic antimicrobial agents are inappropriate. It should not be used in patients with nonbacterial infections
such as most upper respiratory tract infections. Hypertoxin-producing strains of C. difficile cause increased morbidity
and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. C. difficile-
associated diarrhea (CDAD) must be considered in all patients who present with diarrhea following antibiotic use. CDAD
has been observed >2 months postantibiotic treatment. If CDAD is suspected or confirmed, ongoing antibiotic use not
directed against C. difficile may need to be discontinued. Institute appropriate fluid and electrolyte management,
protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation as clinically indicated.
• Hypersensitivity: Severe hypersensitivity reactions, including severe skin reactions (eg, drug reaction with eosinophilia
and systemic symptoms [DRESS], Stevens-Johnson syndrome [SJS], toxic epidermal necrolysis [TEN]), some fatal, and
anaphylactic reactions, including anaphylactic shock, have been reported. Permanently discontinue treatment and
institute appropriate therapy if these reactions occur.
• Superinfection: Use may result in overgrowth of nonsusceptible organisms, particularly yeast. Should superinfection
occur, appropriate measures should be taken as indicated by the clinical situation.
• GI disease: Use with caution in patients with a history of GI disease, particularly colitis.
• Hepatic impairment: Use with caution in patients with moderate to severe liver disease, however, when administered
at every-8-hour intervals, drug accumulation is rare. Monitor hepatic enzymes periodically as dosage adjustments may
be necessary in patients with severe liver disease.
information.
• Atopic patients: Use with caution in atopic patients.
• Elderly: A subgroup of older patients with associated severe illness may tolerate diarrhea less well. Monitor carefully
for changes in bowel frequency.
• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99
mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping
syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including
convulsions, intracranial hemorrhage), hypotension and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some
data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms
containing benzyl alcohol with caution in neonates. See manufacturer’s labeling.
• Tartrazine: Some products may contain tartrazine (FD&C yellow no. 5), which may cause allergic reactions in certain
individuals. Allergy is frequently seen in patients who also have an aspirin hypersensitivity.
• Administration (IV): Do not inject IV undiluted as a bolus. Product should be diluted in compatible fluid and infused
over 10 to 60 minutes.
• Appropriate use: Not appropriate for use in the treatment of meningitis due to inadequate penetration into the CSF.
Oral: Reconstitute powder for oral solution with appropriate amount of water as specified on the bottle. Shake
Parenteral: IV: Dilute with a compatible diluent (eg, D5W, NS) to a final concentration not to exceed 18 mg/mL
Oral: Capsule should be taken with a full glass of water to avoid esophageal irritation; shake oral solution well before
use; may administer with or without meals
Parenteral:
IM: Administer undiluted deep IM; rotate sites. Do not exceed 600 mg in a single injection.
IV: Infuse over at least 10 to 60 minutes, at a rate not to exceed 30 mg/minute; hypotension and cardiopulmonary arrest
have been reported following rapid IV administration
Drug Interactions
Neuromuscular-Blocking Agents: Lincosamide Antibiotics may enhance the neuromuscular-blocking effect of
Neuromuscular-Blocking Agents. Risk C: Monitor therapy
Adverse Reactions
Cardiovascular: Hypotension (rare; IV administration), thrombophlebitis (IV)
Central nervous system: Metallic taste (IV)
Dermatologic: Acute generalized exanthematous pustulosis, erythema multiforme (rare), exfoliative dermatitis (rare),
maculopapular rash, pruritus, skin rash, Stevens-Johnson syndrome (rare), toxic epidermal necrolysis, urticaria,
vesiculobullous dermatitis
Gastrointestinal: Abdominal pain, antibiotic-associated colitis, Clostridium difficile associated diarrhea, diarrhea,
esophageal ulcer, esophagitis, nausea, pseudomembranous colitis, unpleasant taste (IV), vomiting
Genitourinary: Azotemia, oliguria, proteinuria, vaginitis
Hematologic & oncologic: Agranulocytosis, eosinophilia (transient), neutropenia (transient), thrombocytopenia
Hepatic: Abnormal hepatic function tests, jaundice
Hypersensitivity: Anaphylactic shock, anaphylactoid reaction (rare), anaphylaxis, angioedema, hypersensitivity reaction
Immunologic: DRESS syndrome
Local: Abscess at injection site (IM), induration at injection site (IM), irritation at injection site (IM), pain at injection site
(IM)
Neuromuscular & skeletal: Polyarthritis (rare)
Renal: Renal insufficiency (rare)
COLISTIMETATO (COLISTINA)
Dosing: Pediatric
Note: Doses should be based on ideal body weight in obese patients; dosage primarily expressed in terms of colistin
base activity (CBA). CBA 1 mg is defined to be equivalent tocolistimethate sodium (CMS) 30,000 units which is equivalent
to ~2.4 mg CMS (EMA 2014; Falagas 2006; Kassamali 2013; Nation 2017).
General dosing, susceptible infection: Infants, Children, and Adolescents: Colistin base: IM, IV: 2.5 to 5 mg CBA/kg/day
divided every 6 to 12 hours
CNS infection (VP-shunt infection, ventriculitis, meningitis), multidrug resistant: Limited data available; variable doses
reported; optimal dose not defined.
Infants and Children: Very limited data available: Intraventricular/Intrathecal: Colistin base: Reported range: 1 to 4.2 mg
CBA/dose once daily in combination with systemic antibiotics (Dalgic 2009; IDSA [Tunkel 2017]; Ng 2006; Ozdemir 2010).
Doses should be individualized based on culture/sensitivity, MIC, and tolerability while ensuring that patient size and CSF
volume are considered. In one case report, a 4-year old with multidrug resistant Acinetobacter baumanniireceived an
intraventricular dose of 1 mg CBA on Day 1, followed by 2 mg CBA once daily for 2 days, then 4 mg CBA once daily; after
13 days, a dose reduction to 2 mg CBA once daily was necessary due to CSF leukocytosis (Ng 2006). A similar protocol
was described in a 2-month old with multidrug resistant Acinetobacter baumannii; the initial dose on Day 1 was 1 mg
CBA followed by 2 mg CBA once daily for 2 days, then 4 mg CBA once daily; due to failure to sterilize the CSF, the dose
was slowly titrated up to 10 mg CBA/day for a total of 20 days (Dalgic 2009). In a case report of a 3-year old with
multidrug resistant Acinetobacter baumannii, intrathecal colistin was administered without titration at a dose of 4.2 mg
CBA/day (Ozdemir 2010).
Adolescents: Very limited data available: Intraventricular/Intrathecal: Colistin base: 4.2 mg CBA/day (equivalent to 10
mg CMS/day) (IDSA [Tunkel 2017]; Yagmur 2006); Note: Dose in clinical reports in adults has ranged from 0.7 to 8.3 mg
CBA/day in 1 or 2 divided doses (administered with concomitant systemic antimicrobial therapy) (Benifla 2004; Falagas
2007; Imberti 2012; Katragkou 2005)
Cystic fibrosis, pulmonary infection: Limited data available: Children ≥5 years and Adolescents: Colistin base: IV: Usual
reported range: 3 to 5 mg CBA/kg/day divided every 8 hours; maximum dose: 100 mg CBA/dose (Bosso 1991; Reed
2001; Young 2013); doses >5 mg CBA/kg/day (up to 8 mg CBA/kg/day) may be required in some situations; however,
higher doses are associated with more severe toxicity (Bosso 1991; Reed 2001).
Pulmonary infection: Limited data available: Infants, Children, and Adolescents: Colistin base: Inhalation: Usual dose: 75
to 150 mg CBA in 3 mL of NS (4 mL total volume) via nebulizer twice daily is most frequently reported in clinical practice;
reported range: 30 to 150 mg CBA/dose (Le 2010; Tramper-Stranders 2010)
Dosing adjustment for toxicity: Infants, Children, and Adolescents: Based on experience with other aminoglycosides, the
following should be considered:
CNS toxicity: Dose reduction may reduce neurologic symptoms.
Nephrotoxicity: Withhold treatment if signs of renal impairment occur during treatment.
There are no pediatric specific recommendations in the manufacturer’s labeling; in adult patients, dosage adjustment is
suggested.
There are no dosage adjustments provided in the manufacturer’s labeling.
Parenteral:
IV or IM use: Reconstitute vial containing 150 mg of colistin base activity with 2 mL of SWFI resulting in a concentration
of 75 mg colistin base/mL; swirl gently to avoid frothing. May further dilute in D5W or NS for IV infusion.
Continuous IV infusion: The final concentration for continuous infusion should be based on the patient's fluid needs;
infusion should be completed within 24 hours of preparation.
Nebulized inhalation: Reconstitute vial containing 150 mg of colistin base activity with 2 mL SWFI, resulting in a
concentration of 75 mg colistin base activity/mL; further dilute dose to a total volume of 4 mL in NS (Le 2010; Tramper
2010). Storing for >24 hours may increase the risk for potential lung toxicity; preparation immediately prior to
administration is recommended (FDA 2007; Le 2010; Wallace 2008).
Intrathecal/Intraventricular: Very limited data available; case reports in infants and children describe mixing the dose
with 1 to 2 mL of preservative-free NS (Dalgic 2009; Ng 2006)
Parenteral:
IM: Administer deep into a large muscle mass (eg, gluteal muscle or lateral part of the thigh).
IV push: Administer over 3 to 5 minutes.
Intermittent IV infusion: Administer over 30 minutes.
Continuous IV infusion: Initially, one-half of the total daily dose is administered by direct IV injection over 3 to 5 minutes
followed 1 to 2 hours later by the remaining one-half of the total daily dose diluted in a compatible IV solution infused
over 22 to 23 hours. Infusion should be completed within 24 hours of preparation.
Inhalation: Administer solution via nebulizer promptly following preparation of solution to decrease possibility of high
concentrations of colistin from forming which may lead to potentially life-threatening lung toxicity. Consider use of a
bronchodilator (eg, albuterol) within 15 minutes prior to administration (Le 2010).
Note: A case report of fatal lung toxicity implicated in vitro colistin formation from an inhalation solution as a potential
etiology, but data regarding the concentration, formulation, and storage of the inhaled colistin administered to the
patient were not reported (FDA 2007; McCoy 2007; Wallace 2008). An acceptable limit of in vitro colistin formation to
prevent potential toxicity is unknown. Limited stability data are available regarding the storage of colistin solution for
inhaled administration (Healan 2012; Wallace 2008). Storing for >24 hours may increase the risk for potential lung
toxicity; preparation immediately prior to administration is recommended (FDA 2007; Le 2010; Wallace 2008).
Intraventricular/Intrathecal: Administer only preservative-free solutions via intrathecal/intraventricular routes.
Administer promptly after preparation. Discard unused portion of vial. When administering via a ventricular drain,
experts recommend the drain be clamped for 15 to 60 minutes to allow equilibration of colistin with CSF prior to
opening the drain (Tunkel [IDSA 2017).
CBC with differential, renal function tests, urine output; number and type of stools/day for diarrhea; for inhalation
therapy: Pre- and post-treatment spirometry; signs of bronchospasm
Drug Interactions
Aminoglycosides: May enhance the nephrotoxic effect of Colistimethate. Aminoglycosides may enhance the
neuromuscular-blocking effect of Colistimethate. Risk D: Consider therapy modification
Amphotericin B: May enhance the nephrotoxic effect of Colistimethate. Risk D: Consider therapy modification
Bacitracin (Systemic): Colistimethate may enhance the nephrotoxic effect of Bacitracin (Systemic). Risk X: Avoid
combination
BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
Monitor therapy
Capreomycin: May enhance the neuromuscular-blocking effect of Colistimethate. Risk C: Monitor therapy
Cefazedone: May enhance the nephrotoxic effect of Colistimethate. Risk C: Monitor therapy
Cephalothin: May enhance the nephrotoxic effect of Colistimethate. Risk C: Monitor therapy
therapy
Mecamylamine: Colistimethate may enhance the neuromuscular-blocking effect of Mecamylamine. Risk X: Avoid
combination
Methoxyflurane: Colistimethate may enhance the nephrotoxic effect of Methoxyflurane. Risk X: Avoid combination
Neuromuscular-Blocking Agents: Colistimethate may enhance the neuromuscular-blocking effect of Neuromuscular-
Blocking Agents. Risk D: Consider therapy modification
Polymyxin B: May enhance the neuromuscular-blocking effect of Colistimethate. Risk C: Monitor therapy
Vancomycin: May enhance the nephrotoxic effect of Colistimethate. Risk D: Consider therapy modification
Adverse Reactions
Central nervous system: Dizziness, neurotoxicity (higher incidence with high-dose IV use in cystic fibrosis [Bosso 1991;
Koch-Weser 1970]), oral paresthesia, paresthesia, peripheral paresthesia, seizures, slurred speech, vertigo
Dermatologic: Pruritus, skin rash, urticaria
Gastrointestinal: Clostridium difficile associated diarrhea, gastric distress
Genitourinary: Decreased urine output, nephrotoxicity (Dalfino 2012; Oliveira 2009)
Renal: Acute renal failure (Akajagbor 2013; Deryke 2010), decreased creatinine clearance, increased blood urea
nitrogen, increased serum creatinine
Respiratory: Apnea, respiratory distress
DEXAMETASONA
Dosing: Neonatal
Airway edema or extubation: Limited data available: IV: 0.25 mg/kg/dose given ~4 hours prior to scheduled extubation
then every 8 hours for a total of 3 doses (Couser 1992); others have used 0.5 mg/kg/dose every 8 hours for 3
doses with last dose administered 1 hour prior to scheduled extubation (Davis 2001); range: 0.25 to 0.5
mg/kg/dose for 1 to 3 doses; maximum daily dose: 1.5 mg/kg/day. Note: A longer duration of therapy may be
needed with more severe cases. A recent meta-analysis concluded that future neonatal clinical trials should study
a multiple dose strategy with initiation of dexamethasone at least 12 hours before extubation (Khemani 2009).
Bronchopulmonary dysplasia, facilitation of ventilator wean: Limited data available: PNA ≥7 days: Oral, IV: Initial: 0.15
mg/kg/day in divided doses every 12 hours for 3 days, followed by a taper of: 0.1 mg/kg/day for 3 days, then 0.05
mg/kg/day for 2 days, and 0.02 mg/kg/day for 2 days for a total dexamethasone dose of 0.89 mg/kg given over 10
days; tapering doses were administered in divided doses every 12 hours (Doyle 2006). Note: Multiple regimens
have been described. Optimal regimen has not been defined. High doses (~0.5 mg/kg/day) do not confer
additional benefit over lower doses, are associated with higher incidence of adverse effects (including adverse
neurodevelopmental outcomes), and are not recommended for use (Watterberg 2010). However, a meta-analysis
reported total cumulative doses >4 mg/kg reduced the relative risk for the combined outcome, mortality, or
bronchopulmonary dysplasia (Onland 2009).
Dosing: Pediatric
Acute mountain sickness (AMS) (moderate)/high altitude cerebral edema (HACE); treatment: Limited data
available: Infants, Children, and Adolescents: Oral, IM, IV: 0.15 mg/kg/dose every 6 hours; maximum dose:
4 mg/dose; consider using for high altitude pulmonary edema because of associated HACE with this
condition (Luks 2010; Pollard 2001)
Airway edema or extubation: Limited data available: Infants, Children, and Adolescents: Oral, IM, IV: 0.5
mg/kg/dose (maximum dose: 10 mg/dose) administered 6 to 12 hours prior to extubation then every 6
hours for 6 doses (total dexamethasone dose: 3 mg/kg) (Anene 1996; Khemani 2009; Tellez 1991)
Anti-inflammatory: Infants, Children, and Adolescents: Oral, IM, IV: Initial dose range: 0.02 to 0.3
mg/kg/day or 0.6 to 9 mg/m2/day in divided doses every 6 to 12 hours; dose depends upon condition being
treated and response of patient; dosage for infants and children should be based on disease severity and
patient response; usual adult daily dose range: 0.75 to 9 mg/day
Asthma exacerbation: Limited data available: Infants, Children, and Adolescents: Oral, IM, IV: 0.6 mg/kg once
daily as a single dose or once daily for 2 days; maximum dose: 16 mg/dose (AAP [Hegenbarth 2008];
Keeney 2014; Qureshi 2001); single dose regimens as low as 0.3 mg/kg/dose and as high as 1.7 mg/kg/dose
have also been reported (Keeney 2014; Qureshi 2001; Shefrin 2009). Note: Duration >2 days is not
recommended due to increased risk of metabolic effects (GINA 2014).
Bacterial meningitis (H. influenzae type b): Limited data available: Infants >6 weeks and Children: IV: 0.15
mg/kg/dose every 6 hours for the first 2 to 4 days of antibiotic treatment; start dexamethasone 10 to 20
minutes before or with the first dose of antibiotic; if antibiotics have already been administered,
dexamethasone use has not been shown to improve patient outcome and is not recommended (IDSA
[Tunkel 2004]). Note: For pneumococcal meningitis, data has not shown clear benefit from dexamethasone
administration; risk and benefits should be considered prior to use (Red Book [AAP 2012]).
Cerebral edema: Infants, Children, and Adolescents: Oral, IM, IV: Loading dose: 1 to 2 mg/kg/dose as a single
dose; maintenance: 1 to 1.5 mg/kg/day in divided doses every 4 to 6 hours; maximum daily dose: 16
mg/day (Kliegman 2007)
Chemotherapy-induced nausea and vomiting, prevention: Refer to individual protocols and emetogenic
potential: Infants, Children, and Adolescents:
POGO recommendations (Dupuis 2013): Note: Reduce dose by 50% if administered concomitantly with
aprepitant:
Highly/severely emetogenic chemotherapy: Oral, IV: 6 mg/m2/dose every 6 hours
Moderately emetogenic chemotherapy: Oral, IV:
BSA ≤0.6 m2: 2 mg every 12 hours
BSA >0.6 m2: 4 mg every 12 hours

Alternate dosing: Highly/severely emetogenic chemotherapy: IV: Usual: 10 mg/m2/dose once daily on days
of chemotherapy; some patients may require every 12-hour dosing; usual range: 8 to 14
mg/m2/dose (Holdsworth 2006; Jordan 2010; Phillips 2010); others have used: Initial: 10
mg/m2/dose prior to chemotherapy (maximum dose: 20 mg) then 5 mg/m2/dose every 6 hours
(Kliegman 2007)
Congenital adrenal hyperplasia: Adolescents (fully grown): Oral: 0.25 to 0.5 mg once daily; use of a liquid dosage
form may be preferable to allow for better dose titration (AAP 2010; Speiser 2010). Note: For younger
patients who are still growing, hydrocortisone or fludrocortisone are preferred.
Croup (laryngotracheobronchitis): Limited data available; dosing regimens variable: Infants and Children: Oral,
IM, IV: 0.6 mg/kg once; reported maximum dose highly variable; usual maximum dose: 16 mg/dose (AAP
[Hegenbarth 2008]); in trials, maximum doses of 10 to 20 mg/dose have been reported with similar efficacy
findings for mild to moderate croup. The majority of reported experience in infants are those ≥3 months of
age; data available in <3 months of age is very limited (AAP [Hegenbarth 2008]; Bjornson 2004; Cruz 1995;
Petrocheilou 2014; Russell 2011). In one evaluation of 22 children >2 years of age, a maximum dose of 12
mg/dose (at 0.6 mg/kg/dose) did not decrease endogenous glucocorticoid levels (Gill 2017). A single oral
dose of 0.15 mg/kg has also been shown effective in infants ≥3 months and children with mild to moderate
croup (Russell 2004; Sparrow 2006).
Physiologic replacement: Infants, Children, and Adolescents: Oral, IM, IV: 0.03 to 0.15 mg/kg/day in divided doses
every 6 to 12 hours (Kliegman 2007) or Initial: 0.2 to 0.25 mg/m2/day administered once daily; some
patients may require 0.3 mg/m2/day(Gupta 2008)
Infants, Children, and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling; use with
caution. Hemodialysis or peritoneal dialysis: Supplemental dose is not necessary.
Infants, Children, and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling.
Contraindications
Hypersensitivity to dexamethasone or any component of the formulation; systemic fungal infections
Documentation of allergenic cross-reactivity for corticosteroids is limited. However, because of similarities in chemical
structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.
• Adrenal suppression: May cause hypercortisolism or suppression of hypothalamic-pituitary-adrenal (HPA) axis,

particularly in younger children or in patients receiving high doses for prolonged periods. HPA axis
suppression may lead to adrenal crisis. Withdrawal and discontinuation of a corticosteroid should be done
slowly and carefully. Particular care is required when patients are transferred from systemic corticosteroids
to inhaled products due to possible adrenal insufficiency or withdrawal from steroids, including an increase
in allergic symptoms. Adult patients receiving >20 mg per day of prednisone (or equivalent) may be most
susceptible. Fatalities have occurred due to adrenal insufficiency in asthmatic patients during and after
transfer from systemic corticosteroids to aerosol steroids; aerosol steroids do not provide the systemic
steroid needed to treat patients having trauma, surgery, or infections.
• Anaphylactoid reactions: Rare cases of anaphylactoid reactions have been observed in patients receiving
corticosteroids.
• Immunosuppression: Prolonged use of corticosteroids may increase the incidence of secondary infection, cause
activation of latent infections, mask acute infection (including fungal infections), prolong or exacerbate viral
infections, or limit response to killed or inactivated vaccines. Exposure to chickenpox or measles should be
avoided; corticosteroids should not be used to treat ocular herpes simplex. Corticosteroids should not be
used for cerebral malaria, fungal infections, or viral hepatitis. Close observation is required in patients with
latent tuberculosis and/or TB reactivity; restrict use in active TB (only fulminating or disseminated TB in
conjunction with antituberculosis treatment). Amebiasis should be ruled out in any patient with recent
travel to tropic climates or unexplained diarrhea prior to initiation of corticosteroids. Use with extreme
caution in patients with Strongyloides infections; hyperinfection, dissemination and fatalities have
occurred.
• Kaposi sarcoma: Prolonged treatment with corticosteroids has been associated with the development of Kaposi
sarcoma (case reports); if noted, discontinuation of therapy should be considered (Goedert 2002).
• Myopathy: Acute myopathy has been reported with high dose corticosteroids, usually in patients with
neuromuscular transmission disorders; may involve ocular and/or respiratory muscles; monitor creatine
kinase; recovery may be delayed.
• Perineal irritation: Perineal burning, tingling, pain and pruritus have been reported with IV administration. May
occur more commonly in females, with higher doses, and with rapid administration. Symptom onset is
sudden and usually resolves in <1 minute (Allan 1986; Neff 2002; Perron 2003; Singh 2011).
• Psychiatric disturbances: Corticosteroid use may cause psychiatric disturbances, including depression, euphoria,
insomnia, mood swings, personality changes, severe depression to psychotic manifestations. Preexisting
psychiatric conditions may be exacerbated by corticosteroid use.
• Adrenal insufficiency: Dexamethasone does not provide any mineralocorticoid activity in adrenal insufficiency
(may be employed as a single dose while cortisol assays are performed). In the management/prevention of
adrenal crisis in patients with known primary adrenal insufficiency, the Endocrine Society practice
guidelines state dexamethasone (intravenous) is the least preferred alternative agent and should be used
only if no other glucocorticoid is available. For the treatment of chronic primary adrenal insufficiency (ie,
physiologic replacement), dexamethasone (oral) is not recommended due to the risk of Cushingoid side
effects (ES [Bornstein 2016]).
• Cardiovascular disease: Use with caution in patients with HF and/or hypertension; use has been associated with
fluid retention, electrolyte disturbances, and hypertension. Use with caution following acute MI;
corticosteroids have been associated with myocardial rupture.
• Diabetes: Use corticosteroids with caution in patients with diabetes mellitus; may alter glucose
production/regulation leading to hyperglycemia.
• Gastrointestinal disease: Use with caution in patients with GI diseases (diverticulitis, fresh intestinal
anastomoses, active or latent peptic ulcer, ulcerative colitis, abscess or other pyogenic infection) due to
perforation risk.
• Head injury: Increased mortality was observed in patients receiving high-dose IV methylprednisolone. High-dose
corticosteroids should not be used for the management of head injury (BTF [Carney 2016]).
• Hepatic impairment: Use with caution in patients with hepatic impairment, including cirrhosis; long-term use
has been associated with fluid retention.
• Myasthenia gravis: Use with caution in patients with myasthenia gravis; exacerbation of symptoms has occurred
especially during initial treatment with corticosteroids.
• Ocular disease: Use with caution in patients with cataracts and/or glaucoma; increased intraocular pressure,
open-angle glaucoma, and cataracts have occurred with prolonged use. Use with caution in patients with a
history of ocular herpes simplex; corneal perforation has occurred; do not use in active ocular herpes
simplex. Not recommended for the treatment of optic neuritis; may increase frequency of new episodes.
Consider routine eye exams in chronic users.
• Osteoporosis: Use with caution in patients with osteoporosis; high doses and/or long-term use of
corticosteroids have been associated with increased bone loss and osteoporotic fractures.
• Renal impairment: Use with caution in patients with renal impairment; fluid retention may occur.
• Seizure disorders: Use corticosteroids with caution in patients with a history of seizure disorder; seizures have
been reported with adrenal crisis.
• Thyroid disease: Changes in thyroid status may necessitate dosage adjustments; metabolic clearance of
corticosteroids increases in hyperthyroid patients and decreases in hypothyroid ones.
• Elderly: Use with caution in the elderly with the smallest possible effective dose for the shortest duration.
• Pediatric: May affect growth velocity; growth should be routinely monitored in pediatric patients.
• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid
(benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been
associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome”
consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including
convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997];
CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001);
avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See
• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and
have been associated hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution
(AAP ["Inactive" 1997]; Zar 2007).
• Sulfite: Some products may contain sodium sulfite, a sulfite that may cause allergic-type reactions including
anaphylaxis and life-threatening or less severe asthmatic episodes in susceptible patients.
• Discontinuation of therapy: Withdraw therapy with gradual tapering of dose.
• Epidural injection: Corticosteroids are not approved for epidural injection. Serious neurologic events (eg, spinal
cord infarction, paraplegia, quadriplegia, cortical blindness, stroke), some resulting in death, have been
reported with epidural injection of corticosteroids, with and without use of fluoroscopy.
• Intra-articular injection: May produce systemic as well as local effects. Appropriate examination of any joint
fluid present is necessary to exclude a septic process. Avoid injection into an infected site. Do not inject
into unstable joints. Patients should not overuse joints in which symptomatic benefit has been obtained as
long as the inflammatory process remains active. Frequent intra-articular injection may result in damage to
joint tissues.
• Stress: Patients may require higher doses when subject to stress (ie, trauma, surgery, severe infection).
May cause osteoporosis (at any age) or inhibition of bone growth in pediatric patients. Use with caution in patients with
osteoporosis. In a population-based study of children, risk of fracture was shown to be increased with >4 courses of
corticosteroids; underlying clinical condition may also impact bone health and osteoporotic effect of corticosteroids
(Leonard, 2007). In premature neonates, the use of high-dose dexamethasone (approximately >0.5 mg/kg/day) for the
prevention or treatment of BPD has been associated with adverse neurodevelopmental outcomes, including higher rates
of cerebral palsy without additional clinical benefit over lower doses; current data does not support use of high doses,
further studies are needed (Watterberg, 2010). Increased IOP may occur especially with prolonged use; in children,
increased IOP has also been shown to be dose-dependent with a greater IOP observed in children <6 years than older
children after ophthalmic dexamethasone application; monitor closely (Lam 2005).
Some dosage forms may contain propylene glycol; in neonates large amounts of propylene glycol delivered orally,
intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities which can include
metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults
including hyperosmolality, lactic acidosis, seizures and respiratory depression; use caution (AAP 1997; Shehab 2009).

Oral: Oral administration of parenteral solution: In some pediatric croup trials, doses were prepared using a parenteral
dexamethasone formulation and mixing it with an oral flavored syrup (Bjornson 2004).
IV: May be given undiluted (4 mg/mL or 10 mg/mL). High doses may be further diluted in NS or D5W (Allan 1986; Bernini
1998). In neonates, use a preservative-free product.
Oral: May administer with food or milk to decrease GI adverse effects
Parenteral: Use preservative-free dosage forms in neonates.
IM: May administer 4 mg/mL or 10 mg/mL undiluted
IV: May administer as undiluted solution (4 mg/mL or 10 mg/mL) slow IV push, usually over 1 to 4 minutes; rapid
administration is associated with perineal discomfort (burning, tingling) (Allan 1986; Neff 2002); may
consider further dilution of high doses and administration by IV intermittent infusion over 15 to 30 minutes
(Allan 1986; Bernini 1998)
May be taken with meals to decrease GI upset. May need diet with increased potassium, pyridoxine, vitamin C, vitamin
D, folate, calcium, and phosphorus.
Hemoglobin, occult blood loss, blood pressure, serum potassium and glucose; IOP with systemic use >6 weeks; weight
and height in children
Reference Range
Dexamethasone suppression test: 8 AM cortisol <6 mcg/100 mL in adults given dexamethasone 1 mg at 11 PM the
previous night
Drug Interactions
Acetylcholinesterase Inhibitors: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Acetylcholinesterase
Inhibitors. Increased muscular weakness may occur. Risk C: Monitor therapy
Amphotericin B: Corticosteroids (Systemic) may enhance the hypokalemic effect of Amphotericin B. Risk C: Monitor
therapy
Androgens: Corticosteroids (Systemic) may enhance the fluid-retaining effect of Androgens. Risk C: Monitor therapy
Antacids: May decrease the bioavailability of Corticosteroids (Oral). Management: Consider separating doses by 2 or
more hours. Budesonide enteric coated tablets could dissolve prematurely if given with drugs that lower gastric
acid, with unknown impact on budesonide therapeutic effects. Risk D: Consider therapy modification
Monitor therapy
Bile Acid Sequestrants: May decrease the absorption of Corticosteroids (Oral). Risk C: Monitor therapy
Calcitriol (Systemic): Corticosteroids (Systemic) may diminish the therapeutic effect of Calcitriol (Systemic).Risk C:
Monitor therapy
Caspofungin: Inducers of Drug Clearance may decrease the serum concentration of Caspofungin. Management: Consider
using an increased caspofungin dose of 70 mg daily in adults (or 70 mg/m2, up to a maximum of 70 mg, daily in
pediatric patients) when coadministered with known inducers of drug clearance. Risk D: Consider therapy
modification
CycloSPORINE (Systemic): Dexamethasone (Systemic) may decrease the serum concentration of CycloSPORINE
(Systemic). Dexamethasone (Systemic) may increase the serum concentration of CycloSPORINE (Systemic).
CycloSPORINE (Systemic) may increase the serum concentration of Dexamethasone (Systemic). Risk C: Monitor
therapy
Fosphenytoin: May decrease the serum concentration of Dexamethasone (Systemic). Dexamethasone (Systemic) may
decrease the serum concentration of Fosphenytoin. Dexamethasone (Systemic) may increase the serum
concentration of Fosphenytoin. Management: Consider dexamethasone dose increases when combined with
fosphenytoin and monitor closely for reduced steroid efficacy. Monitor phenytoin levels closely, both increased
and decreased phenytoin levels have been reported. Risk D: Consider therapy modification
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X:
Avoid combination
Hyaluronidase: Corticosteroids may diminish the therapeutic effect of Hyaluronidase. Management: Patients receiving
corticosteroids (particularly at larger doses) may not experience the desired clinical response to standard doses of
hyaluronidase. Larger doses of hyaluronidase may be required. Risk D: Consider therapy modification
Isoniazid: Corticosteroids (Systemic) may decrease the serum concentration of Isoniazid. Risk C: Monitor therapy
Loop Diuretics: Corticosteroids (Systemic) may enhance the hypokalemic effect of Loop Diuretics. Risk C: Monitor
therapy
Neuromuscular-Blocking Agents (Nondepolarizing): May enhance the adverse neuromuscular effect of Corticosteroids
(Systemic). Increased muscle weakness, possibly progressing to polyneuropathies and myopathies, may
occur. Risk D: Consider therapy modification
Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): Corticosteroids (Systemic) may enhance the adverse/toxic
effect of Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective). Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (Nonselective): Corticosteroids (Systemic) may enhance the adverse/toxic effect
of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Risk C: Monitor therapy
Phenytoin: May decrease the serum concentration of Dexamethasone (Systemic). Dexamethasone (Systemic) may
decrease the serum concentration of Phenytoin. Dexamethasone (Systemic) may increase the serum
concentration of Phenytoin. Management: Consider dexamethasone dose increases when combined with
phenytoin and monitor closely for reduced steroid efficacy. Monitor phenytoin levels closely when combined with
dexamethasone, both increased and decreased phenytoin levels have been reported. Risk D: Consider therapy
modification
Quinolones: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Quinolones. Specifically, the risk of
tendonitis and tendon rupture may be increased. Risk C: Monitor therapy
Salicylates: May enhance the adverse/toxic effect of Corticosteroids (Systemic). These specifically include
gastrointestinal ulceration and bleeding. Corticosteroids (Systemic) may decrease the serum concentration of
Salicylates. Withdrawal of corticosteroids may result in salicylate toxicity. Risk C: Monitor therapy
Tacrolimus (Systemic): Corticosteroids (Systemic) may decrease the serum concentration of Tacrolimus (Systemic).
Conversely, when discontinuing corticosteroid therapy, tacrolimus concentrations may increase. Risk C: Monitor
therapy
Thiazide and Thiazide-Like Diuretics: Corticosteroids (Systemic) may enhance the hypokalemic effect of Thiazide and
Voriconazole: Dexamethasone (Systemic) may decrease the serum concentration of Voriconazole. Risk C: Monitor
therapy
Warfarin: Corticosteroids (Systemic) may enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy
Test Interactions
May suppress the wheal and flare reactions to skin test antigens
Onset of action: IV: Rapid
Immune thrombocytopenia: Oral: Initial response: 2 to 14 days; Peak response: 4 to 28 days (Neunert 2011)
Duration: IV: Short
Absorption: Oral: 61% to 86% (Czock 2005)
Metabolism: Hepatic
Extremely low birth-weight infants with BPD: 9.26 ± 3.34 hours (range: 5.85 to 16.1 hours) (Charles 1993)
Children 4 months to 16 years: 4.34 ± 4.14 hours (range: 2.33 to 9.54 hours) (Richter 1983)
Adults: Oral: 4 ± 0.9 hours (Czock 2005); IV: ~1 to 5 hours (Hochhaus 2001; Miyabo 1981; Rohdewald 1987; Tóth
1999)
Time to peak, serum: Oral: 1 to 2 hours (Czock 2005); IM: ~30 to 120 minutes (Egerman 1997; Hochhaus 2001); IV: 5 to
10 minutes (free dexamethasone) (Miyabo 1981; Rohdewald 1987)
Excretion: Urine (~10%) (Duggan 1975; Miyabo 1981)
Adverse Reactions
Some reactions listed are based on reports for other agents in this same pharmacologic class and may not be specifically
reported for dexamethasone.
Cardiovascular: Bradycardia, cardiac arrhythmia, cardiac failure, cardiomegaly, circulatory shock, edema, embolism (fat),
hypertension, hypertrophic cardiomyopathy (premature infants), myocardial rupture (post-MI), syncope,
tachycardia, thromboembolism, thrombophlebitis, vasculitis
Central nervous system: Depression, emotional lability, euphoria, headache, increased intracranial pressure, insomnia,
malaise, myasthenia, neuritis, neuropathy, paresthesia, personality changes, pseudotumor cerebri (usually
following discontinuation), psychic disorder, seizure, vertigo
Dermatologic: Acne vulgaris, allergic dermatitis, alopecia, atrophic striae, diaphoresis, ecchymoses, erythema, facial
erythema, fragile skin, hyperpigmentation, hypertrichosis, hypopigmentation, perianal skin irritation (itching,
burning, tingling; following IV injection), petechiae, skin atrophy, skin rash, subcutaneous atrophy, suppression of
skin test reaction, urticaria, xeroderma
Endocrine & metabolic: Adrenal suppression, carbohydrate intolerance, Cushing syndrome, decreased glucose tolerance,
decreased serum potassium, diabetes mellitus, fluid retention, glycosuria, growth suppression (children),
hirsutism, HPA-axis suppression, hyperglycemia, hypokalemic alkalosis, menstrual disease, moon face, negative
nitrogen balance, protein catabolism, redistribution of body fat, sodium retention, weight gain
Gastrointestinal: Abdominal distention, gastrointestinal hemorrhage, gastrointestinal perforation, hiccups, increased

appetite, nausea, pancreatitis, peptic ulcer, pruritus ani (following IV injection), ulcerative esophagitis
Genitourinary: Defective (increased or decreased) spermatogenesis
Hematologic & oncologic: Kaposi sarcoma, petechial, tumor lysis syndrome
Hepatic: Hepatomegaly, increased serum transaminases
Hypersensitivity: Anaphylactoid reaction, anaphylaxis, angioedema, hypersensitivity
Infection: Infection, sterile abscess
Local: Postinjection flare (intra-articular use)
Neuromuscular & skeletal: Amyotrophy, aseptic necrosis of bones (femoral and humoral heads), bone fractures,
Charcot-like arthropathy, myasthenia, myopathy (particularly in conjunction with neuromuscular disease or
neuromuscular-blocking agents), osteoporosis, rupture of tendon, steroid myopathy, vertebral compression
fracture
Ophthalmic: Exophthalmos, glaucoma, increased intraocular pressure, subcapsular posterior cataract
Respiratory: Pulmonary edema

Miscellaneous: Wound healing impairment
DIGOXINA
Dosing: Neonatal
Note: Dosage must be individualized due to substantial individual variation and must take into account renal function.
Doses should be based on lean body weight. When changing from oral solution to IV therapy, dosage should be reduced
by 20% to 25%.
Heart failure: Injection, Oral: The dosage tables below list dosage recommendations for normal renal function and are
based upon average patient response; patients with decreased renal function require decreased doses, especially
patients with end-stage renal disease (ESRD).
Digitalizing dose, initial regimen (optional): Total digitalizing dose should be divided (see below). Digitalizing dose
(loading dose) may not be necessary; consider use if rapid titration is desired. To avoid toxicity, consider
doses at lower end of the recommended range; dosage should be individualized based on patient response
(eg, clinical response, serum drug levels).
Dosage Recommendations for Digitalizing DoseA (Optional)
Total Digitalizing Dose
Administer in 3 divided dosesB

Age
(mcg/kg)
Oral Solution IVC
ABased on lean body weight and normal renal function for age.
BDo not give full total digitalizing dose (TDD) at once. Give one-half of the TDD for the initial dose, then give one-quarter
of the TDD for each of 2 subsequent doses at 6- to 8-hour intervals; prior to additional doses, clinical response should be
fully evaluated (eg, ECG).
CMay also be administered IM; however, not usually recommended.
Preterm neonates 20 to 30 15 to 25
Full-term neonates 25 to 35 20 to 30
Maintenance Dosage Recommendations for DigoxinA,B
Total Daily Maintenance Dose
Administer in equal divided doses every 12 hours

Age
(mcg/kg/day)
Oral Solution IVC,D
ADosing reflects clinical practice and in some cases, varies from manufacturer labeling (Bakir 1994; Bendayan 1983; Latifi
2000; Park 1986).
BBased on lean body weight and normal renal function for age. Decrease maintenance dose in patients with decreased
renal function.
Total Daily Maintenance Dose
Administer in equal divided doses every 12 hours

Age
(mcg/kg/day)
Oral Solution IVC,D
CDaily maintenance IV dose is typically 20% to 30% of total IV digitalizing dose.
DMay also be administered IM; however, not usually recommended.
Preterm neonates 5 to 7.5 4 to 6
Full-term neonates 8 to 10 5 to 8
Tachyarrhythmias (eg, supraventricular tachycardia), prevention: Limited data available: Term neonates: Oral: Initial
digitalizing dose: 20 to 40 mcg/kg divided every 8 hours for 2 to 3 doses followed by maintenance dose: 8 to 10
mcg/kg/day divided every 12 hours (Kugler 1996; O'Sullivan 1995; Sanatani 2012).
Dosing adjustment in renal impairment: Use caution in patients with decreased renal function. Patients with decreased
renal function require decreased doses, especially patients with ESRD; no recommendations exist for pediatric
patients with ESRD; however, it is recommended to decrease total digitalizing and maintenance doses by 50% in
adult patients with ESRD (Aronoff 2007).
Dosing: Pediatric
Note: Dosage must be individualized due to substantial individual variation and must take into account renal function.
Doses should be based on lean body weight. When changing from oral solution to IV therapy, dosage should be
reduced by 20% to 25%.
Heart failure: Injection, Oral: Infants, Children, and Adolescents: The dosage tables below list dosage
recommendations for normal renal function and are based upon average patient response; lower doses are
needed for patients with renal impairment.
Digitalizing dose, initial regimen (optional): Total digitalizing dose should be divided (see below);
digitalizing dose (loading dose) may not be necessary; consider use if rapid titration is desired. To
avoid toxicity, consider doses at lower end of the recommended range; dosage should be
individualized based on patient response (eg, clinical response, serum drug levels).

Age
(mcg/kg)
Oral Solution Tablets IVC
ABased on lean body weight and normal renal function for age.

Age
(mcg/kg)
Oral Solution Tablets IVC
BDo not give full total digitalizing dose (TDD) at once. Give one-half of the TDD for the initial dose, then give one-
quarter of the TDD for each of 2 subsequent doses at 6- to 8-hour intervals; prior to additional doses, clinical response
should be fully evaluated (eg, ECG).
CMay also be administered by IM; however, not recommended.
1 to 24 months 35 to 60 − 30 to 50
2 to 5 years 30 to 45 − 25 to 35
5 to 10 years 20 to 35 20 to 45 15 to 30
>10 years 10 to 15 10 to 15 8 to 12
Daily Maintenance Dose
If ≤10 years, administer in equal divided doses twice daily
Age
If >10 years, administer once daily
(mcg/kg/day)
Oral Solution Tablets IVC,D
ADosing reflects clinical practice and in some cases, varies from manufacturer labeling (Bakir 1994; Bendayan 1983; Latifi
2000; Park 1986).
BBased on lean body weight and normal renal function for age. Decrease maintenance dose in patients with decreased
renal function.
CMay also be administered by IM; however, not recommended.
DDailymaintenance IV dose is typically 20% to 30% of total digitalizing IV dose in pediatric patients ≤24 months and 25%
to 35% in older pediatric patients.
1 to 24 months 10 to 15 − 9 to 15
2 to 5 years 8 to 10 − 6 to 9
5 to 10 years 5 to 10 6 to 12 4 to 8
>10 years 2.5 to 5 2.5 to 5 2 to 3
Tachyarrhythmias, treatment: Limited data available (Escudero 2012): Injection, Oral: Infants, Children, and
Adolescents:
Initial (digitalizing dose):

IV: 10 to 12 mcg/kg/dose every 8 hours for 3 doses
Oral: 13 to 17 mcg/kg/dose every 8 hours for 3 doses
Maintenance: Oral: 8 to 10 mcg/kg/day divided once or twice daily (Escudero 2012); use twice daily dosing
in infants and young children (O'Sullivan 1995)
Infants, Children, and Adolescents: Oral, IV:
Digitalizing (loading) dose: There are no dosage adjustments provided in the manufacturer's labeling for
digitalizing dose; however, 50% to 70% of a digoxin dose is excreted unchanged in the urine. The
following adjustments have been recommended in adults with end-stage renal disease (ESRD):
Reduce usual dose by 50% (Aronoff 2007).
Maintenance dose:
Manufacturer's labeling: Dosage reductions and close monitoring recommended; see product
labeling for CrCl-specific dosage recommendation
Alternate dosing: The following adjustments have been recommended (Aronoff 2007):
GFR >50 mL/minute/1.73 m2: No dosage adjustment necessary
GFR: 30 to 50 mL/minute/1.73 m2: Administer 75% of normal dose at normal intervals
GFR: 10 to 29 mL/minute/1.73 m2: Administer 50% of normal dose at normal

intervals or administer normal dose every 36 hours
GFR: <10 mL/minute/1.73 m2: Administer 25% of normal dose at normal

intervals or administer normal dose every 48 hours
Intermittent hemodialysis: Nondialyzable (0% to 5%). Administer 25% of normal dose at

normal intervals or administer normal dose every 48 hours
Peritoneal dialysis (PD): Administer 25% of normal dose at normal intervals oradminister
normal dose every 48 hours
Continuous renal replacement therapy (CRRT): Administer 75% of normal dose at normal
intervals; titrate to desired effect; monitor serum concentrations
Contraindications
Hypersensitivity to digoxin, other forms of digitalis, or any component of the formulation; ventricular fibrillation
• Digoxin toxicity: Signs and symptoms of digoxin toxicity include anorexia, nausea, vomiting, visual changes, and
cardiac arrhythmias; toxicity is usually associated with digoxin levels >2 ng/mL, although symptoms may
occur at lower levels. Patients at increased risk for digoxin toxicity include those with low body weight,
advanced age, renal impairment, hypokalemia, hypercalcemia, or hypomagnesemia.
• Extravasation: IV administration: Vesicant; ensure proper needle or catheter placement prior to and during
administration; avoid extravasation.
• Proarrhythmic effects: Monitor for proarrhythmic effects (especially with digoxin toxicity)
• Accessory bypass tract (eg, Wolff-Parkinson-White [WPW] syndrome): During an episode of atrial fibrillation or
flutter in patients with an accessory bypass tract or pre-excitation syndrome, use has been associated with
increased anterograde conduction down the accessory pathway leading to ventricular fibrillation; avoid use
in such patients (ACLS [Neumar 2010]; AHA/ACC/HRS [January 2014]).
• Acute coronary syndrome: Use with caution in patients with an acute MI; may increase myocardial oxygen
demand and lead to ischemia. During an acute coronary syndrome, digoxin administered IV may be used to
slow a rapid ventricular response and improve left ventricular (LV) function in the acute treatment of atrial
fibrillation associated with severe LV function and heart failure or hemodynamic instability (AHA/ACC/HRS
[January 2014]).
• Atrial fibrillation: When used for rate control in patients with atrial fibrillation, monitor serum concentrations
closely; may be associated with an increased risk of mortality especially when serum concentrations are not
properly controlled (Vamos 2015).
• Beri beri heart disease: Patients with beri beri heart disease may fail to adequately respond to digoxin therapy;
treat underlying thiamine deficiency concomitantly.
• Electrolyte imbalance: Correct electrolyte disturbances, especially hypokalemia or hypomagnesemia, prior to

use and throughout therapy; toxicity may occur despite therapeutic digoxin concentrations (eg, <2 ng/mL).
Hypercalcemia may increase the risk of digoxin toxicity and hypocalcemia can nullify the effects of digoxin;
maintain normocalcemia.
• Heart failure: Digoxin should be considered for use only in heart failure (HF) with reduced ejection fraction
(HFrEF) when symptoms remain despite guideline-directed medical therapy. It may also be considered in
patients with both HF and atrial fibrillation; however, beta blockers may offer better ventricular rate
control than digoxin (ACCF/AHA [Yancy 2013]). Withdrawal of digoxin in clinically stable patients with HF
may lead to recurrence of HF symptoms (Packer 1993). Monitor serum concentrations closely; may be
associated with an increased risk of mortality especially when serum concentrations are not properly
controlled (Vamos 2015).
• Hypermetabolic states: Atrial arrhythmias associated with hypermetabolic (eg, hyperthyroidism) or

hyperdynamic (hypoxia, arteriovenous shunt) states are very difficult to treat; treat underlying condition
first. If digoxin is used, ensure digoxin toxicity does not occur.
• Hypertrophic cardiomyopathy (HCM) with outflow tract obstruction: Outflow obstruction may worsen due to
the positive inotropic effects of digoxin; avoid use unless used to control ventricular response with atrial
fibrillation. Digoxin is potentially harmful in the treatment of dyspnea in patients with HCM in the absence
of atrial fibrillation (ACCF/AHA [Gersh 2011]).
• Myocarditis: In a murine model of viral myocarditis, digoxin in high doses was shown to be detrimental
(Matsumori 1999). If used in humans, therefore, digoxin should be used with caution and only at low doses
(Frishman 2007). The manufacturer recommends avoiding the use of digoxin in patients with myocarditis.
• Preserved left ventricular function: Decreased cardiac output may occur in patients with preserved left
ventricular systolic function, including restrictive or hypertrophic cardiomyopathy, constrictive pericarditis,
amyloid heart disease, and acute cor pulmonale; in general, the manufacturer recommends to avoid use
unless used to control ventricular response with atrial fibrillation.
• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment needed.
• Sinus node disease and atrioventricular (AV) block: Because digoxin slows sinoatrial and AV conduction, the drug
commonly prolongs the PR interval. Digoxin may cause severe sinus bradycardia or sinoatrial block
particularly in patients with preexisting sinus node disease. Avoid use in patients with second- or third-
degree heart block (except in patients with a functioning artificial pacemaker) (ACCF/AHA [Yancy 2013]);
incomplete AV block (eg, Stokes-Adams attacks) may progress to complete block with digoxin
administration. In such patients, if treatment with digoxin is necessary, consider the insertion of a
pacemaker before treatment.
• Thyroid disease: Use with caution in patients with hypothyroidism, higher digoxin concentrations may result due
to significant reduction in digoxin clearance (Burk 2010). In patients with hyperthyroidism, lower digoxin
concentrations may result due to an increase in renal clearance of digoxin. No significant differences in
absorption were seen in either thyroid condition compared with those with normal thyroid function (Burk
2010). Note: New-onset atrial fibrillation or exacerbation of ventricular arrhythmias should prompt
evaluation of thyroid status.
• Infants: Newborn infants display considerable variability to their tolerance to digoxin; premature and immature
infants are particularly sensitive to the effects of digoxin.
• Low body weight: Patients with decreased body weight are at an increased risk of drug-related toxicity.
(AAP 1997; Zar 2007).
• Elective electrical cardioversion: It is not necessary to routinely reduce or hold digoxin therapy prior to elective
electrical cardioversion for atrial fibrillation; however, exclusion of digoxin toxicity (eg, clinical and ECG
signs) is necessary prior to cardioversion. If signs of digoxin excess exist, withhold digoxin and delay
cardioversion until toxicity subsides (AHA/ACC/HRS [January 2014]).
Parenteral:
IV: May be administered undiluted or diluted at least fourfold in D5W, D10W, NS, or SWFI; less than fourfold dilution
may lead to drug precipitation.
IM: No dilution required.
Oral: Administer consistently with relationship to meals; avoid concurrent administration (ie, administer digoxin 1 hour
before or 2 hours after) with meals high in fiber or pectin and with drugs that decrease oral absorption of digoxin
Oral solution: Only the calibrated manufacturer-provided dropper or a calibrated oral syringe should be used to
measure the dose. For doses <0.2 mL the manufacturer-provided dropper is not accurate and should not be
used; use a calibrated oral syringe.
Parenteral:
IV: May be slowly administered IV over ≥5 minutes (usually 5 to 10 minutes); avoid rapid IV infusion since this may
result in systemic and coronary arteriolar vasoconstriction
Vesicant; ensure proper needle or catheter placement prior to and during administration; avoid
extravasation. If extravasation occurs, stop IV administration immediately and disconnect (leave
cannula/needle in place); gently aspirate extravasated solution (do NOTflush the line); remove
needle/cannula; elevate extremity.
IM: Not usually recommended due to local irritation, pain, and tissue damage; if necessary, administer by deep
injection followed by massage at the injection site. May cause intense pain.
Maintain adequate amounts of potassium in diet to decrease risk of hypokalemia (hypokalemia may increase risk of
digoxin toxicity).
Heart rate and rhythm, periodic ECG; follow serum potassium, magnesium, and calcium closely (especially in patients
receiving diuretics or amphotericin or patient with a history of hypokalemia or hypomagnesemia); decreased serum
potassium and magnesium, or increased serum magnesium and calcium may increase digoxin toxicity; assess renal
function (serum BUN, Scr) in order to adjust dose; obtain serum drug concentrations at least 8 to 12 hours after a dose,
preferably prior to next scheduled dose. Observe patients for noncardiac signs of toxicity, confusion, and depression.
Therapeutic drug monitoring: Digoxin serum concentrations are monitored because digoxin possesses a narrow
therapeutic serum concentration range; the therapeutic endpoint is difficult to quantify and digoxin toxicity may be life-
threatening. Digoxin serum concentrations should be drawn at least 6 to 8 hours after the previous dose, regardless of
route of administration (optimally 12 to 24 hours after a dose). Note: Serum digoxin concentrations may decrease in
response to exercise due to increased skeletal muscle uptake; a period of rest (eg, ~2 hours) after exercise may be
necessary prior to drawing serum digoxin concentrations.
Initiation of therapy:
If a loading dose is given: Digoxin serum concentration may be drawn within 12 to 24 hours after the initial
loading dose administration. Concentrations drawn this early may confirm the relationship of digoxin
plasma concentrations and response but are of little value in determining maintenance doses.
If a loading dose is not given: Digoxin serum concentration should be obtained after 3 to 5 days of therapy.
Maintenance therapy:
Trough concentrations should be followed just prior to the next dose or at a minimum of 6 to 8 hours after last
dose.
Digoxin serum concentrations should be obtained within 5 to 7 days (approximate time to steady-state) after any
dosage changes. Continue to obtain digoxin serum concentrations 7 to 14 days after any change in
maintenance dose. Note: Time to steady state will be longer in patients with decreased renal function (eg,
premature neonates or patients with renal impairment). In patients with end-stage renal disease, it may
take 15 to 20 days to reach steady-state.
Patients who are receiving electrolyte-altering medications such as diuretics, serum potassium, magnesium, and
calcium should be monitored closely.
Digoxin serum concentrations should be obtained whenever any of the following conditions occur:
Questionable patient compliance or to evaluate clinical deterioration following an initial good response
Changing renal function
Suspected digoxin toxicity
Initiation or discontinuation of therapy with drugs (eg, amiodarone, quinidine, verapamil) which potentially
interact with digoxin.
Any disease changes (eg, thyroid disease)
Reference Range
Digoxin therapeutic serum trough concentrations:
Heart failure: 0.5 to 0.9 ng/mL (ACCF/AHA [Yancy 2013])
Adults: <0.5 ng/mL (SI: <0.6 nmol/L); probably indicates underdigitalization unless there are special circumstances
Toxic: >2 ng/mL; (SI: >2.6 nmol/L). Note: Serum concentration must be used in conjunction with clinical symptoms and
ECG to confirm diagnosis of digoxin intoxication.
Digoxin-like immunoreactive substance (DLIS) may cross-react with digoxin immunoassay and falsely increase serum
concentrations. DLIS has been found in patients with renal and liver disease, heart failure, neonates, and pregnant
women (3rd trimester).
Drug Interactions
Adenosine: Digoxin may enhance the adverse/toxic effect of Adenosine. Risk C: Monitor therapy
Aminoglycosides: May decrease the serum concentration of Cardiac Glycosides. This effect has only been demonstrated
with oral aminoglycoside administration.Exceptions: Amikacin (Systemic); Arbekacin; Isepamicin; Plazomicin;
Streptomycin; Tobramycin (Systemic). Risk C: Monitor therapy
Aminoquinolines (Antimalarial): May increase the serum concentration of Cardiac Glycosides. Risk C: Monitor therapy
Amiodarone: May increase the serum concentration of Cardiac Glycosides. Management: Reduce the dose of cardiac
glycosides by 30% to 50% or reduce the frequency of administration when initiating concomitant amiodarone
therapy. Monitor for increased serum concentrations and toxic effects of cardiac glycosides.Risk D: Consider
Amphotericin B: May enhance the adverse/toxic effect of Cardiac Glycosides. Risk C: Monitor therapy
Antithyroid Agents: May increase the serum concentration of Cardiac Glycosides. Risk C: Monitor therapy
AtorvaSTATin: May increase the serum concentration of Digoxin. Risk C: Monitor therapy
Beta-Blockers: May enhance the bradycardic effect of Cardiac Glycosides. Exceptions: Levobunolol; Metipranolol. Risk C:
Monitor therapy
Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Risk C: Monitor
therapy
Calcium Channel Blockers (Nondihydropyridine): May enhance the AV-blocking effect of Cardiac Glycosides. Calcium
Channel Blockers (Nondihydropyridine) may increase the serum concentration of Cardiac Glycosides. Risk C:
Monitor therapy
Calcium Salts: May enhance the arrhythmogenic effect of Cardiac Glycosides. Risk C: Monitor therapy
Carvedilol: Digoxin may enhance the bradycardic effect of Carvedilol. Carvedilol may increase the serum concentration
of Digoxin. Risk C: Monitor therapy
Colchicine: Digoxin may increase the serum concentration of Colchicine. Risk C: Monitor therapy
CycloSPORINE (Systemic): May increase the serum concentration of Digoxin. Risk C: Monitor therapy
Itraconazole: May increase the serum concentration of Cardiac Glycosides. Management: Consider preemptive cardiac
glycoside dose adjustments with initiation / changes / discontinuation of itraconazole. Risk D: Consider therapy
modification
Loop Diuretics: May enhance the adverse/toxic effect of Cardiac Glycosides. Specifically, cardiac glycoside toxicity may
be enhanced by the hypokalemic and hypomagnesemic effect of loop diuretics. Risk C: Monitor therapy
Macrolide Antibiotics: May increase the serum concentration of Cardiac Glycosides. Exceptions: Fidaxomicin;
Roxithromycin; Spiramycin. Risk C: Monitor therapy
MetroNIDAZOLE (Systemic): May enhance the adverse/toxic effect of Products Containing Propylene Glycol. A
disulfiram-like reaction may occur. Risk X: Avoid combination
Neuromuscular-Blocking Agents: May enhance the arrhythmogenic effect of Cardiac Glycosides. Risk C: Monitor therapy
NIFEdipine: May increase the serum concentration of Digoxin. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May increase the serum concentration of Digoxin. Risk C: Monitor therapy
PenicillAMINE: May decrease the serum concentration of Digoxin. Risk C: Monitor therapy
Polyethylene Glycol 3350: May decrease the serum concentration of Digoxin. Risk C: Monitor therapy
Polyethylene Glycol 4000: May decrease the serum concentration of Digoxin. Risk C: Monitor therapy
Posaconazole: May increase the serum concentration of Digoxin. Risk C: Monitor therapy
Potassium-Sparing Diuretics: May diminish the therapeutic effect of Cardiac Glycosides. In particular, the inotropic
effects of digoxin appear to be diminished. Potassium-Sparing Diuretics may increase the serum concentration of
Cardiac Glycosides. This particular effect may be unique to Spironolactone. Risk C: Monitor therapy
QuiNIDine: May increase the serum concentration of Cardiac Glycosides. Management: Upon quinidine initiation,
consider reducing cardiac glycoside dose by 25% to 50%, with continued monitoring of glycoside serum
concentrations and clinical response until the quinidine reaches steady state (5-10 days). Risk D: Consider therapy
modification
QuiNINE: May increase the serum concentration of Digoxin.Risk C: Monitor therapy
Spironolactone: May increase the serum concentration of Digoxin. Spironolactone (and/or its metabolites) may also
interfere with the assays used to determine Digoxin concentrations, falsely increasing or decreasing Digoxin
concentrations. Risk C: Monitor therapy
Sucralfate: May decrease the serum concentration of Digoxin. Specifically, sucralfate may decrease the absorption of
digoxin. Management: Administer digoxin at least 2 hours before or at least 6 hours after sucralfate. Risk D:
Thiazide and Thiazide-Like Diuretics: May enhance the adverse/toxic effect of Cardiac Glycosides. Specifically, cardiac
glycoside toxicity may be enhanced by the hypokalemic and hypomagnesemic effect of thiazide diuretics. Risk C:
Monitor therapy
Trimethoprim: May increase the serum concentration of Digoxin. Risk C: Monitor therapy
Vitamin D Analogs: May enhance the arrhythmogenic effect of Cardiac Glycosides. Risk C: Monitor therapy
Food Interactions
Digoxin peak serum concentrations may be decreased if taken with food. Meals containing increased fiber (bran) or
foods high in pectin may decrease oral absorption of digoxin.
Onset of action: Heart rate control: Oral: 1 to 2 hours; IV: 5 to 60 minutes
Peak effect: Heart rate control: Oral: 2 to 8 hours; IV: 1 to 6 hours; Note: In patients with atrial fibrillation, median
time to ventricular rate control in one study was 6 hours (range: 3 to 15 hours) (Siu 2009)
Duration: Adults: 3 to 4 days
Absorption: By passive nonsaturable diffusion in the upper small intestine; food may delay, but does not affect extent of
absorption
Distribution:
Normal renal function: 6 to 7 L/kg
Vd: Extensive to peripheral tissues, with a distinct distribution phase which lasts 6 to 8 hours; concentrates in
heart, liver, kidney, skeletal muscle, and intestines. Heart/serum concentration is 70:1. Pharmacologic
effects are delayed and do not correlate well with serum concentrations during distribution phase.
Hyperthyroidism: Increased Vd
Hyperkalemia, hyponatremia: Decreased digoxin distribution to heart and muscle
Hypokalemia: Increased digoxin distribution to heart and muscles
Concomitant quinidine therapy: Decreased Vd
Chronic renal failure: 4 to 6 L/kg
Decreased sodium/potassium ATPase activity - decreased tissue binding

Neonates, full-term: 7.5 to 10 L/kg
Children: 16 L/kg
Adults: 7 L/kg, decreased with renal disease
Protein binding: ~25%; in uremic patients, digoxin is displaced from plasma protein binding sites
Metabolism: Via sequential sugar hydrolysis in the stomach or by reduction of lactone ring by intestinal bacteria (in
~10% of population, gut bacteria may metabolize up to 40% of digoxin dose); once absorbed, only ~16% is
metabolized to 3-beta-digoxigenin, 3-keto-digoxigenin, and glucuronide and sulfate conjugates; metabolites may
contribute to therapeutic and toxic effects of digoxin; metabolism is reduced with decompensated HF
Bioavailability: Oral (formulation dependent): Elixir: 70% to 85%; Tablet: 60% to 80%
Half-life elimination (age, renal and cardiac function dependent):
Neonates: Premature: 61 to 170 hours; Full-term: 35 to 45 hours
Infants: 18 to 25 hours
Children: 18 to 36 hours
Adults: 36 to 48 hours
Adults, anephric: 3.5 to 5 days
Half-life elimination: Parent drug: 38 hours; Metabolites: Digoxigenin: 4 hours; Monodigitoxoside: 3 to 12 hours
Time to peak, serum: Oral: 1 to 3 hours
Excretion: Urine (50% to 70% as unchanged drug)
Adverse Reactions
Cardiovascular: Accelerated junctional rhythm, asystole, atrial tachycardia with or without block, AV dissociation, first-,
second- (Wenckebach), or third-degree heart block, facial edema, PR prolongation, PVCs (especially bigeminy or
trigeminy), ST segment depression, ventricular tachycardia or ventricular fibrillation
Central nervous system: Apathy, anxiety, confusion, delirium, depression, dizziness, fever, hallucinations, headache,
mental disturbances
Dermatologic: Rash (erythematous, maculopapular [most common], papular, scarlatiniform, vesicular or bullous),
pruritus, urticaria, angioneurotic edema
Gastrointestinal: Abdominal pain, anorexia, diarrhea, nausea, vomiting
Neuromuscular & skeletal: Weakness

Ophthalmic: Visual disturbances (blurred or yellow vision)
Respiratory: Laryngeal edema
Rare but important or life-threatening: Asymmetric chorea, gynecomastia, thrombocytopenia, palpitation, intestinal
ischemia, hemorrhagic necrosis of the intestines, vaginal cornification, eosinophilia, sexual dysfunction,
diaphoresis
DOBUTAMINA
Dosing: Neonatal
Hemodynamic support: Continuous IV or intraosseous infusion: Initial: 0.5 to 1 mcg/kg/minute; titrate gradually every
few minutes until desired response achieved; usual range: 2 to 20 mcg/kg/minute
Dosing: Pediatric
Hemodynamic support: Infants, Children, and Adolescents: Continuous IV or intraosseous infusion: Initial: 0.5 to 1
mcg/kg/minute, titrate gradually every few minutes until desired response achieved; usual range: 2 to 20
mcg/kg/minute (PALS [Kleinman 2010])
Contraindications
Hypersensitivity to dobutamine or sulfites (some contain sodium metabisulfate), or any component of the formulation;
hypertrophic cardiomyopathy with outflow tract obstruction (formerly known as idiopathic hypertrophic
subaortic stenosis [IHSS])
Note: When utilized for stress testing, additional contraindications according to the American Society of Nuclear
Cardiology (ASNC) include patients with recent (<1 week) MI, unstable angina, severe aortic stenosis, atrial
tachyarrhythmias with uncontrolled ventricular response, prior history of ventricular tachycardia,
uncontrolled hypertension (>200/110 mm Hg), aortic dissection or large aortic aneurysm, and patients on
beta blockers where heart rate and inotropic responses to dobutamine will be attenuated (ASNC [Henzlova
2009])
• Arrhythmias: Ventricular arrhythmias, including nonsustained ventricular tachycardia and supraventricular

arrhythmias, have been reported (Tisdale1995). Observe closely for arrhythmias in patients with acute
heart failure; sudden cardiac death has been observed (O’Connor 1999; Pickworth 1992; Young 2000).
Ensure that ventricular rate is controlled in atrial fibrillation/flutter before initiating; may increase
ventricular response rate. In heart transplant candidates, institute appropriate measures to protect patient
against risks of sudden cardiac death (Young 2000).
• Blood pressure effects: An increase in blood pressure is more common due to augmented cardiac output, but
occasionally a patient may become hypotensive.
• Heart failure complications: An increased risk of hospitalization and death has been observed with prolonged
use in New York Heart Association Class III/IV heart failure patients (O’Connor 1999).
• Tachycardia: May cause dose-related increases in heart rate.
• Ventricular ectopy: May exacerbate ventricular ectopy (dose-related).
• Aortic stenosis: Ineffective therapeutically in the presence of mechanical obstruction such as severe aortic
stenosis.

use and throughout therapy to minimize the risk of arrhythmias (ACC/AHA/ESC [Zipes 2006]; Tisdale 1995).
• Hypovolemia: If needed, correct hypovolemia first to optimize hemodynamics.
• Active myocardial ischemia/myocardial infarction (post): Use with caution in patients with active myocardial
ischemia or recent myocardial infarction; can increase myocardial oxygen demand.
• Monoamine oxidase inhibitors (MAO-I): Use with extreme caution in patients taking MAO inhibitors; prolong
hypertension may result from concurrent use.
• Sodium sulfite: Product may contain sodium sulfite.
• Elderly: Use with caution in the elderly; start at lower end of the dosage range.
• Long-term therapy: According to the ACCF/AHA 2013 heart failure guidelines, long-term use of intravenous
inotropic therapy without a specific indication or for reasons other than palliation is potentially harmful
(ACCF/AHA [Yancy 2013]).
Parenteral: Dilute in D5W or NS to a maximum concentration of 5,000 mcg/mL (5 mg/mL); ISMP and Vermont Oxford
Network recommends a standard concentration of 2,000 mcg/mL (2 mg/mL) for neonates (ISMP 2011)
Parenteral: Administer as a continuous IV infusion via an infusion device; administer into large vein.
Rate of infusion (mL/hour) = dose (mcg/kg/minute) x weight (kg) x 60 minutes/hour divided by the concentration
(mcg/mL)
Blood pressure, ECG, heart rate, CVP, MAP, urine output; if pulmonary artery catheter is in place, monitor CI, PCWP,
RAP, and SVR. Dobutamine lowers central venous pressure and wedge pressure but has little effect on pulmonary
vascular resistance.
Drug Interactions
Calcium Salts: May diminish the therapeutic effect of DOBUTamine. Risk C: Monitor therapy
sympathomimetic agents, and closely monitor for enhanced pressor response, in patients receiving linezolid.
Specific dose adjustment recommendations are not presently available. Risk D: Consider therapy modification
Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Risk C: Monitor therapy
Onset of action: IV: 1 to 10 minutes
Peak effect: 10 to 20 minutes
Metabolism: In tissues and hepatically to inactive metabolites
Half-life elimination: 2 minutes
Excretion: Urine (as metabolites)
Adverse Reactions
Cardiovascular: Angina pectoris, chest pain, hypotension, increased heart rate, increased systolic blood pressure,
palpitations, ventricular ectopy, ventricular premature contractions
Endocrine & metabolic: Decreased serum potassium
Gastrointestinal: Nausea
Respiratory: Dyspnea
Rare but important or life-threatening: Cardiomyopathy (stress), eosinophilia, hypersensitivity reaction, localized
phlebitis
DOPAMINA
Dosing: Neonatal
Hemodynamic support: Continuous IV infusion: 2 to 20 mcg/kg/minute; titrate gradually by 5- to 10-
mcg/kg/minute increments until optimal response is obtained
The hemodynamic effects of dopamine are dose-dependent:
Low dosage: 1 to 5 mcg/kg/minute, increased renal blood flow and urine output
Intermediate dosage: 5 to 15 mcg/kg/minute, increased renal blood flow, heart rate, cardiac contractility, cardiac
output, and blood pressure
High dosage: >15 mcg/kg/minute, alpha-adrenergic effects begin to predominate, vasoconstriction, increased
blood pressure
Dosing: Pediatric
Hemodynamic support: Infants, Children, and Adolescents: Continuous IV or intraosseous infusion: 2 to 20
mcg/kg/minute, titrate gradually by 5- to 10-mcg/kg/minute increments until optimal response is obtained (PALS
[Kleinman 2010])
The hemodynamic effects of dopamine are dose-dependent:
Low dosage: 1 to 5 mcg/kg/minute, increased renal blood flow and urine output
Intermediate dosage: 5 to 15 mcg/kg/minute, increased renal blood flow, heart rate, cardiac contractility, cardiac
output, and blood pressure
High dosage: >15 mcg/kg/minute, alpha-adrenergic effects begin to predominate, vasoconstriction, increased
blood pressure
• Arrhythmias: May cause increases in heart rate, increasing the risk of tachycardia and other tachyarrhythmias
including ventricular arrhythmias (Tisdale 1995). In heart transplant candidates, institute appropriate measures to
protect patient against risks of sudden cardiac death (Young 2000).
• Extravasation: Vesicant; ensure proper needle or catheter placement prior to and during infusion. Avoid
extravasation; infuse into a large vein if possible. Avoid infusion into leg veins. Watch IV site closely. [US Boxed
Warning]: If extravasation occurs, infiltrate the area with diluted phentolamine (5 to 10 mg in 10 to 15 mL of
saline) with a fine hypodermic needle. Phentolamine should be administered as soon as possible after
extravasation is noted to prevent sloughing/necrosis.
• Cardiovascular disease: Use with caution in patients with cardiovascular disease, cardiac arrhythmias and/or
occlusive vascular disease.
• Active myocardial ischemia/post-myocardial infarction: Use with caution in patients with active myocardial
ischemia or recent myocardial infarction; may increase myocardial oxygen consumption.

use and throughout therapy to minimize the risk of arrhythmias (ACC/AHA/ESC [Zipes 2006]; Tisdale 1995).
• Shock: The use of dopamine in adult patients with shock (majority of patients had septic shock) demonstrated a
higher incidence of adverse events (eg, tachyarrhythmias) (De Backer 2010). Higher 28-day mortality was also
seen in patients with septic shock with the use of dopamine as compared to norepinephrine (De Backer 2012;
Vasu 2012).
• Monoamine oxidase inhibitors (MAO-I): Use with extreme caution in patients taking MAO inhibitors; prolong
hypertension may result from concurrent use.
• Sodium metabisulfite: Product may contain sodium metabisulfite.
• Appropriate use: Assure adequate circulatory volume to minimize need for vasoconstrictors when used in
hemodynamic support. Avoid hypertension; monitor blood pressure closely and adjust infusion rate.

Parenteral: Vials (concentrated solution) must be diluted prior to administration; maximum concentration: 3,200
mcg/mL (3.2 mg/mL); concentrations as high as 6,000 mcg/mL (6 mg/mL) have been infused into large veins,
safely and with efficacy, in cases of extreme fluid restriction (Murray 2014). ISMP and Vermont Oxford Network
recommend a standard concentration of 1,600 mcg/mL (1.6 mg/mL) for neonates (ISMP 2011).
Parenteral: Administer as a continuous IV infusion with the use of an infusion pump or an intraosseous infusion
until IV access can be obtained in pediatric patients (PALS [Kleinman 2010]). Administer into large vein to prevent
the possibility of extravasation (central-line administration); administration into an umbilical arterial catheter is
not recommended. Some experts recommend that low-dose dopamine infusion may be administered peripherally
while trying to establish central access; once central access is available, begin central line infusion and wait for
pharmacologic effect prior to stopping peripheral administration (Brierley 2009; Dellinger 2013). Monitor
continuously for free flow; use infusion device to control rate of flow; when discontinuing the infusion, gradually
decrease the dose of dopamine (sudden discontinuation may cause hypotension).
Drug Interactions
Alpha1-Blockers: May diminish the vasoconstricting effect of Alpha-/Beta-Agonists. Similarly, Alpha-/Beta-
Agonists may antagonize Alpha1-Blocker vasodilation. Risk C: Monitor therapy
Monoamine Oxidase Inhibitors: May enhance the hypertensive effect of DOPamine. Management: Initiate
dopamine at no greater than one-tenth (1/10) of the usual dose in patients who are taking (or have taken within
the last 2 to 3 weeks) monoamine oxidase inhibitors. Monitor for an exaggerated hypertensive response to
dopamine. Risk D: Consider therapy modification

Serotonin/Norepinephrine Reuptake Inhibitors may enhance the vasopressor effect of Alpha-/Beta-Agonists. Risk
D: Consider therapy modification
Tricyclic Antidepressants: May enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting).

Management: Avoid, if possible, the use of direct-acting alpha-/beta-agonists in patients receiving tricyclic
antidepressants. If combined, monitor for evidence of increased pressor effects and consider reductions in initial
dosages of the alpha-/beta-agonist. Risk D: Consider therapy modification

Note: Children: Dopamine has exhibited nonlinear kinetics in children; with dose changes, may not achieve
steady-state for ~1 hour rather than 20 minutes
Onset of action: Adults: Within 5 minutes
Duration: Adults: <10 minutes
Metabolism: Renal, hepatic, plasma; 75% to inactive metabolites by monoamine oxidase and 25% to
norepinephrine (active)
Half-life elimination: ~2 minutes
Excretion: Urine (as metabolites)
Clearance: Neonates: Varies and appears to be age related; clearance is more prolonged with combined hepatic
and renal dysfunction
Adverse Reactions
Cardiovascular: Angina pectoris, atrial fibrillation, bradycardia, ectopic beats, hypertension, hypotension,
palpitations, tachycardia, vasoconstriction, ventricular arrhythmia, ventricular conduction, widened QRS complex
on ECG
Central nervous system: Anxiety, headache
Dermatologic: Gangrene (high dose), piloerection
Endocrine & metabolic: Increased serum glucose (usually not above normal limits)

Genitourinary: Azotemia
Ophthalmic: Increased intraocular pressure, mydriasis
Renal: Polyuria
Miscellaneous: Tissue necrosis
FENTANILO
Dosing: Neonatal
Analgesia: Limited data available:
International Evidence-Based Group for Neonatal Pain recommendations (Anand 2001): Opioid-naive:
Intermittent doses: Slow IV push: 0.5 to 3 mcg/kg/dose
Continuous IV infusion: 0.5 to 2 mcg/kg/hour
WHO Guidelines for Pediatric Pain (WHO 2012): Opioid-naive:
Intermittent doses: Slow IV push: Initial: 1 to 2 mcg/kg/dose; may repeat every 2 to 4 hours, titrate dose to
effectiveness
Continuous IV infusion: Initial IV bolus: Slow IV push: 1 to 2 mcg/kg, then 0.5 to 1 mcg/kg/hour; titrate
upward; usual range: 1 to 3 mcg/kg/hour
Alternate dosing: Intermittent doses: Some centers have used the following: Slow IV push: 1 to 4 mcg/kg/dose;
may repeat every 2 to 4 hours (Nelson 1996)
Continuous analgesia/sedation; mechanically ventilated patient: Limited data available: Initial IV bolus: 1 to 2 mcg/kg,
then 0.5 to 1 mcg/kg/hour; titrate carefully to effect. Dosing based on a trial of 20 neonates ventilated for
respiratory distress syndrome; mean required dose was age-dependent: GA <34 weeks (n=12): 0.64
mcg/kg/hour and for GA ≥34 weeks (n=8): 0.75 mcg/kg/hour (Roth 1991).
Continuous analgesia/sedation during ECMO: Limited data available: Initial IV bolus: 5 to 10 mcg/kg slow IV push over
10 minutes, then 1 to 5 mcg/kg/hour; titrate carefully to effect; tolerance may develop; higher doses (up to 20
mcg/kg/hour) may be needed by day 6 of ECMO (Arnold 1991; Leuschen 1993).
Endotracheal intubation: Limited data available: IV: 1 to 4 mcg/kg slow IV push (Cloherty 2012; Kumar 2010)
Dosing: Pediatric
Infants, Children and Adolescents <18 years of age:

Acute, short-term uses:
Acute pain: Opioid-naïve:
Infants: Limited data available: IV: Initial: 1 to 2 mcg/kg/dose; may repeat at 2 to 4 hour intervals; in opioid-
tolerant or younger infants, titration to higher doses may be required (up to 4 mcg/kg/dose)
(Hegenbarth 2008; Nelson 1996; WHO 2012)
Children: Limited data available in <2 years of age: IV: Initial: 1 to 2 mcg/kg/dose; may repeat at 30- to 60-
minute intervals; in opioid-tolerant children, titration to higher doses may be required. Note: Usual
adolescent starting dose is 25 to 50 mcg (Hegenbarth 2008; Nelson 1996; WHO 2012).
Adolescents <18 years: Note: After the first dose, if severe pain persists and adverse effects are minimal at
the time of expected peak effect, may repeat dose (APS 2008)
<50 kg: Initial: IV: 0.5 to 1 mcg/kg/dose may repeat every 1 to 2 hours although some patients may
require more frequent dosing (eg, 30-minute intervals) (APS 2008; Berde 2002)
≥50 kg: Initial: IV: 25 to 50 mcg every 1 to 2 hours although some patients may require more
frequent dosing (eg, 30-minute intervals) (APS 2008; Berde 2002)
Analgesia for minor procedures/sedation:
Parenteral:
Infants and Children: Limited data available in <2 years of age: IM, IV: 1 to 2 mcg/kg/dose; administer
3 minutes before the procedure; maximum dose: 50 mcg/dose; may repeat 1/2 original dose
every 3 to 5 minutes if necessary; titrate to effect (Cramton 2012; Krauss 2006; Zeltzer 1990)
Adolescents <18 years: IV: 0.5 to 1 mcg/kg/dose; may repeat after 30 to 60 minutes; or 25 to 50 mcg,
repeat full dose in 5 minutes if needed, may repeat 4 to 5 times with 25 mcg at 5-minute
intervals if needed. Note: Higher doses are used for major procedures.
Intranasal (using parenteral preparation): Limited data available: Infants and Children weighing ≥10 kg:
Intranasal: 1.5 mcg/kg once (maximum: 100 mcg/dose); reported range: 1 to 2 mcg/kg; some studies
that used an initial dose of 1.5 mcg/kg allowed for additional incremental doses of 0.3 to 0.5 mcg/kg
to be administered every 5 minutes, not to exceed a total dose of 3 mcg/kg depending on pain type
and severity (Borland 2002; Borland 2005; Borland 2007; Chung 2010; Cole 2009; Crellin 2010; Herd
2009; Manjushree 2002; Saunders 2010)
Anesthesia, general; adjunct:
Children 2 to 12 years: IM, IV: 2 to 3 mcg/kg/dose; Note: An IV should be in place with general anesthesia
so the IM route is rarely used but still maintained as an option in the manufacturer's labeling.
Adolescents <18 years: IV:
Low dose: 0.5 to 2 mcg/kg/dose depending on the indication

Moderate dose: Initial: 2 to 20 mcg/kg/dose; Maintenance (bolus or infusion): 1 to 2 mcg/kg/hour.
Discontinuing fentanyl infusion 30 to 60 minutes prior to the end of surgery will usually allow
adequate ventilation upon emergence from anesthesia. For "fast-tracking" and early
extubation following major surgery, total fentanyl doses are limited to 10 to 15 mcg/kg.
High dose: 20 to 50 mcg/kg/dose; Note: High-dose fentanyl as an adjunct to general anesthesia is

rarely used, but is still described in the manufacturer's label.
Anesthesia, general without additional anesthetic agents: Adolescents <18 years: IV: 50 to 100 mcg/kg/dose
with O2 and skeletal muscle relaxant
Anesthesia, regional; adjunct: Adolescents <18 years: IM, IV: 50 to 100 mcg; Note: An IV should be in place with
regional anesthesia so the IM route is rarely used but still maintained as an option in the manufacturer's
labeling.
Continuous analgesia/sedation:
Infants and Children: Limited data available in <2 years of age: Initial IV bolus: 1 to 2 mcg/kg followed by
continuous IV infusion at initial rate: 1 mcg/kg/hour; titrate to effect; usual range: 1 to 3
mcg/kg/hour; some patients may require higher rates (5 mcg/kg/hour) (WHO 2012)
Adolescents <18 years:
≤50 kg: Initial IV bolus: 0.5 to 2 mcg/kg followed by continuous IV infusion at initial rate: 0.5 to 2
mcg/kg/hour based on expert recommendations for children and pediatric patients ≤50 kg
(APS 2008; Berde 2002; WHO 2012)
>50 kg: Initial IV bolus: 25 to 100 mcg/dose followed by continuous IV infusion at initial rate: 25 to
200 mcg/hour based on expert recommendations for pediatric patients and experience in
adult patients (APS 2008; Berde 2002; Liu 2003; Peng 1999)
Endotracheal intubation, emergent: Limited data available: Infants and Children: IV: 1 to 5 mcg/kg/dose
(Hegenbarth 2008)
Preoperative sedation: Adolescents <18 years: IM, IV: 50 to 100 mcg administered 30 to 60 minutes prior to
surgery or slow IV: 25 to 50 mcg given shortly before induction (Barash 2009)
Patient-controlled analgesia (PCA): Limited data available: Children ≥5 years and Adolescents <18 years; opioid-
naïve: Note: PCA has been used in children as young as 5 years; however, clinicians need to assess children
5 to 8 years of age to determine if they are able to use the PCA device correctly. All patients should receive
an initial loading dose of an analgesic (to attain adequate control of pain) before starting PCA for
maintenance. Adjust doses, lockouts, and limits based on required loading dose, age, state of health, and
presence of opioid tolerance. Use lower end of dosing range for opioid-naïve. Assess patient and pain
control at regular intervals and adjust settings if needed (APS 2008): IV:
Patient weight ≤50 kg:
Usual concentration: Determined by weight; some centers use the following:
Children <12 kg: 10 mcg/mL

Children 12 to 30 kg: 25 mcg/mL
Children >30 kg: 50 mcg/mL
Demand dose: Usual initial: 0.5 to 1 mcg/kg/dose; usual range: 0.5 to 1 mcg/kg/dose
Lockout: Usual initial: 5 doses/hour
Lockout interval: Range: 6 to 8 minutes
Usual basal rate: 0 to 0.5 mcg/kg/hour
Patient weight >50 kg:
Usual concentration: 50 mcg/mL
Demand dose: Usual initial: 20 mcg; usual range: 10 to 50 mcg
Lockout interval: Usual initial: 6 minutes; usual range: 5 to 8 minutes
Usual basal rate: ≤50 mcg/hour
Chronic uses or opioid-tolerant patients (eg, cancer pain):
Chronic pain, moderate to severe (opioid-tolerant):Transdermal patch: Duragesic: Children ≥2 years and
Adolescents <18 years who are opioid-tolerant receiving at least 60 mg oral morphine equivalents per
day: Note: Discontinue or taper all other around-the-clock or extended release opioids when initiating
therapy with fentanyl transdermal patch:
Initial: 25 mcg/hour system or higher based on previous opioid dosing. To convert patients from oral or
parenteral opioids to transdermal patch, a 24-hour analgesic requirement should be calculated
(based on prior opioid use). Using the following tables, the appropriate initial dose can be
determined. The initial fentanyl dosage may be approximated from the 24-hour morphine dosage
equivalent and titrated to minimize adverse effects and provide analgesia. Substantial interpatient
variability exists in relative potency. Therefore, it is safer to underestimate a patient's daily fentanyl
requirement and provide breakthrough pain relief with rescue medication (eg, immediate release
opioid) than to overestimate requirements. With the initial application, the absorption of
transdermal fentanyl requires several hours to reach plateau; therefore, transdermal fentanyl is
inappropriate for management of acute pain. Change patch every 72 hours.
Conversion from continuous infusion of fentanyl: In patients who have adequate pain relief with a fentanyl
infusion, fentanyl may be converted to transdermal dosing at a rate equivalent to the intravenous
rate. Based on experience in adults, a two-step taper of the infusion to be completed over 12 hours
may be considered (Kornick 2001) after the patch is applied. The infusion is decreased to 50% of the
original rate 6 hours after the application of the first patch, and subsequently discontinued twelve
hours after application.
Titration: Short-acting agents may be required until analgesic efficacy is established and/or as supplements
for “breakthrough” pain. The amount of supplemental doses should be closely monitored.
Appropriate dosage increases may be based on daily supplemental dosage using the ratio of 45
mg/24 hours of oral morphine to a 12.5 mcg/hour increase in fentanyl dosage
Frequency of adjustment: The dosage should not be titrated more frequently than every 3 days after the
initial dose or every 6 days thereafter. Titrate dose based on the daily dose of supplemental opioids
required by the patient on the second or third day of the initial application. Note: Upon
discontinuation, ~17 hours are required for a 50% decrease in fentanyl levels.
Frequency of application: The majority of patients may be controlled on every 72-hour administration;
however, a small number of adult patients have required every 48-hour administration.
Discontinuation: When discontinuing transdermal fentanyl and not converting to another opioid, use a
gradual downward titration, such as decreasing the dose by 50% every 6 days, to reduce the
possibility of withdrawal symptoms.
Cancer pain; breakthrough: Transmucosal lozenge: Actiq: Adolescents ≥16 years: Note: For patients who are
tolerant to and currently receiving opioid therapy for persistent cancer pain; dosing should be individually
titrated to provide adequate analgesia with minimal side effects. Patients must remain on around-the-
clock opioids during use.
Initial dose: 200 mcg (consumed over 15 minutes) for all patients; if after 30 minutes from the start of the
lozenge (ie, 15 minutes following the completion of the lozenge), the pain is unrelieved, a second
200 mcg dose may be given over 15 minutes. A maximum of 1 additional dose can be given per pain
episode; must wait at least 4 hours before treating another episode. To limit the number of units in
the home during titration, only prescribe an initial titration supply of six 200 mcg lozenges. Note: Do
not convert patients from any other fentanyl product to Actiq on a mcg-per-mcg basis. Patients
previously using another fentanyl product should be initiated at a dose of 200 mcg; individually
titrate to provide adequate analgesia while minimizing adverse effects.
Dose titration: Dose titration should be done if patient requires more than 1 dose/breakthrough pain
episode for several consecutive episodes. From the initial dose, closely follow patients and modify
the dose until patient reaches a dose providing adequate analgesia using a single dosage unit per
breakthrough cancer pain episode. If signs/symptoms of excessive opioid effects (eg, respiratory
depression) occur, immediately remove the dosage unit from the patient's mouth, dispose of
properly, and reduce subsequent doses. If adequate relief is not achieved 15 minutes after
completion of the first dose (ie, 30 minutes after the start of the lozenge), only 1 additional lozenge
of the same strength may be given for that episode; must wait at least 4 hours before treating
another episode.
Maintenance dose: Once titrated to an effective dose, patients should generally use a single dosage unit
per breakthrough pain episode. During any pain episode, if adequate relief is not achieved 15
minutes after completion of the first dose (ie, 30 minutes after the start of the lozenge), only 1
additional lozenge of the same strength may be given over 15 minutes for that episode; must wait at
least 4 hours before treating another episode. Consumption should be limited to ≤4 units per day
(once an effective breakthrough dose is found). If adequate analgesia is not provided after treating
several episodes of breakthrough pain using the same dose, increase dose to next highest lozenge
strength (initially dispense no more than 6 units of the new strength). Consider increasing the
around-the-clock opioid therapy in patients experiencing >4 breakthrough pain episodes per day and
have their long-term opioid re-evaluated. If signs/symptoms of excessive opioid effects (eg,
respiratory depression) occur, immediately remove the dosage unit from the patient's mouth,
dispose of properly, and reduce subsequent doses.
Injection: There are no dosage adjustments provided in the manufacturer’s labeling; however, the following
guidelines have been used by some clinicians (Aronoff 2007):
Infants, Children, and Adolescents: The following assumes dosages of 0.5 to 2 mcg/kg/dose or 1 to 5
mcg/kg/hour in normal renal function: IV:
GFR >50 mL/minute/1.73 m2: No adjustment required
GFR 10 to 50 mL/minute/1.73 m2: Administer 75% of usual dose
GFR <10 mL/minute/1.73 m2: Administer 50% of usual dose
Intermittent hemodialysis: Administer 50% of usual dose
Peritoneal dialysis (PD): Administer 50% of usual dose
Continuous renal replacement therapy (CRRT): Administer 75% of usual dose
Injection: There are no dosage adjustments provided in the manufacturer’s labeling.
• CNS depression:
• Hypotension
• Respiratory depression.
• Serotonin syndrome: May occur with concomitant use of serotonergic agents (eg, SSRIs, SNRIs, triptans, TCAs),
lithium, St John's wort, agents that impair metabolism of serotonin (eg, MAO inhibitors), or agents that
impair metabolism of tramadol (eg, CYP2D6 and 3A4 inhibitors). Monitor patients for symptoms of
serotonin syndrome such as mental status changes (eg, agitation, hallucinations, coma); autonomic
instability (eg, tachycardia, labile blood pressure, hyperthermia); neuromuscular changes (eg, hyperreflexia,
incoordination); and/or GI symptoms (eg, nausea, vomiting, diarrhea).
• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.
• Adrenocortical insufficiency: Use with caution in patients with adrenal insufficiency, including Addison's disease.
Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction,
infertility, mood disorders, and osteoporosis (Brennan 2013).
• Allergic rhinitis: Intranasal: Allergic rhinitis is not expected to alter fentanyl absorption following nasal
administration; however, use of nasal decongestants (eg, oxymetazoline) during episodes of rhinitis may
result in lower peak concentrations and delayed Tmax, therefore, titration of intranasal fentanyl is not
recommended during use of nasal decongestants.
• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction, including acute pancreatitis;
may cause constriction of sphincter of Oddi.
• Bradycardia: Use with caution in patients with bradycardia or bradyarrhythmias (may produce further
bradycardia).
• CNS depression/coma: Avoid use in patients with impaired consciousness or coma as these patients are
susceptible to intracranial effects of CO2retention.
• Delirium tremens: Use with caution in patients with delirium tremens.
• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial
pressure (ICP); exaggerated elevation of ICP may occur.
• Hepatic impairment: Use with caution in patients with hepatic impairment. Avoid transdermal (patch) in
patients with severe hepatic impairment.
• Mental health conditions: Use opioids with caution for chronic pain in patients with mental health conditions
(eg, depression, anxiety disorders, post-traumatic stress disorder) due to increased risk for opioid use
disorder and overdose; more frequent monitoring is recommended (Dowell [CDC 2016]).
• Obesity: Use with caution in patients who are morbidly obese.
• Oral mucositis: Sublingual spray (Subsys): Cancer patients with oral mucositis experienced increased fentanyl
exposure following sublingual spray administration; avoid use in patients with ≥ grade 2 mucositis; use with
caution in patients with grade 1 mucositis, and closely monitor for respiratory and CNS depression.
• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary
stricture.
• Psychosis: Use with caution in patients with toxic psychosis.
• Renal impairment: Use with caution in patients with renal impairment.
• Respiratory disease: Use with caution and monitor for respiratory depression in patients with significant chronic
obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory
reserve, hypoxia, hypercapnia, or preexisting respiratory depression, particularly when initiating and
titrating therapy; critical respiratory depression may occur, even at therapeutic dosages. Consider the use
of alternative nonopioid analgesics in these patients.
• Seizures: Use with caution in patients with a history of seizure disorders; may cause or exacerbate seizures.
• Sleep-disordered breathing: Use opioids with caution for chronic pain and titrate dosage cautiously in patients
with risk factors for sleep-disordered breathing, including HF and obesity. Avoid opioids in patients with
moderate to severe sleep-disordered breathing (Dowell [CDC 2016]).
• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.
• Benzodiazepines or other CNS depressants: [US Boxed Warning]: Concomitant use of opioids with
benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation,
respiratory depression, coma, and death. Reserve concomitant prescribing of oxycodone/acetaminophen
and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment
options are inadequate. Limit dosage and durations to the minimum required and follow patients for
signs and symptoms of respiratory depression and sedation.
• Cachectic or debilitated patients: Use with caution in cachectic or debilitated patients; there is a greater
potential for critical respiratory depression, even at therapeutic dosages. Consider the use of alternative
nonopioid analgesics in these patients.
• Neonates: Neonatal withdrawal syndrome: [US Boxed Warning]: Prolonged use of opioids during pregnancy
can cause neonatal withdrawal syndrome in the newborn which may be life-threatening if not
recognized and treated according to protocols developed by neonatology experts. If opioid use is
required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid
withdrawal syndrome and ensure that appropriate treatment will be available. Signs and symptoms
include irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea
and failure to gain weight. Onset, duration and severity depend on the drug used, duration of use, maternal
dose, and rate of drug elimination by the newborn.
• Injection: IV: Inject slowly over 1 to 2 minutes; rapid IV infusion may result in skeletal muscle and chest wall
rigidity, impaired ventilation, or respiratory distress/arrest; nondepolarizing skeletal muscle relaxant may
be required.
• Appropriate use: Chronic pain (outside of end-of-life or palliative care, active cancer treatment, sickle cell
disease, or medication-assisted treatment for opioid use disorder) in outpatient setting in adults: Opioids
should not be used as first-line therapy for chronic pain management (pain >3-month duration or beyond
time of normal tissue healing) due to limited short-term benefits, undetermined long-term benefits, and
association with serious risks (eg, overdose, MI, auto accidents, risk of developing opioid use disorder).
Preferred management includes nonpharmacologic therapy and nonopioid therapy (eg. NSAIDs,
acetaminophen, certain anticonvulsants and antidepressants). If opioid therapy is initiated, it should be
combined with nonpharmacologic and non-opioid therapy, as appropriate. Prior to initiation, known risks
of opioid therapy should be discussed and realistic treatment goals for pain/function should be established,
including consideration for discontinuation if benefits do not outweigh risks. Therapy should be continued
only if clinically meaningful improvement in pain/function outweighs risks. Therapy should be initiated at
the lowest effective dosage using immediate-release opioids (instead of extended-release/long-acting
opioids). Risk associated with use increases with higher opioid dosages. Risks and benefits should be re-
evaluated when increasing dosage to ≥50 morphine milligram equivalents (MME)/day orally; dosages ≥90
MME/day orally should be avoided unless carefully justified (Dowell [CDC 2016]).
• Optimal regimen: An opioid-containing analgesic regimen should be tailored to each patient's needs and based
upon the type of pain being treated (acute versus chronic), the route of administration, degree of tolerance
for opioids (naive versus chronic user), age, weight, and medical condition. The optimal analgesic dose
varies widely among patients; doses should be titrated to pain relief/prevention.
• Surgery: Opioids decrease bowel motility; monitor for decreased bowel motility in postop patients receiving
opioids. Use with caution in the perioperative setting; individualize treatment when transitioning from
parenteral to oral analgesics.
• Withdrawal: Concurrent use of mixed agonist/antagonist analgesics (eg, pentazocine, nalbuphine, butorphanol)
or partial agonist (eg, buprenorphine) analgesics may precipitate withdrawal symptoms and/or reduced
analgesic efficacy in patients following prolonged therapy with mu opioid agonists. Abrupt discontinuation
following prolonged use may also lead to withdrawal symptoms. Taper dose gradually when discontinuing.
Opioid withdrawal may occur after conversion of one dosage form to another or after dosage adjustment; with
prolonged use, taper dose to prevent withdrawal symptoms. Neonates who receive a total fentanyl dose >1.6 mg/kg or
continuous infusion duration >5 days are more likely to develop opioid withdrawal symptoms; for infants and children 1
week to 22 months of age, those who receive a total dose of 1.5 mg/kg or duration >5 days have a 50% chance of
developing opioid withdrawal and those receiving a total dose >2.5 mg/kg or duration of infusion >9 days have a 100%
chance of developing withdrawal.
Dosage form specific:
Use transdermal patch in pediatric patients only if they are opioid-tolerant, receiving at least 60 mg oral morphine
equivalents per day, and ≥2 years of age.
Use of Actiq was evaluated in a clinical trial of 15 opioid-tolerant pediatric patients (age: 5 to 15 years) with
breakthrough pain; 12 of the 15 patients received doses of 200 mcg to 600 mcg; no conclusions about
safety and efficacy could be drawn due to the small sample size.
including hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Shehab 2009).

Intermittent doses or continuous IV infusion: May further dilute in NS or D5W. ISMP and Vermont Oxford Network
recommend a standard concentration of 10 mcg/mL for neonates (ISMP 2011).
Parenteral: IV:
Neonates: Administer by intermittent infusion very slowly over 15 to 30 minutes or by continuous IV infusion
(ISMP 2011).
Infants, Children, and Adolescents: Administer by slow IV push over 3 to 5 minutes or by continuous infusion.
Larger bolus doses (>5 mcg/kg) should be given by slow IV push over 5 to 10 minutes.
Respiratory rate, blood pressure, heart rate, oxygen saturation, bowel sounds, abdominal distention; signs of misuse,
abuse, or addiction; signs or symptoms of hypogonadism or hypoadrenalism (Brennan 2013)
Drug Interactions
Alpha-/Beta-Agonists (Indirect-Acting): May decrease the serum concentration of FentaNYL. Specifically, fentanyl nasal
spray serum concentrations may decrease and onset of effect may be delayed. Risk C: Monitor therapy
Alpha1-Agonists: May decrease the serum concentration of FentaNYL. Specifically, fentanyl nasal spray serum
concentrations may decrease and onset of effect may be delayed. Exceptions: Midodrine; Naphazoline
(Ophthalmic); Phenylephrine (Ophthalmic); Phenylephrine (Topical). Risk C: Monitor therapy
Amphetamines: May enhance the analgesic effect of Opioid Agonists. Risk C: Monitor therapy
Anticholinergic Agents: May enhance the adverse/toxic effect of Opioid Agonists. Specifically, the risk for constipation
and urinary retention may be increased with this combination. Risk C: Monitor therapy
Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonin Modulators. This could result in
serotonin syndrome. Risk C: Monitor therapy
Antiplatelet Agents (P2Y12 Inhibitors): FentaNYL may diminish the antiplatelet effect of Antiplatelet Agents (P2Y12
Inhibitors). FentaNYL may decrease the serum concentration of Antiplatelet Agents (P2Y12 Inhibitors).Risk C:
Monitor therapy
Beta-Blockers: Opioids (Anilidopiperidine) may enhance the bradycardic effect of Beta-Blockers. Opioids
(Anilidopiperidine) may enhance the hypotensive effect of Beta-Blockers. Risk C: Monitor therapy
Calcium Channel Blockers (Nondihydropyridine): Opioids (Anilidopiperidine) may enhance the bradycardic effect of
Calcium Channel Blockers (Nondihydropyridine). Opioids (Anilidopiperidine) may enhance the hypotensive effect
of Calcium Channel Blockers (Nondihydropyridine). Risk C: Monitor therapy
CNS Depressants: May enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of
opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be
combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each
drug. Risk D: Consider therapy modification
Desmopressin: Opioid Agonists may enhance the adverse/toxic effect of Desmopressin. Risk C: Monitor therapy
Diuretics: Opioid Agonists may enhance the adverse/toxic effect of Diuretics. Opioid Agonists may diminish the
therapeutic effect of Diuretics. Risk C: Monitor therapy
Avoid combination
Gastrointestinal Agents (Prokinetic): Opioid Agonists may diminish the therapeutic effect of Gastrointestinal Agents
(Prokinetic). Risk C: Monitor therapy
Metoclopramide: Serotonin Modulators may enhance the adverse/toxic effect of Metoclopramide. This may be manifest
as symptoms consistent with serotonin syndrome or neuroleptic malignant syndrome. Risk C: Monitor therapy
Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid
concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents
duration of each drug.Risk D: Consider therapy modification
Opioids (Mixed Agonist / Antagonist): May diminish the analgesic effect of Opioid Agonists. Management: Seek
alternatives to mixed agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for
symptoms of therapeutic failure/high dose requirements (or withdrawal in opioid-dependent patients) if patients
receive these combinations. Risk X: Avoid combination
PHENobarbital: May enhance the CNS depressant effect of FentaNYL. PHENobarbital may decrease the serum
concentration of FentaNYL. Management: Avoid use of fentanyl and phenobarbital when possible. Monitor for
respiratory depression/sedation. Because phenobarbital is also a strong CYP3A4 inducer, monitor for decreased
fentanyl efficacy and withdrawal if combined. Risk D: Consider therapy modification
Succinylcholine: May enhance the bradycardic effect of Opioid Agonists. Risk C: Monitor therapy
Onset of action:
Children 3 to 12 years: Intranasal: 5 to 10 minutes (Borland 2002)

Adults: Analgesic: IM: 7 to 8 minutes; IV: Almost immediate (maximal analgesic and respiratory depressant effects
may not be seen for several minutes); Transdermal patch (initial placement): 6 hours; Transmucosal: 5 to
15 minutes
Duration: IM: 1 to 2 hours; IV: 0.5 to 1 hour; Transdermal (removal of patch/no replacement): Related to blood level;
some effects may last 72 to 96 hours due to extended half-life and absorption from the skin, fentanyl
concentrations decrease by ~50% in 20 to 27 hours; Transmucosal: Related to blood level; respiratory depressant
effect may last longer than analgesic effect
Distribution: Highly lipophilic, redistributes into muscle and fat; Note: IV fentanyl exhibits a 3-compartment distribution
model. Changes in blood pH may alter ionization of fentanyl and affect its distribution between plasma and CNS
Vdss: Children: 0.05 to 14 years of age (after long-term continuous infusion): ~15 L/kg (range: 5 to 30 L/kg)
Vdss: Adults: 4 to 6 L/kg
Protein binding: 79% to 87%, primarily to alpha-1 acid glycoprotein; also binds to albumin and erythrocytes; Note: Free
fraction increases with acidosis
Metabolism: Hepatic, primarily via CYP3A4 by N-dealkylation (to norfentanyl) and hydroxylation to other inactive
metabolites
Bioavailability: Note: Comparative studies have found the buccal film to have a 40% greater systemic exposure (ie, AUC)
than the transmucosal lozenge, and the buccal tablet to have a 30% to 50% greater exposure than the
transmucosal lozenge.
Buccal film: 71% (mucositis did not have a clinically significant effect on Cmax and AUC; however, bioavailability is
expected to decrease if film is inappropriately chewed and swallowed)
Buccal tablet: 65%
Lozenge: ~50%
Sublingual spray: 76%
Sublingual tablet: 54%
IV:
Pediatric patients 5 months to 4.5 years: 2.4 hours
Pediatric patients 6 months to 14 years (after long-term continuous infusion): ~21 hours (range: 11-36
hours)
Adults: 2 to 4 hours; when administered as a continuous infusion, the half-life prolongs with infusion
duration due to the large volume of distribution (Sessler 2008)
SubQ bolus injection: 10 hours (Capper 2010)
Transdermal device: Terminal: ~16 hours
Transdermal patch: 20 to 27 hours (apparent half-life is influenced by continued fentanyl absorption from skin)
Transmucosal products: 3 to 14 hours (dose dependent)
Intranasal: 15 to 25 hours (based on a multiple-dose pharmacokinetic study when doses are administered in the
same nostril and separated by a 1-, 2-, or 4-hour time lapse)
Buccal film: ~14 hours
Buccal tablet: 100-200 mcg: 3 to 4 hours; 400 to 800 mcg: 11 to 12 hours
Time to peak:
Buccal film: 0.75 to 4 hours (median: 1 hour)
Buccal tablet: 20 to 240 minutes (median: 47 minutes)
Lozenge: 20 to 480 minutes (median: 20 to 40 minutes)
Intranasal: Median: 15 to 21 minutes
SubQ bolus injection: 10 to 30 minutes (median: 15 minutes) (Capper 2010)
Sublingual spray: 10 to 120 minutes (median: 90 minutes)
Sublingual tablet: 15 to 240 minutes (median: 30 to 60 minutes)
Transdermal patch: 20 to 72 hours; steady state serum concentrations are reached after two sequential 72-hour
applications
Excretion: Urine 75% (primarily as metabolites, <7% to 10% as unchanged drug); feces ~9%
Clearance: Newborn infants: Clearance may be significantly correlated to gestational age and birth weight
(Saarenmaa 2000)
Renal function impairment: May alter kinetics because of alterations in clearance and plasma proteins.
Hepatic function impairment: May alter kinetics because of alterations in clearance and plasma proteins.
Pediatric: Plasma concentrations with transdermal use were approximately twice as high in pediatric patients 1.5 to 5
years of age, who are not opioid-tolerant, compared with adults. Pharmacokinetic parameters in older pediatric
patients were similar to those seen in adults.
Geriatric: Reduced clearance and terminal half-life is prolonged (transdermal).
Gender: Systemic exposure was higher in women after administration of buccal fentanyl (Fentora); this difference was
largely attributed to differences in weight.
Race: Systemic exposure was higher in Japanese subjects after administration of buccal fentanyl (Fentora); this
difference was largely attributed to differences in weight.
Adverse Reactions
Cardiovascular: Atrial fibrillation, bigeminy, cardiac arrhythmia, chest pain, deep vein thrombosis, edema, hypertension,
hypotension, myocardial infarction, orthostatic hypotension, palpitations, peripheral edema, pulmonary
embolism (nasal spray), sinus tachycardia, syncope, tachycardia, vasodilatation
Central nervous system: Abnormal dreams, abnormal gait, abnormality in thinking, agitation, altered sense of smell,
amnesia, anxiety, ataxia, chills, confusion, depression, disorientation, dizziness, drowsiness, dysphoria, euphoria,
fatigue, hallucination, headache, hypertonia, hypoesthesia, hypothermia, insomnia, irritability, lack of
concentration, lethargy, malaise, mental status changes, migraine, nervousness, neuropathy, paranoia,
paresthesia, restlessness, sedated state, speech disturbance, stupor, vertigo, withdrawal syndrome
Dermatologic: Alopecia, cellulitis, decubitus ulcer, diaphoresis, erythema, exfoliation of skin (application site,
transdermal device), hyperhidrosis, night sweats, pallor, papule (application site, transdermal device), pruritus,
pustules (application site, transdermal device), skin rash, vesicobullous rash (application site, transdermal device)
Endocrine & metabolic: Dehydration, hot flash, hypercalcemia, hyperglycemia, hypoalbuminemia, hypocalcemia,
hypokalemia, hypomagnesemia, hyponatremia, weight loss
Gastrointestinal: Abdominal distention, abdominal pain, anorexia, constipation, decreased appetite, diarrhea, dysgeusia,
dyspepsia, dysphagia (buccal tablet/film/sublingual spray), flatulence, gastritis, gastroenteritis, gastroesophageal
reflux disease, gastrointestinal hemorrhage, gastrointestinal ulcer (gingival, lip, mouth; transmucosal use/nasal
spray), gingival pain (buccal tablet), gingivitis (lozenge), glossitis (lozenge), hematemesis, intestinal obstruction,
nausea, periodontal abscess (lozenge/buccal tablet), rectal pain, stomatitis (lozenge/buccal tablet/sublingual
tablet/sublingual spray), tongue disease (sublingual tablet), vomiting, xerostomia
Genitourinary: Difficulty in micturition, dysuria, erectile dysfunction, mastalgia, urinary incontinence, urinary retention,
urinary tract infection, urinary urgency, vaginal hemorrhage, vaginitis
Hematologic & oncologic: Anemia, bruise, leukopenia, lymphadenopathy, neutropenia, thrombocytopenia
Hepatic: Ascites, increased serum alkaline phosphatase, increased serum AST, jaundice
Infection: Abscess
Local: Application site burning (transdermal device), application site discharge (transdermal device), application site
edema (transdermal device), application site erythema (transdermal device), application site irritation, application
site itching (transdermal device), application site pain, application site rash (transdermal device), application site
vesicles (transdermal device)
Neuromuscular & skeletal: Arthralgia, asthenia, back pain, limb pain, lower limb cramp, myalgia, tremor
Ophthalmic: Blepharoptosis, blurred vision, diplopia, dry eye syndrome, strabismus, swelling of eye, visual disturbance
Renal: Renal failure syndrome
Respiratory: Apnea, asthma, atelectasis, bronchitis, cough, dyspnea, dyspnea on exertion, epistaxis, flu-like symptoms,
hemoptysis, hyperventilation, hypoventilation, hypoxia, laryngitis, nasal congestion (nasal spray), nasal discomfort
(nasal spray), nasopharyngitis, pharyngitis, pharyngolaryngeal pain, pneumonia, post nasal drip (nasal spray),
rhinitis, rhinorrhea (nasal spray), sinusitis, upper respiratory tract infection, wheezing
Rare but important or life-threatening: Allergic dermatitis, anaphylactoid shock, angina pectoris, bradycardia,
bronchoconstriction, chest wall rigidity, clonus, cyanosis, drug dependence (physical and psychological; with
prolonged use), eczema, esophageal stenosis, exfoliative dermatitis, fecal impaction, flushing, genitourinary tract
spasm, gingival hemorrhage, gingival recession, hematuria, hostility, hypoglycemia, hypogonadism (Brennan
2013; Debono 2011), impaired consciousness, local hemorrhage, local hypersensitivity reaction, localized
infection, local tissue necrosis, loss of consciousness, muscle spasm, muscle twitching, nocturia, oliguria,
pancytopenia, pleural effusion, polyuria, respiratory distress, seizure, sexual disorder, skin erosion, Stevens-
Johnson syndrome, swelling, swollen tongue, tonic-clonic epilepsy, tooth loss, upper abdominal pain
FUROSEMIDA
Dosing: Neonatal
Note: Oral and parenteral (IV, IM) doses may not be interchangeable; due to differences in bioavailability, oral doses are
typically higher than IV. Oral solution is available in multiple concentrations (8 mg/mL and 10 mg/mL); extra precautions
should be taken to verify and avoid confusion between the different concentrations; dose should be clearly presented as
mg (not mL).
Edema (diuresis): Note: Dosing information is limited in neonates, close monitoring is suggested, especially in patients
with very low birth weight, as accumulation can occur and increase risk of toxicity (Chemtob 1989; Mirochnick
1988).
Oral:
PMA <31 weeks: Usual dose: 1 mg/kg/dose; reported range: 0.5 to 2 mg/kg/dose every 24 hours
(Mirochnick 1988; Pacifici 2013; van der Vorst 2006); a longitudinal, pharmacokinetic study observed
drug accumulation and increased risk of toxicity with doses >2 mg/kg/dose administered more
frequently than every 24 hours (Mirochnick 1988)
PMA ≥31 weeks: Usual dose: 1 mg/kg/dose; reported range: 0.5 to 2 mg/kg/dose every 12 hours
(MacDonald 2016; Mirochnick 1988; Pacifici 2013; van der Vorst 2006; Wells 1990)
Parenteral:
IM, intermittent IV:

PMA <31 weeks: Usual dose: 1 mg/kg/dose every 24 hours; reported range: 0.5 to 2 mg/kg/dose
every 24 hours (Chemtob 1989; Eichenwald 2017; Mirochnick 1988; Pacifici 2013; van der
Vorst 2006); a longitudinal, pharmacokinetic study observed drug accumulation and increased
risk of toxicity with doses of 1 mg/kg/dose administered more frequently than every 24 hours
(Mirochnick 1988).
PMA ≥31 weeks and Term neonates: Usual dose: 1 mg/kg/dose every 12 to 24 hours; reported
range: 0.5 to 2 mg/kg/dose every 12 to 24 hours (Chemtob 1989; Eichenwald 2017;
MacDonald 2016; Mirochnick 1988; Pacifici 2013; van der Vorst 2006; Wells 1990)
Continuous IV infusion: Term neonates: Initial IV bolus dose (optional): 1 to 2 mg/kg, followed by
continuous IV infusion at a reported rate range of 0.1 to 0.4 mg/kg/hour. In most clinical trials,
infusions were initiated at 0.1 to 0.2 mg/kg/hour and titrated based on urine output every 12 to 24
hours in 0.1 mg/kg/hourincrements up to the maximum of 0.4 mg/kg/hour (Schoemaker 2002; van
der Vorst 2001).
Chronic lung disease (improve pulmonary mechanics):Limited data available; efficacy results variable and most experts
do not suggest inhaled furosemide in the overall management of chronic lung disease (Brion 2006; MacDonald
2016): Inhalation: 1 to 2 mg/kg/dose diluted in 2 mL NS as a single dose (Brion 2006); others have suggested
doses of 1 mg/kg/dose every 6 hours; however, long-term benefits have not been established (Pacifici 2013).
Dosing: Pediatric
Note: Oral and parenteral (IV, IM) doses may not be interchangeable; due to differences in bioavailability, oral doses are
typically higher than IV. Oral solution is available in multiple concentrations (8 mg/mL and 10 mg/mL); extra precautions
should be taken to verify and avoid confusion between the different concentrations; dose should be clearly presented as
mg (not mL). Oral dose equivalency for adult patients with normal renal function (approximate): Furosemide 40 mg =
bumetanide 1 mg = torsemide 20 mg = ethacrynic acid 50 mg (Brater 1983; Cody 1994; Vargo 1995)
Edema (diuresis):
Oral: Infants, Children, and Adolescents: Limited data available: Initial: 0.5 to 2 mg/kg/dose every 6 to 24 hours;
usual initial adult dose: 20 to 80 mg/dose; if initial dose ineffective, may increase dose in increments of 1 to
2 mg/kg/dose; maximum daily dose: 6 mg/kg/day not to exceed maximum adult daily dose: 600 mg/day;
adjust dose to minimal effective dose for maintenance (Flynn 2011; Kliegman 2016; NHBPEP 2004; van der
Vorst 2006). Note: Smaller doses on a mg/kg basis may be needed in larger children, especially in those
who are diuretic naive.
IM, intermittent IV: Infants, Children, and Adolescents: Limited data available: Initial: 0.5 to 2 mg/kg/dose every 6
to 12 hours; usual initial adult dose: 20 to 40 mg/dose; if initial dose ineffective after 2 hours, may increase
dose by 1 mg/kg/dose; maximum dose: 6 mg/kg/dose not to exceed maximum adult dose: 200 mg/dose;
adjust to minimal effective dose for maintenance (Brater 1998; Fuhrman 2017; Kliegman 2016; van der
Vorst 2006; Wells 1990). Note: Smaller doses on a mg/kg basis may be needed in larger children, especially
in those who are diuretic naive. Dosing in adolescents based on experience in adult and pediatric patients.
Continuous IV infusion:
Infants and Children: Limited data available: Initial: IV bolus dose of 0.1 mg/kg followed by continuous IV
infusion of 0.05 to 0.4 mg/kg/hour; titrate dosage to clinical effect (Copeland 1983; Luciani 1997;
Singh 1992; van der Vorst 2001)
Adolescents: Very limited data available; dosing in adolescents based on reported experience in adult and
pediatric patients (ACCF/AHA [Yancy 2013]); Brater 1998; Copeland 1983; Howard 2001; Luciani
1997; Singh 1992; van der Vorst 2001): IV bolus dose of 0.1 mg/kg; usual adult bolus dose: 40 to 100
mg over 1 to 2 minutes; followed by continuous IV infusion of 0.1 to 0.4 mg/kg/hour; usual adult
dosing range: 10 to 40 mg/hour.
There are no pediatric specific recommendations; in adults with acute renal failure, very high doses may be necessary to
initiate diuretic effect; avoid use in oliguric states.
Dialysis: Not removed by hemo- or peritoneal dialysis; supplemental dose is not necessary.
Diminished natriuretic effect with increased sensitivity to hypokalemia and volume depletion in cirrhosis; monitor
effects, particularly with high doses
Contraindications
Hypersensitivity to furosemide or any component of the formulation; anuria
Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to sulfonamide-derived drugs;

complete renal shutdown; hepatic coma and precoma; uncorrected states of electrolyte depletion, hypovolemia,
dehydration, or hypotension; jaundiced newborn infants or infants with disease(s) capable of causing
hyperbilirubinemia and possibly kernicterus; breast-feeding. Note: Manufacturer labeling for Lasix Special and
Furosemide Special Injection also includes: GFR <5 mL/minute or GFR >20 mL/minute; hepatic cirrhosis; renal
failure accompanied by hepatic coma and precoma; renal failure due to poisoning with nephrotoxic or
hepatotoxic substances.
Note: Although the approved product labeling states this medication is contraindicated with other sulfonamide-
containing drug classes, the scientific basis of this statement has been challenged. See
“Warnings/Precautions” for more detail.
• Fluid/electrolyte loss: [US Boxed Warning]: If given in excessive amounts, furosemide, similar to other loop
diuretics, can lead to profound diuresis, resulting in fluid and electrolyte depletion. Close medical
supervision and dose evaluation are required. Watch for and correct electrolyte disturbances; adjust dose
to avoid dehydration. When electrolyte depletion is present, therapy should not be initiated unless serum
electrolytes, especially potassium, are normalized. Risk of hypokalemia may be increased by: rapid diuresis,
poor oral potassium intake, cirrhosis, and combined use with large amounts of licorice, corticosteroids, or
laxatives (chronic use). In contrast to thiazide diuretics, a loop diuretic can also lower serum calcium
concentrations. Electrolyte disturbances can predispose a patient to serious cardiac arrhythmias.
• Hyperuricemia: Asymptomatic hyperuricemia has been reported with use; rarely, may precipitate gout.
• Nephrotoxicity: Monitor fluid status and renal function in an attempt to prevent oliguria, azotemia, and
reversible increases in BUN and creatinine; close medical supervision of aggressive diuresis required. May
increase risk of radiocontrast-induced nephropathy in high-risk patients.
• Ototoxicity: Rapid IV administration, severe renal impairment, excessive doses, hypoproteinemia, and
concurrent use of other ototoxins is associated with ototoxicity.
• Photosensitivity: Photosensitization may occur.
• Sulfonamide (“sulfa”) allergy: The approved product labeling for many medications containing a sulfonamide
chemical group includes a broad contraindication in patients with a prior allergic reaction to sulfonamides.
There is a potential for cross-reactivity between members of a specific class (eg, two antibiotic
sulfonamides). However, concerns for cross-reactivity have previously extended to all compounds
containing the sulfonamide structure (SO2NH2). An expanded understanding of allergic mechanisms
indicates cross-reactivity between antibiotic sulfonamides and nonantibiotic sulfonamides may not occur or
at the very least this potential is extremely low (Brackett 2004; Johnson 2005; Slatore 2004; Tornero 2004).
In particular, mechanisms of cross-reaction due to antibody production (anaphylaxis) are unlikely to occur
with nonantibiotic sulfonamides. T-cell-mediated (type IV) reactions (eg, maculopapular rash) are less well
understood and it is not possible to completely exclude this potential based on current insights. In cases
where prior reactions were severe (Stevens-Johnson syndrome/TEN), some clinicians choose to avoid
exposure to these classes.
• Thyroid effects: Doses >80 mg may result in transient increase in free thyroid hormones, followed by an overall
decrease in total thyroid hormone levels.
• Adrenal insufficiency: Avoid use of diuretics for treatment of elevated blood pressure in patients with primary
adrenal insufficiency (Addison disease). Adjustment of glucocorticoid/mineralocorticoid therapy and/or use
of other antihypertensive agents is preferred to treat hypertension (Bornstein 2016; Inder 2015).
• Cirrhosis: In cirrhosis, avoid electrolyte and acid/base imbalances that might lead to hepatic encephalopathy;
correct electrolyte and acid/base imbalances prior to initiation when hepatic coma is present.
Supplemental potassium or an aldosterone antagonist, when appropriate, may reduce risk of hypokalemia
and metabolic alkalosis. Close monitoring warranted, especially with initiation of therapy.
• Diabetes: Use with caution in patients with prediabetes or diabetes mellitus; may see a change in glucose
control.
• Prostatic hyperplasia/urinary stricture: May cause urinary retention due to increased urine production,
especially upon initiation of therapy.
• Systemic lupus erythematosus (SLE): May cause SLE exacerbation or activation.
• Pediatric: May lead to nephrocalcinosis or nephrolithiasis in premature infants and in infants and children <4
years of age with chronic use. May prevent closure of patent ductus arteriosus in premature infants.
• Surgical patients: If given the morning of surgery, furosemide may render the patient volume depleted and
blood pressure may be labile during general anesthesia.
(AAP 1997; Zar 2007).
Other warnings and precautions:
• Diuretic resistance: For some patients, despite higher doses of loop diuretic treatment, an adequate diuretic
response cannot be attained. Diuretic resistance can usually be overcome by intravenous administration,
the use of two diuretics together (eg, furosemide and chlorothiazide), or the use of a diuretic with a
positive inotropic agent. When such combinations are used, serum electrolytes need to be monitored even
more closely (ACC/AHA [Yancy 2013]; Cody 1994; HFSA 2010).
Premature very low birth weight (VLBW) neonates are at increased risk for toxicity (eg, ototoxicity) due to immature
renal function allowing for elevated plasma concentrations if dosed too frequently. A pharmacokinetic study in
premature neonates (n=10, birthweight <1,250 g, GA 26.6 ± 2.9 weeks) reported drug accumulation and increased risk of
toxicity in premature neonates PMA ≤31 weeks with doses given more frequently than every 24 hours; more frequent
dosing of every 12 hours can be administered in premature neonates PMA >32 weeks due to maturing renal function
(Mirochnick 1988).
Furosemide stimulates prostaglandin E2 (PGE2) which may prevent closure of patent ductus arteriosus (PDA) in
premature infants. However, one large, retrospective cohort study involving 43,576 VLBW infants (median birth weight
and GA: 1,120 g and 29 weeks) evaluated the association between the exposure to furosemide and the occurrence of
PDA. Exposure to furosemide was not associated with an increased odds of PDA treatment (Thompson 2018). Another
smaller placebo-controlled study (n=68, GA <34 weeks, birth weight <2,000 g) found no difference in PDA closure rate
between patients treated with furosemide or placebo in combination with indomethacin (Lee 2010).
Parenteral: IV: May be further diluted in NS or D5W to a concentration of 1 to 2 mg/mL for IV infusion; maximum
concentration: 10 mg/mL. ISMP and Vermont Oxford Network recommend a standard concentration of 2 or 10 mg/mL
for neonates (ISMP 2011).
Oral: May administer with food or milk to decrease GI distress

Parenteral: IV: May be administered undiluted direct IV at a maximum rate of 0.5 mg/kg/minute (not to exceed 4
mg/minute); may also be diluted and infused over 10 to 15 minutes (following maximum rate as above); in adults,
20 to 40 mg undiluted solution may be administered over 1 to 2 minutes
May cause potassium loss; potassium supplement or dietary changes may be required.
Serum electrolytes (baseline and frequently during therapy); blood pressure; urine output and renal function
parameters (baseline and frequently during therapy); fluid balance (body weight; neonatal and young pediatric patients
may require more frequent monitoring than older patients); hearing (with high doses or extended duration)
Drug Interactions
Allopurinol: Loop Diuretics may enhance the adverse/toxic effect of Allopurinol. Loop Diuretics may increase the serum
concentration of Allopurinol. Specifically, Loop Diuretics may increase the concentration of Oxypurinol, an active
metabolite of Allopurinol. Risk C: Monitor therapy
Amikacin (Oral Inhalation): Loop Diuretics may enhance the nephrotoxic effect of Amikacin (Oral Inhalation). Loop
Diuretics may enhance the ototoxic effect of Amikacin (Oral Inhalation). Risk C: Monitor therapy
Aminoglycosides: Loop Diuretics may enhance the adverse/toxic effect of Aminoglycosides. Specifically, nephrotoxicity
and ototoxicity. Risk C: Monitor therapy
Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Angiotensin-Converting Enzyme Inhibitors: Loop Diuretics may enhance the hypotensive effect of Angiotensin-
Converting Enzyme Inhibitors. Loop Diuretics may enhance the nephrotoxic effect of Angiotensin-Converting
Enzyme Inhibitors. Risk C: Monitor therapy
Monitor therapy
Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive
effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapy
Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Beta2-Agonists: May enhance the hypokalemic effect of Loop Diuretics. Risk C: Monitor therapy
Cardiac Glycosides: Loop Diuretics may enhance the adverse/toxic effect of Cardiac Glycosides. Specifically, cardiac
glycoside toxicity may be enhanced by the hypokalemic and hypomagnesemic effect of loop diuretics. Risk C:
Monitor therapy
Cefazedone: May enhance the nephrotoxic effect of Loop Diuretics. Risk C: Monitor therapy
Cefotiam: Loop Diuretics may enhance the nephrotoxic effect of Cefotiam. Risk C: Monitor therapy
Cefpirome: Loop Diuretics may enhance the nephrotoxic effect of Cefpirome. Risk C: Monitor therapy
Ceftizoxime: Loop Diuretics may enhance the nephrotoxic effect of Ceftizoxime. Risk C: Monitor therapy
Cephalothin: Loop Diuretics may enhance the nephrotoxic effect of Cephalothin. Risk C: Monitor therapy
Cephradine: May enhance the nephrotoxic effect of Loop Diuretics. Risk C: Monitor therapy
Chloral Hydrate: Furosemide may enhance the adverse/toxic effect of Chloral Hydrate. Risk X: Avoid combination
CISplatin: Loop Diuretics may enhance the nephrotoxic effect of CISplatin. Loop Diuretics may enhance the ototoxic
effect of CISplatin. Risk C: Monitor therapy
Corticosteroids (Orally Inhaled): May enhance the hypokalemic effect of Loop Diuretics. Risk C: Monitor therapy
Corticosteroids (Systemic): May enhance the hypokalemic effect of Loop Diuretics. Risk C: Monitor therapy
CycloSPORINE (Systemic): May enhance the adverse/toxic effect of Loop Diuretics. Risk C: Monitor therapy
Desmopressin: Loop Diuretics may enhance the hyponatremic effect of Desmopressin. Risk X: Avoid combination
Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Fosphenytoin: May diminish the diuretic effect of Loop Diuretics. Risk C: Monitor therapy
Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-
Associated Agents. Risk C: Monitor therapy
Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-
Containing Products. Risk C: Monitor therapy
Methotrexate: May diminish the therapeutic effect of Loop Diuretics. Loop Diuretics may increase the serum
concentration of Methotrexate. Methotrexate may increase the serum concentration of Loop Diuretics.
Management: Monitor for increased methotrexate and/or loop diuretic levels/toxicity with concomitant use of
these agents and monitor for decreased therapeutic effects of loop diuretics. Methotrexate and/or loop diuretic
dose reductions may be necessary.Risk D: Consider therapy modification
Neuromuscular-Blocking Agents: Loop Diuretics may diminish the neuromuscular-blocking effect of Neuromuscular-
Blocking Agents. Loop Diuretics may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking
Agents. Risk C: Monitor therapy
Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor
therapy
Nonsteroidal Anti-Inflammatory Agents: May diminish the diuretic effect of Loop Diuretics. Loop Diuretics may enhance
the nephrotoxic effect of Nonsteroidal Anti-Inflammatory Agents. Management: Monitor for evidence of kidney
injury or decreased therapeutic effects of loop diuretics with concurrent use of an NSAID. Consider avoiding
concurrent use in CHF or cirrhosis. Concomitant use of bumetanide with indomethacin is not recommended. Risk
Phenytoin: May diminish the diuretic effect of Loop Diuretics. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents.Risk C: Monitor
therapy
Probenecid: May enhance the adverse/toxic effect of Loop Diuretics. Probenecid may diminish the diuretic effect of
Loop Diuretics. Probenecid may increase the serum concentration of Loop Diuretics. Management: Monitor for
decreased diuretic effects or increased adverse effects of loop diuretics with concomitant use of probenecid.
Bumetanide prescribing information recommends against concomitant use of probenecid.Risk C: Monitor therapy
RisperiDONE: Loop Diuretics may enhance the adverse/toxic effect of RisperiDONE. Risk C: Monitor therapy
Salicylates: May diminish the diuretic effect of Loop Diuretics. Loop Diuretics may increase the serum concentration of
Salicylates. Risk C: Monitor therapy
Sodium Phosphates: Diuretics may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute
phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily
suspending treatment with diuretics, or seeking alternatives to oral sodium phosphate bowel preparation. If the
combination cannot be avoided, hydrate adequately and monitor fluid and renal status.Risk D: Consider therapy
modification
Sucralfate: May decrease the serum concentration of Furosemide. Sucralfate may impair the absorption of furosemide.
Management: Avoid concomitant oral administration of furosemide and sucralfate. Separate administration by at
least 2 hours. Does not apply to parenterally administered furosemide. Risk D: Consider therapy modification
Tobramycin (Oral Inhalation): Loop Diuretics may enhance the nephrotoxic effect of Tobramycin (Oral Inhalation). Loop
Diuretics may enhance the ototoxic effect of Tobramycin (Oral Inhalation). Risk C: Monitor therapy
Food Interactions
Furosemide serum levels may be decreased if taken with food. Management: Administer on an empty stomach.
Test Interactions
May lead to false-negative aldosterone/renin ratio (ARR) (Funder 2016).
Adverse Reactions
Cardiovascular: Necrotizing angiitis, orthostatic hypotension, thrombophlebitis, vasculitis
Central nervous system: Dizziness, headache, paresthesia, restlessness, vertigo
Dermatologic: Acute generalized exanthematous pustulosis, bullous pemphigoid, erythema multiforme, exfoliative
dermatitis, pruritus, skin photosensitivity, skin rash, Stevens-Johnson syndrome, toxic epidermal necrolysis,
urticaria
Endocrine & metabolic: Glycosuria, hyperglycemia, hyperuricemia, increased serum cholesterol, increased serum
triglycerides
Gastrointestinal: Abdominal cramps, anorexia, constipation, diarrhea, gastric irritation, mouth irritation, nausea,
pancreatitis, vomiting
Genitourinary: Bladder spasm
Hematologic & oncologic: Agranulocytosis, anemia, aplastic anemia, eosinophilia, hemolytic anemia, leukopenia,
purpura, thrombocytopenia
Hepatic: Hepatic encephalopathy, intrahepatic cholestatic jaundice, liver enzymes increased
Hypersensitivity: Anaphylaxis, anaphylactoid reaction, anaphylactic shock
Immunologic: DRESS syndrome
Local: Pain at injection site (following IM injection)
Neuromuscular & skeletal: Muscle spasm, weakness
Ophthalmic: Blurred vision, xanthopsia
Otic: Deafness, tinnitus
Renal: Interstitial nephritis (allergic), renal disease
HALOPERIDOL
Dosing: Pediatric
Note: Dosing should be individualized based on patient response. Gradually decrease dose to the lowest effective
maintenance dosage once a satisfactory therapeutic response is obtained.
Note: Dosing presented as fixed (mg) dosing and weight-based (mg/kg) dosing; use caution when prescribing and
dispensing.
Behavior disorders, nonpsychotic:
Children 3 to 12 years weighing 15 to 40 kg: Oral: Initial: 0.5 mg/day in 2 to 3 divided doses; may increase
by 0.5 mg every 5 to 7 days to usual maintenance range of 0.05 to 0.075 mg/kg/day in 2 to 3 divided
doses. Maintenance range calculates to a fixed dose of 0.75 to 3 mg/day in divided doses; maximum
dose not established; children with severe, nonpsychotic disturbance may require higher doses;
however, no improvement has been shown with doses >6 mg/day.
Children >40 kg and Adolescents: Limited data available: Oral: 0.5 to 15 mg/day in 2 to 3 divided doses;
begin at lower end of the range and may increase as needed (no more frequently than every 5 to 7
days); maximum daily dose: 15 mg/day. Note: Higher doses may be necessary in severe or refractory
cases (Kliegman 2011).
Delirium: Limited data available; optimal dose not established; Note: Reported experience in infants is very
limited and suggests that lower doses may be required. Infants ≥3 months, Children, and Adolescents: IV
(lactate, immediate release): Loading dose: 0.15 to 0.25 mg/dose infused slowly over 30 to 45 minutes
(Schieveld 2007); maintenance dose: 0.05 to 0.5 mg/kg/day in divided doses (Brown 1996; Schieveld 2007);
a retrospective review of 27 patients (ages: 3 months to 17 years) using this dosing showed the
signs/symptoms of delirium responded well to treatment in all patients; however, two patients
experienced dystonic reactions (Schieveld 2007). In a small case-series, loading doses of 0.025 to 0.1
mg/kg/dose administered every 10 minutes until sedation achieved (reported total haloperidol loading
dose: 0.09 to 0.25 mg/kg total) followed by maintenance doses of 0.06 to 0.45 mg/kg/day in divided doses
every 6 to 8 hours were described (n=5; age range: 9 months to 16 years); infants (n=2) were noted to
require lower doses (total loading dose: 0.09 to 0.1 mg/kg total; maintenance: 0.015 to 0.025 mg/kg/dose
every 6 hours); one patient experienced a dystonic reaction (Harrison 2002)
Psychotic disorders:
Children 3 to 12 years weighing 15 to 40 kg: Oral: Initial: 0.5 mg/day in 2 to 3 divided doses; increase by 0.5
mg every 5 to 7 days to usual maintenance range of 0.05 to 0.15 mg/kg/day in 2 to 3 divided doses
(maintenance range calculates to a fixed dose of 0.75 to 6 mg/day in divided doses); higher doses
may be necessary in severe or refractory cases; maximum dose not established; in adolescents, the
maximum daily dose is 15 mg/day (Kliegman 2011)
Children >40 kg and Adolescents: Limited data available: Oral: 0.5 to 15 mg/day in 2 to 3 divided doses;
begin at lower end of the range and may increase as needed (no more frequently than every 5 to 7
days); maximum daily dose: 15 mg/day (Kliegman 2011; Willner 1969). Note: Higher doses may be
necessary in severe or refractory cases (Kliegman 2011).
Agitation (acute); psychosis: Limited data available: Infants, Children, and Adolescents: IM, IV (lactate, immediate
release): 0.05 to 0.15 mg/kg; may be repeated hourly as needed; maximum dose: 5 mg/dose (Hegenbarth
2008)
Agitation (palliative care): Limited data available: Children ≥3 years and Adolescents: Oral: 0.01 mg/kg/dose 3
times daily as needed; to manage new-onset acute episode: 0.025 to 0.05 mg/kgonce then may repeat
0.025 mg/kg/dose in one hour as needed (Kliegman 2011)
Tourette syndrome:
Children 3 to 12 years weighing 15 to 40 kg: Oral:
Manufacturer's labeling: Initial: 0.5 mg/day in 2 to 3 divided doses; increase by 0.25 to 0.5 mg every
5 to 7 days to usual maintenance of 0.05 to 0.075 mg/kg/day in 2 to 3 divided doses
(maintenance range calculates to a fixed dose of 0.75 to 3 mg/day in divided doses); maximum
dose not established; however, no improvement has been shown with doses >6 mg/day in
patients with nonpsychotic disturbances
Alternate dosing: Limited data available: Initial: 0.25 to 0.5 mg/day in 2 to 3 divided doses titrated to
a usual daily dose range of 1 to 4 mg/day (Roessner 2011; Scahill 2006)
Children weighing >40 kg and Adolescents: Limited data available: Oral: 0.25 to 15 mg/day in 2 to 3 divided
doses; begin at lower end of the range and may increase as needed (no more frequently than every 5
to 7 days) (Kleigman 2011; Roessner 2011); usual dose range: 1 to 4 mg/day (Roessner 2011; Scahill
2006); maximum dose not established; however, no improvement has been shown with doses >6
mg/day in patients with nonpsychotic disturbances
Discontinuation of psychosis therapy: Children and Adolescents: The manufacturer and American Academy of Child and
Adolescent Psychiatry (AACAP), American Psychiatric Association (APA), Canadian Psychiatric Association (CPA),
National Institute for Health and Care Excellence (NICE), and World Federation of Societies of Biological Psychiatry
(WFSBP) guidelines recommend gradually tapering antipsychotics to avoid withdrawal symptoms and minimize
the risk of relapse (AACAP [McClellan 2007]; APA [Lehman 2004]; Cerovecki 2013; CPA 2005; NICE 2013; WFSBP
[Hasan 2012]); risk for withdrawal symptoms may be highest with highly anticholinergic or dopaminergic
antipsychotics (Cerovecki 2013). When stopping antipsychotic therapy in patients with schizophrenia, the CPA
guidelines recommend a gradual taper over 6 to 24 months and the APA guidelines recommend reducing the dose
by 10% each month (APA [Lehman 2004]; CPA 2005). Continuing antiparkinsonism agents for a brief period after
discontinuation may prevent withdrawal symptoms (Cerovecki 2013). When switching antipsychotics, three
strategies have been suggested: Cross-titration (gradually discontinuing the first antipsychotic while gradually
increasing the new antipsychotic), overlap and taper (maintaining the dose of the first antipsychotic while
gradually increasing the new antipsychotic, then tapering the first antipsychotic), and abrupt change (abruptly
discontinuing the first antipsychotic and either increasing the new antipsychotic gradually or starting it at a
treatment dose). Evidence supporting ideal switch strategies and taper rates is limited and results are conflicting
(Cerovecki 2013; Remington 2005).
Children ≥3 years and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling.
Hemodialysis/peritoneal dialysis: Supplemental dose is not necessary.
Children ≥3 years and Adolescents: There are no dosage adjustments provided in manufacturer's labeling.
Contraindications
Hypersensitivity to haloperidol or any component of the formulation; Parkinson disease; severe CNS depression; coma;
dementia with Lewy bodies
Canadian labeling: Additional contraindications (not in US labeling): Significant depressive states; previous spastic
diseases; young children
• Altered cardiac conduction: Cases of sudden death, QT prolongation, and torsades de pointes have been
reported with haloperidol use; risk may be increased with doses exceeding recommendations and/or
intravenous administration (off-label route) of intramuscular lactate injection. Use with caution or avoid
use in patients with electrolyte abnormalities (eg, hypokalemia, hypomagnesemia), hypothyroidism,
familial long QT syndrome, concomitant medications which may augment QT prolongation, or any
underlying cardiac abnormality which may also potentiate risk. Prior to initiation of intravenous therapy,
obtain a baseline ECG. Consider continuous ECG monitoring, especially if the patient has risk factors for QTc
prolongation, the baseline ECG reveals a prolonged QTc, or cumulative doses of ≥2 mg are needed. Monitor
electrolyte concentrations throughout therapy. If the baseline QTc interval increases by 20% to 25%,
increases >500 msec, or if T-waves flatten or U-waves develop on the ECG, reduce the dosage or consider
alternative therapy (Hassballa 2003; Meyer-Massetti 2010).
• Anticholinergic effects: May cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary
retention); use with caution in patients with decreased gastrointestinal motility, paralytic ileus, urinary
retention, BPH, xerostomia, or visual problems. Relative to other neuroleptics, haloperidol has a low
potency of cholinergic blockade (Richelson 1999).
• Blood dyscrasias: Leukopenia, neutropenia, and agranulocytosis (sometimes fatal) have been reported in clinical
trials and postmarketing reports with antipsychotic use; presence of risk factors (eg, preexisting low WBC
or history of drug-induced leuko-/neutropenia) should prompt periodic blood count assessment.
Discontinue therapy at first signs of blood dyscrasias or if absolute neutrophil count <1,000/mm 3.
cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).
• Esophageal dysmotility/aspiration: Antipsychotic use has been associated with esophageal dysmotility and
aspiration; risk increases with age. Use with caution in patients at risk for aspiration pneumonia (ie,
Alzheimer disease), particularly in patients >75 years of age (Herzig 2017; Maddalena 2004).
• Extrapyramidal symptoms: May cause extrapyramidal symptoms (EPS), including pseudoparkinsonism, acute
dystonic reactions, akathisia, and tardive dyskinesia. Risk of dystonia (and possibly other EPS) may be
greater with increased doses, use of conventional antipsychotics, males, and younger patients. Factors
associated with greater vulnerability to tardive dyskinesia include older in age, female gender combined
with postmenopausal status, Parkinson disease, pseudoparkinsonism symptoms, affective disorders
(particularly major depressive disorder), concurrent medical diseases such as diabetes, previous brain
damage, alcoholism, poor treatment response, and use of high doses of antipsychotics (APA [Lehman
2004]; Soares-Weiser 2007). Consider therapy discontinuation with signs/symptoms of tardive dyskinesia.
• Falls: May increase the risk for falls due to somnolence, orthostatic hypotension, and motor or sensory
instability. Complete fall risk assessments at baseline and periodically during treatment in patients with
diseases or on medications that may also increase fall risk.
• Hyperprolactinemia: May increase prolactin levels; clinical significance of hyperprolactinemia in patients with
breast cancer or other prolactin-dependent tumors is unknown.
• Hypersensitivity: Hypersensitivity reactions (including anaphylactic reactions, angioedema, exfoliative

dermatitis, hypersensitivity vasculitis, rash, urticaria, face edema, laryngeal edema, bronchospasm, and
laryngospasm) have been reported.
• Neuroleptic malignant syndrome (NMS): Use may be associated with NMS; monitor for mental status changes,
fever, muscle rigidity, and/or autonomic instability. Following recovery from NMS, reintroduction of drug
therapy should be carefully considered; if an antipsychotic agent is resumed, allow at least 2 weeks to
elapse after recovery before rechallenge, consider a lower potency antipsychotic and monitor closely for
the reemergence of NMS (Strawn 2007).
• Orthostatic hypotension: May cause orthostatic hypotension; use with caution in patients at risk of this effect or
in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular
disease, hypovolemia, or concurrent medication use that may predispose to hypotension/bradycardia).
Relative to other neuroleptics, the risk of orthostatic hypotension is low (APA [Lehman 2004]).
• Temperature regulation: Impaired core body temperature regulation may occur; caution with strenuous
exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects (Kwok
2005; Martinez 2002).
• Cardiovascular disease: Use with caution in patients with severe cardiovascular disease because of the
possibility of transient hypotension and/or precipitation of angina pain.
• Bipolar disorder: Use with caution in patients with bipolar disorder; when used to control mania, there may be a
rapid mood swing to depression. Haloperidol does not possess antidepressant effects (Cipriani 2006).
• Dementia: [US Boxed Warning]: Elderly patients with dementia-related psychosis treated with antipsychotics
are at an increased risk of death compared to placebo. Most deaths appeared to be either cardiovascular
(eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Avoid the first-line use of oral
haloperidol in elderly patients with dementia-related psychosis due to a greater risk of harm relative to
other antipsychotics (APA [Reus 2016]). Haloperidol is not approved for the treatment of dementia-related
psychosis. Haloperidol is contraindicated in patients with dementia with Lewy bodies; these patients are
reported to be more sensitive to antipsychotic medications and use may result in severe extrapyramidal
symptoms, confusion, sedation, and falls.
• Parkinson disease: Haloperidol is contraindicated in patients with Parkinson disease; these patients are reported
to be more sensitive to antipsychotic medications and use may result in severe extrapyramidal symptoms,
confusion, sedation, and falls.
• Seizure disorder: Use with caution in patients at risk of seizures, including those with a history of seizures, EEG
abnormalities, or concurrent anticonvulsant therapy; haloperidol may lower the seizure threshold.
• Thyroid dysfunction: Avoid in thyrotoxicosis; severe neurotoxicity (rigidity, inability to walk or talk) may occur
with use.
• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol
(≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates;
the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS
dysfunction (including convulsions, intracranial hemorrhage), hypotension and cardiovascular collapse (AAP
["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding
sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See
• Discontinuation of therapy: When discontinuing antipsychotic therapy, the manufacturer and the American
Psychiatric Association (APA), Canadian Psychiatric Association (CPA), and World Federation of Societies of
Biological Psychiatry (WFSBP) guidelines recommend gradually tapering antipsychotics to avoid physical
withdrawal symptoms, including anorexia, anxiety, diaphoresis, diarrhea, dizziness, dyskinesia, headache,
myalgia, nausea, paresthesia, restlessness, tremulousness, and vomiting (APA [Lehman 2004]; CPA
[Addington 2005]; Lambert 2007; WFSBP [Hasan 2012]). The risk of withdrawal symptoms is highest
following abrupt discontinuation of highly anti-cholinergic or dopaminergic antipsychotics (Cerovecki 2013).
Additional factors such as duration of antipsychotic exposure, the indication for use, medication half-life,
and risk for relapse should be considered. In schizophrenia, there is no reliable indicator to differentiate the
minority who will not from the majority who will relapse with drug discontinuation. However, studies in
which the medication of well-stabilized patients were discontinued indicate that 75% of patients relapse
within 6 to 24 months. Indefinite maintenance antipsychotic medication is generally recommended, and
especially for patients who have had multiple prior episodes or 2 episodes within 5 years (APA [Lehman
2004]).
• Parenteral administration: Hypotension may occur, particularly with parenteral administration. Risk of QT
prolongation, torsade de pointes, and sudden death appear to be increased with intravenous
administration, particularly at higher doses. Although the short-acting form (lactate) is used clinically
intravenously, the IV use of the injection is not an FDA-approved route of administration; the decanoate
form should never be administered intravenously.
For the management of delirium in pediatric patients, intravenous haloperidol has been widely studied for efficacy and
has been frequently used due to lower sedative effects and rapid onset of action; however, its use is associated with
adverse effects including cardiac effects (eg, arrhythmias and QT prolongation, circulatory and respiratory insufficiency,
extrapyramidal symptoms (eg, cogwheel rigidity, tremor, dystonia, oculogyric crisis), and neuroleptic malignant
syndrome (Harrison 2006; Slooff 2014; Turkel 2014). Newer atypical antipsychotics have shown similar efficacy with less
adverse effects and are being utilized more frequently. Intravenous haloperidol for delirium may be considered in
patients that are unresponsive to an atypical agent or who require intravenous therapy; ECG monitoring could be
considered (Turkel 2014).
Oral: Oral concentrated solution: Dilute oral concentrate with ≥2 ounces of water or acidic beverage; do not mix oral
concentrate with coffee or tea. Avoid skin contact with oral suspension or solution; may cause contact dermatitis.
Parenteral: IV infusion or IVPB: Lactate (Immediate release): May further dilute in D5W solutions to a concentration <5
mg/mL; in adults, dose (0.5 to 100 mg) is usually added to 50 to 100 mL. Do not use NS solutions due to reports of
decreased stability and incompatibility.
Oral: Administer with food or milk to decrease GI distress. Avoid skin contact with oral suspension or solution; may
cause contact dermatitis.
Parenteral:
IM: Lactate (immediate release): May be administered undiluted IM
IV: Infusion or IVPB: Lactate (immediate release): May be administered undiluted (5 mg/mL), or diluted in D5W.
Rate of IV administration is not well defined but should be slow; in pediatric delirium patients, loading
doses have been administered over 30 to 45 minutes (Schieveld 2005; Schieveld 2007); in adults, rates of a
maximum of 5 mg/minute (Lerner 1979) and 0.125 mg/kg (in 10 mL NS) over 1 to 2 minutes (Magliozzi
1985) have been reported. Note: IV administration has been associated with QT prolongation and the
manufacturer recommends ECG monitoring for QT prolongation and arrhythmias. Consult individual
institutional policies and procedures prior to administration.
Blood pressure, heart rate, CBC with differential, liver enzymes with long-term use; serum glucose, sodium, magnesium;
ECG (with non-FDA approved intravenous administration); mental status, abnormal involuntary movement scale (AIMS),
extrapyramidal symptoms (EPS)
Drug Interactions
Acetylcholinesterase Inhibitors (Central): May enhance the neurotoxic (central) effect of Antipsychotic Agents. Severe
extrapyramidal symptoms have occurred in some patients. Risk C: Monitor therapy
Amiodarone: May enhance the QTc-prolonging effect of Haloperidol. Management: Consider alternatives to this drug
combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with
additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Anticholinergic Agents: May enhance the adverse/toxic effect of other Anticholinergic Agents. Risk C: Monitor therapy
CarBAMazepine: May decrease the serum concentration of Haloperidol. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor
therapy
FLUoxetine: May enhance the QTc-prolonging effect of Haloperidol. FLUoxetine may increase the serum concentration
of Haloperidol. Risk C: Monitor therapy
Avoid combination
Ipratropium (Oral Inhalation): May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid
combination
Metoclopramide: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk X: Avoid combination
Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Haloperidol. Specifically including
drowsiness and confusion. Risk C: Monitor therapy
Ondansetron: May enhance the QTc-prolonging effect of Haloperidol. Management: Monitor for QTc interval
prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors
for QTc prolongation may be at even higher risk.Risk C: Monitor therapy
Potassium Citrate: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Citrate. Risk X: Avoid
combination
Onset of action: Lactate:
IM: Sedation: Mean: 28.3 minutes (Nobay 2004)
IV: Sedation: 3 to 20 minutes (Jacobi 2002)
Peak effect: Lactate: IV: Sedation: ~30 minutes (Magliozzi 1985; Forsman 1976; Jacobi 2002)
Duration: Lactate (dose dependent):
IM: Sedation: Mean: 126.5 minutes (Nobay 2004)
IV: Sedation: Reported range: 3 to 24 hours (Magliozzi 1985)
Distribution:
IV: Vz: 9.5 to 21.7 L/kg (Kudo 1999)

Oral: Vz/F: 52.6 ± 14.5 L/kg (Kudo 1999)
Protein binding: 88.4% to 92.5% (Kudo 1999)
Metabolism: Hepatic: 50% to 60% glucuronidation (inactive); 23% CYP3A4-mediated reduction to inactive metabolites
(some back-oxidation to haloperidol); and 20% to 30% CYP3A4-mediated N-dealkylation, including minor
oxidation pathway to toxic pyridinium derivative (Kudo 1999)
Bioavailability: Oral: 60% to 70% (Kudo 1999)
Decanoate: 21 days
Lactate:
IM: 20 hours (Kudo 1999)
IV: 14 to 26 hours (Kudo 1999)
Oral: 14 to 37 hours (Kudo 1999)
Time to peak, serum:
Decanoate: 6 days
Lactate:
IM: 20 minutes (Kudo 1999)
Oral: 2 to 6 hours (Kudo 1999)
Excretion: Urine (30%, 1% as unchanged drug) (Kudo 1999)
Adverse Reactions
Central nervous system: Akathisia (more common with decanoate), anxiety, drowsiness (more common with lactate),
dystonia (more common with lactate), euphoria, extrapyramidal reaction (more common with lactate), headache
(more common with decanoate), hypertonia (more common with lactate), lethargy, parkinsonism (more common
with decanoate), psychotic symptoms (exacerbation), vertigo
Dermatologic: Diaphoresis
Endocrine & metabolic: Hyperglycemia, hyponatremia, increased libido, menstrual disease
Gastrointestinal: Abdominal pain (decanoate), anorexia, constipation (more common with lactate), diarrhea, dyspepsia,
sialorrhea, xerostomia
Genitourinary: Breast engorgement, impotence, lactation

Neuromuscular & skeletal: Akinesia (decanoate), bradykinesia (lactate), hyperkinetic muscle activity (lactate), tremor
Ophthalmic: Cataract, oculogyric crisis (more common with decanoate), retinopathy, visual disturbance
Respiratory: Increased depth of respiration
Rare but important or life-threatening: Abnormal hepatic function tests, abscess at injection site, acneiform eruption,
acute hepatic failure, agitation, agranulocytosis, akathisia, alopecia, amenorrhea, anaphylaxis, anemia,
angioedema, blurred vision, bronchopneumonia, bronchospasm, cardiac arrhythmia, cholestasis, cogwheel
rigidity, confusion, decreased libido, depression, dizziness, dyskinesia, dysmenorrhea, dyspnea, edema, erectile
dysfunction, exfoliative dermatitis, extrasystoles, facial edema, galactorrhea not associated with childbirth,
gynecomastia, heatstroke, heavy menstrual bleeding, hepatic insufficiency, hepatitis, hyperammonemia,
hyperhidrosis, hyperprolactinemia, hyperpyrexia, hypersensitivity angiitis, hypersensitivity reaction, hypertension,
hyperthermia, hypoglycemia, hypokinesia, hypotension, hypothermia, injection site reaction, insomnia, jaundice,
laryngeal edema, laryngospasm, leukocytosis, leukopenia, lymphocytosis with monocytosis, maculopapular rash,
mask-like face, mastalgia, motor dysfunction, muscle rigidity, muscle twitching, nausea, neonatal withdrawal,
neuroleptic malignant syndrome, neutropenia, nystagmus, opisthotonus, orthostatic hypotension, pancytopenia,
priapism, prolonged Q-T interval on ECG, pruritus, restlessness, rhabdomyolysis, sedated state, seizure, SIADH,
skin photosensitivity, skin rash, tachycardia, tardive dyskinesia, tardive dystonia, thrombocytopenia, torsades de
pointes, torticollis, trismus, urinary retention, urticaria, ventricular arrhythmia, ventricular fibrillation, ventricular
tachycardia, vomiting, weight gain, weight loss
HEPARINA
Dosing: Neonatal
Note: Many concentrations of heparin are available and range from 1 to 20,000 units/mL. Carefully examine each
prefilled syringe, bag, or vial prior to use to ensure that the correct concentration is chosen. Heparin lock flush solution
is intended only to maintain patency of IV devices and is not to be used for anticoagulant therapy.
Prophylaxis:
Central line flush; patency (intermittent doses): Limited data available: Various recommendations exist for
intermittent flushes of heparin used to maintain patency of single and double lumen central catheters;
dose of heparin flush used should not approach therapeutic unit per kg dose; refer to institution specific
protocols. In neonates, the 10 units/mL concentration is used with frequency and volume of flushing
determined by the type of catheter; capped polyvinyl chloride catheters and peripheral heparin locks
require flushing more frequently (eg, every 6 to 8 hours). Volume of heparin flush is usually similar to
volume of catheter (or slightly greater) or may be standardized according to specific NICU policy (eg, 0.5 to
1 mL/flush). Additional flushes should be given when stagnant blood is observed in catheter, after catheter
is used for drug or blood administration, and after blood withdrawal from catheter (Cloherty 2012).
Central venous access device (CVAD), patency:Continuous IV infusion: 0.5 unit/kg/hour (ACCP [Monagle 2012])
ECMO; venoarterial (VA)/Cardiac, anticoagulation: Note:While used to prevent thrombosis, full anticoagulation
dosing is necessary; IV: 100 units/kg prior to ECMO cannulation followed by continuous heparin infusion to
maintain the ACT between 180 and 220 seconds; ACT should be checked hourly while patient is on ECMO;
additional monitoring targets for heparin therapy are prolongation of the PTT to 1.5 to 2.5 times the
control value or an anti-Xa level of 0.3 to 0.7 units/mL (AHA [Giglia 2013])
Parenteral nutrition (PN) additive, venous access patency:0.5 to 1 unit/mL (final heparin concentration in the PN
solution), both central and peripheral PN solutions. The final concentration of heparin used for PN solutions
may need to be decreased in small neonates receiving larger PN volumes in order to avoid approaching
therapeutic amounts (Corkins 2015).
Peripheral arterial catheters in situ: Intra-arterial (via arterial catheter): Continuous infusion of heparin at a final
concentration of 5 units/mL at 1 mL/hour (ACCP [Monagle 2012]; Butt 1987)
Umbilical artery catheter (UAC): Intra-arterial (via UAC): Continuous infusion of heparin at a final concentration of
0.25 to 1 unit/mL; total heparin dose of 25 to 200 units/kg/day to maintain patency (ACCP [Monagle 2012])
Thromboprophylaxis in CHD patients with systemic to pulmonary artery shunts (eg, Sano shunt, Blalock-Taussig
shunt, central shunt) or central venous lines in certain CHD patients (eg, previous thrombosis or
hypercoagulable state): Low dose: Continuous IV infusion: 10 to 15 units/kg/hour (AHA [Giglia 2013])
Thrombosis; treatment:
Systemic heparinization: IV: Initial loading dose: 75 units/kg over 10 minutes; then initial continuous maintenance
infusion at 28 units/kg/hour; adjust dose to maintain an anti-Xa activity of 0.35 to 0.7 units/mL or an aPTT
range that correlates to this anti-Xa range or a protamine titration range of 0.2 to 0.4 units/mL (ACCP
[Monagle 2012])
Note: Because of variation among hospitals with reagents (lot numbers) and corresponding control of aPTT
values, individual institutions should establish unique, institution-specific nomograms based on
current reagent. Due to extensive variability within reagents and anti-Xa levels with corresponding
aPTTs, a specific nomogram has not been provided; refer to guidelines for a specific nomogram
(ACCP [Monagle 2012]).
Systemic to pulmonary artery shunt thrombosis (eg, Sano shunt, Blalock-Taussig shunt, central shunt); treatment
in CHD patients: 50 to 100 units/kg, ongoing continuous infusion should be considered (AHA [Giglia 2013])
Dosing: Pediatric
Prophylaxis:
Central line flush; patency (intermittent doses):Limited data available (ACCP [Monagle 2012]; Conway 2014;
Lee 2005): Infants, Children, and Adolescents: When using intermittent flushes of heparin to
maintain patency of single and double lumen central catheters, various recommendations exist;
refer to institution specific protocols. Capped polyvinyl chloride catheters and peripheral heparin
locks require flushing more frequently (eg, every 6 to 8 hours). Volume of heparin flush is usually
similar to volume of catheter (or slightly greater). Dose of heparin flush used should not approach
therapeutic unit per kg dose. Additional flushes should be given when stagnant blood is observed in
catheter, after catheter is used for drug or blood administration, and after blood withdrawal from
catheter.
ECMO venoarterial (VA)/Cardiac, anticoagulation:Note: While used to prevent thrombosis, full
anticoagulation dosing is necessary; Infants, Children, and Adolescents: IV: 100 units/kg prior to
ECMO cannulation followed by continuous IV heparin infusion to maintain the ACT between 180 and
220 seconds; ACT should be checked hourly while patient is on ECMO; additional monitoring targets
for heparin therapy are prolongation of the PTT to 1.5 to 2.5 times the control value or an anti-Xa
level of 0.3 to 0.7 units/mL (AHA [Giglia 2013])
Parenteral nutrition (PN) additive, venous access patency: Infants, Children, and Adolescents: 1 unit/mL
(final heparin concentration in PN), both central and peripheral. The final concentration of heparin
used for PN solutions may need to be decreased to 0.5 units/mL in small infants receiving larger PN
volumes in order to avoid approaching therapeutic amounts (Corkins 2015).
Peripheral arterial catheters in situ: Infants and Children: Intra-arterial (via arterial catheter): Continuous
infusion of heparin at a final concentration of 5 units/mL at 1 mL/hour (ACCP [Monagle 2012]; Butt
1987)
Thromboprophylaxis in CHD patients with systemic to pulmonary artery shunts (eg, Sano shunt, Blalock-
Taussig shunt, central shunt) or central venous lines in certain CHD patients (eg, previous thrombosis
or hypercoagulable states):Infants, Children, and Adolescents: Low Dose: Continuous IV infusion: 10
to 15 units/kg/hour (AHA [Giglia 2013])
Thrombosis, treatment:
Systemic heparinization:
Infants: IV: Initial loading dose: 75 units/kg over 10 minutes; then initial continuous maintenance
infusion at: 28 units/kg/hour; adjust dose to maintain an anti-Xa activity of 0.35 to 0.7
units/mL or an aPTT range that correlates to this anti-Xa range or a protamine titration range
of 0.2 to 0.4 units/mL (ACCP [Monagle 2012])
Children and Adolescents: IV: Initial loading dose: 75 units/kg over 10 minutes, then initial
continuous maintenance infusion at: 20 units/kg/hour; adjust dose to maintain an anti-Xa
activity of 0.35 to 0.7 units/mL or an aPTT range that correlates to this anti-Xa range or a
protamine titration range of 0.2 to 0.4 units/mL (ACCP [Monagle 2012])
Note: Because of variation among hospitals with reagents (lot numbers) and corresponding control
of aPTT values, individual institutions should establish unique, institution-specific nomograms
based on current reagent. Due to extensive variability within reagents and anti-Xa levels with
corresponding aPTTs, a specific nomogram has not been provided; refer to guidelines for a
specific nomogram (ACCP [Monagle 2012]).
Systemic to pulmonary artery shunt thrombosis (eg, Sano shunt, Blalock-Taussig shunt, central shunt);
treatment in CHD patients: Infants, Children, and Adolescents: IV: 50 to 100 units/kg, ongoing
continuous infusion should be considered (AHA [Giglia 2013])
All patients: No dosage adjustment required; adjust therapeutic heparin according to aPTT or anti-Xa activity

All patients: No dosage adjustment required; adjust therapeutic heparin according to aPTT or anti-Xa activity
Contraindications
Hypersensitivity to heparin or any component of the formulation (unless a life-threatening situation necessitates use
and use of an alternative anticoagulant is not possible); severe thrombocytopenia; history of heparin-induced
thrombocytopenia (HIT); uncontrolled active bleeding except when due to disseminated intravascular coagulation
(DIC); cases where the administration of sodium or chloride could be clinically detrimental (applies to large
volume heparin 2 unit/mL IV solutions only); not for use when appropriate blood coagulation tests cannot be
obtained at appropriate intervals (applies to full-dose heparin only).
Note: Some products contain benzyl alcohol as a preservative; their use in neonates, infants, or pregnant or breast-
feeding mothers is contraindicated by some manufacturers.
• Bleeding: May occur, including fatal events. Use with caution in patients with an increased risk of bleeding,
including subacute bacterial endocarditis; congenital or acquired bleeding disorders; active ulcerative or
angiodysplastic GI diseases; continuous GI tube drainage; severe uncontrolled hypertension; history of
hemorrhagic stroke; use shortly after brain, spinal, or ophthalmologic surgery or other invasive procedures
including spinal tap or spinal anesthesia; concomitant treatment with platelet inhibitors; recent GI
bleeding; impaired hemostasis; thrombocytopenia or platelet defects; patients with hereditary
antithrombin deficiency receiving concurrent antithrombin replacement therapy; severe liver disease;
hypertensive or diabetic retinopathy; renal failure; or in patients (especially women) >60 years of age.
Monitor patient closely for signs or symptoms of bleeding. Discontinue if bleeding occurs; severe
hemorrhage or overdosage may require protamine (consult Protamine monograph for dosing
recommendations).
• Heparin resistance: Dose requirements >35,000 units/24 hours to maintain a therapeutic aPTT may occur in
patients with antithrombin deficiency, increased heparin clearance, elevations in heparin-binding proteins,
elevations in factor VIII and/or fibrinogen; frequently encountered in patients with fever, thrombosis,
thrombophlebitis, infections with thrombosing tendencies, MI, cancer, and in postsurgical patients;
measurement of anticoagulant effects using antifactor Xa levels may be of benefit.
• Hyperkalemia: Monitor for hyperkalemia; can cause hyperkalemia by suppressing aldosterone production.
• Hypersensitivity reactions: May occur; only in life-threatening situations when use of an alternative
anticoagulant is not possible should heparin be cautiously used in patients with a documented
hypersensitivity reaction. Some products are derived from animal tissue and may be contraindicated in
patients with animal allergies (ie, pork); consult individual prescribing information.
• Osteoporosis: May occur with prolonged use (>6 months) due to a reduction in bone mineral density.
• Thrombocytopenia: May occur. Heparin-induced thrombocytopenia (HIT), a serious antibody-mediated reaction

resulting from irreversible aggregation of platelets, may also occur. Patients who develop HIT may be at risk
of developing a new thrombus (heparin-induced thrombocytopenia and thrombosis [HITT]). Monitor
platelets closely; discontinue therapy and consider alternatives if platelets are <100,000/mm3 and/or
thrombosis develops. HIT or HITT may be delayed and can occur up to several weeks after discontinuation
of heparin. Use with extreme caution (for a limited duration) or avoid in patients with history of HIT,
especially if administered within 100 days of HIT episode (Dager 2007; Warkentin 2001).
• Drug-drug interactions: Potentially significant drug-drug interactions may exist, requiring dose or frequency
adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions
database for more detailed information.
• Elderly: Use with caution in patients >60 years of age, particularly women; older adults can be more sensitive to
heparin and a higher incidence of bleeding has been reported in these patients. May require lower doses.
• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol as a preservative. In neonates,
large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity
("gasping syndrome"); the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping
respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and
cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces
bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol
with caution in neonates. See manufacturer's labeling. Use in neonates, infants, or pregnant or nursing
mothers is contraindicated by some manufacturers; the use of preservative-free heparin is, therefore,
recommended in these populations.
• Sulfites: Some preparations contain sulfite which may cause allergic reactions.
• Fatal medications errors: Many concentrations of heparin are available ranging from 1 unit/mL to 20,000
units/mL. Clinicians must carefully examine each prefilled syringe or vial prior to use ensuring that the
correct concentration is chosen; fatal hemorrhages have occurred related to heparin overdose especially in
pediatric patients.
Confirm the concentration of all heparin injection vials prior to administration; do not use heparin injection as a
"catheter lock flush" as the injection is supplied in various concentrations including highly concentrated strengths. Fatal
hemorrhages have occurred in pediatric patients when higher concentrations of heparin injection were confused with
lower concentrations of heparin lock flush.
Heparin-induced thrombocytopenia (HIT) has been reported in pediatric patients; incidence and risk factors are not well-
defined due to variability related to patient inclusion and laboratory techniques; incidence rates up to 2.3% in PICU
patients have been reported, and cases observed at both low and high levels of heparin exposure (eg, venous access
device line flushes and supratherapeutic doses associated with hemodialysis and during cardiopulmonary bypass).
Monitor platelet count closely; if HIT develops, consider alternate anticoagulation therapy (eg, danaparoid, argatroban)
(ACCP [Monagle 2012]).
Heparin resistance should be suspected in pediatric patients if unable to achieve an ACT >300 seconds after
administration of >600 units/kg (ACCP [Giglia 2013]).
Parenteral: Concentration should be determined based on indication and dose to allow for safe and accurate
administration of the correct dose. After addition of heparin to the infusion solution, invert the solution at least 6
times to ensure adequate mixing and prevent pooling of heparin. Products containing benzyl alcohol or
derivatives should not be used to prepare products for neonates. ISMP and Vermont Oxford Network recommend
a standard concentration of 0.5 units/mL (in 0.45% NS) for maintaining line patency in neonates (ISMP 2011).
prefilled syringe, bag, or vial prior to use to ensure that the correct concentration is chosen.
Parenteral: Do not administer IM due to pain, irritation, and hematoma formation.
IV:
Continuous IV infusion: Infuse via infusion pump. IV bolus should be administered over 10 minutes
Heparin lock: Inject via injection cap using positive pressure flushing technique. Heparin lock flush solution
Central venous catheters: Must be flushed with heparin solution when newly inserted, daily (at the time of
tubing change), after blood withdrawal or transfusion, and after an intermittent infusion through an
injectable cap.
SubQ: Not all preparation intended for SubQ administration, verify product selection. Inject in subcutaneous
tissue only (not muscle tissue). Injection sites should be rotated (usually left and right portions of the
abdomen, above iliac crest)
Hemoglobin, hematocrit, signs of bleeding; fecal occult blood test; aPTT (or antifactor Xa activity levels) or ACT
depending upon indication
Platelet counts should be routinely monitored (eg, every 2 to 3 days on days 4 to 14 of heparin therapy) when the risk of
HIT is >1% (eg, receiving therapeutic dose heparin, postoperative antithrombotic prophylaxis), if the patient has received
heparin or low molecular weight heparin (eg, enoxaparin) within the past 100 days, if preexposure history is uncertain,
or if anaphylactoid reaction to heparin occurs. When the risk of HIT is <1% (eg, medical/obstetrical patients receiving
heparin flushes), routine platelet count monitoring is not recommended (Guyatt 2012).
For patients on ECMO, ACT should be checked hourly while patient is on ECMO (AHA [Giglia 2013]).
For intermittent IV injections, aPTT is measured 3.5 to 4 hours after IV injection.
Note: Continuous IV infusion is preferred over IV intermittent injections. For full-dose heparin (ie, nonlow-dose), the
dose should be titrated according to aPTT results. For anticoagulation, an aPTT 1.5 to 2.5 times normal is usually desired.
Because of variation among hospitals in the control aPTT values, nomograms should be established at each institution,
designed to achieve aPTT values in the target range (eg, for a control aPTT of 30 seconds, the target range [1.5 to 2.5
times control] would be 45 to 75 seconds). Measurements should be made prior to heparin therapy, 6 hours (pediatric:
4 hours) after initiation, and 6 hours (pediatric: 4 hours) after any dosage change, and should be used to adjust the
heparin infusion until the aPTT exhibits a therapeutic level. When two consecutive aPTT values are therapeutic,
subsequent measurements may be made every 24 hours, and if necessary, dose adjustment carried out. In addition, a
significant change in the patient's clinical condition (eg, recurrent ischemia, bleeding, hypotension) should prompt an
immediate aPTT determination, followed by dose adjustment if necessary. In general, may increase or decrease infusion
by 2 to 4 units/kg/hour dependent upon aPTT.
Heparin infusion dose adjustment: A number of adult dose-adjustment nomograms have been developed which target
an aPTT range of 1.5 to 2.5 times control (Cruickshank 1991; Flaker 1994; Hull 1992; Raschke 1993). However,
institution-specific and indication-specific nomograms should be consulted for dose adjustment. Note: aPTT values vary
throughout the day with maximum values occurring during the night (Decousus 1985).
Reference Range
Venous thromboembolism: Heparin: pediatric patients: 0.35 to 0.7 unit/mL; adults: 0.3 to 0.7 unit/mL anti-Xa activity (by
chromogenic assay) or 0.2 to 0.4 unit/mL (by protamine titration); aPTT: 1.5 to 2.5 times control (usually reflects
an aPTT of 60 to 85 seconds) (Garcia 2012; ACCP [Monagle 2012])
ECMO anticoagulation: Maintain the ACT between 180 and 220 seconds; additional monitoring targets for heparin
therapy are prolongation of the PTT to 1.5 to 2.5 times the control value and an anti-Xa level of 0.3 to 0.7
units/mL (AHA [Giglia 2013])
Drug Interactions
Angiotensin II Receptor Blockers: Heparin may enhance the hyperkalemic effect of Angiotensin II Receptor Blockers.Risk
C: Monitor therapy
Angiotensin-Converting Enzyme Inhibitors: Heparin may enhance the hyperkalemic effect of Angiotensin-Converting
Enzyme Inhibitors. Risk C: Monitor therapy
Nitroglycerin: May diminish the anticoagulant effect of Heparin. Nitroglycerin may decrease the serum concentration of
Heparin. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor
therapy
Potassium Salts: Heparin may enhance the hyperkalemic effect of Potassium Salts. Risk C: Monitor therapy
Potassium-Sparing Diuretics: Heparin may enhance the hyperkalemic effect of Potassium-Sparing Diuretics.
Management: Monitor serum potassium concentrations closely. The spironolactone Canadian product
monograph lists its combination with heparin or low molecular weight heparins as contraindicated. Risk C:
Monitor therapy
Streptokinase: May enhance the anticoagulant effect of Heparin. Risk X: Avoid combination
Test Interactions
Increased thyroxine (competitive protein binding methods); increased PT
Aprotinin significantly increases aPTT and celite Activated Clotting Time (ACT) which may not reflect the actual degree of
anticoagulation by heparin. Kaolin-based ACTs are not affected by aprotinin to the same degree as celite ACTs. While
institutional protocols may vary, a minimal celite ACT of 750 seconds or kaolin-ACT of 480 seconds is recommended in
the presence of aprotinin. Consult the manufacturer’s information on specific ACT test interpretation in the presence of
aprotinin.
Note: Increased interpatient variability of pharmacokinetic parameters in pediatric patients compared to adults;
however, age-related decreases in volume of distribution and clearance with increasing pediatric patient age have been
reported (ACCP [Monagle 2012]; McDonald 1981).
Onset of action: Anticoagulation: IV: Immediate; SubQ: ~20 to 30 minutes
Absorption: Oral, rectal: Erratic at best from these routes of administration; SubQ absorption is also erratic, but
considered acceptable for prophylactic use
Distribution:
Premature neonates (data based on single dose of 100 units/kg within 4 hours of birth) (McDonald 1981):
Inversely proportional to gestational age
GA 25 to 28 weeks: 81 ± 41 mL/kg
GA 29 to 32 weeks: 73.3 ± 24.8 mL/kg
GA 33 to 36 weeks: 57.8 ± 32.2 mL/kg
Adults: Following a single 75 unit/kg dose: 36.6 ± 7.4 mL/kg (McDonald 1981)
Metabolism: Complex; thought to occur by depolymerization and desulphation via the reticuloendothelial system
primarily in the liver and spleen (ACCP [Garcia 2012]; Dawes 1979; Estes 1980; Kandrotas 1992)
Age-related: Shorter half-life reported in premature neonates compared to adult patients

Premature neonates GA 25 to 36 weeks (data based on single dose of 100 units/kg within 4 hours of birth): Mean
range: 35.5 to 41.6 minutes (McDonald 1981)
Dose-dependent: IV bolus: 25 units/kg: 30 minutes (Bjornsson 1982); 100 units/kg: 60 minutes (de Swart 1982);
400 units/kg: 150 minutes (Olsson 1963)
Mean: 1.5 hours; Range: 1 to 2 hours; affected by obesity, renal function, malignancy, presence of pulmonary
embolism, and infections
Note: At therapeutic doses, elimination occurs rapidly via nonrenal mechanisms. With very high doses, renal
elimination may play more of a role; however, dosage adjustment remains unnecessary for patients with
renal impairment (Kandrotas 1992).
Excretion: Urine (small amounts as unchanged drug); Note: At therapeutic doses, elimination occurs rapidly via nonrenal
mechanisms. With very high doses, renal elimination may play more of a role; however, dosage adjustment
remains unnecessary for patients with renal impairment (Kandrotas 1992).
Clearance: Age-related changes; within neonatal population, slower clearance with lower GA; however, when
compared to adults, the overall clearance in neonatal and pediatric patients is faster than adults (ACCP
[Monagle 2012 ]; McDonald 1981)
Renal function impairment: The half-life may be increased.
Hepatic function impairment: The half-life may be increased or decreased.
Geriatric: Plasma levels may be higher.
Adverse Reactions
Immunologically mediated heparin-induced thrombocytopenia (HIT) occurs in a small percentage of patients, and is
marked by a progressive fall in platelet counts and, in some cases, thromboembolic complications (skin necrosis,
pulmonary embolism, gangrene of the extremities, cerebrovascular accident, or myocardial infarction).
Cardiovascular: Chest pain, shock (including hemorrhagic shock), thrombosis, vasospasm (allergic; possibly related to
thrombosis)
Central nervous system: Chills, dysesthesia (feet), headache, peripheral neuropathy
Dermatologic: Dermal ulcer (rarely reported with deep subcutaneous injections; intramuscular injection [not
recommended] is associated with a higher incidence of this effect), eczema, erythematous plaques (case reports),
localized erythema (rarely reported with deep subcutaneous injections; intramuscular injection [not
recommended] is associated with a higher incidence of this effect), skin necrosis, transient alopecia (delayed),
urticaria
Endocrine & metabolic: Adrenal hemorrhage, hyperkalemia (suppression of aldosterone synthesis), hyperlipidemia
(rebound; on discontinuation), ovarian hemorrhage
Gastrointestinal: Constipation, hematemesis, melena, nausea, vomiting
Genitourinary: Erectile dysfunction (frequent or persistent erection), hematuria
Hematologic & oncologic: Bruise (unexplained), gingival hemorrhage, hematoma (rarely reported with deep
subcutaneous injections; intramuscular injection [not recommended] is associated with a higher incidence of this
effect), hemorrhage, pulmonary hemorrhage, purpura, retroperitoneal hemorrhage, thrombocytopenia
Hepatic: Increased liver enzymes
Hypersensitivity: Anaphylactoid reaction, hypersensitivity reaction
Local: Local irritation, local pain (rarely reported with deep subcutaneous injections; intramuscular injection [not
recommended] is associated with a high incidence of these effects)
Neuromuscular & skeletal: Osteoporosis (chronic therapy effect)
Ophthalmic: Allergic conjunctivitis, lacrimation
Respiratory: Asthma, bronchospasm (case reports), epistaxis, hemoptysis, rhinitis
Miscellaneous: Drug tolerance, fever
HIDROCORTISONA
Dosing: Neonatal
Bronchopulmonary dysplasia, prevention (preterm neonates with prenatal inflammatory exposure): PNA ≤48 hours:
IV: 1 mg/kg/day divided every 12 hours for 9 or 12 days followed by 0.5 mg/kg/day divided every 12 hours for 3
days; low-dose (ie, physiologic replacement) has been shown to be effective at improving survival without BPD in
chorioamnionitis-exposed ELBW neonates (birth weight: 500 to 999 g) (Watterberg 1999; Watterberg 2004;
Watterberg 2010); of note, a higher incidence of gastrointestinal perforation in the treatment arm resulted in
early study closure of the largest trial (Watterberg 2004). In another trial of VLBW neonates (PNA ≤36 hours, GA
<30 weeks, birth weight: 500 to 1,250 g), higher dosages (ie, stress dose): 2 mg/kg/day divided every 8 hours for 2
days followed by 1.5 mg/kg/day divided every 8 hours for 2 days followed by 0.75 mg/kg/day divided every 12
hours for 6 days showed a trend in the treatment arm of decreased severity of respiratory failure, shorten length
of oxygen therapy and promotion of PDA closure; this trial was closed early due to higher incidence of
gastrointestinal perforation in the treatment arm versus placebo (Peltoniemi 2005). Note: The AAP suggests that
for neonates with prenatal inflammatory exposure, low-dose hydrocortisone therapy (1 mg/kg/day) during the
first 2 weeks of life may improve survival without BPD and without adverse neurodevelopmental outcomes
(Watterberg 2010).
Congenital adrenal hyperplasia: Oral [tablets (crushed)]: Initial: 10 to 15 mg/m2/day in 3 divided doses; higher initial
doses (20 mg/m2/day) may be required to achieve initial target hormone serum concentrations. Administer
morning dose as early as possible. Due to uneven distribution of the drug in the liquid, use of oral suspension
is not recommended [AAP 2000; Speiser (Endocrine Society) 2010]
Hypoglycemia, refractory (refractory to continuous glucose infusion of >12-15 mg/kg/minute): Oral, IV: 5 mg/kg/day
divided every 8 to 12 hours or 1 to 2 mg/kg/dose every 6 hours
Hypotension, refractory; shock: IV: Limited data available; dosage regimens variable (Brierley 2009; Higgins 2010): 3
mg/kg/day divided every 8 hours for 5 days; dosing based on the largest, prospective, randomized, placebo-
controlled trial of 48 hypotensive, VLBW neonates (PNA: <7 days; GA: <32 weeks; birth weight: <1,500 g) who
were also receiving dopamine at doses ≥10 mcg/kg/minute (Ng 2006); other smaller trials have used 2 mg/kg/day
divided every 12 hours for 1 to 3 days (Seri 2001) or 2 mg/kg once, followed by 2 mg/kg/day divided every 12
hours for 4 doses (Noori 2006)
Dosing: Pediatric
Note: Adjust dose depending upon condition being treated and response of patient. The lowest possible dose should be
used to control the condition; when dose reduction is possible, the dose should be reduced gradually. In life-threatening
situations, parenteral doses larger than the oral dose may be needed.
Adrenal insufficiency; acute (adrenal crisis): Dosage regimens variable: IM, IV (preferred):
Weight-directed: Limited data available: Infants, Children, and Adolescents: Initial: 2 to 3 mg/kg; maximum dose:
100 mg/dose; then for infants: 1 to 5 mg/kg/dose every 6 hours; for children and adolescents, see BSA- or
age-directed dosing; may also be administered I.O. if necessary (Cameron 2012; Hegenbarth 2008; Marx
2014)
BSA-directed dosing: Limited data available: Infants, Children, and Adolescents: Initial: 50 to 100 mg/m2once
followed by 50 to 100 mg/m2/day in 4 divided doses (Ahmet 2011; Auron 2015; Hegenbarth 2008; Shulman
2007)
Age-directed dosing (fixed dosing): Limited data available (Cameron 2012; Elder 2015; Kliegman 2016):
Infants: 10 to 25 mg once followed by 10 to 25 mg/day in divided doses every 6 hours for 24 hours then
subsequent dose reductions and rate determined by patient response
Children <5 years (eg, young children): 25 to 50 mg once followed by 25 to 50 mg/day in divided doses
every 6 hours for 24 hours then subsequent dose reductions and rate determined by patient
response
Children ≥5 years (eg, older children): 50 to 100 mg once followed by 50 mg/day in divided doses every 6
hours for 24 hours then subsequent dose reductions and rate determined by patient response
Adolescents: 100 mg once followed by 100 mg/day in divided doses every 6 hours for 24 hours then
subsequent dose reduction and rate determined by patient response
Anti-inflammatory or immunosuppressive: Note: Dosing range variable; individualize dose for disease state and patient
response.
Infants and Children:
Oral: 2.5 to 10 mg/kg/day or 75 to 300 mg/m2/day divided every 6 to 8 hours (Kliegman 2007)
IM, IV:
Manufacturer's labeling: Initial: 0.56 to 8 mg/kg/day or 20 to 240 mg/m2/day in 3 or 4 divided doses

Alternate dosing: Limited data available: 1 to 5 mg/kg/day or 30 to 150 mg/m2/day divided every 12
to 24 hours (Kliegman 2007)
Adolescents: Oral, IM, IV, SubQ: 15 to 240 mg every 12 hours (Kliegman 2007)
Congenital adrenal hyperplasia: Infants, Children, and Adolescents: AAP Recommendations: Note: Administer morning
dose as early as possible. Tablets may result in more reliable serum concentrations than oral liquid formulation;
use of oral suspension is not recommended. Individualize dose by monitoring growth, hormone levels, and bone
age; mineralocorticoid (eg, fludrocortisone) and sodium supplement may be required in salt losers (AAP 2000;
AAP 2010; Endocrine Society 2010)
Initial: Oral (tablets): 10 to 15 mg/m2/day in 3 divided doses; higher initial doses (20 mg/m2/day) may be required
to achieve initial target hormone serum concentrations (AAP 2010; Endocrine Society 2010).
Maintenance dose: Oral (tablets): Usual requirement:
Infants: 2.5 to 5 mg/dose 3 times/day
Children: 5 to 10 mg/dose 3 times/day
Adolescents (fully grown): 15 to 25 mg/day divided in 2 to 3 daily doses
Physiologic replacement: Infants and Children: Oral: 8 to 10 mg/m2/day divided every 8 hours; up to 12 mg/m2/day in
some patients; to replicate diurnal variation, the highest doses are typically administered in the morning and
midday dose with the lower dose in the evening (Ahmet 2011; Elder 2015; Gupta 2008; Maguire 2007; Shulman
2007)
Stress dosing; supplemental: Limited data available; dosage regimens variable: Infants, Children, and
Adolescents: Note: Dosing based on the level of physiological stress related to condition, dose should be
individualized based on patient and continued until resolution of stressful condition (usually 24 to 48 hours)
(Shulman 2007). Typically, supplementation for emotional or minimal physiological stress conditions or prior to
exercise is not necessary (Elder 2010; Endocrine Society [Speiser 2010]; Shulman 2007). Dosing is generally 2 to 3
times physiologic replacement level (Elder 2010; Shulman 2007).
BSA-directed dosing (Ahmet 2011; Shulman 2007): Oral, IM, IV:
Mild to moderate stress: 20 to 50 mg/m2/day divided into 3 or 4 doses; doses on the lower end of the
range (20 to 30 mg/m2/day) may be divided twice daily
Major stress or surgery: 100 mg/m2/day in divided doses every 6 hours
Planned surgery: Pre-anesthesia of 50 mg/m2 IV or IM administered 30 to 60 minutes prior to surgery

followed by second dose of 50 mg/m2as a continuous IV infusion or in divided doses every 6 hours
for at least 24 hours
Age-directed for moderate stress in patients with congenital adrenal hyperplasia (Endocrine Society [Speiser
2010]):
Infants and preschool children: IV: Initial dose: 25 mg once, followed by a daily dose that is 3 to 4 times the
patient's standard maintenance dose in divided doses every 6 hours
School-age children: IV: Initial dose: 50 mg once, followed by a daily dose that is 3 to 4 times the patient's
standard maintenance dose in divided doses every 6 hours
Adolescents: IV: Initial dose: 100 mg once, followed by a daily dose that is 3 to 4 times the patient's
standard maintenance dose in divided doses every 6 hours
Septic shock; catecholamine-refractory with suspected/proved adrenal insufficiency: Limited data available: Infants,
Children, and Adolescents: IV: 50 to 100 mg/m2/day (Dellinger 2013; Marx 2014; Shulman 2007); in some cases,
doses may be titrated up to 50 mg/kg/day if necessary for shock reversal; however, efficacy data variable with the
higher doses (Brierley 2009; Menon 2012)
There are no dosage adjustments provided in the manufacturer's labeling; use with caution.
There are no dosage adjustments provided in the manufacturer's labeling; use with caution.
Contraindications
Hypersensitivity to hydrocortisone or any component of the formulation; systemic fungal infections; use in premature
infants (formulations containing benzyl alcohol only); idiopathic thrombocytopenia purpura (IM administration
only); intrathecal administration; live or live, attenuated virus vaccines (with immunosuppressive doses of
corticosteroids).
Canadian labeling: Additional contraindications (not in US labeling): Herpes simplex of the eye (except for short-term or
emergency therapy); vaccinia and varicella (except for short-term or emergency therapy)

in allergic symptoms. Patients receiving >20 mg per day of prednisone (or equivalent) may be most
corticosteroids.
• Dermal changes: Avoid injection or leakage into the dermis; dermal and/or subdermal skin depression may
occur at the site of injection. Avoid deltoid muscle injection; subcutaneous atrophy may occur.
• Immunosuppression: Prolonged use of corticosteroids may increase the incidence of secondary infection, mask
acute infection (including fungal infections), prolong or exacerbate viral infections, or limit response to
killed or inactivated vaccines. Exposure to chickenpox or measles should be avoided. Corticosteroids should
not be used for cerebral malaria, fungal infections, or viral hepatitis. Close observation is required in
patients with latent tuberculosis and/or TB reactivity; restrict use in active TB (only fulminating or
disseminated TB in conjunction with antituberculosis treatment). Latent or active amebiasis should be ruled
out in any patient with recent travel to tropical climates or unexplained diarrhea prior to corticosteroid
initiation. Use with extreme caution in patients with Strongyloides infections; hyperinfection, dissemination
and fatalities have occurred.
sarcoma (case reports); if noted, discontinuation of therapy should be considered (Goedert 2002).
• Psychiatric disturbances: Corticosteroid use may cause psychiatric disturbances, including euphoria, insomnia,
mood swings, personality changes, severe depression, or psychotic manifestations. Pre-existing psychiatric
conditions may be exacerbated by corticosteroid use.
• Cardiovascular disease: Use with caution in patients with HF and/or hypertension; use has been associated with
fluid retention, electrolyte disturbances, and hypertension. Use with caution following acute MI;
corticosteroids have been associated with myocardial rupture.
perforation risk.
• Head injury: Increased mortality was observed in patients receiving high-dose IV methylprednisolone; high-dose
corticosteroids should not be used for the management of head injury.
open-angle glaucoma, and cataracts have occurred with prolonged use. Oral steroid treatment is not
recommended for the treatment of acute optic neuritis; may increase frequency of new episodes and does
not affect short- or long-term visual outcomes. Use with caution in patients with ocular herpes simplex;
corneal perforation may occur; do not use in active ocular herpes simplex. Consider routine eye exams in
chronic users.
• Pheochromocytoma: Pheochromocytoma crisis has been reported with corticosteroids (may be fatal). Consider
the risk of pheochromocytoma crisis prior to administering corticosteroids in patients with suspected
pheochromocytoma.
• Septic shock or sepsis syndrome: Corticosteroids should not be administered for the treatment of sepsis in the
absence of shock (SCCM/ESICM [Annane 2017]).
• Benzyl alcohol and derivatives: Diluent for injection may contain benzyl alcohol and some dosage forms may
contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large
amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping
syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress,
gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension and
cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces
bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol
and/or benzyl alcohol derivative with caution in neonates. See manufacturer’s labeling.
(Leonard 2007). In premature neonates, reports of gastrointestinal perforation in the hydrocortisone treatment arm
have resulted in the closure of two large BPD clinical trials (Peltoniemi 2005; Watterberg 2004); concomitant use with
indomethacin or ibuprofen may increase the risk and should be avoided in this population (Seri 2006). Increased IOP
may occur especially with prolonged use; in children, increased IOP has been shown to be dose dependent and produce
a greater IOP in children <6 years than older children treated with ophthalmic dexamethasone (Lam 2005). Hypertrophic
cardiomyopathy has been reported in premature neonates.
Parenteral: Reconstitute vial with appropriate diluent, either bacteriostatic water or NS (see manufacturer's labeling for
details). For the commonly used 100 mg vial, reconstitute with a volume of diluent not to exceed 2 mL resulting in
a concentration ≥ 50 mg/mL. Act-O-Vial (self-contained powder for injection plus diluent [preservative free SWFI])
may be reconstituted by pressing the activator to force diluent into the powder compartment. Following gentle
agitation, solution may be withdrawn via syringe through a needle inserted into the center of the stopper. May be
administered (IV or IM) without further dilution.
Intermittent IV infusion: Reconstituted solutions may be further diluted in an appropriate volume of compatible solution
for infusion. Concentration should generally not exceed 1 mg/mL. In pediatric patients, a concentration of 5
mg/mL has been used (Miller 1980). The manufacturer suggests, in cases where administration of a small volume
of fluid is desirable, concentrations up to 60 mg/mL (100 to 3,000 mg in 50 mL of D5W or NS; stability limited to 4
hours) may be used.
Oral: Administer with food or milk to decrease GI upset; for physiologic replacement in pediatric patients, higher doses
are typically administered in the morning and midday with lower doses in the evening to replicate diurnal
variation; early evening doses (18:00) may be necessary in some children (doses too close to bedtime can
interfere with sleep) (Elder 2015)
Parenteral: Hydrocortisone sodium succinate may be administered by IM or IV routes. Dermal and/or subdermal skin
depression may occur at the site of injection.
IM: Avoid injection into deltoid muscle (high incidence of SubQ atrophy)
IV bolus: Administer undiluted over at least 30 seconds; for large doses (≥500 mg), administer over 10 minutes
Intermittent IV infusion: Further dilute in a compatible fluid and administer over 20 to 30 minutes (Miller 1980)
Systemic use of corticosteroids may require a diet with increased potassium, vitamins A, B6, C, D, folate, calcium, zinc,
phosphorus, and decreased sodium. Some products may contain sodium.
Extemporaneous Preparations
2 mg/mL Oral Suspension (ASHP Standard Concentration)(ASHP 2017)
A 2 mg/mL oral suspension may be made with 10 mg tablets and a 1:1 mixture of Ora-Sweet and Ora-Plus. Crush ten 10
mg hydrocortisone tablets in a mortar and reduce to a fine powder. Add a small amount of vehicle and mix to a
uniform paste; mix while adding the vehicle in incremental proportions to almost 50 mL; transfer to a calibrated
amber bottle, rinse mortar with vehicle, and add sufficient quantity of vehicle to make 50 mL. Label “shake well.”
Stable under refrigeration or at room temperature for 90 days.
Chong G, Decarie D, Ensom MHH. Stability of hydrocortisone in extemporaneously compounded suspension. J Inform
Pharmacother. 2003;13:100-110.
2.5 mg/mL Oral Suspension
A 2.5 mg/mL oral suspension may be made with either tablets or powder and a vehicle containing sodium
carboxymethylcellulose (1 g), syrup BP (10 mL), hydroxybenzoate 0.1% preservatives (0.1 g), polysorbate 80 (0.5
mL), citric acid (0.6 g), and water. To make the vehicle, dissolve the hydroxybenzoate, citric acid, and syrup BP in
hot water. Cool solution and add the carboxymethylcellulose; leave overnight. Crush twelve-and-one-half 20 mg
hydrocortisone tablets (or use 250 mg of powder) in a mortar and reduce to a fine powder while adding
polysorbate 80. Add small portions of vehicle and mix to a uniform paste; mix while adding the vehicle in
incremental proportions to almost 100 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add
sufficient quantity of vehicle to make 100 mL. Label “shake well” and “refrigerate.” Stable for 90 days.
Fawcett JP, Boulton DW, Jiang R, et al. Stability of hydrocortisone oral Suspensions prepared from tablets and
powder. Ann Pharmacother. 1995;29(10):987-990.[PubMed 8845559]
Blood pressure; weight; serum glucose; electrolytes; growth in pediatric patients; presence of infection, bone mineral
density; assess HPA axis suppression (eg, ACTH stimulation test, morning plasma cortisol test, urinary free cortisol test).
Monitor IOP with therapy >6 weeks.
Reference Range
Hydrocortisone (normal endogenous morning levels): 4 to 30 mcg/mL
Substrate of CYP3A4 (minor), P-glycoprotein/ABCB1; Note:Assignment of Major/Minor substrate status based on

clinically relevant drug interaction potential
Drug Interactions
Aldesleukin: Corticosteroids may diminish the antineoplastic effect of Aldesleukin. Risk X: Avoid combination
therapy
Monitor therapy
Aprepitant: May increase the serum concentration of Corticosteroids (Systemic). Management: No dose adjustment is
needed for single 40 mg aprepitant doses. For other regimens, reduce oral dexamethasone or
methylprednisolone doses by 50%, and IV methylprednisolone doses by 25%. Antiemetic regimens containing
dexamethasone reflect this adjustment. Risk D: Consider therapy modification
Axicabtagene Ciloleucel: Corticosteroids (Systemic) may diminish the therapeutic effect of Axicabtagene Ciloleucel.
Management: Avoid use of corticosteroids as premedication before axicabtagene ciloleucel. Corticosteroids may,
however, be required for treatment of cytokine release syndrome or neurologic toxicity. Risk D: Consider therapy
modification
Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of
baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not
recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying
antirheumatic drugs (DMARDs) is permitted. Risk D: Consider therapy modification
BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid
combination
Monitor therapy
Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Risk X: Avoid combination
Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin
Test. Risk C: Monitor therapy
Corticorelin: Corticosteroids may diminish the therapeutic effect of Corticorelin. Specifically, the plasma ACTH response
to corticorelin may be blunted by recent or current corticosteroid therapy. Risk C: Monitor therapy
Cosyntropin: Hydrocortisone (Systemic) may diminish the diagnostic effect of Cosyntropin. Management: Patients
receiving hydrocortisone should omit their pre-test dose on the day selected for cosyntropin testing. Risk D:
CYP3A4 Inducers (Strong): May decrease the serum concentration of Hydrocortisone (Systemic). Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Corticosteroids (Systemic). Risk C: Monitor therapy
Deferasirox: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI
ulceration/irritation or GI bleeding may be increased. Risk C: Monitor therapy
Deferasirox: Corticosteroids may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI
ulceration/irritation or GI bleeding may be increased.Risk C: Monitor therapy
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections
may be increased. Risk C: Monitor therapy
Desirudin: Corticosteroids (Systemic) may enhance the anticoagulant effect of Desirudin. More specifically,
corticosteroids may increase hemorrhagic risk during desirudin treatment. Management: Discontinue treatment
with systemic corticosteroids prior to desirudin initiation. If concomitant use cannot be avoided, monitor patients
receiving these combinations closely for clinical and laboratory evidence of excessive anticoagulation. Risk D:
Desmopressin: Corticosteroids (Systemic) may enhance the hyponatremic effect of Desmopressin. Risk X: Avoid
combination
DilTIAZem: May increase the serum concentration of Corticosteroids (Systemic). Risk C: Monitor therapy
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Risk C: Monitor therapy
Estrogen Derivatives: May increase the serum concentration of Corticosteroids (Systemic). Risk C: Monitor therapy
Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the
concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients
closely for additive immunosuppressant effects (eg, infections). Risk D: Consider therapy modification
Fosaprepitant: May increase the serum concentration of Corticosteroids (Systemic). The active metabolite aprepitant is
likely responsible for this effect. Risk D: Consider therapy modification
Indacaterol: May enhance the hypokalemic effect of Corticosteroids (Systemic). Risk C: Monitor therapy
Indium 111 Capromab Pendetide: Corticosteroids (Systemic) may diminish the diagnostic effect of Indium 111 Capromab
Pendetide. Risk X: Avoid combination
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for
hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased.
Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants.
Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow
suppression at least monthly. Risk D: Consider therapy modification
therapy
Lumacaftor: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. Lumacaftor may increase the
serum concentration of P-glycoprotein/ABCB1 Substrates. Risk C: Monitor therapy
Macimorelin: Corticosteroids (Systemic) may diminish the diagnostic effect of Macimorelin. Risk X: Avoid combination
Mifamurtide: Corticosteroids (Systemic) may diminish the therapeutic effect of Mifamurtide. Risk X: Avoid combination
MiFEPRIStone: May diminish the therapeutic effect of Corticosteroids (Systemic). MiFEPRIStone may increase the serum
concentration of Corticosteroids (Systemic). Management: Avoid mifepristone in patients who require long-term
corticosteroid treatment of serious illnesses or conditions (e.g., for immunosuppression following
transplantation). Corticosteroid effects may be reduced by mifepristone treatment. Risk X: Avoid combination
Mitotane: May decrease the serum concentration of Corticosteroids (Systemic). Risk D: Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of
concurrent infection may be increased. Risk X: Avoid combination
Nicorandil: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Nicorandil. Gastrointestinal perforation
has been reported in association with this combination. Risk C: Monitor therapy
Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Risk D: Consider therapy
modification
Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Risk C: Monitor therapy
P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-

glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific
cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.).Risk
C: Monitor therapy
P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-

glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific
cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.).Risk
C: Monitor therapy
Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Risk C: Monitor therapy
Ritodrine: Corticosteroids may enhance the adverse/toxic effect of Ritodrine. Risk C: Monitor therapy
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Risk D: Consider therapy modification
Sargramostim: Corticosteroids (Systemic) may enhance the therapeutic effect of Sargramostim. Specifically,
corticosteroids may enhance the myeloproliferative effects of sargramostim. Risk C: Monitor therapy
Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Risk C: Monitor therapy
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients
to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating
sipuleucel-T therapy. Risk D: Consider therapy modification
Somatropin: Corticosteroids (Systemic) may diminish the therapeutic effect of Somatropin. Risk C: Monitor therapy
therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Risk C: Monitor therapy
Tisagenlecleucel: Corticosteroids (Systemic) may diminish the therapeutic effect of Tisagenlecleucel. Management:
Avoid use of corticosteroids as premedication or at any time during treatment with tisagenlecleucel, except in the
case of life-threatening emergency (such as resistant cytokine release syndrome). Risk D: Consider therapy
modification
Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent
use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is
permitted, and this warning seems particularly focused on more potent immunosuppressants. Risk D: Consider
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Urea Cycle Disorder Agents: Corticosteroids (Systemic) may diminish the therapeutic effect of Urea Cycle Disorder
Agents. More specifically, Corticosteroids (Systemic) may increase protein catabolism and plasma ammonia
concentrations, thereby increasing the doses of Urea Cycle Disorder Agents needed to maintain these
concentrations in the target range. Risk C: Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated).
Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior
to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3
months after immunosuppressant discontinuation. Risk D: Consider therapy modification
Vaccines (Live): Corticosteroids (Systemic) may enhance the adverse/toxic effect of Vaccines (Live). Corticosteroids
(Systemic) may diminish the therapeutic effect of Vaccines (Live). Management: Doses equivalent to less than 2
mg/kg or 20 mg per day of prednisone administered for less than 2 weeks are not considered sufficiently
immunosuppressive to create vaccine safety concerns. Higher doses and longer durations should be avoided. Risk
Test Interactions
May decrease response to skin tests
Onset of action: IV: 1 hour
Absorption: Rapid
Bioavailability: Oral: 96% ± 20% (Czock 2005)
Distribution: Vd: IV: 27 ± 7 L (Czock 2005)
Protein binding: IV: 92% ± 2% (Czock 2005)
Metabolism: Hepatic
Half-life elimination: IV: 2 ± 0.3 hours; Oral: 1.8 ± 0.5 hours (Czock 2005)
Time to peak, plasma: Oral: 1.2 ± 0.4 hours (Czock 2005)

Excretion: Urine (Czock 2005)
Adverse Reactions
Cardiovascular: Atheromatous embolism, bradycardia, cardiac arrhythmia, cardiac failure (especially in susceptible
patients), cardiomegaly, circulatory shock, hypertension, hypertrophic cardiomyopathy (premature infants),
myocardial rupture (post-myocardial infarction), syncope, tachycardia, thromboembolism, thrombophlebitis,
vasculitis
Central nervous system: Arachnoiditis (intrathecal administration), depression, emotional lability, euphoria, headache,
increased intracranial pressure (with pseudotumor cerebri; usually following discontinuation), insomnia, malaise,
meningitis (intrathecal administration), myasthenia, neuritis, neuropathy, paraplegia (intrathecal administration),
paresthesia, personality changes, psychic disorder, seizure, sensory disturbance (intrathecal administration),
tingling of skin (especially in the perineal area after IV injection), vertigo
Dermatologic: Acne vulgaris, allergic dermatitis, alopecia, atrophic striae, burning sensation of skin (especially in the
perineal area after IV injection), diaphoresis, ecchymosis, erythema (including facial), exfoliation of skin,
hyperpigmentation, hypertrichosis, hypopigmentation, skin atrophy, skin rash, suppression of skin test reaction,
urticaria, xeroderma
Endocrine & metabolic: Adrenal suppression, Cushing syndrome, diabetes mellitus (latent), fluid retention, glycosuria,
growth suppression, hirsutism, HPA-axis suppression, hypercalcemia (associated with cancers), hyperglycemia
(including increased requirements for insulin or oral hypoglycemic agents in diabetes mellitus), hypokalemia,
hypokalemic alkalosis, impaired glucose tolerance, lipodystrophy, lipomatosis (epidural), menstrual disease
(menstrual irregularities), moon face, negative nitrogen balance, protein catabolism, sodium retention, weight
gain
Gastrointestinal: Abdominal distention, carbohydrate intolerance, dyspepsia, gastrointestinal disease (intrathecal

administration), gastrointestinal perforation (small and large intestine, particularly in patients with inflammatory
bowel disease), hiccups, increased appetite, nausea, pancreatitis, peptic ulcer (with possible perforation and
hemorrhage), ulcerative esophagitis, vomiting
Genitourinary: Asthenospermia, bladder dysfunction (intrathecal administration)
Hematologic & oncologic: Leukocytosis, petechia
Hepatic: Hepatomegaly, increased serum transaminases (usually mild elevations and reversible on discontinuation)
Hypersensitivity: Anaphylaxis, angioedema, hypersensitivity reaction
Infection: Increased susceptibility to infection, infection, sterile abscess
Local: Atrophy at injection site (cutaneous and subcutaneous), postinjection flare (intra-articular use), skin edema
Neuromuscular & skeletal: Amyotrophy, Charcot-like arthropathy, lower extremity weakness (intrathecal
administration), osteonecrosis (aseptic necrosis of femoral and humoral heads), osteoporosis, pathological
fracture (long bones), rupture of tendon (particularly Achilles tendon), steroid myopathy, vertebral compression
fracture
Ophthalmic: Cataract (posterior subcapsular), exophthalmos, glaucoma, increased intraocular pressure, retinopathy
(central serous chorioretinopathy)
Respiratory: Pulmonary edema
Miscellaneous: Wound healing impairment
Rare but important or life-threatening: Anaphylactoid reaction, blindness (periocular injection)
IMIPENEM AND CILASTATIN

Dosing: Pediatric
Note: Dosage recommendations are based on imipenem component.
General dosing, susceptible infection; severe infections (Red Book [AAP 2018]): Infants, Children, and Adolescents: IV: 60
to 100 mg/kg/day divided every 6 hours; maximum daily dose: 4,000 mg/day
Burkholderia pseudomallei (melioidosis): Infants, Children, and Adolescents: IV: Initial: 60 to 100 mg/kg/day divided
every 6 to 8 hours for at least 10 days; maximum daily dose: 4,000 mg/day; continue parenteral therapy until clinical
improvement, then switch to oral therapy if tolerated and/or appropriate (Currie 2003; White 2003)
Febrile neutropenia, empiric therapy: Limited data available: Children and Adolescents: IV: 60 mg/kg/day divided every 6
hours (Caselli 2012; Erbey 2009; Riikonen 1991); some centers use doses as high as 100 mg/kg/day; maximum daily
dose: 4,000 mg/day
Intra-abdominal infection, complicated: Infants, Children, and Adolescents: IV: 60 to 100 mg/kg/day divided every 6
hours; maximum dose: 500 mg (Solomkin 2010)
Non-tuberculosis mycobacterium, cystic fibrosis: Infants, Children, and Adolescents: IV: 15 to 20 mg/kg/dose every 12
hours; maximum dose: 1,000 mg/dose (USCFF/ECFS [Floto 2016])
Peritonitis (peritoneal dialysis): Infants, Children, and Adolescents: Intraperitoneal: Continuous: Loading dose: 250 mg
per liter of dialysate; maintenance dose: 50 mg per liter (ISPD [Warady 2012])
Pulmonary exacerbation, cystic fibrosis: Infants, Children, and Adolescents: IV: 100 mg/kg/day divided every 6 hours;
maximum daily dose: 4,000 mg/day; efficacy may be limited due to rapid development of resistance (Döring 2000; Zobell
2012)
Infants, Children, and Adolescents: IV:
Manufacturer's labeling: Patient weight <30 kg and impaired renal function (not defined): Use not recommended
The following adjustments have been recommended (Aronoff 2007): Note: Renally adjusted dose recommendations are
based on doses of 60 to 100 mg/kg/day divided every 6 hours.
GFR 30 to 50 mL/minute/1.73 m2: Administer 7 to 13 mg/kg/dose every 8 hours
GFR 10 to 29 mL/minute/1.73 m2: Administer 7.5 to 12.5 mg/kg/dose every 12 hours
GFR <10 mL/minute/1.73 m2: Administer 7.5 to 12.5 mg/kg/dose every 24 hours
Intermittent hemodialysis (IHD): Dialysis: Moderately dialyzable (20% to 50%): 7.5 to 12.5 mg/kg/dose every 24 hours
(administer after hemodialysis on dialysis days)
Peritoneal dialysis (PD): 7.5 to 12.5 mg/kg/dose every 24 hours
• CNS effects: Carbapenems have been associated with CNS adverse effects, including confusional states and seizures
(myoclonic); use caution with CNS disorders (eg, brain lesions and history of seizures) and adjust dose in renal
impairment to avoid drug accumulation, which may increase seizure risk. However, there have been reports of adverse
CNS effects in patients who had no recognized or documented underlying CNS disorder or compromised renal function.
• Hypersensitivity reactions: Serious hypersensitivity/anaphylactic reactions have been reported, including fatalities;
may be more common in patients with a history of sensitivity to multiple allergens. Patients with a history of penicillin
hypersensitivity may experience severe hypersensitivity reactions when treated with other beta-lactams; carefully
inquire about previous hypersensitivity reactions to penicillins, cephalosporins, other beta-lactams, and other allergens.
Serious anaphylactic reactions require immediate discontinuation and supportive care as clinically indicated.
• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment required in patients with
moderate to severe renal dysfunction. Increased seizure risk has been reported in patients with significant renal
dysfunction. Do not use in patients with CrCl ≤15 mL/minute unless hemodialysis is instituted within 48 hours. For
patients on hemodialysis, use is recommended only when the benefit outweighs the potential risk of seizures.
• Valproic acid and derivatives: Carbapenems, including imipenem, may decrease the serum concentration of divalproex
sodium/valproic acid increasing the risk of breakthrough seizures. Concurrent use of carbapenem antibiotics with
divalproex sodium/valproic acid is generally not recommended. Alternative antimicrobial agents should be considered,
but if a concurrent carbapenem is necessary, consider additional antiseizure medication.
• Drug-drug interactions: Additional potentially significant interactions may exist, requiring dose or frequency
adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more
• Pediatric: Not recommended in pediatric CNS infections due to seizure potential. Not recommended in pediatric
patients <30 kg with impaired renal function (no data available).
IV: Reconstitute vials with approximately 10 mL of NS, D5W, D10W, D5NS, D51/2NS, or D51/4NS and shake well.
Withdraw desired dose and dilute in a compatible solution to a final concentration not to exceed 5 mg/mL;
concentrations >5 mg/mL may have shortened stability; a final admixture of imipenem-cilastatin 10 mg/mL in NS was
shown to maintain solubility for 4 hours at room temperature however, an 8 mg/mL solution showed >90% stability for
<3 hours (Trissel 1999; Viaene 2002). Imipenem is inactivated at acidic or alkaline pH.
IV: Administer by IV intermittent infusion; doses ≤500 mg may be infused over 20 to 30 minutes; doses >500 mg should
be infused over 40 to 60 minutes. If nausea and/or vomiting occur during administration, decrease the rate of IV
infusion.
Periodic renal, hepatic, and hematologic function tests; bowel movement frequency. Monitor for signs of anaphylaxis
during first dose.
Drug Interactions
Monitor therapy
CycloSPORINE (Systemic): May enhance the neurotoxic effect of Imipenem. Imipenem may decrease the serum
concentration of CycloSPORINE (Systemic). Imipenem may increase the serum concentration of CycloSPORINE
(Systemic). Risk C: Monitor therapy
Ganciclovir-Valganciclovir: May enhance the adverse/toxic effect of Imipenem. Specifically, the risk of seizures may be
increased. Management: Avoid concomitant use of these agents unless the prospective benefits of therapy outweigh the
risks. Risk D: Consider therapy modification
therapy
Probenecid: May increase the serum concentration of Imipenem. Risk C: Monitor therapy
Valproate Products: Carbapenems may decrease the serum concentration of Valproate Products. Management:
Concurrent use of carbapenem antibiotics with valproic acid is generally not recommended. Alternative antimicrobial
agents should be considered, but if a concurrent carbapenem is necessary, consider additional anti-seizure
medication.Risk D: Consider therapy modification
Adverse Reactions
Cardiovascular: Phlebitis, tachycardia
Dermatologic: Skin rash
Gastrointestinal: Diarrhea, gastroenteritis, nausea, oral candidiasis, vomiting
Genitourinary: Oliguria, proteinuria, urine discoloration
Hematologic & oncologic: Decreased hematocrit (more common in infants and children 3 months to 12 years),
decreased hemoglobin, decreased platelet count, eosinophilia, increased hematocrit, neutropenia, thrombocythemia,
Hepatic: Decreased serum bilirubin, increased serum alkaline phosphatase, increased serum ALT, increased serum AST
(more common in infants and children 3 months to 12 years), increased serum bilirubin
Local: Irritation at injection site
Renal: Increased serum creatinine
Rare but important or life-threatening: Acute renal failure, agranulocytosis, back pain (thoracic spinal), basophilia,
bilirubinuria, bone marrow depression, brain disease, candidiasis, casts in urine, change in prothrombin
time, Clostridium difficile associated diarrhea, confusion, cyanosis, decreased serum sodium, dental discoloration, drug
fever, dyskinesia, erythema multiforme, hallucination, hearing loss, heartburn, hematuria, hemolytic anemia,
hemorrhagic colitis, hepatic failure, hepatitis (including fulminant onset), hyperchloremia, hypersensitivity,
hyperventilation, hypotension, increased blood urea nitrogen, increased lactate dehydrogenase, increased serum
potassium, increased urinary urobilinogen, injection site infection, jaundice, leukocytosis, leukocyturia, leukopenia,
lymphocytosis, myoclonus, neutropenia, pancytopenia, positive direct Coombs' test, pseudomembranous colitis,
pseudomonas infection (resistant P. aeruginosa), psychiatric disturbances, Stevens-Johnson syndrome,
thrombocytopenia, toxic epidermal necrolysis
INSULIN ASPART
Dosing: Pediatric
Insulin aspart is a rapid-acting insulin analog which is normally administered SubQ as a premeal component of the
insulin regimen or as a continuous SubQ infusion and should be used with intermediate- or long-acting insulin. When
compared to insulin regular, insulin aspart has a more rapid onset and shorter duration of activity. In carefully controlled
clinical settings with close medical supervision and monitoring of blood glucose and potassium, insulin aspart may also
be administered IV in some situations. Insulin requirements vary dramatically between patients and dictate frequent
monitoring and close medical supervision. See Insulin Regular for additional information.
General insulin dosing:
Type 1 diabetes mellitus: Children and Adolescents: Note: Multiple daily doses or continuous subcutaneous
infusions guided by blood glucose monitoring are the standard of diabetes care. Combinations of insulin
formulations are commonly used. The daily doses presented below are expressed as the total units/kg/day
of all insulin formulations combined.
Initial total insulin dose: SubQ: 0.2-0.6 units/kg/day in divided doses. Conservative initial doses of 0.2-0.4
units/kg/day are often recommended to avoid the potential for hypoglycemia. A rapidly acting
insulin may be the only insulin formulation used initially.
Usual maintenance range: SubQ: 0.5-1 unit/kg/day in divided doses. An estimate of anticipated needs may
be based on body weight and/or activity factors as follows:
Nonobese: 0.4-0.6 units/kg/day
Obese: 0.8-1.2 units/kg/day
Pubescent Children and Adolescents: During puberty, requirements may substantially increase to >1
unit/kg/day and in some cases up to 2 units/kg/day (IDF/ISPAD, 2011)
Adjustment of dose: Dosage must be titrated to achieve glucose control and avoid hypoglycemia. Adjust
dose to maintain premeal and bedtime glucose in target range. Since combinations of agents are
frequently used, dosage adjustment must address the individual component of the insulin regimen
which most directly influences the blood glucose value in question, based on the known onset and
duration of the insulin component.
Continuous SubQ insulin infusion (insulin pump): A combination of a "basal" continuous insulin infusion
rate with preprogrammed, premeal bolus doses which are patient controlled. When converting from
multiple daily SubQ doses of maintenance insulin, it is advisable to reduce the basal rate to less than
the equivalent of the total daily units of longer acting insulin (eg, NPH); divide the total number of
units by 24 to get the basal rate in units/hour. Do not include the total units of regular insulin or
other rapid-acting insulin formulations in this calculation. The same premeal regular insulin dosage
may be used.
There are no dosage adjustments provided in manufacturer's labeling; insulin requirements are reduced due to changes
in insulin clearance or metabolism; monitor blood glucose closely.
There are no dosage adjustments provided in manufacturer's labeling; insulin requirements may be reduced due to
changes in insulin clearance or metabolism; monitor blood glucose closely.
Contraindications
Hypersensitivity to insulin aspart or any component of the formulation; during episodes of hypoglycemia

• Glycemic control: Hyper- or hypoglycemia may result from changes in insulin strength, manufacturer, type,
and/or administration method. The most common adverse effect of insulin is hypoglycemia. The timing of
hypoglycemia differs among various insulin formulations. Hypoglycemia may result from changes in meal
pattern (eg, macronutrient content, timing of meals), changes in the level of physical activity, increased
work or exercise without eating, or changes to coadministered medications. Use of long-acting insulin
preparations (eg, insulin degludec, insulin detemir, insulin glargine) may delay recovery from hypoglycemia.
Patients with renal or hepatic impairment may be at a higher risk. Symptoms differ in patients and may
change over time in the same patient; awareness may be less pronounced in those with long-standing
diabetes, diabetic nerve disease, patients taking beta-blockers, or in those who experience recurrent
hypoglycemia. Profound and prolonged episodes of hypoglycemia may result in convulsions,
unconsciousness, temporary or permanent brain damage, or even death. Insulin requirements may be
altered during illness, emotional disturbances, or other stressors. Instruct patients to use caution with
ethanol; may increase risk of hypoglycemia.
• Hypersensitivity: Hypersensitivity reactions (serious, life-threatening and anaphylaxis) have occurred. If

hypersensitivity reactions occur, discontinue administration and initiate supportive care measures.
• Hypokalemia: Insulin (especially IV insulin) causes a shift of potassium from the extracellular space to the
intracellular space, possibly producing hypokalemia. If left untreated, hypokalemia may result in respiratory
paralysis, ventricular arrhythmia and even death. Use with caution in patients at risk for hypokalemia (eg,
loop diuretic use). Monitor serum potassium frequently with IV use and supplement potassium when
necessary.
• Cardiac disease: Concurrent use with peroxisome proliferator-activated receptor (PPAR)-gamma agonists,
including thiazolidinediones (TZDs), may cause dose-related fluid retention and lead to or exacerbate heart
failure, particularly when used in combination with insulin. If PPAR-gamma agonists are prescribed,
monitor for signs and symptoms of heart failure. If heart failure develops, consider PPAR-gamma agonist
dosage reduction or therapy discontinuation.
• Hepatic impairment: Use with caution in patients with hepatic impairment. Risk of hypoglycemia may be
increased; more frequent monitoring and dosage adjustments may be required.
• Renal impairment: Use with caution in patients with renal impairment. Risk of hypoglycemia may be increased;
more frequent monitoring and dosage adjustments may be required.
• Hospitalized patients with diabetes: Exclusive use of a sliding scale insulin regimen (insulin regular) in the
inpatient hospital setting is strongly discouraged. In the critical care setting, continuous IV insulin infusion
(insulin regular) has been shown to best achieve glycemic targets. In noncritically ill patients with either
poor oral intake or taking nothing by mouth, basal insulin or basal plus bolus is preferred. In noncritically ill
patients with adequate nutritional intake, a combination of basal insulin, nutritional, and correction
components is preferred. An effective insulin regimen will achieve the goal glucose range without the risk
of severe hypoglycemia). A blood glucose value <70 mg/dL should prompt a treatment regimen review and
change, if necessary, to prevent further hypoglycemia (ADA 2019).
• Multiple dose injection pens: According to the Centers for Disease Control and Prevention (CDC), pen-shaped
injection devices should never be used for more than one person (even when the needle is changed)
because of the risk of infection. The injection device should be clearly labeled with individual patient
information to ensure that the correct pen is used (CDC 2012).
• Appropriate use: Due to the short duration of action of insulin aspart, a longer acting insulin or CSII via an
external insulin pump is needed to maintain adequate glucose control in patients with type 1 diabetes
mellitus (insulin dependent, IDDM). In both type 1 and type 2 diabetes, preprandial administration of
insulin aspart should be immediately followed by a meal within 5 to 10 minutes.
• Continuous subcutaneous insulin infusion (CSII) administration: NovoLog may be administered via CSII; do not
dilute or mix with other insulin formulations. Rule out external pump failure if unexplained hyperglycemia
or ketosis occurs; temporary SubQ insulin administration may be required until the problem is identified
and corrected.
• IV administration: Insulin aspart may be administered IV in selected clinical situations to control hyperglycemia;
close monitoring of blood glucose and serum potassium as well as medical supervision is required.
• Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of
therapy.
Parenteral:
SubQ: NovoLog vials: May be diluted with Insulin Diluting Medium for NovoLog to a concentration of 10 units/mL (U-10)
or 50 units/mL (U-50). Do not dilute insulin contained in a cartridge, prefilled pen, or external insulin pump. May
be mixed in the same syringe with NPH insulin. When mixing insulin aspart with NPH insulin, aspart should be
drawn into the syringe first.
IV: May be diluted in NS, D5W, or D10W to concentrations of 0.05 to 1 unit/mL.
Parenteral: Do not use if solution is viscous or cloudy; use only if clear and colorless.
SubQ: Administration is usually made into the subcutaneous fat of the thighs, arms, buttocks, or abdomen, with sites
rotated; cold injections should be avoided. May be mixed in the same syringe with NPH insulin. When mixing
insulin aspart with NPH insulin, aspart should be drawn into the syringe first. Administer immediately before
meals (within 5 to 10 minutes of the start of a meal).
Continuous SubQ insulin infusion (insulin pump): Do not use if solution is viscous or cloudy; use only if clear and
colorless. Patients should be trained in the proper use of their external insulin pump and in intensive insulin
therapy. Infusion sets and infusion set insertion sites should be changed at least every 3 days; rotate infusion
sites. Do not dilute or mix other insulin formulations with insulin aspart that is to be used in an external insulin
pump.
IV: Insulin aspart may be administered IV in selected clinical situations to control hyperglycemia. Closely monitor blood
glucose and serum potassium; appropriate medical supervision is required. Do not administer insulin mixtures
intravenously.
To minimize insulin adsorption to IV tubing: Flush the IV tubing with a priming infusion of 20 mL from the insulin
infusion, whenever a new IV tubing set is added to the insulin infusion container (Jacobi 2012; Thompson
2012). Also refer to institution-specific protocols where appropriate.
Because of insulin adsorption to IV tubing or infusion bags, the actual amount of insulin being administered via IV
infusion could be substantially less than the apparent amount. Therefore, adjustment of the IV infusion
rate should be based on effect and not solely on the apparent insulin dose. The apparent dose may be used
as a starting point for determining the subsequent SubQ dosing regimen (Moghissi 2009); however, the
transition to SubQ administration requires continuous medical supervision, frequent monitoring of blood
glucose, and careful adjustment of therapy. In addition, SubQ insulin should be given 1 to 4 hours prior to
the discontinuation of IV insulin to prevent hyperglycemia (Moghissi 2009).
Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy.
Urine sugar and acetone, serum glucose, electrolytes, Hb A1c, lipid profile; when used intravenously, close monitoring of
serum glucose and potassium are required to avoid hypoglycemia and/or hypokalemia
Reference Range
Plasma Blood Glucose and HbA1c Goals for Diabetes Patients (ADA 2016): Note: Goals should be individualized based on
individual needs/circumstances (eg, patients who experience severe hypoglycemia, patients with hypoglycemic
unawareness); lower goals may be reasonable if they can be achieved without excessive
hypoglycemia. Note:Postprandial blood glucose should be measured when there is a discrepancy between preprandial
blood glucose concentrations and HbA1c values and to help assess glycemia for patients who receive basal/bolus
regimens. It is usually drawn 1 to 2 hours after starting a meal and is considered to be the "peak."
Preprandial glucose: 90 to 130 mg/dL
Bedtime/overnight glucose: 90 to 150 mg/dL
HbA1c: <7.5%
Adults, nonpregnant:
Preprandial glucose: 80 to 130 mg/dL
Postprandial glucose: <180 mg/dL
HbA1c: <7%
None known.
Drug Interactions
Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Risk C:
Monitor therapy
Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy
Beta-Blockers: May enhance the hypoglycemic effect of Insulins. Exceptions: Levobunolol; Metipranolol. Risk C: Monitor
therapy
Dipeptidyl Peptidase-IV Inhibitors: May enhance the hypoglycemic effect of Insulins. Management: Consider a decrease
in insulin dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for
hypoglycemia. Risk D: Consider therapy modification
Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor
therapy
Edetate CALCIUM Disodium: May enhance the hypoglycemic effect of Insulins. Risk C: Monitor therapy
Glucagon-Like Peptide-1 Agonists: May enhance the hypoglycemic effect of Insulins. Management: Consider insulin dose
reductions when used in combination with glucagon-like peptide-1 agonists. Avoid the use of lixisenatide in
patients receiving both basal insulin and a sulfonylurea. Exceptions: Liraglutide. Risk D: Consider therapy
modification
Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C:
Monitor therapy
Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Risk
C: Monitor therapy
Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-
Liraglutide: May enhance the hypoglycemic effect of Insulins. Management: If liraglutide is used for the treatment of
diabetes (Victoza), consider insulin dose reductions. The combination of liraglutide and insulin should be avoided
if liraglutide is used exclusively for weight loss (Saxenda). Risk D: Consider therapy modification
Macimorelin: Insulins may diminish the diagnostic effect of Macimorelin. Risk X: Avoid combination
Maitake: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Risk C: Monitor therapy
Metreleptin: May enhance the hypoglycemic effect of Insulins. Management: Insulin dosage adjustments (including
potentially large decreases) may be required to minimize the risk for hypoglycemia with concurrent use of
metreleptin. Monitor closely. Risk D: Consider therapy modification
Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents.Risk C: Monitor
therapy
Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Risk C: Monitor therapy
Pioglitazone: May enhance the adverse/toxic effect of Insulins. Specifically, the risk for hypoglycemia, fluid retention,
and heart failure may be increased with this combination. Management: If insulin is combined with pioglitazone,
dose reductions should be considered to reduce the risk of hypoglycemia. Monitor patients for fluid retention and
signs/symptoms of heart failure. Risk D: Consider therapy modification
Pramlintide: May enhance the hypoglycemic effect of Insulins. Management: Upon initiation of pramlintide, decrease
mealtime insulin dose by 50% to reduce the risk of hypoglycemia. Monitor blood glucose frequently and
individualize further insulin dose adjustments based on glycemic control. Risk D: Consider therapy modification
Prothionamide: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Risk C: Monitor therapy
Quinolones: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolones may diminish the
therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss
of blood sugar control may occur with quinolone use. Risk C: Monitor therapy
Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Rosiglitazone: Insulins may enhance the adverse/toxic effect of Rosiglitazone. Specifically, the risk of fluid retention,
heart failure, and hypoglycemia may be increased with this combination. Risk X: Avoid combination
Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents.Risk C:
Monitor therapy
Sodium-Glucose Cotransporter 2 (SLGT2) Inhibitors: May enhance the hypoglycemic effect of Insulins. Management:
Consider a decrease in insulin dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and
monitor patients for hypoglycemia. Risk D: Consider therapy modification
Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Note: Onset and duration of hypoglycemic effects depend upon the route of administration, site of injection (onset and
duration are progressively slower with SubQ injection into the abdomen, arm, buttock, or thigh respectively), volume
and concentration of injection, and the preparation administered. Rate of absorption, onset, and duration of activity
may be affected by exercise, presence of lipodystrophy, local blood supply, and/or temperature.
Onset of action: ~0.2 to 0.3 hours
Peak effect: 1 to 3 hours (Novolog); ~1.5 to 2.22 hours (Fiasp)
Duration: 3 to 5 hours (Novolog); ~5 to 7 hours (Fiasp)
Protein binding: <10%
Half-life elimination: SubQ: 81 minutes (Novolog); 1.1 hours (Fiasp)
Time to peak, plasma: 40 to 50 minutes (Novolog); ~63 minutes (Fiasp)
Excretion: Urine
Clearance: Adults: 1.22 L/hour/kg
Obesity: Novolog clearance is reduced 28% in patients with a BMI >32 kg/m2 compared with patients with a BMI <23
kg/m2.
Adverse Reactions
Cardiovascular: Chest pain
Central nervous system: Abnormal sensory symptoms, headache, hyporeflexia, peripheral neuropathy
Dermatologic: Allergic skin rash, onychomycosis, skin changes
Endocrine & metabolic: Diabetic retinopathy, severe hypoglycemia, weight gain
Gastrointestinal: Abdominal pain, diarrhea, nausea
Genitourinary: Urinary tract infection
Immunologic: Antibody development
Local: Erythema at injection site, injection site reaction, injection site pruritus, swelling at injection site
Neuromuscular & skeletal: Back pain
Ophthalmic: Error of refraction

Respiratory: Nasopharyngitis, sinusitis, upper respiratory tract infection
Miscellaneous: Accidental injury
Rare but important or life-threatening: Anaphylaxis, facial edema, hypersensitivity reaction, lipoatrophy at injection site,
peripheral edema
INSULINA REGULAR
Dosing: Neonatal
Hyperglycemia: Limited data available (Cloherty 2012): Note: Neonates are extremely sensitive to the effects of insulin;
initiate therapy at the lower end of infusion rate and monitor closely; routine use in neonates is not
recommended: IV:
Intermittent IV infusion: 0.05 to 0.1 units/kg infused over 15 minutes every 4 to 6 hours as needed; Note: Should
be used as initial management; monitor blood glucose every 30 minutes to 1 hour following doses
Continuous IV infusion: Initial rate: 0.05 units/kg/hour, monitor blood glucose every 30 minutes and titrate in 0.01
units/kg/hour increments, usual range: 0.01 to 0.2 units/kg/hour
Hyperkalemia: Limited data available:
IV: 0.1 units/kg with 400 mg/kg of glucose; Note: Ratio of 1 unit of insulin for every 4 g of glucose (Hegenbarth
2008)
Continuous IV infusion: Initial bolus: 0.05 units/kg with 2 mL/kg of D10W followed by continuous IV infusion of
insulin at 0.1 unit/kg/hour in combination with D10W infusion at 2 to 4 mL/kg/hour (Cloherty 2012); insulin
infusions as low as 0.05 units/kg/hour in conjunction with dextrose infusion have been used in premature
neonates (GA: <28 weeks) (Malone 1991).
Dosing: Pediatric
The general objective of insulin replacement therapy is to approximate the physiologic pattern of insulin secretion. This
requires a basal level of insulin throughout the day, supplemented by additional insulin at mealtimes. Since
combinations using different types of insulins are frequently used, dosage adjustment must address the individual
component of the insulin regimen which most directly influences the blood glucose value in question, based on the
known onset and duration of the insulin component. The frequency of doses and monitoring must be individualized in
consideration of the patient's ability to manage therapy.
Type 1 diabetes mellitus: Infants (Limited data available), Children, and Adolescents: Note: Insulin regimens
should be individualized to achieve glycemic goals without causing hypoglycemia. Multiple daily doses or
continuous subcutaneous infusion guided by blood glucose monitoring are the standard of diabetes care.
The daily doses presented are expressed as the total units/kg/day of all insulin formulations combined.
Initial dose: SubQ: 0.2 to 0.6 units/kg/day in divided doses. Conservative initial doses of 0.2 to 0.4
units/kg/day are often recommended to avoid the potential for hypoglycemia.
Division of daily insulin requirement ("conventional therapy"): Generally, 50% to 75% of the daily insulin
dose is given as an intermediate- or long-acting form of insulin (in 1 to 2 daily injections). The
remaining portion of the 24-hour insulin requirement is divided and administered as either regular
insulin or a rapid-acting form of insulin at the same time before breakfast and dinner.
Division of daily insulin requirement ("intensive therapy"): Basal insulin delivery with 1 or 2 doses of
intermediate- or long-acting insulin formulations superimposed with doses of rapid- or very rapid-
acting insulin formulations 3 or more times daily.
Adjustment of dose: Dosage must be titrated to achieve glucose control and avoid hypoglycemia. Adjust
dose to maintain premeal and bedtime glucose in target range. Since combinations of agents are
frequently used, dosage adjustment must address the individual component of the insulin regimen
which most directly influences the blood glucose value in question, based on the known onset and
duration of the insulin component.
Usual maintenance range: 0.5 to 1 unit/kg/day in divided doses; doses must be individualized; however an
estimate can be determined based on phase of diabetes and level of maturity (ISPAD [Danne 2014])
Partial remission phase (Honeymoon phase): <0.5 units/kg/day
Prepubertal children (not in partial remission): 0.7 to 1 units/kg/day
Pubescent Children and Adolescents: During puberty, requirements may substantially increase to
>1.2 unit/kg/day and in some cases up to 2 units/kg/day
Continuous SubQ insulin infusion (insulin pump): A combination of a "basal" continuous insulin infusion rate
with preprogrammed, premeal bolus doses which are patient controlled. When converting from
multiple daily SubQ doses of maintenance insulin, it is advisable to reduce the basal rate to less than
the equivalent of the total daily units of longer acting insulin (eg, NPH). Divide the total number of
units by 24 to get the basal rate in units/hour. Do not include the total units of regular insulin or
other rapid-acting insulin formulations in this calculation. The same premeal regular insulin dosage
may be used.
Type 2 diabetes mellitus: Children ≥10 years and Adolescents: SubQ: The goal of therapy is to achieve an
HbA1c <6.5% as quickly as possible using the safe titration of medications. Initial therapy in metabolically
unstable patients (eg, plasma glucose ≥ 250 mg/dL, HbA1c >9% and symptoms excluding acidosis) may
include once daily intermediate-acting insulin or basal insulin in combination with lifestyle changes and
metformin. In patients who fail to achieve glycemic goals with metformin and basal insulin, may consider
initiating prandial insulin (regular insulin or rapid acting insulin) and titrate to achieve goals. Once initial
goal reached, insulin should be slowly tapered and the patient transitioned to lowest effective doses or
metformin monotherapy if able (AAP [Copeland 2013]; ISPAD [Zeitler 2014]). Note: Patients who are
ketotic or present with ketoacidosis require aggressive management as indicated.
Diabetic ketoacidosis (DKA): Limited data available: Infants, Children, and Adolescents: Note: Only IV regular
insulin should be used for treatment of DKA; the rare exception where the use of SubQ rapid-acting insulin
analogs (eg, aspart, lispro) may be appropriate is for patients with uncomplicated DKA in whom peripheral
circulation is adequate and continuous IV regular insulin administration is not possible. Treatment should
continue until resolution of acid-base abnormalities (eg, pH >7.3, serum HCO3 >15 mEq/L, and/or closure of
anion gap); serum glucose is not a direct indicator of these abnormalities, and may decrease more rapidly
than correction of the metabolic abnormalities. As part of overall DKA management, dextrose should be
added to IV fluids to prevent hypoglycemia, usually once serum glucose is between 250 to 300 mg/dL but it
may be required sooner if serum glucose has decreased precipitously. Generally, only dextrose 5% is
necessary and is added to NS or 1/2NS; however, dextrose 10% or 12.5% may be necessary in some cases
(ADA [Wolfsdorf 2006]; ISPAD [Wolfsdorf 2014]). Refer to institution-specific protocols where appropriate.
Continuous IV infusion:
Initial: 0.05 to 0.1 units/kg/hour; continue the rate at 0.05 to 0.1 units/kg/hour if tolerated until
resolution of ketoacidosis (pH >7.3; bicarbonate >15 mEq/L and/or closure of anion
gap); Note: Some patients (eg, some young children with DKA, or older children with
established diabetes) may have marked sensitivity to insulin requiring lower infusion rates;
these lower infusion rates should only be used provided that resolution of the acidosis
continues (ADA [Wolfsdorf 2006]; ISPAD [Wolfsdorf 2014]).
After resolution of DKA: Once ketoacidosis has resolved and oral intake is tolerated, transition to a
SubQ insulin regimen. An overlap between discontinuation of IV insulin and administration of
SubQ insulin is recommended to ensure adequate plasma insulin levels; timing of SubQ insulin
administration prior to infusion discontinuation is dependent on type of insulin used; for SubQ
regular insulin: 1 to 2 hours, or for rapid-acting insulin: 15 to 30 minutes (IPSAD [Wolfsdorf
2014]).
Hyperkalemia: Limited data available: Infants, Children, and Adolescents: IV: 0.1 unit/kg with 400 mg/kg of
glucose; usual ratio of combination therapy of insulin to glucose is 1 unit of insulin for every 4 g of glucose
(Hegenbarth 2008). An alternate approach is glucose 1 g/kg followed by 0.2 units of insulin/g of glucose
administered over 15 to 30 minutes then infused continuously as a similar amount per hour (Fuhrman
2011). In adults, the usual dose is 10 units of insulin mixed with 25 g of dextrose (50 mL of D50W)
administered over 15 to 30 minutes (ACLS [Vanden Hoek 2010]).
Hyperosmolar hyperglycemic state (HHS): Limited data available: Children and Adolescents: Note: Only regular IV
insulin should be used. Insulin administration should be initiated when serum glucose concentration is no
longer declining at a rate ≥50 mg/dL per hour with fluid administration alone; earlier initiation may be
required in patients with severe ketosis and acidosis. Infusion should continue until reversal of mental
status changes and hyperosmolality. Serum glucose is not a direct indicator of these abnormalities, and
may decrease more rapidly than correction of the metabolic abnormalities. Refer to institution-specific
protocols where appropriate.
Continuous IV infusion: Initial: 0.025 to 0.05 units/kg/hour; titrate dose to achieve a decrease in serum
glucose concentration at a rate of 50 to 75 mg/dL per hour; higher rates of decline may be required
in some patients; however, if rate of decline exceeds 100 mg/dL per hour discontinue infusion
(ISPAD [Wolfsdorf 2014]; Zeitler 2011)
There are no dosage adjustments provided in manufacturer's labeling; insulin requirements are reduced due to changes
in insulin clearance or metabolism;
There are no dosage adjustments provided in manufacturer's labeling; insulin requirements may be reduced due to
changes in insulin clearance or metabolism; monitor blood glucose closely.
Contraindications
Hypersensitivity to regular insulin or any component of the formulation; during episodes of hypoglycemia.
Documentation of allergenic cross-reactivity for insulin is limited. However, because of similarities in chemical structure
and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.
• Glycemic control: Hyper- or hypoglycemia may result from changes in insulin strength, manufacturer, type,
and/or administration method. The most common adverse effect of insulin is hypoglycemia. The timing of
hypoglycemia differs among various insulin formulations. Hypoglycemia may result from changes in meal
pattern (eg, macronutrient content, timing of meals), changes in the level of physical activity, increased
work or exercise without eating, or changes to coadministered medications. Use of long-acting insulin
preparations (eg, insulin degludec, insulin detemir, insulin glargine) may delay recovery from hypoglycemia.
Patients with renal or hepatic impairment may be at a higher risk. Symptoms differ in patients and may
change over time in the same patient; awareness may be less pronounced in those with long-standing
diabetes, diabetic nerve disease, patients taking beta-blockers, or in those who experience recurrent
hypoglycemia. Profound and prolonged episodes of hypoglycemia may result in convulsions,
unconsciousness, temporary or permanent brain damage, or even death. Insulin requirements may be
altered during illness, emotional disturbances, or other stressors. Instruct patients to use caution with
ethanol; may increase risk of hypoglycemia.
• Hypersensitivity: Severe, life-threatening, generalized allergic reactions, including anaphylaxis, may occur. If
hypersensitivity reactions occur, discontinue therapy, treat the patient with supportive care and monitor
until signs and symptoms resolve.
• Hypokalemia: Insulin (especially IV insulin) causes a shift of potassium from the extracellular space to the
intracellular space, possibly producing hypokalemia. If left untreated, hypokalemia may result in respiratory
paralysis, ventricular arrhythmia and even death. Use with caution in patients at risk for hypokalemia (eg,
loop diuretic use). Monitor serum potassium frequently with IV insulin use and supplement potassium
when necessary.
• Cardiac disease: Concurrent use with peroxisome proliferator-activated receptor (PPAR)-gamma agonists,
including thiazolidinediones (TZDs) may cause dose-related fluid retention and lead to or exacerbate heart
failure, particularly when used in combination with insulin. If PPAR-gamma agonists are prescribed,
monitor for signs and symptoms of heart failure. If heart failure develops, consider PPAR-gamma agonist
dosage reduction or therapy discontinuation.
• Hepatic impairment: Use with caution in patients with hepatic impairment; increased risk of hypoglycemia.
Dosage requirements may be reduced and patients may require more frequent dose adjustment and
glucose monitoring.
• Renal impairment: Use with caution in patients with renal impairment; increased risk of hypoglycemia. Dosage
requirements may be reduced and patients may require more frequent dose adjustment and glucose
monitoring.

• Hospitalized patients with diabetes: Exclusive use of a sliding scale insulin regimen in the inpatient hospital
setting is strongly discouraged. In the critical care setting, continuous IV insulin infusion has been shown to
best achieve glycemic targets. In noncritically ill patients with either poor oral intake or taking nothing by
mouth, basal insulin or basal plus bolus is preferred. In noncritically ill patients with adequate nutritional
intake, a combination of basal insulin, nutritional, and correction components is preferred. An effective
insulin regimen will achieve the goal glucose range without the risk of severe hypoglycemia. A blood
glucose value <70 mg/dL should prompt a treatment regimen review and change, if necessary, to prevent
further hypoglycemia (ADA 2019).
• Multiple-dose injection pens: According to the Centers for Disease Control and Prevention (CDC), pen-shaped
injection devices should never be used for more than one person (even when the needle is changed)
because of the risk of infection. The injection device should be clearly labeled with individual patient
information to ensure that the correct pen is used (CDC 2012).
• Product variation: Human insulin differs from animal-source insulin. Any change of insulin should be made
cautiously; changing manufacturers, type, and/or method of manufacture may result in the need for a
change of dosage. Verify product label prior to administration to prevent medication errors.
• U-500 regular insulin: U-500 regular insulin is a concentrated insulin formulation which contains 500 units of
insulin per mL and is intended for subQ administration only; do not administer IV or IM. U-500 regular
insulin is generally not recommended for use in an insulin pump, but may be used in select patients under
the supervision of a qualified provider (AACE [Grunberger 2010]; Endocrine Society [Peters 2016]).
Prescribe only to patients who require more than 200 units of insulin per day. Doses from a U-500 regular
insulin vial should be drawn up only with a dedicated U-500 insulin syringe. Do not mix or dilute U-500
regular insulin with other insulin formulations. Insulin U-500 also has a delayed onset and longer duration
of action compared to regular insulin U-100, and has both prandial and basal properties (ADA 2018). Do not
perform dose conversions when using the KwikPen, the dose window shows the number of units to be
injected. Do not transfer insulin from the KwikPen to a syringe for administration.
• IV administration: Regular insulin U-100 (ie, 100 units/mL) may be administered IV in selected clinical situations
(eg, critical illness, DKA, hyperkalemia); close monitoring of blood glucose and serum potassium as well as
medical supervision is required. Do not administer U-500 regular insulin IV.
• Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of
therapy.
Parenteral:
SubQ:
Humulin R U-100: May be diluted with the universal diluent, Sterile Diluent for Humalog, Humulin N, Humulin R,
Humulin 70/30, and Humulin R U-500, to a concentration of 10 units/mL (U-10) or 50 units/mL (U-50).
Novolin R: Insulin Diluting Medium for NovoLog is notintended for use with Novolin R or any insulin product other
than insulin aspart.
Regular Insulin may be mixed with other insulins; when mixing regular insulin with other insulin preparations,
regular insulin should be drawn into syringe first.
IV infusion: Only use U-100 preparations.
Humulin R: May be diluted in NS or D5W to concentrations of 0.1 to 1 unit/mL.
Novolin R: May be diluted in NS, D5W, or D10W with 40 mEq/L potassium chloride at concentrations of 0.05 to 1
unit/mL.
Note: ISMP and Vermont Oxford Network recommend a standard concentration of 0.1 or 0.5 units/mL for
neonates (ISMP 2011).
Parenteral: Do not use if solution is viscous or cloudy; use only if clear and colorless.
SubQ: Administer 30 to 60 minutes before meals. Cold injections should be avoided. Administration is usually made into
the subcutaneous fat of the thighs, arms, buttocks, or abdomen, with sites rotated. When mixing regular insulin
with other insulin preparations, regular insulin should be drawn into the syringe first. While not preferred, regular
insulin may be infused SubQ by external insulin pump (eg, when rapid-acting insulin not available) (Danne [ISPAD],
2014); however, when used in an external pump, it is not recommended to be diluted with other solutions.
Concentrated preparation: U-500 formulation: Do not dilute or mix U-500 regular insulin. U-500 regular insulin
vials are to be used only in conjunction with a dedicated U-500 insulin syringe; dosage conversion is not
required with the U-500 syringe. Only in cases where the U-500 insulin syringe is not available, a U-100
insulin syringe or a tuberculin syringe may be necessary.When using a U-100 syringe or a tuberculin syringe
to deliver Humulin R U-500 (from vial), a conversion step is required to ensure the correct amount of
Humulin R U-500 is drawn up in the syringe. To avoid dosing errors when using a U-100 insulin syringe, the
prescribed dose should be written in actual insulin units and as unit markings on the U-100 insulin syringe
(eg, Humulin R U-500 50 units = 10 units on a U-100 insulin syringe). To avoid dosing errors when using a
tuberculin syringe, the prescribed dose should be written in actual insulin units and as a volume (eg,
Humulin R U-500 50 units = 0.1 mL on a tuberculin syringe). Do not perform dose conversions when using
the KwikPen; the dose window shows the number of units to be injected. Do not transfer KwikPen insulin
into a syringe for administration.
IM: May be administered IM in selected clinical situations; close monitoring of blood glucose and serum potassium as
well as medical supervision is required.
IV: Regular U-100 insulin is the preferred insulin formulation approved for IV administration; requires close monitoring
of blood glucose and serum potassium; appropriate medical supervision. If possible, do not administer mixtures of
insulin formulations intravenously. IV administration of U-500 regular insulin is not recommended.
Continuous IV Infusion: Insulin loss will occur by adsorption to plastic (ie, PVC, polyethylene, polyolefin,
polypropylene) IV containers and tubing (Greenwood 2012; Hirsch 1977; Hirsch 1981; Rocchio 2013;
Thompson 2012). To minimize insulin adsorption to plastic (eg, PVC, polyethylene polyolefin,
polypropylene) IV tubing: Prior to administration, flush IV tubing with a priming volume of 20 mL from the
insulin infusion, whenever a new IV tubing set is added to the insulin infusion container (Goldberg 2006;
Jacobi 2012; Thompson 2012). Studies examining this issue in neonates suggest that flushing the IV tubing
prior to administration reduces adsorption and provides improved and more predictable insulin delivery;
however, the combination of flushing along with preconditioning (waiting a predefined time after flushing
the IV line before infusing) provides the greatest reduction in insulin adsorption; wait times for
preconditioning varied among studies from 20 to 60 minutes; flush volumes varied and were as high as 20
mL (Fuloria 1998; Hewson 2000; Simeon 1994). Refer to institution-specific protocols where appropriate.
If insulin is required prior to the availability of the insulin drip, regular insulin should be administered by IV push
injection.
Because of adsorption to plastic IV tubing or infusion bags, the actual amount of insulin being administered could
be substantially less than the apparent amount. Therefore, adjustment of the IV infusion rate should be
based on the effect and not solely on the apparent insulin dose. The apparent dose may be used as a
starting point for determining the subsequent SubQ dosing regimen (Moghissi 2009); however, the
transition to SubQ administration requires continuous medical supervision, frequent monitoring of blood
glucose, and careful adjustment of therapy. In addition, SubQ insulin should be given 1 to 4 hours prior to
the discontinuation of IV insulin to prevent hyperglycemia (Moghissi 2009)
Diabetes: Plasma glucose, electrolytes, HbA1c
DKA/HHS: Vital signs, arterial blood gases (initial), venous pH, CBC with differential, urinalysis, serum glucose BUN,
creatinine, electrolytes, calcium, magnesium, phosphate, anion gap, fluid status blood β-hydroxybutyrate
(β-OH) concentration; neurological observations; mental status (ISPAD [Wolfsdorf 2014]).
Hyperglycemia, neonatal: Monitor serum glucose 30 to 60 minutes after intermittent IV dose, initiation of continuous
infusion, or rate change (Cloherty 2012; Hemachandra 1999); must be closely monitored to avoid hypoglycemia
and/or hypokalemia. Consult individual institutional policies and procedures.
Hyperkalemia: Serum potassium and glucose must be closely monitored to avoid hypoglycemia and/or hypokalemia.
Drug Interactions
Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Risk C:
Monitor therapy
Beta-Blockers: May enhance the hypoglycemic effect of Insulins. Exceptions: Levobunolol; Metipranolol. Risk C: Monitor
therapy
Dipeptidyl Peptidase-IV Inhibitors: May enhance the hypoglycemic effect of Insulins. Management: Consider a decrease
in insulin dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for
hypoglycemia. Risk D: Consider therapy modification
Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor
therapy
Edetate CALCIUM Disodium: May enhance the hypoglycemic effect of Insulins. Risk C: Monitor therapy
Glucagon-Like Peptide-1 Agonists: May enhance the hypoglycemic effect of Insulins. Management: Consider insulin dose
reductions when used in combination with glucagon-like peptide-1 agonists. Avoid the use of lixisenatide in
patients receiving both basal insulin and a sulfonylurea. Exceptions: Liraglutide. Risk D: Consider therapy
modification
Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C:
Monitor therapy
Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Risk
C: Monitor therapy
Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-
Liraglutide: May enhance the hypoglycemic effect of Insulins. Management: If liraglutide is used for the treatment of
diabetes (Victoza), consider insulin dose reductions. The combination of liraglutide and insulin should be avoided
if liraglutide is used exclusively for weight loss (Saxenda). Risk D: Consider therapy modification
Macimorelin: Insulins may diminish the diagnostic effect of Macimorelin. Risk X: Avoid combination
Maitake: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Risk C: Monitor therapy
Metreleptin: May enhance the hypoglycemic effect of Insulins. Management: Insulin dosage adjustments (including
potentially large decreases) may be required to minimize the risk for hypoglycemia with concurrent use of
metreleptin. Monitor closely. Risk D: Consider therapy modification
Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents.Risk C: Monitor
therapy
Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Risk C: Monitor therapy
Pioglitazone: May enhance the adverse/toxic effect of Insulins. Specifically, the risk for hypoglycemia, fluid retention,
and heart failure may be increased with this combination. Management: If insulin is combined with pioglitazone,
dose reductions should be considered to reduce the risk of hypoglycemia. Monitor patients for fluid retention and
signs/symptoms of heart failure. Risk D: Consider therapy modification
Pramlintide: May enhance the hypoglycemic effect of Insulins. Management: Upon initiation of pramlintide, decrease
mealtime insulin dose by 50% to reduce the risk of hypoglycemia. Monitor blood glucose frequently and
individualize further insulin dose adjustments based on glycemic control. Risk D: Consider therapy modification
Prothionamide: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Risk C: Monitor therapy
Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Rosiglitazone: Insulins may enhance the adverse/toxic effect of Rosiglitazone. Specifically, the risk of fluid retention,
heart failure, and hypoglycemia may be increased with this combination. Risk X: Avoid combination
Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Risk C: Monitor therapy
Monitor therapy
Sodium-Glucose Cotransporter 2 (SLGT2) Inhibitors: May enhance the hypoglycemic effect of Insulins. Management:
Consider a decrease in insulin dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and
monitor patients for hypoglycemia. Risk D: Consider therapy modification
Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Note: Onset and duration of hypoglycemic effects depend upon the route of administration (absorption and onset of
action are more rapid after deeper IM injections than after SubQ), site of injection (onset and duration are progressively
slower with SubQ injection into the abdomen, arm, buttock, or thigh respectively), volume and concentration of
injection, and the preparation administered. Rate of absorption, onset, and duration of activity may be affected by
exercise, presence of lipodystrophy, local blood supply, and/or temperature.
Onset of action: SubQ: 0.25 to 0.5 hours
Peak effect: SubQ: U-100: 2.5 to 5 hours; U-500: 4 to 8 hours
Duration:
IV: U-100: 2 to 6 hours
SubQ: U-100: 4 to 12 hours (may increase with dose); U-500: 13 to 24 hours
Distribution: IV, SubQ: Vd: 0.26 to 0.36 L/kg
Bioavailability: SubQ: 55% to 77%

Half-life elimination: IV: ~0.5 to 1 hour (dose-dependent); SubQ: 1.5 hours
Time to peak, plasma: SubQ: 0.8 to 2 hours
Excretion: Urine
Adverse Reactions
Cardiovascular: Peripheral edema
Dermatologic: Erythema at injection site, injection site pruritus
Endocrine & metabolic: Hypoglycemia, hypokalemia, weight gain
Hypersensitivity: Anaphylaxis, hypersensitivity, hypersensitivity reaction
Local: Hypertrophy at injection site, lipoatrophy at injection site
IVERMECTINA
Dosing: Pediatric
Head lice: Topical: Lotion (Sklice): Infants ≥6 months, Children, and Adolescents: Apply sufficient amount (up to 1 tube)
to completely cover dry hair and scalp; for single use only
All patients: There are no dosage adjustments provided in the manufacturer’s labeling.
All patients: There are no dosage adjustments provided in the manufacturer’s labeling.
• Appropriate use:
Topical lotion: For topical use on scalp and scalp hair only; avoid contact with eyes. Wash hands after
application.
Topical cream: Not for oral, ophthalmic, or vaginal use; avoid contact with eyes and lips. Wash hands after
application.
In infants <6 months, systemic absorption may be increased due to higher skin surface area to body mass ratio and
immature skin barrier; risk for ivermectin toxicity potentially increased; avoid use in these patients.
For external use only. Not for use in the eye, mouth, or vagina.
Head lice: Topical lotion: Apply to dry scalp and hair closest to scalp first, then apply outward towards ends of hair,
completely covering scalp and hair. Leave on for 10 minutes (start timing treatment after the scalp and hair have
been completely covered). The hair should then be rinsed thoroughly with warm water. Wait 24 hours after
application before applying shampoo. Avoid contact with the eyes. Nit combing is not required, although a fine-
tooth comb may be used to remove treated lice and nits. Lotion is for one-time use; discard any unused portion.
Ivermectin should be a portion of a whole lice removal program, which should include washing or dry cleaning all
clothing, hats, bedding, and towels recently worn or used by the patient and washing combs, brushes, and
hair accessories in hot, soapy water.
Rosacea: Topical cream: Wash hands with soap and water prior to application and after application. Apply a pea-size
amount as a thin layer on each affected area (eg, forehead, chin, nose, each cheek).
Protein binding: >99%
Metabolism: Metabolized hepatically by CYP3A4
Half-life elimination: Cream: ~6.5 days
Time to peak: Cream: ~10 hours post application
Adverse Reactions
Central nervous system: Localized burning
Dermatologic: Skin irritation
Rare but important or life-threatening: Allergic dermatitis, conjunctivitis, contact dermatitis, eye irritation, ocular
hyperemia, seborrheic dermatitis of scalp, xeroderma
KETAMINA
Dosing: Pediatric
Note: Titrate dose to effect. May be used in combination with anticholinergic agents to decrease
hypersalivation. Note: The American College of Emergency Physicians considers the use of ketamine in infants <3
months of age to be an absolute contraindication, due to the higher risk of airway complications (ACEP [Green 2011]).
Anesthesia:
Induction of anesthesia:
Infants ≥3 months, Children, and Adolescents <16 years: Limited data available:
IM: 5 to 10 mg/kg has been reported and suggested by experts (Coté 2013; Lin 2005; Sungur Ulke 2008).
IV: 1 to 3 mg/kg has been reported and suggested by experts (Coté 2013; Lin 2005).
Adolescents ≥16 years:
IM: 6.5 to 13 mg/kg.
IV: 1 to 4.5 mg/kg.
Maintenance of anesthesia: Adolescents ≥16 years: May administer supplemental doses of one-half to the full induction
dose as needed.
Endotracheal intubation: Limited data available: Infants, Children, and Adolescents: IV: 1 to 2 mg/kg as part of rapid
sequence sedation (AAP [Hegenbarth 2008]; Ballow 2012; Fuhrman 2011).
Sedation/analgesia, procedural: Limited data available: Infants, Children, and Adolescents: Note: Due to risk of airway
obstruction, laryngospasm, and apnea, ACEP only recommends use in patients ≥3 months of age (ACEP [Green 2011]).
Ketamine without propofol:
IM: 4 to 5 mg/kg as a single dose; may give a repeat dose (range: 2 to 5 mg/kg) if sedation inadequate after 5 to 10
minutes or if additional doses are required (ACEP [Green 2011]). Some have recommended smaller doses (2 to 2.5
mg/kg) for minor procedures (eg, wound suture with local anesthetic) (McGlone 2004).
IV: 1 to 2 mg/kg over 30 to 60 seconds. If initial sedation inadequate or repeated doses are necessary to accomplish a
longer procedure, may administer additional doses of 0.5 to 1 mg/kg every 5 to 15 minutes as needed (ACEP [Green
2011]; Asadi 2013; Berkenbosch 2004, Koruk 2010).
Ketamine with propofol ("ketofol"): Infants ≥3 months, Children, and Adolescents: IV: 0.5 to 0.75 mg/kg of each agent.
This combination has been used to decrease the dose of each agent required. It has been proposed that these lower
doses help decrease adverse effects, ketamine may decrease the propofol-related hypotension and respiratory
depression, and propofol may decrease the ketamine associated nausea and emergence reactions (ACEP [Godwin 2014];
Alletag 2012; Shah 2011; Willman 2007).
Sedation/analgesia, critically ill patients: Very limited data available: Infants ≥5 months, Children, and Adolescents: Initial
dose: IV: 0.5 to 2 mg/kg, then continuous IV infusion: 5 to 20 mcg/kg/minute (0.3 to 1.2 mg/kg/hour); start at lower
dosage listed and titrate to effect (Denmark 2006; Rock 1986; Tobias 1990; White 1982); doses as high as 60
mcg/kg/minute (3.6 mg/kg/hour) have been reported in patients with refractory bronchospasm (Youssef-Ahmed 1996).
Contraindications
Hypersensitivity to ketamine or any component of the formulation; conditions in which an increase in blood pressure
would be hazardous
Note: When used for procedural sedation and analgesia in the emergency department, the following additional absolute
contraindications according to the American College of Emergency Physicians have been asserted (ACEP [Green 2011]):
Infants <3 months of age; known or suspected schizophrenia (even if currently stable or controlled with medications)
Canadian labeling: Additional contraindications (not in US labeling): History of cerebrovascular accident; severe cardiac
decompensation; surgery of the pharynx, larynx, or bronchial tree unless adequate muscle relaxants are used
• Airway complications: When used for procedural sedation for major procedures involving the posterior pharynx (eg,
endoscopy) or when used for patients with an active pulmonary infection or disease (including upper respiratory disease
or asthma), the use of ketamine increases the risk of laryngospasm. Patients with a history of airway instability, tracheal
surgery, or tracheal stenosis may be at a higher risk of airway complications. The American College of Emergency
Physicians considers these situations relative contraindications for the use of ketamine (ACEP [Green 2011]). The
manufacturer recommends against the use of ketamine alone in surgery or diagnostic procedures of the pharynx, larynx,
or bronchial tree; mechanical stimulation of the pharynx should be avoided, whenever possible, if ketamine is used
alone.
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned
about performing tasks that require mental alertness (eg, operating machinery, driving). When used for outpatient
surgery, the patient should be accompanied by a responsible adult. Driving, operating hazardous machinery, or engaging
in hazardous activities should not be undertaken for ≥24 hours after anesthesia, according to the manufacturer.
• Dependence: May cause dependence (withdrawal symptoms on discontinuation) and tolerance with prolonged use. A
withdrawal syndrome with psychotic features has been described following discontinuation of long-term use.
• Emergence reactions: Postanesthetic emergence reactions, which can manifest as vivid dreams, hallucinations, and/or
frank delirium, occur; these reactions are less common in patients <16 years of age and >65 years and when given IM
(White 1982). Emergence reactions, confusion, or irrational behavior may occur up to 24 hours postoperatively and may
be reduced by pretreatment with a benzodiazepine, use of ketamine at the lower end of the dosing range, and
minimizing verbal and tactile stimulation of the patient during the recovery period. Use with caution in patients with
schizophrenia; may exacerbate psychotic symptoms (Lahti 1995; Malhotra 1997). When used for procedural sedation
and analgesia, the American College of Emergency Physicians considers the use of ketamine in patients with known or
suspected schizophrenia (even if currently stable or controlled with medications) an absolute contraindication (ACEP
[Green 2011]).
• Genitourinary symptoms: Lower urinary tract and bladder symptoms, including dysuria, increased frequency/urgency,
urge incontinence, and hematuria have been reported in patients with a history of chronic ketamine use or abuse and
may be related to ketamine treatment, not the underlying condition. Additional findings from diagnostic studies have
included cystitis, hydronephrosis, and reduced bladder capacity. Consider discontinuation of ketamine for continued
genitourinary pain in the setting of other genitourinary symptoms.
• Increased intracranial pressure: Some consider the use of ketamine in patients with CNS masses, CNS abnormalities, or
hydrocephalus a relative contraindication due to multiple reports that ketamine may increase intracranial pressure in
these patients (ACEP [Green 2011]). However, assuming adequate ventilation, some evidence suggests that ketamine
has minimal effects on intracranial pressure and may even improve cerebral perfusion and reduce intracranial pressure
(Albanese 1997; Bowles 2012; Zeiler 2014).
• Increased ocular pressure: Use with caution in patients with increased intraocular pressure (IOP). Some recommend
avoiding use in patients with an open eye injury or other ophthalmologic disorder where an increase in IOP would prove
to be detrimental; however, the effects of ketamine on IOP is mixed with some evidence demonstrating no clinically
significant effect on IOP (ACEP [Green 2011]; Cunningham 1986; Drayna 2012; Miller 2010; Nagdeve 2006).
• Porphyria: The American College of Emergency Physicians considers the use of ketamine in patients with porphyria a
relative contraindication due to enhanced sympathomimetic effect produced by ketamine (ACEP [Green 2011]).
• Respiratory depression: Rapid IV administration or overdose may cause respiratory depression or apnea. Resuscitative
equipment should be available during use.
• Thyroid disorders: The American College of Emergency Physicians considers the use of ketamine in patients with a
thyroid disorder or receiving a thyroid medication a relative contraindication due to enhanced sympathomimetic effect
produced by ketamine (ACEP [Green 2011]).
• Cardiovascular disease: Use with caution in patients with coronary artery disease, catecholamine depletion,
hypertension, and tachycardia. Cardiac function should be continuously monitored in patients with increased blood
pressure or cardiac decompensation. Ketamine increases blood pressure, heart rate, and cardiac output thereby
increasing myocardial oxygen demand. The mechanism by which ketamine causes a sympathetic surge to stimulate the
cardiovascular system has yet to be elucidated. The use of concurrent benzodiazepine, inhaled anesthetics, and propofol
or administration of ketamine as a continuous infusion may reduce these cardiovascular effects (Miller 2010). The
American College of Emergency Physicians recommends avoidance in patients who are already hypertensive and in older
adults with risk factors for coronary artery disease (ACEP [Green 2011]). In a scientific statement from the American
Heart Association, ketamine has been determined to be an agent that may exacerbate underlying myocardial
dysfunction (magnitude: major) (AHA [Page 2016]).
• Cerebrospinal fluid (CSF) pressure elevation: Use with caution in patients with CSF pressure elevation; an increase in
CSF pressure may be associated with use.
• Ethanol use: Use with caution in the chronic alcoholic or acutely alcohol-intoxicated.
• Pediatric neurotoxicity: In pediatric and neonatal patients <3 years and patients in third trimester of pregnancy (ie,
times of rapid brain growth and synaptogenesis), the repeated or lengthy exposure to sedatives or anesthetics during
surgery/procedures may have detrimental effects on child or fetal brain development and may contribute to various
cognitive and behavioral problems. Epidemiological studies in humans have reported various cognitive and behavioral
problems, including neurodevelopmental delay (and related diagnoses), learning disabilities, and ADHD. Human clinical
data suggest that single, relatively short exposures are not likely to have similar negative effects. No specific
anesthetic/sedative has been found to be safer. For elective procedures, risk versus benefits should be evaluated and
discussed with parents/caregivers/patients; critical surgeries should not be delayed (FDA 2016).
• Experienced personnel: Use requires careful patient monitoring, should only be used by experienced personnel who
are not actively engaged in the procedure or surgery. If used in a nonintubated and/or nonmechanically ventilated
patient, qualified personnel and appropriate equipment for rapid institution of respiratory and/or cardiovascular
support must be immediately available. Use to induce moderate (conscious) sedation in patients warrants monitoring
equivalent to that seen with deep anesthesia. Consult local regulations and individual institutional policies and
procedures.
In pediatric and neonatal patients <3 years of age and patients in third trimester of pregnancy (ie, times of rapid brain
growth and synaptogenesis), the repeated or lengthy exposure to sedatives or anesthetics during surgery/procedures
may have detrimental effects on the child's or fetus’ brain development and may contribute to various cognitive and
behavioral problems; the FDA is requiring warnings be included in the manufacturer's labeling for all general
anesthetic/sedative drugs. Multiple animal species studies have shown adverse effects on brain maturation; in juvenile
animals, drugs that potentiate GABA activity and/or block NMDA receptors for >3 hours demonstrated widespread
neuronal and oligodendrocyte cell loss along with alteration in synaptic morphology and neurogenesis. Epidemiological
studies in humans have reported various cognitive and behavioral problems including neurodevelopmental delay (and
related diagnoses), learning disabilities, and ADHD. Human clinical data suggest that single, relatively short exposures
are not likely to have similar negative effects. Further studies are needed to fully characterize findings and ensure that
these findings are not related to underlying conditions or the procedure itself. No specific anesthetic/sedative has been
found to be safer. For elective procedures, risk vs benefits should be evaluated and discussed with
parents/caregivers/patients; critical surgeries should not be delayed (FDA 2016).
May produce postanesthetic emergence reactions; may be minimized by limiting verbal, tactile, and visual patient
stimulation during recovery, or by pretreatment with a benzodiazepine (using lower recommended doses of ketamine).
Severe emergent reactions may require treatment with a small hypnotic dose of a short or ultrashort acting barbiturate.
Data suggest that exposure to ketamine during critical neurodevelopment periods (eg, neonates, infants, and young
children) may negatively affect neurodevelopment; mechanisms and risk factors have not been fully defined (eg,
number of exposures to ketamine); clinical decisions regarding use should be judicious and patients monitored closely. A
study followed infants and young children <24 months of age who received ketamine anesthesia for outpatient laser
surgery treatments for benign facial growth (n=49, including 13 subjects with three exposures to ketamine); results
showed decreases in both the mental development and psychomotor development index scores (measured by Bayley
Scales) after three exposures, but not after one or two exposures of ketamine when compared to preexposure scores
(Yan 2014). Animal data suggests that exposure of the developing brain to anesthetics like ketamine (especially during
the critical time of synaptogenesis) may result in long-term impairment of cognitive function (Patel 2009).
Note: Three concentrations are available (10 mg/mL, 50 mg/mL and 100 mg/mL); preparation information may be
product specific.
Intranasal (using parenteral dosage form): Use the 50 mg/mL or 100 mg/mL solution; may administer undiluted or
further dilute in NS to a concentration of 20 mg/ml (Bahetwar 2011; Louon 1994; Surendar 2014; Weksler 1993)
Oral (using parenteral dosage form): Use the 100 mg/mL solution and mix the appropriate dose in 0.2 to 0.4 mL/kg of
cola, sour cherry juice, or other beverage (Gutstein 1992; Tobias 1992; Turhanoğlu 2003)
Parenteral:
IV push: If using the 100 mg/mL concentration, must further dilute with an equal volume of SWFI, NS, or D5W; maximum
concentration: 50 mg/mL
IV infusion: The 50 mg/mL and 100 mg/mL vials may be further diluted in D5W or NS to a final concentration of 1
mg/mL; in fluid restricted patients a concentration of 2 mg/mL may be used
Note: Do not mix with barbiturates or diazepam (precipitation may occur).
Intranasal (using parenteral dosage form): Use the 50 or 100 mg/mL solution; may administer undiluted or further dilute
in NS to a concentration of 20 mg/mL (Bahetwar 2011; Louon 1994; Surendar 2014). Administer half dose in each nostril
using a needleless syringe.
Oral (using parenteral dosage form): Use the 100 mg/mL IV solution and mix the appropriate dose in 0.2 to 0.4 mL/kg of
cola, sour cherry juice, or other beverage (Gutstein 1992; Tobias 1992, Turhanoğlu 2003)
Parenteral:
IV push: May administer the 10 mg/mL and 50 mg/mL undiluted. Administer slowly over 60 seconds, do not exceed 0.5
mg/kg/minute; more rapid administration may result in respiratory depression and enhanced pressor response. Some
experts suggest administration over 2 to 3 minutes (Miller 2010).
IV infusion: May be administered as a continuous IV infusion
Rectal (using parenteral dosage form): May use the 50 mg/mL solution undiluted or use the 100 mg/mL solution and
further dilute prior to administration (Tanaka 2000; Van der Bijl 1991)
Cardiovascular effects, heart rate, blood pressure, respiratory rate, transcutaneous O2 saturation, emergence reactions
Drug Interactions
Avoid combination
Thiopental: Ketamine may enhance the adverse/toxic effect of Thiopental. Risk C: Monitor therapy
Adverse Reactions
Cardiovascular: Bradycardia, cardiac arrhythmia, hypotension, increased blood pressure, increased pulse
Central nervous system: Drug dependence, hypertonia (tonic-clonic movements sometimes resembling seizures),
increased cerebrospinal fluid pressure, prolonged emergence from anesthesia (includes confusion, delirium, dreamlike
state, excitement, hallucinations, irrational behavior, vivid imagery)
Dermatologic: Erythema, morbilliform rash, rash at injection site
Endocrine & metabolic: Central diabetes insipidus (Hatab 2014)
Gastrointestinal: Anorexia, nausea, sialorrhea (Hatab 2014), vomiting
Genitourinary: Bladder dysfunction (reduced capacity), cystitis (including cystitis noninfective, cystitis interstitial, cystitis
ulcerative, cystitis erosive, cystitis hemorrhagic), dysuria, hematuria, urinary frequency, urinary incontinence, urinary
urgency
Neuromuscular & skeletal: Laryngospasm
Ophthalmic: Diplopia, increased intraocular pressure, nystagmus
Renal: Hydronephrosis
Respiratory: Airway obstruction, apnea, respiratory depression
MAGNESIUM SULFATE
Dosing: Pediatric
Note: 1,000 mg of magnesium sulfate = 98.7 mg elemental magnesium = 8.12 mEq elemental magnesium = 4.06
mmol elemental magnesium. Serum magnesium is poor reflection of repletion status as the majority of magnesium is
intracellular; serum concentrations may be transiently normal for a few hours after a dose is given, therefore, aim for
consistently high normal serum concentrations in patients with normal renal function for most efficient repletion.
Hypomagnesemia: Infants, Children, and Adolescents: Note: Dose depends on clinical condition and serum magnesium
concentration.
Dose expressed as magnesium sulfate: IV, IO: 25 to 50 mg /kg/dose every 6 hours for 2 to 3 doses, then recheck serum
concentration; maximum dose: 2,000 mg/dose (Hegenbarth 2008; Kliegman 2011; PALS [Kleinman 2010]).
Dose expressed as elemental magnesium: IV: 2.5 to 5 mg/kg/dose every 6 hours for 2 to 3 doses (Kliegman 2011).
Constipation, occasional: Oral: Note: With OTC use, should not exceed recommended treatment duration (7 days) unless
directed by health care provider.
Children 6 to <12 years: 1 to 2 level teaspoons of granules dissolved in 8 ounces of water; may repeat in 4 to 6 hours. Do
not exceed 2 doses per day.
Children ≥12 years and Adolescents: 2 to 4 level teaspoons of granules dissolved in 8 ounces of water; may repeat in 4 to
6 hours. Do not exceed 2 doses per day.
Parenteral nutrition, maintenance requirement (ASPEN [Mirtallo 2004]): Dose expressed as elemental magnesium: IV:
Infants and Children <50 kg: 0.3 to 0.5 mEq/kg/day.
Children >50 kg and Adolescents: 10 to 30 mEq/day.
Torsade de pointes or VF/pulseless VT associated with torsade de pointes: Dose expressed as magnesium sulfate: IV:
Infants, Children, and Adolescents: IV, IO: 25 to 50 mg/kg/dose; maximum dose: 2,000 mg /dose (PALS [Kleinman 2010]).
Asthma, acute refractory status: Limited data available: Dose expressed as magnesium sulfate.
IV: Infants, Children, and Adolescents: 25 to 75 mg/kg/dose as a single dose; maximum dose: 2,000 mg/dose;
recommended as adjunctive therapy in severe acute asthma for patients who have life-threatening exacerbations and in
those whose exacerbations remain in the severe category after 1 hour of intensive conventional therapy (GINA 2014;
Hegenbarth 2008; NAEPP 2007). Efficacy results variable. Two trials (Ciarallo 1996; Ciarallo 2000) showed significant
improvement in pulmonary function in children who received a single dose of 25 mg/kg or 40 mg/kg magnesium sulfate
vs. placebo; in another trial, pulmonary index scores after magnesium sulfate 75 mg/kg (maximum dose: 2,500 mg/dose)
vs. placebo were not statistically different in 54 children between 1 to 18 years of age (Scarfone 2000).
Oral inhalation: Nebulization (prepared from injectable formulation); given with a nebulized beta2-agonist (eg,
albuterol): Limited data available: Optimal dose not established; efficacy results variable:
Mild to moderate asthma: Single dose: Children ≥5 years and Adolescents: 2.5 mL isotonic magnesium sulfate solution
mixed with albuterol 2.5 mg (0.5 mL) as a single dose. Magnesium was supplied as a 6.3% solution of magnesium
heptahydrate, which is equivalent to anhydrous magnesium sulfate 3.18%. Doses were nebulized with 8 to 10 L/min of
oxygen. Magnesium was found to have an additive effect on albuterol response (Mahajan 2004).
Moderate to severe asthma: Three-dose series: Children ≥2 years and Adolescents ≤16 years: 151 mg isotonic
magnesium sulfate mixed with albuterol and ipratropium was administered every 20 minutes for 3 doses to patients
with severe acute asthma who did not respond to standard inhalation treatment. In this large randomized, placebo-
controlled trial (n=508, including 252 who received magnesium sulfate treatment; ages: 2 to 16 years) improvement was
statistically significant, but clinically significant changes were only observed in the most severe patients (SaO2 <92%)
(Powell 2013). Note: Higher doses 500 mg magnesium sulfate mixed with albuterol (1 mL of 500 mg/mL parenteral
solution and albuterol 1 mL nebulization solution mixed with 8 mL of distilled water; total volume: 10 mL) have been
described for use in adolescents; however, the addition of magnesium showed no therapeutic benefit compared to
albuterol alone (Aggarwal 2006).
Hypomagnesemia: Infants, Children, and Adolescents: Use with caution; monitor closely for hypermagnesemia.
No dosage adjustment necessary.
Contraindications
Hypersensitivity to any component of the formulation; heart block (see Note); myocardial damage; IV use for
preeclampsia/eclampsia during the 2 hours prior to delivery (see Note)
Note: Although the manufacturers' labeling for some IV formulations state use in preeclampsia/eclampsia during the 2
hours prior to (cesarean) delivery is contraindicated due to interaction with neuromuscular-blocking agents
intraoperatively; stopping magnesium sulfate prior to cesarean delivery in these patients is not recommended and
increases the risk of seizure. Instead, magnesium should be continued prior to and during the delivery (ACOG 2013).
Additionally, the manufacturers' labeling for some IV formulations contraindicate the use of magnesium sulfate in the
setting of heart block; however, the use of magnesium is appropriate in patients with serious conditions requiring
magnesium therapy who either have mild degrees of heart block (eg, first degree) or more severe forms of heart block
with a temporary or permanent cardiac pacemaker.
• Neuromuscular disease: Use with extreme caution in patients with myasthenia gravis or other neuromuscular disease.
• Renal impairment: Use with caution in patients with renal impairment; accumulation of magnesium may lead to
magnesium intoxication.
• Obstetrics: Vigilant monitoring and safe administration techniques (ISMP 2005) recommended to avoid potential for
errors resulting in toxicity. Monitor mother and fetus closely. Use longer than 5 to 7 days may cause adverse fetal
events.
• Aluminum: The parenteral product may contain aluminum; toxic aluminum concentrations may be seen with high
doses, prolonged use, or renal dysfunction. Premature neonates are at higher risk due to immature renal function and
aluminum intake from other parenteral sources. Parenteral aluminum exposure of >4 to 5 mcg/kg/day is associated with
CNS and bone toxicity; tissue loading may occur at lower doses (Federal Register 2002). See manufacturer's labeling.
• Appropriate use: Unlikely to effectively terminate irregular/polymorphic VT (with normal baseline QT interval) (AHA
[Neumar 2010]).
• Electrolyte abnormalities: Concurrent hypokalemia or hypocalcemia can accompany a magnesium deficit.
Hypomagnesemia is frequently associated with hypokalemia and requires correction in order to normalize potassium.
• Parenteral administration: Magnesium toxicity can lead to fatal cardiovascular arrest and/or respiratory paralysis.
• Self-medication (OTC Use): When used as a soaking aid, patients should not use if there is evidence of infection or
prompt relief is not obtained. When used as a laxative, patients should consult a health care provider prior to use if they
have: kidney disease; are on a magnesium-restricted diet; have abdominal pain, nausea, or vomiting; change in bowel
habits lasting >2 weeks; have already used a laxative for >1 week.
Multiple salt forms of magnesium exist; close attention must be paid to the salt form when ordering and administering
magnesium; incorrect selection or substitution of one salt for another without proper dosage adjustment may result in
serious over- or underdosing.
Oral: Dissolve granules in 8 ounces of water prior to administration.
Oral inhalation: Limited data available: Nebulizer solution: Use injectable solution to prepare dose and add to albuterol
solution for nebulization; see Dosing: Pediatric for details (Aggarwal 2006; Mahajan 2004; Powell 2013)
Parenteral:
IM: Infants and Children: Dilute to a maximum concentration of 20% (ie, 200 mg/mL of magnesium sulfate or 1.6
mEq/mL of magnesium) prior to administration
IV: Dilute in a compatible solution (eg, D5W, NS) to a usual concentration of 0.5 mEq/mL of magnesium (ie, 60 mg/mL
of magnesium sulfate); maximum concentration: 20% (ie, 200 mg/mL of magnesium sulfate or 1.6 mEq/mL of
magnesium)
Oral: Must dissolve granules prior to administration. When used as a laxative, the patient should drink a full 8 ounces of
liquid following each dose. Lemon juice may be added to the initial solution to improve the taste. Note: Most effective
when taken on an empty stomach.
Oral inhalation: Nebulization: Mix injectable solution with albuterol ± ipratropium and administer over 10 to 20 minutes
(Aggarwal 2006; Mahajan 2004; Powell 2013)
Parenteral:
IM: Infants and Children: Dilute prior to injection; in adults, doses are administered undiluted (50%) or diluted in a
compatible fluid
IV: Dilute in an appropriate fluid prior to administration. Rate of infusion dependent upon use:
For general replacement therapy: Pediatric patients: Infuse slowly generally over 1 to 4 hours; in asymptomatic patients,
a rate of ≤0.1 mEq/kg/hour may be considered (in adults, the usual rate is ≤1,000 mg/hour of magnesium sulfate); faster
rates could be used up to a maximum infusion rate: 1 mEq/kg/hour (125 mg/kg/hour of magnesium sulfate); rate should
be slowed if patient experiences diaphoresis, flushing or a warm sensation (Corkins 2010; Kliegman 2007)
Acute/emergent therapy: Pediatric patients:
Pulseless torsades or VT: May administer as a bolus (Hegenbarth 2008)
Hypomagnesemia or torsades with pulses: 10 to 20 minutes (Hegenbarth 2008)
Status asthmaticus: 15 to 30 minutes (Ciarallo 1996; Ciarallo 2000; Hegenbarth 2008)
Continuous IV infusion: After dilution, administer via an infusion pump
Dosage Forms Considerations
1 g of magnesium sulfate = elemental magnesium 98.6 mg = magnesium 8.12 mEq = magnesium 4.06 mmol
Magnesium sulfate 1% [10 mg/mL] in Dextrose 5% injection is equivalent to elemental magnesium 0.081 mEq/mL.
Magnesium sulfate 2% [20 mg/mL] in Dextrose 5% injection is equivalent to elemental magnesium 0.162 mEq/mL.
Magnesium sulfate 4% [40 mg/mL] in Water injection is equivalent to elemental magnesium 0.325 mEq/mL.
Magnesium sulfate 8% [80 mg/mL] in Water injection is equivalent to elemental magnesium 0.65 mEq/mL.
Magnesium sulfate 50% injection is equivalent to elemental magnesium 4 mEq/mL.
Magnesium sulfate USP is supplied as magnesium sulfate heptahydrate
Oral: Stool output (laxative use)
IV: Rapid administration: ECG monitoring, vital signs, deep tendon reflexes; magnesium concentrations if frequent or
prolonged dosing required particularly in patients with renal dysfunction, calcium, and potassium concentrations; renal
function
Obstetrics: Patient status including vital signs, oxygen saturation, deep tendon reflexes, level of consciousness, fetal
heart rate, maternal uterine activity
Reference Range
Typical values: Total magnesium: 1.5 to 2.5 mEq/L
Drug Interactions
Alfacalcidol: May increase the serum concentration of Magnesium Salts. Risk D: Consider therapy modification
Alpha-Lipoic Acid: Magnesium Salts may decrease the absorption of Alpha-Lipoic Acid. Alpha-Lipoic Acid may decrease
the absorption of Magnesium Salts. Risk D: Consider therapy modification
Baloxavir Marboxil: Polyvalent Cation Containing Products may decrease the serum concentration of Baloxavir
Marboxil. Risk X: Avoid combination
Bictegravir: Polyvalent Cation Containing Products may decrease the serum concentration of Bictegravir. Management:
Administer bictegravir/emtricitabine/tenofovir alafenamide under fasting conditions at least 2 hours before polyvalent
cation containing products. Coadministration of bictegravir with or 2 hours after most polyvalent cation products is not
recommended. Risk D: Consider therapy modification
Bisphosphonate Derivatives: Polyvalent Cation Containing Products may decrease the serum concentration of
Bisphosphonate Derivatives. Management: Avoid administration of oral medications containing polyvalent cations
within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after oral ibandronate; or 30 minutes
after alendronate/risedronate. Exceptions: Pamidronate; Zoledronic Acid. Risk D: Consider therapy modification
Calcitriol (Systemic): May increase the serum concentration of Magnesium Salts. Management: Consider using a non-
magnesium-containing antacid or phosphate-binding product in patients also receiving calcitriol. If magnesium-
containing products must be used with calcitriol, serum magnesium concentrations should be monitored closely. Risk D:
Calcium Channel Blockers: May enhance the adverse/toxic effect of Magnesium Salts. Magnesium Salts may enhance the
hypotensive effect of Calcium Channel Blockers.Risk C: Monitor therapy
Calcium Polystyrene Sulfonate: Laxatives (Magnesium Containing) may enhance the adverse/toxic effect of Calcium
Polystyrene Sulfonate. More specifically, concomitant use of calcium polystyrene sulfonate with magnesium-containing
laxatives may result in metabolic alkalosis or with sorbitol may result in intestinal necrosis. Management: Avoid
concomitant use of calcium polystyrene sulfonate (rectal or oral) and magnesium-containing laxatives. Risk X: Avoid
combination
CNS Depressants: Magnesium Sulfate may enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor
therapy
Deferiprone: Polyvalent Cation Containing Products may decrease the serum concentration of Deferiprone.
Management: Separate administration of deferiprone and oral medications or supplements that contain polyvalent
cations by at least 4 hours. Risk D: Consider therapy modification
Dolutegravir: Magnesium Salts may decrease the serum concentration of Dolutegravir. Management: Administer
dolutegravir at least 2 hours before or 6 hours after oral magnesium salts. Administer the dolutegravir/rilpivirine
combination product at least 4 hours before or 6 hours after oral magnesium salts. Risk D: Consider therapy modification
Doxercalciferol: May enhance the hypermagnesemic effect of Magnesium Salts. Management: Consider using a non-
magnesium-containing antacid or phosphate-binding product in patients also receiving doxercalciferol. If magnesium-
containing products must be used with doxercalciferol, serum magnesium concentrations should be monitored
closely. Risk D: Consider therapy modification
Eltrombopag: Polyvalent Cation Containing Products may decrease the serum concentration of Eltrombopag.
Management: Administer eltrombopag at least 2 hours before or 4 hours after oral administration of any polyvalent
cation containing product. Risk D: Consider therapy modification
Gabapentin: Magnesium Salts may enhance the CNS depressant effect of Gabapentin. Specifically, high dose
intravenous/epidural magnesium sulfate may enhance the CNS depressant effects of gabapentin. Magnesium Salts may
decrease the serum concentration of Gabapentin. Management: Administer gabapentin at least 2 hours after use of a
magnesium-containing antacid. Monitor patients closely for evidence of reduced response to gabapentin therapy.
Monitor for CNS depression if high dose IV/epidural magnesium sulfate is used. Risk D: Consider therapy modification
Levothyroxine: Magnesium Salts may decrease the serum concentration of Levothyroxine. Management: Separate
administration of oral levothyroxine and oral magnesium salts by at least 4 hours. Risk D: Consider therapy modification
Multivitamins/Fluoride (with ADE): Magnesium Salts may decrease the serum concentration of Multivitamins/Fluoride
(with ADE). Specifically, magnesium salts may decrease fluoride absorption. Management: To avoid this potential
interaction separate the administration of magnesium salts from administration of a fluoride-containing product by at
least 1 hour. Risk D: Consider therapy modification
Mycophenolate: Magnesium Salts may decrease the serum concentration of Mycophenolate. Management: Separate
doses of mycophenolate and oral magnesium salts. Monitor for reduced effects of mycophenolate if taken concomitant
with oral magnesium salts. Risk D: Consider therapy modification
Neuromuscular-Blocking Agents: Magnesium Salts may enhance the neuromuscular-blocking effect of Neuromuscular-
PenicillAMINE: Polyvalent Cation Containing Products may decrease the serum concentration of PenicillAMINE.
Management: Separate the administration of penicillamine and oral polyvalent cation containing products by at least 1
hour. Risk D: Consider therapy modification
Phosphate Supplements: Magnesium Salts may decrease the serum concentration of Phosphate Supplements.
Management: Administer oral phosphate supplements as far apart from the administration of an oral magnesium salt as
possible to minimize the significance of this interaction. Exceptions: Sodium Glycerophosphate Pentahydrate.Risk D:
Quinolones: Magnesium Salts may decrease the serum concentration of Quinolones. Management: Administer oral
quinolones several hours before (4 h for moxi/pe/spar-, 2 h for others) or after (8 h for moxi-, 6 h for cipro/dela-, 4 h for
lome/pe-, 3 h for gemi-, and 2 h for levo-, nor-, or ofloxacin or nalidixic acid) oral magnesium
salts. Exceptions: LevoFLOXacin (Oral Inhalation). Risk D: Consider therapy modification
Raltegravir: Magnesium Salts may decrease the serum concentration of Raltegravir. Management: Avoid the use of oral /
enteral magnesium salts with raltegravir. No dose separation schedule has been established that adequately reduces the
magnitude of interaction. Risk X: Avoid combination
Ritodrine: May enhance the adverse/toxic effect of Magnesium Sulfate. Risk C: Monitor therapy
Sodium Polystyrene Sulfonate: Laxatives (Magnesium Containing) may enhance the adverse/toxic effect of Sodium
Polystyrene Sulfonate. More specifically, concomitant use of sodium polystyrene sulfonate with magnesium-containing
laxatives may result in metabolic alkalosis or with sorbitol may result in intestinal necrosis. Management: Avoid
concomitant use of sodium polystyrene sulfonate (rectal or oral) and magnesium-containing laxatives. Risk X: Avoid
combination
Tetracyclines: Magnesium Salts may decrease the absorption of Tetracyclines. Only applicable to oral preparations of
each agent. Exceptions: Eravacycline. Risk D: Consider therapy modification
Trientine: Polyvalent Cation Containing Products may decrease the serum concentration of Trientine. Management:
Avoid concomitant administration of trientine and oral products that contain polyvalent cations. If oral iron supplements
are required, separate the administration by 2 hours. If other oral polyvalent cations are needed, separate
administration by 1 hour. Risk D: Consider therapy modification
Adverse Reactions
Adverse effects on neuromuscular function may occur at lower concentrations in patients with neuromuscular disease
(eg, myasthenia gravis).
Cardiovascular: Flushing (IV; dose related), hypotension (IV; rate related), vasodilation (IV; rate related)
Endocrine & metabolic: Hypermagnesemia
Additional Information
1,000 mg of magnesium sulfate = 98.7 mg elemental magnesium = 8.12 mEq elementalmagnesium = 4.06
mmol elemental magnesium
Elemental Magnesium Content of Magnesium Salts

Elemental Magnesium Magnesium
Magnesium Salt
(mg/1,000 mg salt) (mEq/1,000 mg salt)
Magnesium chloride 119.7 9.85
Magnesium gluconate 54 4.44
Magnesium L-aspartate 99.18 8.16
Magnesium oxide 603.25 49.64
Magnesium sulfate 98.7 8.12
MANITOL
Dosing: Neonatal
Acute renal failure: IV: 0.5 to 1 g/kg/dose (Andreoli 2004); some experts recommend against routine use due to the risk
of IVH in low birth weight neonates (solution is hypertonic) or the precipitation of CHF if a lack of response occurs
(Andreoli 2004; Chua 2005)
Dosing: Pediatric
Note: The manufacturer's labeling recommends a test dose prior to starting IV mannitol therapy in patients with marked
oliguria or suspected renal insufficiency.
Acute renal failure (oliguria): Infants, Children, and Adolescents: IV: Initial: 0.5 to 1 g/kg/dose infused over 2 to 6
hours; usual range: 0.25 to 2 g/kg/dose; may repeat dose every 4 to 6 hours; do not repeat dose if oliguria
persists. Note: Although FDA-labeled indications, the use of mannitol for the prevention of acute renal
failure and/or promotion of diuresis is not routinely recommended (Kellum 2008).
Test dose (to assess adequate renal function): IV: 0.2 g/kg (maximum dose: 12.5 g) over 3 to 5 minutes to
produce a urine flow of at least 1 mL/kg/hour for 1 to 3 hours
Intracranial pressure (ICP), reduction: Infants, Children, and Adolescents: IV: Usual range: 0.25 to 1 g/kg/dose
infused over 20 to 30 minutes; repeat as needed to maintain serum osmolality <300 to 320 mOsm/kg (BTF
[Carney 2016]; Hegenbarth 2008; Kochanek 2012). Note: The manufacturer's labeling allows for higher
single doses up to 2 g/kg/dose.
Intraocular pressure (IOP), reduction: Infants, Children, and Adolescents: IV: 1 to 2 g/kg/dose or 30 to 60
g/m2/dose infused over 30 to 60 minutes administered 1 to 1.5 hours prior to surgery
IOP (traumatic hyphema), reduction: Infants, Children, and Adolescents: IV: 1.5 g/kg/dose infused over 45
minutes twice daily for IOP >35 mm Hg; may administer every 8 hours in patients with extremely high
pressure (Crouch 1999)
Contraindicated in severe renal impairment. Use with caution in patients with underlying renal disease. May be used to
reduce the incidence of acute tubular necrosis when administered prior to revascularization during kidney
transplantation.
No adjustment required.
Contraindications
Injection: Hypersensitivity to mannitol or any component of the formulation; severe renal disease (anuria); severe
dehydration/hypovolemia; active intracranial bleeding except during craniotomy; progressive heart failure or
pulmonary congestion after mannitol administration; severe pulmonary edema or congestion
Genitourinary irrigation solution: Anuria
• Extravasation: Vesicant (at concentrations >5%); ensure proper catheter or needle position prior to and during
IV infusion. Avoid extravasation of IV infusions; may cause compartment syndrome. Administration into a
large central vein is recommended.
• Fluid/electrolyte imbalance: May cause hypervolemia and electrolyte disturbances; monitor for new onset or
worsening cardiac or pulmonary congestion. Also may cause profound diuresis with fluid and electrolyte
loss; close medical supervision and dose evaluation are required. Correct electrolyte disturbances; adjust
dose to avoid dehydration.
• Hypersensitivity: Serious hypersensitivity reactions (eg, anaphylaxis), including fatalities, have been reported.
Discontinue mannitol immediately if hypersensitivity reaction develops and treat accordingly.
• Nephrotoxicity: May cause renal dysfunction especially with high doses; use caution in patients taking other
nephrotoxic agents, with sepsis or preexisting renal disease. To minimize adverse renal effects, adjust to
keep serum osmolality less than 320 mOsm/L. Discontinue if evidence of acute tubular necrosis.
• Cerebral edema: In patients being treated for cerebral edema, mannitol may accumulate in the brain (causing
rebound increases in intracranial pressure) if circulating for long periods of time as with continuous
infusion; intermittent boluses preferred. Cardiovascular status should also be evaluated; do not administer
electrolyte-free mannitol solutions with blood. If hypotension occurs, monitor cerebral perfusion pressure
to ensure adequate.
• CNS effects: CNS toxicity (eg, coma, confusion, lethargy) may occur; risk may be increased in patients with
impaired renal function or with concomitant use of neurotoxic drugs.
• Renal impairment: Use with caution. In patients with severe impairment, do not use until adequacy of renal
function and urine flow is established; use 1 to 2 test doses to assess renal response.
Mannitol may increase cerebral blood flow, increase the risk of postoperative bleeding in neurosurgical patients, and
worsen intracranial hypertension in children who develop generalized cerebral hyperemia during the first 24 to 48 hours
after traumatic brain injury.
IV: Do not administer IM or SubQ. In-line filter set (≤5 micron) should always be used for mannitol infusion with
concentrations ≥20% (WHO 2011); maximum concentration for administration: 25%. Inspect for crystals prior to
administration; if crystals are present, redissolve by warming solution. Do not administer with blood; crenation
and agglutination of red blood cells may occur. Infusion rate is dependent upon indication:
Acute renal failure: Administer over 2 to 6 hours
Cerebral edema or increased intracranial pressure: Administer over 20 to 30 minutes
Test dose (for oliguria): Administer over 3 to 5 minutes
Vesicant (at concentrations >5%); ensure proper catheter or needle position prior to and during IV infusion. Avoid
extravasation of IV infusions. If extravasation occurs, stop infusion immediately and disconnect (leave
needle/cannula in place); gently aspirate extravasated solution (do NOT flush the line); initiate hyaluronidase
antidote (see Management of Drug Extravasations for more details); remove needle/cannula; apply dry cold
compresses (Hurst 2004); elevate extremity.
Renal function, daily fluid I & O, serum electrolytes, serum and urine osmolality; for treatment of elevated intracranial
pressure, maintain serum osmolality <300 to 320 mOsm/kg
Drug Interactions
Amikacin (Oral Inhalation): May enhance the nephrotoxic effect of Mannitol (Systemic). Risk X: Avoid combination
Aminoglycosides: Mannitol (Systemic) may enhance the nephrotoxic effect of Aminoglycosides. Risk X: Avoid
combination
Diacerein: May enhance the therapeutic effect of Diuretics. Specifically, the risk for dehydration or hypokalemia may be
increased. Risk C: Monitor therapy
Opioid Agonists: May enhance the adverse/toxic effect of Diuretics. Opioid Agonists may diminish the therapeutic effect
of Diuretics. Risk C: Monitor therapy
Sodium Phosphates: Diuretics may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute
phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily
suspending treatment with diuretics, or seeking alternatives to oral sodium phosphate bowel preparation. If the
combination cannot be avoided, hydrate adequately and monitor fluid and renal status.Risk D: Consider therapy
modification
Tobramycin (Oral Inhalation): Mannitol (Systemic) may enhance the nephrotoxic effect of Tobramycin (Oral
Inhalation). Risk X: Avoid combination
Test Interactions
May cause false positive results for blood ethylene glycol concentrations. High mannitol concentrations may cause false
low results for inorganic phosphorus blood concentrations if assay based on the conversion of phosphate
(orthophosphate) to the phosphomolybdate complex is used.
Onset of action: Diuresis: 1 to 3 hours; Reduction in intracranial pressure: ~15 to 30 minutes
Duration: Reduction in intracranial pressure: 1.5 to 6 hours
Distribution: 17 L; remains confined to extracellular space (except in extreme concentrations); does not penetrate the
blood-brain barrier (generally, penetration is low)
Metabolism: Minimally hepatic to glycogen
Half-life elimination: 0.5 to 2.5 hours; 6 to 36 hours in renal failure
Excretion: Urine (~80% as unchanged drug)
Adverse Reactions
Cardiovascular: Chest pain, cardiac failure, hypertension, hypotension, local thrombophlebitis, peripheral edema,
tachycardia
Central nervous system: Chills, dizziness, headache, seizure
Dermatologic: Bullous rash, urticaria

Endocrine & metabolic: Dehydration (secondary to rapid diuresis), dilutional hyponatremia, electrolyte disturbance
(increased osmolar gap), fluid and electrolyte disturbance, hypovolemia (secondary to rapid diuresis),
hyperglycemia, hyperkalemia (hyperosmolality-induced), hypernatremia, hypervolemia, metabolic acidosis
(dilutional), water intoxication
Gastrointestinal: Nausea, vomiting, xerostomia
Genitourinary: Dysuria
Local: Local pain
Ophthalmic: Blurred vision
Renal: Acute renal failure, tubular necrosis (adult dose: >200 g/day; serum osmolality >320 mOsm/L), polyuria
Respiratory: Pulmonary edema, rhinitis
Miscellaneous: Fever, tissue necrosis
MEROPENEM
Dosing: Pediatric
General dosing, susceptible infection (non-CNS): Infants, Children, and Adolescents: IV: 20 mg/kg/dose every 8 hours;
maximum dose: 1,000 mg/dose (Bradley 2017)
Cystic fibrosis, pulmonary exacerbation: Limited data available: Infants, Children, and Adolescents: IV: 40 mg/kg/dose
every 8 hours; maximum dose: 2,000 mg/dose (Zobell 2012)
Febrile neutropenia, empiric treatment: Limited data available: Infants, Children, and Adolescents: IV: 20 mg/kg/dose
every 8 hours; maximum dose: 1,000 mg/dose (Bradley 2017; Lehrnbecher 2017)
Intra-abdominal infection, complicated: Note: IDSA guidelines recommend treatment duration of 4 to 7 days (Solomkin
2010)
Infants 1 to <3 months:
GA <32 weeks: IV: 20 mg/kg/dose every 8 hours
GA ≥32 weeks: IV: 30 mg/kg/dose every 8 hours
Infants ≥3 months, Children, and Adolescents: IV: 20 mg/kg/dose every 8 hours; maximum dose: 1,000 mg/dose
Meningitis: Infants (Limited data available <3 months of age), Children, and Adolescents: IV: 40 mg/kg/dose every 8
hours; maximum dose: 2,000 mg/dose (Bradley 2017); duration of therapy dependent upon pathogen: N.
meningitidis, H. influenza: 7 days; S. pneumoniae: 10 to 14 days; aerobic gram-negative bacilli: 21 days (Tunkel 2004)
Skin and skin structure infection, complicated:
Manufacturer's labeling: Infants ≥3 months, Children, and Adolescents: IV: 10 mg/kg/dose every 8 hours; maximum
dose: 500 mg/dose
Severe or necrotizing infections: Infants, Children, and Adolescents: IV: 20 mg/kg/dose every 8 hours; maximum dose:
1,000 mg/dose (IDSA [Stevens 2014])
Infants, Children, and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling. Some
clinicians have used the following (Aronoff 2007): Note: Renally adjusted dose recommendations are based on doses of
20 to 40 mg/kg/dose every 8 hours:
GFR >50 mL/minute/1.73 m2: No adjustment required.
GFR <10 mL/minute/1.73 m2: Administer 10 to 20 mg/kg/dose every 24 hours
Intermittent hemodialysis (IHD): Meropenem and metabolite are readily dialyzable: 10 to 20 mg/kg/dose every 24
hours; on dialysis days give dose afterhemodialysis
No dosage adjustment necessary.
• Anaphylaxis/hypersensitivity reactions: Serious hypersensitivity reactions, including anaphylaxis, have been reported
(some without a history of previous allergic reactions to beta-lactams).
• CNS effects: Carbapenems have been associated with CNS adverse effects, including confusional states and seizures
(myoclonic); use caution with CNS disorders (eg, brain lesions and history of seizures) and adjust dose in renal
impairment to avoid drug accumulation, which may increase seizure risk. Outpatient use may result in paresthesias,
seizures, delirium and/or headaches that can impair neuromotor function and alertness; patients should not operate
machinery or drive until it is established that meropenem is well tolerated.
• Dermatological effects: Severe cutaneous adverse reactions, including Stevens-Johnson syndrome, toxic epidermal
necrolysis, drug reaction with eosinophilia and systemic symptoms, erythema multiforme, and acute generalized
exanthematous pustulosis have occurred; discontinue immediately for severe reactions.
• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment required in patients with
creatinine clearance ≤50 mL/minute. Increased seizure risk and thrombocytopenia have been reported in patients with
renal impairment.
• Drug-drug interactions. Potentially significant interactions may exist, requiring dose or frequency adjustment,
information.
• Elderly: Lower doses (based upon renal function) are often required in the elderly.
Parenteral: Reconstitute meropenem 500 mg and 1 g vials with 10 mL and 20 mL SWFI respectively to yield a
concentration of 50 mg/mL. For IV infusion, may further dilute with D5W or NS to a final concentration ranging from 1 to
20 mg/mL.
Parenteral:
IV push: Infants ≥3 months, Children, and Adolescents: Administer reconstituted solution (up to 1 g) over 3 to 5 minutes;
safety data is limited with 40 mg/kg doses up to a maximum of 2 g
Intermittent IV infusion: Further dilute reconstituted solution prior to administration
Infants <3 months: Administer as an IV infusion over 30 minutes
Infants ≥3 months, Children, and Adolescents: Administer IV infusion over 15 to 30 minutes
Note: Some studies have demonstrated enhanced pharmacodynamic effects when extending intermittent infusions to 4
hours (van den Anker 2009)
Drug Interactions
Monitor therapy
therapy
Probenecid: May increase the serum concentration of Meropenem. Risk X: Avoid combination
Valproate Products: Carbapenems may decrease the serum concentration of Valproate Products. Management:
Concurrent use of carbapenem antibiotics with valproic acid is generally not recommended. Alternative antimicrobial
agents should be considered, but if a concurrent carbapenem is necessary, consider additional anti-seizure
medication.Risk D: Consider therapy modification
Test Interactions
Positive Coombs' [direct]
Adverse Reactions
Cardiovascular: Bradycardia, cardiac arrest, cardiac failure, chest pain, hypertension, hypotension, myocardial infarction,
peripheral edema, peripheral vascular disease, pulmonary embolism, shock, syncope, tachycardia
Central nervous system: Agitation, anxiety, chills, confusion, delirium, depression, dizziness, drowsiness, hallucination,
headache, insomnia, nervousness, pain, paresthesia, seizure
Dermatologic: Dermal ulcer, diaphoresis, pruritus, skin rash (includes diaper-area moniliasis in infants), urticaria
Endocrine & metabolic: Hypervolemia, hypoglycemia, hypokalemia, increased lactate dehydrogenase
Gastrointestinal: Abdominal pain, anorexia, constipation, diarrhea, dyspepsia, enlargement of abdomen, flatulence,
gastrointestinal disease, glossitis, intestinal obstruction, nausea, oral candidiasis, vomiting
Genitourinary: Dysuria, hematuria, pelvic pain, urinary incontinence, vulvovaginal candidiasis
Hematologic & oncologic: Anemia, decreased hematocrit, decreased hemoglobin, decreased partial thromboplastin
time, decreased prothrombin time, decreased white blood cell count, eosinophilia, hypochromic anemia, leukocytosis,
quantitative disorders of platelets
Hepatic: Cholestatic jaundice, hepatic failure, increased serum alanine aminotransferase, increased serum alkaline
phosphatase, increased serum aspartate aminotransferase, increased serum bilirubin, jaundice
Infection: Sepsis
Local: Inflammation at injection site
Neuromuscular & skeletal: Asthenia, back pain
Renal: Increased blood urea nitrogen, increased serum creatinine, renal failure
Respiratory: Apnea, asthma, cough, dyspnea, hypoxia, pharyngitis, pleural effusion, pneumonia, pulmonary edema,
respiratory tract disease
Miscellaneous: Accidental injury, fever
Rare but important or life-threatening: Acute generalized exanthematous pustulosis, agranulocytosis,
angioedema, Clostridium difficile associated diarrhea, DRESS syndrome, edema at insertion site, epistaxis, erythema
multiforme, gastrointestinal hemorrhage, hemolytic anemia, hemoperitoneum, injection site reaction, leukopenia,
localized phlebitis, local thrombophlebitis, melena, neutropenia, pain at injection site, positive direct Coombs test,
positive indirect Coombs test, Stevens-Johnson syndrome, toxic epidermal necrolysis
METILPREDNISOLONA
Dosing: Pediatric
Note: Adjust dose depending upon condition being treated and response of patient. The lowest possible dose should be
used to control the condition; when dose reduction is possible, the dose should be reduced gradually. In life-threatening
situations, parenteral doses larger than the oral dose may be needed. Only sodium succinate salt may be given IV
Asthma, exacerbation:
Acute, short-course “burst” (NAEPP 2007):
Infants and Children <12 years:
Oral: 1 to 2 mg/kg/day in divided doses once or twice daily for 3 to 10 days; maximum daily dose: 60
mg/day; Note: Burst should be continued until symptoms resolve or patient achieves peak
expiratory flow 80% of personal best; usually requires 3 to 10 days of treatment (~5 days on
average); longer treatment may be required
IM (acetate): Note: This may be given in place of short-course “burst” of oral steroids in patients
who are vomiting or if compliance is a problem.
Children ≤4 years: 7.5 mg/kg as a one-time dose; maximum dose: 240 mg
Children 5 to 11 years: 240 mg as a one-time dose
Oral: 40 to 60 mg/day in divided doses once or twice daily for 3 to 10 days; Note: Burst should be
continued until symptoms resolve and peak expiratory flow is at least 80% of personal best;
usually requires 3 to 10 days of treatment (~5 days on average); longer treatment may be
required
IM (acetate): 240 mg as a one-time dose; Note:This may be given in place of short-course “burst” of
oral steroids in patients who are vomiting or if compliance is a problem
Hospital/emergency medical care doses:
Infants and Children <12 years: Oral, IV: 1 to 2 mg/kg/day in 2 divided doses; maximum daily dose: 60
mg/day; continue until peak expiratory flow is 70% of predicted or personal best
Children ≥12 years and Adolescents: Oral, IV: 40 to 80 mg/day in divided doses once or twice daily until
peak expiratory flow is 70% of predicted or personal best
Status asthmaticus (previous NAEPP guidelines; still used by some clinicians): Children: IV: Loading dose: 2
mg/kg/dose, then 0.5 to 1 mg/kg/dose every 6 hours; Note: See NAEPP 2007 guidelines for asthma
exacerbations (emergency medical care or hospital doses) listed above
Asthma, long-term treatment (maintenance) (NAEPP 2007):
Infants and Children <12 years: Oral: 0.25 to 2 mg/kg/day once daily in the morning or every other day as needed
for asthma control; maximum daily dose: 60 mg/day
Children ≥12 years and Adolescents: Oral: 7.5 to 60 mg daily once daily in the morning or every other day as
needed for asthma control
General dosing; anti-inflammatory or immunosuppressive:Infants, Children, and Adolescents: Note: Dosing range
variable; individualize dose for disease state and patient response; Oral, IM (acetate or succinate), IV (succinate):
Initial: 0.11 to 1.6 mg/kg/day or 3.2 to 48 mg/m2/day; usual range: 0.5 to 1.7 mg/kg/day (Kliegman 2015); for oral,
IM (succinate) and IV (succinate) administer in divided doses every 6 to 12 hours; for IM (acetate) administer as a
single daily dose
“Pulse” therapy: IV (succinate): 15 to 30 mg/kg/dose once daily for 3 days; maximum dose: 1,000 mg
Long-acting: IM (acetate): 4 to 80 mg every 1 to 2 weeks
Kawasaki disease: Limited data available; optimal regimen not established; efficacy variable.
Primary treatment, patients at high risk for coronary artery aneurysms:
Pulse dosing: Infants and Children: IV: 30 mg/kg/dose as a single dose in combination with IVIG and aspirin
(AHA [McCrindle 2017]; Ogata 2012; Okada 2009)
Taper dosing: Infants and Children: IV: 1.6 mg/kg/day in divided doses every 8 hours for 5 days or until
afebrile, then transition to oral prednisolone; maximum daily dose: 48 mg/day; give in combination
with aspirin and an additional dose of IVIG (AHA [McCrindle 2017]; Kobayashi 2012). Note: Dosing
based on use of IV prednisolone product (2 mg/kg/day) which is not available in US; dosing
converted to equivalent methylprednisolone dosing; however, clinical necessity of conversion is
unknown.
Treatment, refractory/resistant disease: Note: Reserve use for patients who remain febrile after initial IVIG dose:
Pulse dosing: Infants and Children: IV: 30 mg/kg/dose once daily for 1 or 3 days; may be given in
combination with additional IVIG dose (AHA [McCrindle 2017]; Ebato 2017; Miura 2008).
Taper dosing: Infants and Children: IV: 1.6 mg/kg/day in divided doses every 8 hours for 5 days or until
afebrile, then transition to oral prednisolone; maximum daily dose: 48 mg/day; give in combination
with aspirin and an additional dose of IVIG (AHA [McCrindle 2017]; Kobayashi 2012; Kobayashi
2013). Note:Dosing based on use of IV prednisolone product (2 mg/kg/day) which is not available in
US; dosing converted to equivalent methylprednisolone dosing; however, clinical necessity of
conversion is unknown.
Lupus nephritis: Children and Adolescents: IV (succinate): High-dose "pulse" therapy: 30 mg/kg/dose or 600 to 1,000
mg/m2/dose once daily for 3 days; maximum dose: 1,000 mg (Adams 2006; Marks 2010)
Spinal cord injury, acute: Limited data available: Children and Adolescents: IV (succinate): 30 mg/kg over 15 minutes
followed in 45 minutes by a continuous infusion of 5.4 mg/kg/hour for 23 hours (Bracken 1992; Jaffe
1991); Note: Due to insufficient evidence of clinical efficacy (ie, preserving or improving spinal cord function), the
routine use of methylprednisolone in the treatment of acute spinal cord injury is no longer recommended. If used
in this setting, methylprednisolone should not be initiated >8 hours after the injury; not effective in penetrating
trauma (eg, gunshot) (Consortium for Spinal Cord Medicine 2008).
Pneumocystis pneumonia; moderate or severe infection:Note: Initiate therapy within 72 hours of diagnosis, if possible.
Infants and Children: IV (succinate): 1 mg/kg/dose every 6 hours on days 1 to 7, then 1 mg/kg/dose twice daily on
days 8 to 9, then 0.5 mg/kg/dose twice daily on days 10 and 11, and 1 mg/kg/dose once daily on days 12 to
16 (CDC 2009)
Adolescents: IV (succinate): 30 mg twice daily on days 1 to 5, then 30 mg once daily on days 6 to 10, then 15 mg
once daily on days 11 to 21 (CDC 2009a)
Graft-versus-host disease, acute (GVHD): Infants, Children and Adolescents: IV (succinate): 1 to 2 mg/kg/dose once
daily; if using low dose (1 mg/kg) and no improvement after 3 days, increase dose to 2 mg/kg. Continue therapy
for 5 to 7 days; if improvement observed, may taper by 10% of starting dose every 4 days; if no improvement,
then considered steroid-refractory GVHD and additional agents should be considered (Carpenter 2010)
There are no dosage adjustments provided in the manufacturer's labeling; use with caution; slightly dialyzable (5% to
20%); administer dose posthemodialysis
Contraindications
Hypersensitivity to methylprednisolone or any component of the formulation; systemic fungal infection (except intra-
articular injection for localized joint conditions); intrathecal administration; live or attenuated virus vaccines (with
immunosuppressive doses of corticosteroids); use in premature infants (formulations containing benzyl alcohol
preservative only); immune thrombocytopenia (formerly known as idiopathic thrombocytopenic purpura) (IM
administration only)
Additional contraindication: Methylprednisolone sodium succinate 40 mg vial only: Hypersensitivity to cow's milk or its
components or other dairy products which may contain trace amounts of milk ingredients (known or suspected).
Canadian labeling: Additional contraindications (not in US labeling):
Methylprednisolone tablets: Herpes simplex of the eye, vaccinia and varicella (except for short-term or
emergency therapy)
Methylprednisolone acetate injection: Epidural or intravascular administration; intra-articular injections in

unstable joints; herpes simplex of the eye, vaccinia and varicella (except for short-term or emergency
therapy)
Methylprednisolone sodium succinate: Epidural administration; herpes simplex keratitis, vaccinia and varicella,
arrested tuberculosis, acute psychoses, Cushing syndrome, peptic ulcer, markedly elevated serum
creatinine (except for short-term or emergency therapy)

in allergic symptoms. Adult patients receiving >20 mg per day of prednisone (or equivalent) may be most
corticosteroids.
• Dermal changes: Avoid injection or leakage into the dermis; dermal and/or subdermal skin depression may
occur at the site of injection. Avoid deltoid muscle injection; subcutaneous atrophy may occur.
• Hepatic effects: High doses of methylprednisolone IV (usually doses of 1 g/day in adults) may induce a toxic
form of acute hepatitis (rare); serious hepatic injury may occur, resulting in acute liver failure and death.
Time to onset can be several weeks or longer; resolution has been observed after discontinuation of
therapy. Discontinue methylprednisolone if toxic hepatitis occurs. Avoid use of high doses in patients with a
history of methylprednisone-induced toxic hepatitis.
• Immunosuppression: Prolonged use of corticosteroids may increase the incidence of secondary infection, cause
activation of latent infections, mask acute infection (including fungal infections), prolong or exacerbate viral
or parasitic infections, or limit response to killed or inactivated vaccines. Exposure to chickenpox or measles
should be avoided; corticosteroids should not be used to treat ocular herpes simplex. Corticosteroids
should not be used for cerebral malaria, fungal infections, or viral hepatitis. Close observation is required in
patients with latent tuberculosis and/or TB reactivity; restrict use in active TB (only fulminating or
disseminated TB in conjunction with antituberculosis treatment). Amebiasis should be ruled out in any
patient with recent travel to tropic climates or unexplained diarrhea prior to initiation of corticosteroids.
Use with extreme caution in patients with Strongyloides infections; hyperinfection, dissemination and
fatalities have occurred.
sarcoma (case reports); discontinuation may result in clinical improvement (Goedert 2002).
• Psychiatric disturbances: Corticosteroid use may cause psychiatric disturbances, including euphoria, insomnia,
mood swings, personality changes, severe depression, or psychotic manifestations. Preexisting psychiatric
conditions may be exacerbated by corticosteroid use.
• Septic arthritis: May occur as a complication to parenteral therapy; institute appropriate antimicrobial therapy
as required.
• Cardiovascular disease: Use with caution in patients with heart failure (HF) and/or hypertension; use has been
associated with fluid retention, electrolyte disturbances, and hypertension. Use with caution following
acute myocardial infarction (MI); corticosteroids have been associated with myocardial rupture.
perforation risk.
• Head injury: Increased mortality was observed in patients receiving high-dose IV methylprednisolone; high-dose
corticosteroids should not be used for the management of head injury.
open-angle glaucoma, and cataracts have occurred with prolonged use. Not recommended for the
treatment of optic neuritis; may increase frequency of new episodes. Use with caution in patients with a
history of ocular herpes simplex; corneal perforation has occurred; do not use in active ocular herpes
simplex. Consider routine eye exams in chronic users.
• Systemic sclerosis: Use with caution in patients with systemic sclerosis; an increase in scleroderma renal crisis
incidence has been observed with corticosteroid use.
• Septic shock or sepsis syndrome: Corticosteroids should not be administered for the treatment of sepsis in the
absence of shock (SCCM/ESICM [Annane 2017]). A study has failed to demonstrate efficacy in septic shock
or sepsis syndrome treatment; use may increase mortality in some populations (eg, patients with elevated
serum creatinine, patients who develop secondary infections after use).
Concurrent drug therapy issues
• Benzyl alcohol and derivatives: Methylprednisolone acetate IM injection (multiple-dose vial) and the diluent for
methylprednisolone sodium succinateinjection may contain benzyl alcohol; large amounts of benzyl
alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in
neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations,
CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse
(AAP ["Inactive" 1997], CDC 1982); some data suggests that benzoate displaces bilirubin from protein
binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates.
Additionally, benzyl alcohol may also be toxic to neural tissue when administered locally (eg, intra-articular,
intralesional). See manufacturer's labeling.
• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity
reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products
containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995).
Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in
premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984).
See manufacturer's labeling.
(Leonard, 2007). Increased IOP may occur, especially with prolonged use; in children, increased IOP has been shown to
be dose dependent and produce a greater IOP in children <6 years than older children treated with ophthalmic
dexamethasone (Lam, 2005). Hypertrophic cardiomyopathy has been reported in premature neonates.
Parenteral: Reconstitute vials with provided diluent or bacteriostatic water (see manufacturer's labeling for details). Act-
O-Vial (self-contained powder for injection plus diluent [preservative-free SWFI or bacteriostatic water]) may be
reconstituted by pressing the activator to force diluent into the powder compartment. Following gentle agitation,
solution may be withdrawn via syringe through a needle inserted into the center of the stopper. Neonates should
only receive doses reconstituted with preservative free SWFI.
IV infusion: Dilute reconstituted dose in D5W, NS or D5NS. Limited published information is available regarding dilution
in pediatric patients; in one case series, pediatric patients with rheumatic diseases received a pulse dose of 30
mg/kg up to 1,000 mg added to 100 mL of diluent (NS or D51/4NS) (Akikusa 2007); in another rheumatic disease
trial, a pulse dose of 30 mg/kg up to 2,000 mg was added to 100 mL of diluent (D5W) (Miller 1980).
Oral: Administer after meals or with food or milk; do not administer with grapefruit juice; if prescribed once daily,
administer dose in the early morning to mimic the normal diurnal variation of endogenous cortisol
Parenteral:
IM: Acetate, Succinate: Avoid injection into the deltoid muscle due to a high incidence of subcutaneous atrophy.
Do not inject into areas that have evidence of acute local infection. Discard contents of single-dose vial
after use.
IV: Succinate: Rate dependent upon dose and severity of condition; typically intermittent infusion is administered
over 15 to 60 minutes. Administer large doses over at least 30 to 60 minutes; do not administer large dose
as IV push; severe adverse effects, including hypotension, cardiac arrhythmia, and sudden death, have
been reported in patients receiving methylprednisolone doses ≥250 mg administered over <30 minutes
(Ditzian-Kadanoff 1987; Erstad 1989; Guillén 1998; Lucas 1993). Note: In some spinal cord injury trials,
bolus doses (30 mg/kg) have been administered over 15 minutes. Do not administer acetate form IV.
Take tablets with meals to decrease GI upset; need diet rich in pyridoxine, vitamin C, vitamin D, folate, calcium,
phosphorus, and protein.
Blood pressure, serum glucose, potassium, calcium, hemoglobin, occult blood loss, and clinical presence of adverse
effects. Monitor intraocular pressure (if therapy >6 weeks), weight, height, and linear growth of pediatric patients (with
chronic use), assess HPA suppression
Drug Interactions
Aldesleukin: Corticosteroids may diminish the antineoplastic effect of Aldesleukin. Risk X: Avoid combination
therapy
Monitor therapy
Aprepitant: May increase the serum concentration of Corticosteroids (Systemic). Management: No dose adjustment is
needed for single 40 mg aprepitant doses. For other regimens, reduce oral dexamethasone or
methylprednisolone doses by 50%, and IV methylprednisolone doses by 25%. Antiemetic regimens containing
dexamethasone reflect this adjustment. Risk D: Consider therapy modification
Axicabtagene Ciloleucel: Corticosteroids (Systemic) may diminish the therapeutic effect of Axicabtagene Ciloleucel.
Management: Avoid use of corticosteroids as premedication before axicabtagene ciloleucel. Corticosteroids may,
however, be required for treatment of cytokine release syndrome or neurologic toxicity. Risk D: Consider therapy
modification
Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of
baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not
recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying
antirheumatic drugs (DMARDs) is permitted. Risk D: Consider therapy modification
BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid
combination
Monitor therapy
Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Risk X: Avoid combination
Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin
Test. Risk C: Monitor therapy
Corticorelin: Corticosteroids may diminish the therapeutic effect of Corticorelin. Specifically, the plasma ACTH response
to corticorelin may be blunted by recent or current corticosteroid therapy. Risk C: Monitor therapy
Cosyntropin: Corticosteroids (Systemic) may diminish the diagnostic effect of Cosyntropin. Risk C: Monitor therapy
CycloSPORINE (Systemic): May increase the serum concentration of MethylPREDNISolone. MethylPREDNISolone may
increase the serum concentration of CycloSPORINE (Systemic). MethylPREDNISolone may decrease the serum
concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of MethylPREDNISolone. Management: Consider
methylprednisolone dose increases in patients receiving strong CYP3A4 inducers and monitor closely for reduced
steroid efficacy. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Strong): May increase the serum concentration of MethylPREDNISolone. Management: Consider
methylprednisolone dose reduction in patients receiving strong CYP3A4 inhibitors and monitor for increased
steroid related adverse effects. Risk D: Consider therapy modification
Deferasirox: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI
ulceration/irritation or GI bleeding may be increased. Risk C: Monitor therapy
Deferasirox: Corticosteroids may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI
ulceration/irritation or GI bleeding may be increased.Risk C: Monitor therapy
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections
may be increased. Risk C: Monitor therapy
Desirudin: Corticosteroids (Systemic) may enhance the anticoagulant effect of Desirudin. More specifically,
corticosteroids may increase hemorrhagic risk during desirudin treatment. Management: Discontinue treatment
with systemic corticosteroids prior to desirudin initiation. If concomitant use cannot be avoided, monitor patients
receiving these combinations closely for clinical and laboratory evidence of excessive anticoagulation. Risk D:
Desmopressin: Corticosteroids (Systemic) may enhance the hyponatremic effect of Desmopressin. Risk X: Avoid
combination
DilTIAZem: May increase the serum concentration of Corticosteroids (Systemic). Risk C: Monitor therapy
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Estrogen Derivatives: May increase the serum concentration of Corticosteroids (Systemic). Risk C: Monitor therapy
Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the
concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients
closely for additive immunosuppressant effects (eg, infections). Risk D: Consider therapy modification
Fosaprepitant: May increase the serum concentration of Corticosteroids (Systemic). The active metabolite aprepitant is
likely responsible for this effect. Risk D: Consider therapy modification
Indacaterol: May enhance the hypokalemic effect of Corticosteroids (Systemic). Risk C: Monitor therapy
Indium 111 Capromab Pendetide: Corticosteroids (Systemic) may diminish the diagnostic effect of Indium 111 Capromab
Pendetide. Risk X: Avoid combination
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for
hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased.
Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants.
Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow
suppression at least monthly. Risk D: Consider therapy modification
therapy
Macimorelin: Corticosteroids (Systemic) may diminish the diagnostic effect of Macimorelin. Risk X: Avoid combination
Mifamurtide: Corticosteroids (Systemic) may diminish the therapeutic effect of Mifamurtide. Risk X: Avoid combination
MiFEPRIStone: May diminish the therapeutic effect of Corticosteroids (Systemic). MiFEPRIStone may increase the serum
concentration of Corticosteroids (Systemic). Management: Avoid mifepristone in patients who require long-term
corticosteroid treatment of serious illnesses or conditions (e.g., for immunosuppression following
transplantation). Corticosteroid effects may be reduced by mifepristone treatment. Risk X: Avoid combination
Mitotane: May decrease the serum concentration of Corticosteroids (Systemic). Risk D: Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of
concurrent infection may be increased. Risk X: Avoid combination
Nicorandil: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Nicorandil. Gastrointestinal perforation
has been reported in association with this combination. Risk C: Monitor therapy
Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Risk D: Consider therapy
modification
Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Risk C: Monitor therapy
Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Ritodrine: Corticosteroids may enhance the adverse/toxic effect of Ritodrine. Risk C: Monitor therapy
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Risk D: Consider therapy modification
Sargramostim: Corticosteroids (Systemic) may enhance the therapeutic effect of Sargramostim. Specifically,
corticosteroids may enhance the myeloproliferative effects of sargramostim. Risk C: Monitor therapy
Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Risk C: Monitor therapy
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients
to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating
sipuleucel-T therapy. Risk D: Consider therapy modification
Somatropin: Corticosteroids (Systemic) may diminish the therapeutic effect of Somatropin. Risk C: Monitor therapy
therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Risk C: Monitor therapy
Tisagenlecleucel: Corticosteroids (Systemic) may diminish the therapeutic effect of Tisagenlecleucel. Management:
Avoid use of corticosteroids as premedication or at any time during treatment with tisagenlecleucel, except in the
case of life-threatening emergency (such as resistant cytokine release syndrome). Risk D: Consider therapy
modification
Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent
use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is
permitted, and this warning seems particularly focused on more potent immunosuppressants. Risk D: Consider
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Urea Cycle Disorder Agents: Corticosteroids (Systemic) may diminish the therapeutic effect of Urea Cycle Disorder
Agents. More specifically, Corticosteroids (Systemic) may increase protein catabolism and plasma ammonia
concentrations, thereby increasing the doses of Urea Cycle Disorder Agents needed to maintain these
concentrations in the target range. Risk C: Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated).
Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior
to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3
months after immunosuppressant discontinuation. Risk D: Consider therapy modification
Vaccines (Live): Corticosteroids (Systemic) may enhance the adverse/toxic effect of Vaccines (Live). Corticosteroids
(Systemic) may diminish the therapeutic effect of Vaccines (Live). Management: Doses equivalent to less than 2
mg/kg or 20 mg per day of prednisone administered for less than 2 weeks are not considered sufficiently
immunosuppressive to create vaccine safety concerns. Higher doses and longer durations should be avoided. Risk
Test Interactions
Decreased response to skin tests
Onset of action: IV (succinate): Within 1 hour; Intra-articular (IV acetate): 1 week
Duration: Intra-articular (IV acetate): 1 to 5 weeks
Absorption: Oral: Well absorbed (Czock 2005)
Bioavailability: Oral: 88% ± 23% (Czock 2005)
Distribution: Vd: IV (succinate): 24 L ± 6 L (Czock 2005)
Metabolism: Hepatic to metabolites (Czock 2005)
Adolescents: IV: 1.9 ± 0.7 hours (age range: 12 to 20 years; Rouster-Stevens 2008)
Adults: Oral: 2.5 ± 1.2 hours (Czock 2005); IV (succinate): 0.25 ± 0.1 hour (Czock 2005)
Time to peak, plasma:
Oral: 2.1 ± 0.7 hours (Czock 2005)
IV (succinate): 0.8 hours (Czock 2005)
Excretion: Urine (1.3% [oral], 9.2% [IV succinate] as unchanged drug) (Czock 2005)
Geriatric: Decreased clearance and increased half-life (Czock 2005)
Obesity: Decreased clearance and increased half-life (Czock 2005)
Adverse Reactions
Cardiovascular: Bradycardia, cardiac arrest, cardiac arrhythmia, cardiac failure, cardiomegaly, circulatory shock, edema,
embolism (fat), hypertension, hypertrophic cardiomyopathy (in neonates), myocardial rupture (post MI), syncope,
tachycardia, thromboembolism, thrombophlebitis, vasculitis
Central nervous system: Arachnoiditis, depression, emotionallability, euphoria, headache, increased intracranial
pressure, insomnia, malaise, meningitis, myasthenia, neuritis, neuropathy, paraplegia, paresthesia, personality
changes, psychic disorders, pseudotumor cerebri (usually following discontinuation), seizure, sensory disturbance,
vertigo
Dermatologic: Acne vulgaris, allergic dermatitis, alopecia, atrophic striae, diaphoresis, ecchymoses, epidermal thinning,
erythema, exfoliation of skin, facial erythema, hyperpigmentation, hypertrichosis, hypopigmentation, skin
atrophy, skin rash, suppression of skin test reaction, thinning hair, urticaria, xeroderma
Endocrine & metabolic: Adrenal suppression, calcinosis, cushingoid state, Cushing syndrome, decreased glucose
tolerance, diabetes mellitus, fluid retention, glycosuria, growth suppression (children), hirsutism, HPA-axis
suppression, hyperglycemia, hyperlipidemia, hypokalemia, hypokalemic alkalosis, insulin resistance (increased
requirements for insulin or oral hypoglycemic agents in diabetes), menstrual disease, moon face, negative
nitrogen balance, protein catabolism, sodium retention, weight gain
Gastrointestinal: Abdominal distention, bladder dysfunction (after intrathecal administration, including bowel
dysfunction), carbohydrate intolerance (increased), gastrointestinal hemorrhage, gastrointestinal perforation,
hiccups, increased appetite, intestinal perforation (of both of the small and large intestines; especially in patients
with inflammatory bowel disease), nausea, pancreatitis, peptic ulcer, spermatozoa disorder (decreased motility
and number of spermatozoa), ulcerative esophagitis
Hematologic: Leukocytosis (transient), malignant neoplasm (secondary), petechia
Hepatic: Hepatomegaly, increased liver enzymes, increased serum transaminases
Hypersensitivity: Anaphylactoid reaction, anaphylaxis, angioedema, hypersensitivity reaction
Infection: Increased susceptibility to infection, infection (ophthalmic), sterile abscess
Local: Injection site infection
Neuromuscular & skeletal: Amyotrophy, arthropathy, aseptic necrosis of femoral head, aseptic necrosis of humoral
head, bone fracture, Charcot-like arthropathy, lipotrophy, osteoporosis, rupture of tendon, steroid myopathy,
vertebral compression fracture
Ophthalmic: Blindness, exophthalmoses, glaucoma, increased intraocular pressure, ophthalmic inflammation

(ophthalmic), subcapsular posterior cataract, visual impairment
Respiratory: Pulmonary edema, rhinitis
Miscellaneous: Anaphylactoid reaction, anaphylaxis, angioedema, hypersensitivity reactions, tissue sloughing (residue or
slough at injection site), wound healing impairment
Rare but important or life-threatening: Venous thrombosis (Johannesdottir 2013)
METRONIDAZOL
Dosing: Neonatal
General dosing, susceptible infection: Limited data available; dosing regimens variable:
Weight-directed dosing (Bradley 2018): IV, Oral:
Loading dose: 15 mg/kg
Maintenance dose:

≤28 days 7.5 mg/kg/dose every 12 hours
≤2 kg
≤7 days 7.5 mg/kg/dose every 8 hours
>2 kg
Age-directed dosing (Cohen-Wolkowiez 2012; Cohen-Wolkowiez 2013; Red Book [AAP 2018]): IV:
Loading dose: 15 mg/kg
Maintenance dose:
Postmenstrual age (PMA) Dose

≤34 weeks 7.5 mg/kg/dose every 12 hours
>34 to 40 weeks 7.5 mg/kg/dose every 8 hours
>40 weeks 7.5 mg/kg/dose every 6 hours or 10 mg/kg/dose every 8 hours
Surgical prophylaxis (IDSA/ASHP [Bratzler 2013]): Limited data available: IV:
Body Weight Dose

<1.2 kg 7.5 mg/kg as a single dose 30 to 60 minutes prior to procedure
≥1.2 kg 15 mg/kg as a single dose 30 to 60 minutes prior to procedure
Dosing: Pediatric
Note: Some clinicians recommend using adjusted body weight in obese children. Dosing weight = IBW + 0.45 (TBW-IBW)
General dosing, susceptible infection (Red Book [AAP 2018]): Infants, Children, and Adolescents:
Oral: 15 to 50 mg/kg/day in divided doses 3 times daily; maximum daily dose: 2,250 mg/day
IV: 22.5 to 40 mg/kg/day in divided doses 3 or 4 times daily; maximum daily dose: 4,000 mg/day
Amebiasis: Infants, Children, and Adolescents: Oral: 35 to 50 mg/kg/day in divided doses every 8 hours for 7 to 10 days;
maximum dose: 750 mg/dose; for severe infection or extraintestinal disease, IV may be necessary (Bradley
2018; Red Book [AAP 2018])
Appendicitis, perforated (divided dosing): Children and Adolescents: IV: 30 mg/kg/day in divided doses 3 times daily
(Emil 2003)
Appendicitis, perforated (once-daily dosing): Limited data available: Children and Adolescents: IV: 30 mg/kg/dose once
daily in combination with ceftriaxone; maximum reported daily dose: 1,500 mg/day (Yardeni 2013); however,
other pediatric trials did not report a maximum; in adult patients, a maximum daily dose of 1,500 mg/day for
once-daily dosing is suggested (IDSA [Solomkin 2010]); in pediatric patients, once-daily metronidazole in
combination with ceftriaxone has been shown to have similar efficacy as triple-combination therapy with
ampicillin, clindamycin, and gentamicin (Fraser 2010; St Peter 2006; St Peter 2008)
Balantidiasis: Infants, Children, and Adolescents: Oral: 35 to 50 mg/kg/day in divided doses every 8 hours for 5 days;
maximum dose: 750 mg/dose (Red Book [AAP 2018])
Catheter (peritoneal dialysis); exit-site or tunnel infection:Infants, Children, and Adolescents: Oral: 10 mg/kg/dose 3
times daily. Maximum dose: 500 mg/dose (ISPD [Warady 2012])
Clostridioides (formerly Clostridium) difficile infection:
Infants: Mild to moderate infection: Oral, IV: 7.5 mg/kg/dose every 6 hours for 10 days (Red Book[AAP 2018])
Children and Adolescents:
Non-severe infection, initial or first recurrence: Oral: 7.5 mg/kg/dose 3 to 4 times daily for 10 days;
maximum dose: 500 mg/dose (IDSA/SHEA [McDonald 2018])
Severe/fulminant infection, initial: IV: 10 mg/kg/dose every 8 hours for 10 days; maximum dose: 500
mg/dose; use concomitantly with oral or rectal vancomycin (IDSA/SHEA [McDonald 2018])
Dientamoeba fragilis: Infants, Children, and Adolescents: Oral: 35 to 50 mg/kg/day in divided doses every 8 hours for 10
days; maximum dose: 750 mg/dose (Red Book[AAP 2018])
Giardiasis: Infants, Children, and Adolescents: Oral: 15 to 30 mg/kg/day in divided doses every 8 hours for 5 to 7 days;
maximum dose: 250 mg/dose (Bradley 2018; Gardner 2001; Granados 2012; Ross 2013; Red Book [AAP 2018])
Helicobacter pylori infection: Children and Adolescents: Oral: 20 mg/kg/day in 2 divided doses for 10 to 14 days in
combination with amoxicillin and proton pump inhibitor with or without clarithromycin; maximum daily dose:
1,000 mg/day (NASPGHAN/ESPGHAN [Koletzko 2011])
Inflammatory bowel disease:
Crohn disease, perianal disease; induction: Children and Adolescents: Oral: 7.5 mg/kg/dose 3 times daily for 6
weeks with or without ciprofloxacin; maximum dose: 500 mg/dose (Sandhu 2010)
Ulcerative colitis, pouchitis, persistent: Children and Adolescents: Oral: 20 to 30 mg/kg/day in divided doses 3
times daily for 14 days with or without ciprofloxacin or oral budesonide; maximum dose: 500 mg/dose
(Turner 2012)
Intra-abdominal infection: Infants, Children, and Adolescents: IV: 30 to 40 mg/kg/day in divided doses 3 times daily as
part of combination therapy; maximum dose: 500 mg/dose (IDSA [Solomkin 2010])
Pelvic inflammatory disease: Adolescents: Oral: 500 mg twice daily for 14 days; give with doxycycline plus a
cephalosporin (CDC [Workowski 2015])
Peritonitis (peritoneal dialysis) (ISPD [Warady 2012]):
Prophylaxis: Gastrointestinal or genitourinary procedures: Infants, Children, and Adolescents: IV: 10 mg/kg once
prior to procedure in combination with cefazolin; Maximum dose: 1,000 mg/dose
Treatment: Infants, Children, and Adolescents: Oral: 10 mg/kg/dose 3 times daily. Maximum daily dose: 1,200
mg/day
Prophylaxis against sexually transmitted diseases following sexual assault (CDC [Workowski 2015]): Adolescents: Oral:
2,000 mg as a single dose in combination with azithromycin and ceftriaxone
Surgical prophylaxis: Children and Adolescents: IV: 15 mg/kg as a single dose 30 to 60 minutes prior to procedure;
maximum single dose: 500 mg (IDSA/ASHP [Bratzler 2013])
Surgical prophylaxis, colorectal: Children and Adolescents: Oral: 15 mg/kg/dose every 3 to 4 hours for 3 doses,
starting after mechanical bowel preparation the afternoon and evening before the procedure, with or
without additional oral antibiotics and with an appropriate IV antibiotic prophylaxis regimen; maximum
dose: 1,000 mg/dose (IDSA/ASHP [Bratzler 2013])
Tetanus (Clostridium tetani infection): Infants, Children, and Adolescents: IV, Oral: 30 mg/kg/day in divided doses 4
times daily for 7 to 10 days; maximum daily dose: 4,000 mg/day (Red Book [AAP 2018])
Trichomoniasis; treatment: Oral:
Children <45 kg: 45 mg/kg/day in divided doses 3 times daily for 7 days; maximum daily dose: 2,000 mg/day (Red
Book [AAP 2018])
Children ≥45 kg and Adolescents: 2,000 mg as a single dose once or 500 mg twice daily for 7 days (CDC
[Workowski 2015]; Red Book [AAP 2018])
Vaginosis, bacterial: Oral: Children >45 kg and Adolescents: 500 mg twice daily for 7 days (CDC [Workowski 2015]; Red
Book [AAP 2018])
Manufacturer's labeling:
Mild, moderate, or severe impairment: There are no dosage adjustments provided in the manufacturer's
labeling; however, decreased renal function does not alter the single-dose pharmacokinetics.
ESRD requiring dialysis: Metronidazole metabolites may accumulate; monitor for adverse events;
accumulated metabolites may be rapidly removed by dialysis.
Intermittent hemodialysis (IHD): If administration cannot be separated from hemodialysis, consider
supplemental dose following hemodialysis.
Peritoneal dialysis (PD): No dosage adjustment necessary
Alternate dosing: Others have used the following adjustments (Aronoff 2007). Note: Renally adjusted dose
recommendations are based on doses of 15 to 30 mg/kg/day divided every 6 to 8 hours.
GFR ≥10 mL/minute/1.73 m2: No adjustment required
Intermittent hemodialysis (IHD): Extensively removed by hemodialysis: 4 mg/kg/dose every 6 hours
Peritoneal dialysis (PD): Extensively removed by peritoneal dialysis: 4 mg/kg/dose every 6 hours
Continuous renal replacement therapy (CRRT): No adjustment required
Manufacturer labeling:
Mild or moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary; use with caution and
monitor for adverse events
Severe impairment (Child-Pugh class C):
Immediate release tablets, injection: Reduce dose by 50%
Extended release tablets: Use is not recommended.
Alternate dosing: The pharmacokinetics of a single oral 500 mg dose were not altered in patients with cirrhosis; initial
dose reduction is therefore not necessary (Daneshmend 1982). In one study of IV metronidazole, adult patients
with alcoholic liver disease (with or without cirrhosis) demonstrated a prolonged elimination half-life (eg, ~18
hours). The authors recommended the dose be reduced accordingly (clearance was reduced by ~62%) and the
frequency may be prolonged (eg, every 12 hours instead of every 6 hours) (Lau 1987). In another single IV dose
study using metronidazole metabolism to predict hepatic function, patients classified as Child-Pugh class C
demonstrated a half-life of ~21.5 hours (Muscara 1995).
Contraindications
Hypersensitivity to metronidazole, nitroimidazole derivatives, or any component of the formulation; pregnant patients
(first trimester) with trichomoniasis; use of disulfiram within the past 2 weeks; use of alcohol or propylene glycol-
containing products during therapy or within 3 days of therapy discontinuation
Canadian labeling: Additional contraindications (not in the US labeling): Active neurological disorders; history of blood
dyscrasia; hypothyroidism; hypoadrenalism
• Carcinogenic: [US Boxed Warning]: Possibly carcinogenic based on animal data. Reserve use for conditions
described in Use; unnecessary use should be avoided.
• CNS effects: Severe neurological disturbances, including aseptic meningitis (may occur within hours of a dose),
cerebellar symptoms (ataxia, dizziness, dysarthria), convulsive seizures, encephalopathy, optic neuropathy,
and peripheral neuropathy (usually of sensory type and characterized by numbness or paresthesia of an
extremity) have been reported. CNS symptoms and CNS lesions are generally reversible within days to
weeks of discontinuation of therapy; peripheral neuropathy symptoms may be prolonged after
discontinuation. Avoid repeated or prolonged courses due to risk of cumulative neurotoxicity (IDSA/SHEA
[McDonald 2018]). Monitor for neurologic symptoms and discontinue therapy if any abnormal neurologic
symptoms occur.
treatment. Candidiasis infection (known or unknown) may be more prominent during metronidazole
treatment, antifungal treatment required.
• Blood dyscrasias: Use with caution in patients with or history of blood dyscrasias; agranulocytosis, leukopenia,
and neutropenia have occurred. Monitor CBC with differential at baseline, during and after treatment.
• Cockayne syndrome: Severe hepatotoxicity/acute hepatic failure (has been fatal) has been reported with
systemic metronidazole in patients with Cockayne syndrome; onset is rapid after initiation of treatment.
Use metronidazole only after risk vs benefit assessment and if there are no appropriate alternatives in
patients with Cockayne syndrome. Obtain LFTs prior to treatment initiation, within the first 2 to 3 days of
initiation, frequently during therapy, and after treatment is complete. Discontinue treatment if elevated
LFTs occur and monitor until LFTs return to baseline.
• Hepatic impairment: Use with caution in patients with hepatic impairment due to potential accumulation;
dosage adjustment recommended in patients with severe hepatic impairment.
• Renal impairment: Use with caution in patients with severe renal impairment or ESRD due to potential
accumulation. Accumulated metabolites may be rapidly removed by hemodialysis; supplemental doses may
be needed.
• Seizure disorder: Use with caution in patients with a history of seizure disorder.
Dosage-form specific issues:

• Injection: Use injection with caution in patients with heart failure, edema, or other sodium-retaining states,
including corticosteroid treatment due to high sodium content. In patients receiving continuous nasogastric
secretion aspiration, sufficient metronidazole may be removed in the aspirate to cause a reduction in
serum levels.
• Ethanol use: Abdominal cramps, nausea, vomiting, headaches, and flushing have been reported with oral and
injectable metronidazole and concomitant alcohol consumption (disulfiram-like reactions); avoid alcoholic
beverages or products containing propylene glycol during oral or injectable therapy and for at least 3 days
after therapy.
Oral:
Immediate-release tablets and capsules: May administer with food to minimize GI upset
Extended release: Should be taken on an empty stomach (1 hour before or 2 hours after meals); do not split,
chew, or crush.
Parenteral: IV: Administer undiluted (5 mg/mL) by slow intermittent infusion over 30 to 60 minutes. Avoid contact of
drug solution with equipment containing aluminum.
Take with food to minimize stomach upset.
Sodium: Injectable dosage form may contain sodium.
Ethanol: Use of ethanol is contraindicated during therapy and for 3 days after therapy discontinuation.
Monitor CBC with differential at baseline, during, and after prolonged or repeated courses of therapy. Monitor LFTs in
patients with Cockayne syndrome. Closely monitor patients with severe hepatic impairment or ESRD for adverse
reactions. Observe patients carefully if neurologic symptoms occur and consider discontinuation of therapy.
Drug Interactions
Fosphenytoin: May decrease the serum concentration of MetroNIDAZOLE (Systemic). MetroNIDAZOLE (Systemic) may
increase the serum concentration of Fosphenytoin. Risk C: Monitor therapy
Mebendazole: May enhance the adverse/toxic effect of MetroNIDAZOLE (Systemic). Particularly the risk for Stevens-
Johnson syndrome or toxic epidermal necrolysis may be increased. Risk X: Avoid combination
Mycophenolate: MetroNIDAZOLE (Systemic) may decrease the serum concentration of Mycophenolate. Specifically,
metronidazole may decrease concentrations of the active metabolite of mycophenolate. Risk C: Monitor therapy
PHENobarbital: May decrease the serum concentration of MetroNIDAZOLE (Systemic). Risk C: Monitor therapy
Phenytoin: May decrease the serum concentration of MetroNIDAZOLE (Systemic). MetroNIDAZOLE (Systemic) may
increase the serum concentration of Phenytoin. Risk C: Monitor therapy
Vecuronium: MetroNIDAZOLE (Systemic) may enhance the neuromuscular-blocking effect of Vecuronium. Risk C:
Monitor therapy
Vitamin K Antagonists (eg, warfarin): MetroNIDAZOLE (Systemic) may increase the serum concentration of Vitamin K
Antagonists. Management: Consider alternatives to concomitant therapy with these agents. If concomitant
therapy cannot be avoided, consider reducing the dose of the vitamin K antagonist and monitor for increased
INR/bleeding. Risk D: Consider therapy modification
Test Interactions
May interfere with AST, ALT, triglycerides, glucose, and LDH testing
Absorption: Oral: Well absorbed
Distribution: To bile, seminal fluid, bone, liver, and liver abscesses, lung and vaginal secretions; crosses blood-brain
barrier; saliva and CSF concentrations similar to those in plasma
Protein binding: <20%
Metabolism: Hepatic (30% to 60%) to several metabolites including an active hydroxyl metabolite which maintains
activity ~30% to 65% of the parent compound (Lamp 1999)
Neonates <7 days (Jager-Roman 1982): Within first week of life, more prolonged than with lower GA:
GA 28 to 30 weeks: 75.3 ± 16.9 hours
GA 32 to 35 weeks: 35.4 ± 1.5 hours
GA 36 to 40 weeks: 24.8 ± 1.6 hours
Neonates ≥7 days: ~22.5 hours (Upadhyaya 1988)
Children and Adolescents: 6 to 10 hours (Lamp 1999)
Adults: ~8 hours
Time to peak, serum: Oral: 1 to 2 hours
Excretion: Urine (unchanged drug and metabolites: 60% to 80%; ~20% of total as unchanged drug); feces (6% to 15%)
Renal function impairment: CrCl ≤65 mL/minute: Half-life: 18 to 32 hours (hydroxy metabolite [active]) (Lamp 1999)
Hepatic function impairment: Half-life: 18.31 hours (mean) in one study (Lau 1987)
According to Child-Pugh classification (Muscara 1995):
Child-Pugh class A: ~10.7 hours
Child-Pugh class B: ~13.5 hours
Child-Pugh class C: ~21.5 hours
Adverse Reactions
Cardiovascular: Chest pain, facial edema, flattened T-wave on ECG, flushing, palpitations, peripheral edema, syncope,
tachycardia
Central nervous system: Aseptic meningitis, ataxia, brain disease, cerebral lesion, chills, confusion, convulsions,
depression, disulfiram-like reaction (with alcohol), dizziness, drowsiness, dysarthria, headache, hypoesthesia,
insomnia, irritability, malaise, metallic taste, numbness, paresthesia, peripheral neuropathy, psychosis, seizure,
vertigo
Dermatologic: Erythematous rash, genital pruritus, hyperhidrosis, pruritus, Stevens-Johnson syndrome, toxic epidermal
necrolysis, urticaria
Endocrine & metabolic: Decreased libido
Gastrointestinal: Abdominal cramps, abdominal distress, abdominal pain, anorexia, constipation, decreased appetite,
diarrhea, dysgeusia, glossitis, hairy tongue, nausea, pancreatitis (rare), proctitis, stomatitis, vomiting, xerostomia
Genitourinary: Cystitis, dark urine (rare), dysmenorrhea, dyspareunia, dysuria, urinary incontinence, urinary tract
infection, urine abnormality, urine discoloration, vaginal dryness, vaginitis, vulvovaginal candidiasis
Hematologic & oncologic: Agranulocytosis, eosinophilia, leukopenia, neutropenia (reversible), thrombocytopenia

(reversible, rare)
Hepatic: Increased liver enzymes, jaundice, severe hepatotoxicity (patients with Cockayne syndrome)
Hypersensitivity: Anaphylaxis, hypersensitivity
Immunologic: DRESS syndrome, serum sickness-like reaction (joint pains)
Infection: Bacterial infection, candidiasis
Local: Inflammation at injection site (IV), injection site reaction
Neuromuscular & skeletal: Arthralgia, muscle spasm, myalgia, weakness

Ophthalmic: Abnormal eye movements (saccadic), nystagmus, optic neuropathy
Renal: Polyuria
Respiratory: Dyspnea, flu-like symptoms, nasal congestion, pharyngitis, rhinitis, sinusitis, upper respiratory tract
infection
MIDAZOLAM
Dosing: Neonatal
Sedation, intermittent dosing or procedural (intubation): IM, IV: 0.05 to 0.1 mg/kg/dose over 5 minutes (Kumar 2010;
VanLooy 2008)
Sedation, mechanically ventilated patient: IV: Note: Use the lowest effective dose.
Manufacturer's labeling: Continuous IV infusion:
GA ≤32 weeks: Initial: 0.03 mg/kg/hour (0.5 mcg/kg/minute)
GA >32 weeks: Initial: 0.06 mg/kg/hour (1 mcg/kg/minute)
Alternative dosing:
Loading dose:
GA <34 weeks: Note: Some have recommended against the use of a loading or bolus dose due to
associated hypotension; to rapidly achieve sedation, it has been suggested to begin the
continuous infusion at a faster rate for the first several hours (Jacqz-Aigrain 1992). Others
have successfully used loading doses of 0.2 mg/kg given over 1 hour to prevent hypotension
(Anand 1999; Treluyer 2005)
GA ≥34 weeks: 0.2 mg/kg/dose once (Anand 1999; Jacqz-Aigrain 1990; Treluyer 2005)
Continuous IV infusion (Anand 1999; Jacqz-Aigrain 1994; Treluyer 2005):
GA 24 to 26 weeks: Initial: 0.02 to 0.03 mg/kg/hour (0.33 to 0.5 mcg/kg/minute)
GA 27 to 29 weeks: Initial: 0.03 to 0.04 mg/kg/hour (0.5 to 0.67 mcg/kg/minute)
GA ≥30 weeks: Initial: 0.03 to 0.06 mg/kg/hour(0.5 to 1 mcg/kg/minute)
Note: After prolonged therapy, consider a slow wean of therapy to prevent signs and symptoms of
withdrawal. The following regimen has been reported: If duration of therapy ≤4 days, wean over at
least 2 days beginning with an initial dosage reduction of 30% to 50% followed by 20% to 30%
dosage reductions every 6-8 hours; monitor closely for signs and symptoms of withdrawal with each
reduction in dose. If duration of therapy is >4 days, decrease infusion rate by 25% to 50% every 12
hours, then convert to an intermittent dose every 4 hours and lastly, every 8 hours (Anand 1999).
Seizures, refractory; status epilepticus: IV: Dosage regimens variable, reported doses are higher than sedative
doses: Note: Consider omitting loading dose if patient has received an IV dose of a benzodiazepine; begin
continuous IV infusion at lower end of range and titrate to lowest effective dose: Loading dose: 0.06 to 0.15
mg/kg/dose followed by a continuous infusion of 0.06 to 0.4 mg/kg/hour (1 to 7 mcg/kg/minute); maximum
reported rate: 1.1 mg/kg/hour (18 mcg/kg/minute) (Boylan 2004; Conde 2005; Holmes 1999)
Dosing: Pediatric
Dosage must be individualized and based on patient's age, underlying diseases, concurrent medications, and desired
effect; decrease dose (by ∼30%) if opioids or other CNS depressants are administered concomitantly; use multiple small
doses and titrate to desired sedative effect; allow 3 to 5 minutes between doses to decrease the chance of oversedation.
Sedation, anxiolysis, and amnesia prior to procedure or before induction of anesthesia:
IM: Infants, Children and Adolescents: Usual: 0.1 to 0.15 mg/kg 30-60 minutes before surgery or procedure;
range: 0.05 to 0.15 mg/kg; doses up to 0.5 mg/kg have been used in more anxious patients; maximum total
dose: 10 mg
IV:
Infants 1 to 5 months: Limited data available in nonintubated infants; infants <6 months are at higher risk
for airway obstruction and hypoventilation; titrate dose with small increments to desired clinical
effect; monitor carefully
Infants 6 months to Children 5 years: Initial: 0.05 to 0.1 mg/kg; titrate dose carefully; total dose of 0.6
mg/kg may be required; usual total dose maximum: 6 mg
Children 6 to 12 years: Initial: 0.025 to 0.05 mg/kg; titrate dose carefully; total doses of 0.4 mg/kg may be
required; usual total dose maximum: 10 mg
Children 12 to 16 years: Dose as adults; usual total dose maximum: 10 mg
Intranasal: Limited data available: Note: Some investigators suggest premedication with intranasal lidocaine to
decrease irritation and subsequent agitation (Chiaretti 2011; Lugo 1993):
Infants 1 to 5 months: 0.2 mg/kg (single dose) (Harcke 1995; Mittal 2006)
Infants ≥6 months, Children, and Adolescents: 0.2 to 0.3 mg/kg (maximum single dose: 10 mg); may repeat
in 5 to 15 minutes to a maximum of 0.5 mg/kg (maximum total dose: 10 mg) (Acworth 2001;
Chiaretti 2011; Harcke 1995; Lane 2008)
Oral: Infants >6 months, Children, and Adolescents <16 years: Single dose: 0.25 to 0.5 mg/kg once, depending on
patient status and desired effect, usual: 0.5 mg/kg; maximum dose: 20 mg; Note:Younger patients (6
months to <6 years) and those less cooperative may require higher doses (up to 1 mg/kg); use lower initial
doses (0.25 mg/kg) in older patients (6 to <16 years) and in patients with cardiac or respiratory
compromise, concomitant CNS depressant, or high-risk surgical patients.
Rectal: Limited data available: Infants >6 months and Children: Usual: 0.25-0.5 mg/kg once (Krauss 2006); doses
up to 1 mg/kg have been used in infants and young children (7 months to 5 years of age) but may be
associated with a higher incidence of postprocedural agitation (Kanegaye 2003; Tanaka 2000)
Sedation, mechanically ventilated patient: Infants, Children, and Adolescents: IV: Loading dose: 0.05 to 0.2 mg/kg given
slow IV over 2 to 3 minutes, then follow with initial continuous IV infusion: 0.06 to 0.12 mg/kg/hour (1 to
2 mcg/kg/minute); titrate to the desired effect; range: 0.024 to 0.36 mg/kg/hour (0.4 to 6 mcg/kg/minute)
Seizures, acute treatment: Limited data available:
Buccal: Reserve for patients without IV access (Ashrafi 2010; Kutlu 2003; McIntyre 2005; Mpimbaza 2008;
Talukdar 2009):
Weight-based dosing: Infants ≥3 months, Children, and Adolescents: 0.2 to 0.5 mg/kg once; maximum
dose: 10 mg
Age-based dosing (McIntyre 2005):
Infants 6 to 11 months: 2.5 mg
Children 1 to 4 years: 5 mg
Children 5 to 9 years: 7.5 mg
Children and Adolescents ≥10 years: 10 mg
IM: Infants, Children, and Adolescents: 0.2 mg/kg/dose; repeat every 10 to 15 minutes; maximum dose: 6 mg
(Hegenbarth 2008)
Intranasal (Bhattachyaryya 2006; Fişgin 2000; Fişgin 2002; Holsti 2007; Holsti 2010; Kutlu 2000): Reserve for
patients without IV access; divide dose between nares:
Infants 1 to 5 months: 0.2 mg/kg once; maximum dose: 10 mg
Infants and Children ≥6 months: 0.2 mg/kg; one study used 0.3 mg/kg (n=9); maximum dose: 10 mg; may
repeat once to a total maximum of 0.4 mg/kg
Status epilepticus:
Standard treatment: Infants, Children, and Adolescents: Limited data available:
IM:
Weight-based dosing: 0.2 mg/kg once; maximum dose: 10 mg/dose (NCS [Brophy 2012])
Fixed dosing (AES [Glauser 2016]; NCS [Brophy 2012]):
13 to 40 kg: 5 mg once
>40 kg: 10 mg once
Intranasal: 0.2 mg/kg once; maximum dose: 10 mg/dose (AES [Glauser 2016]; NCS [Brophy 2012])
Buccal: 0.5 mg/kg once; maximum dose: 10 mg/dose (AES [Glauser 2016]; McIntyre 2005; NCS [Brophy
2012])
Refractory to standard treatment (NCS [Brophy 2012]): Note: Mechanical ventilation and cardiovascular
monitoring required; titrate dose to cessation of electrographic seizures or burst suppression. Infants,
Children, and Adolescents: Limited data available:
Loading dose: IV: 0.2 mg/kg followed by a continuous infusion
Continuous IV infusion: 0.05 to 2 mg/kg/hour (0.83 to 33.3 mcg/kg/minute) titrated to cessation of

electrographic seizures or burst suppression. If patient experiences breakthrough status epilepticus
while on the continuous infusion, administer a bolus of 0.1 to 0.2 mg/kg and increase infusion rate
by 0.05 to 0.1 mg/kg/hour (0.83 to 1.66 mcg/kg/minute) every 3 to 4 hours.
NO
Multiple dosing or continuous infusion: Expect longer duration of action and accumulation; based on patient response,
dosage reduction likely to be necessary (Trouvin 1988).
Contraindications
Concurrent use of oral midazolam with protease inhibitors (atazanavir, atazanavir-cobicistat, darunavir, indinavir,
lopinavir-ritonavir, nelfinavir, ritonavir, saquinavir, tipranavir); concurrent use of oral or injectable midazolam
with fosamprenavir.
Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to benzodiazepines; acute

pulmonary insufficiency; severe chronic obstructive pulmonary disease.
• Anterograde amnesia: Benzodiazepines have been associated with anterograde amnesia (Nelson 1999).
• Cardiorespiratory effects: [US Boxed Warning]: Has been associated with respiratory depression and
respiratory arrest, especially when used for sedation in noncritical care settings; airway obstruction,
desaturation, hypoxia, and apnea have also been reported, most often when used concomitantly with
other CNS depressants (eg, opioids). In some cases, death or hypoxic encephalopathy resulted. Use only
in hospital or ambulatory care settings that provide for continuous monitoring of respiratory and cardiac
function (ie, pulse oximetry). Immediate availability of resuscitative drugs and age- and size-appropriate
equipment for bag/valve/mask ventilation and intubation, and personnel trained in their use and skilled
in airway management should be assured. For deeply sedated patients, a dedicated individual, other
than the practitioner performing the procedure, should monitor the patient throughout the
procedure. Risk of cardiorespiratory adverse events is increased in patients with abnormal airway anatomy,
cyanotic congenital heart disease, sepsis or severe pulmonary disease.
cautioned about performing tasks that require mental alertness (eg, operating machinery, driving). A
minimum of 1 day should elapse after midazolam administration before attempting these tasks. Elapsed
time to resume these tasks must be individualized, as pharmacologic effects are dependent on dose, route,
duration of procedure, and presence of other medications.
• Hypotension: May cause hypotension, particularly in pediatric patients or patients with hemodynamic
instability. Hypotension may occur more frequently in patients who have received opioid analgesics.
• Paradoxical reactions: Paradoxical reactions, including hyperactive or aggressive behavior, have been reported
with benzodiazepines; risk may be increased in adolescent/pediatric patients, geriatric patients, or patients
with a history of alcohol use disorder or psychiatric/personality disorders (Mancuso 2004).
• Acute illness: Use IV midazolam with caution in patients with uncompensated acute illnesses, such as severe
fluid or electrolyte disturbances.
• Cardiovascular disease: Use with caution in patients with heart failure. Adverse hemodynamic events have been
reported in pediatric patients with cardiovascular instability; avoid rapid IV administration in these
patients.
• Glaucoma: Use with caution in patients with glaucoma; contraindicated in patients with acute narrow angle
glaucoma; may use in patients with open-angle glaucoma only if receiving appropriate therapy.
• Renal impairment: Use with caution in patients with renal impairment; half-life of midazolam and metabolites
may be prolonged.
• Respiratory disease: Use with caution in patients with respiratory disease (eg, COPD); these patients may be
sensitive to the respiratory depressant effects of midazolam.
• Concomitant use with opioids: [US Boxed Warning]: Concomitant use of benzodiazepines and opioids may
result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing
of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages
and durations to the minimum required. Follow patients for signs and symptoms of respiratory
depression and sedation.
• Elderly: Use with caution in the elderly; decreased dosages and slower titration is recommended due to an
increased volume of distribution seen with lipophilic drugs in the elderly, resulting in slower distribution
and lower clearance. Older patients can also take longer to recover completely after midazolam
administration for the induction of anesthesia (Strøm 2016). Use of oral midazolam is not recommended in
the elderly. Elderly patients may be at an increased risk of death with use; risk has been found highest
within the first 4 months of use in elderly dementia patients (Jennum 2015; Saarelainen 2018).
• Obese patients: Use benzodiazepines with caution in obese patients; may have prolonged action when
discontinued.
• Neonates: Injection: [US Boxed Warning]: Do not administer by rapid IV injection in neonates; severe
hypotension and seizures have been reported following rapid IV administration, particularly with
concomitant fentanyl use.Neonates are also vulnerable to profound and/or prolonged respiratory effects
of midazolam.
• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol
(≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome") in neonates;
the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS
dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse
(AAP ["Inactive" 1997]; CDC 1982); some data suggest that benzoate displaces bilirubin from protein
binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates.
• Injection: [US Boxed Warning]: Midazolam must never be used without individualization of dosage. The initial
IV dose for sedation in adults may be as little as 1 mg, but should not exceed 2.5 mg in a healthy adult.
Lower doses are necessary for older (>60 years of age) or debilitated patients and in patients receiving
concomitant opioids or other CNS depressants. The initial dose and all subsequent doses should always
be titrated slowly; administer over at least 2 minutes and allow an additional 2 or more minutes to fully
evaluate the sedative effect. The use of the 1 mg/mL formulation or dilution of the 1 mg/mL or 5 mg/mL
formulation is recommended to facilitate slower injection. Doses of sedative medications in pediatric
patients must be calculated on a mg/kg basis, and initial doses and all subsequent doses should always
be titrated slowly. The initial pediatric dose of midazolam for sedation/anxiolysis/amnesia is age,
procedure, and route dependent.
• Appropriate use: Do not use in shock, coma, or acute alcohol intoxication with depression of vital signs. Avoid
intra-arterial administration or extravasation of parenteral formulation. Use during upper airway
procedures (ie, endoscopy, dental care) may increase risk of hypoventilation. Prolonged responses have
been noted following extended administration by continuous infusion (possibly due to metabolite
accumulation) or in the presence of drugs which inhibit midazolam metabolism. Oral midazolam is intended
for use in monitored settings only and not for chronic or home use.
• Tolerance: Midazolam is a short half-life benzodiazepine and may be of benefit in patients where a rapidly and
short-acting agent is desired (acute agitation). Duration of action after a single dose is determined by
redistribution rather than metabolism. Tolerance develops to the sedative and anticonvulsant effects. It
does not develop to the anxiolytic effects (Vinkers 2012).
• Withdrawal: Withdrawal symptoms (convulsions, hallucinations, tremor, abdominal and muscle cramps,
vomiting and sweating) may occur following abrupt discontinuation or large decreases in dose. Use caution
when reducing dose or withdrawing therapy; decrease slowly and monitor for withdrawal symptoms.
Parenteral:
Intermittent IV: For procedural sedation/anxiolysis/amnesia the 1 mg/mL concentration is recommended per the
manufacturer. For neonates, use the preservative-free injection; alternatively, if the preservative-free
product is not available, may use the 5 mg/mL injection and dilute to 0.5 mg/mL with SWFI (preservative
free) to decrease the amount of benzyl alcohol delivered to the neonate (since both concentrations of
midazolam injection contain 1% benzyl alcohol)
Continuous IV infusion: Dilute with NS or D5W to a final concentration of 0.5 mg/mL per the manufacturer; in
patients requiring high doses or fluid restriction higher concentrations up to 5 mg/mL (undiluted) may be
necessary (Murray 2014; Phillips 2011). ISMP and Vermont Oxford Network recommend a standard
concentration of 0.5 mg/mL for neonates (ISMP 2011).
Buccal: A buccal formulation is not currently available in the US. Some trials used an injectable solution administered
buccally. International studies used a 10 mg/mL commercially available buccal formulation. Administer to the
buccal mucosa between the gums and the cheek using an oral syringe; gently massage cheek; dose may be
divided to both sides of the mouth.
Intranasal: Administer using a needleless syringe into the nares over 15 to 30 seconds; use the 5 mg/mL injection; 1/2 of
the dose may be administered to each nare; Note:The 5 mg/mL injection has also been administered as a nasal
spray using a graded pump device (Ljungman 2000) or using an atomizer such as the MAD Nasal Drug delivery
device (Holsti 2007; Holsti 2010).
Oral: Administer on empty stomach (feeding is usually contraindicated prior to sedation for procedures).
Parenteral: Avoid extravasation; do not administer intra-arterially
IV (bolus, loading doses, intermittent therapy): Administer by slow IV injection at a concentration of 1 to 5 mg/mL
over at least 2 to 5 minutes. In adults: For induction of anesthesia, may administer IV push over 20 to 30
seconds per the manufacturer. For refractory status epilepticus, the loading dose is recommended to be
infused at a rate of 2 mg/minute (NCS [Brophy 2012]).
Neonates: Rapid administration (<2 minutes) has been reported to cause severe hypotension especially if
administered concurrently with fentanyl. For procedural sedation (eg, intubation) or intermittent
sedation dosing, administration over at least 2 to 5 minutes has been used, monitor for hypotension
(Cloherty 2012). For loading doses, administration over 1 hour have successfully prevented
hypotension in neonates (Anand 1999; Treluyer 2005); manufacturer recommends against loading
doses in neonates and suggests using a faster continuous infusion rate for the first several hours.
Continuous IV infusion: Administer via an infusion pump.

IM: Administer undiluted deep IM into large muscle, generally into anterior-lateral aspect of thigh (vastus
lateralis) in pediatric patients (Lam 2005; Malamed 1989)
Rectal: Clinical trials utilized parenteral midazolam for rectal administration; administer a 1 to 5 mg/mL solution through
a small, lubricated catheter or tube inserted rectally; hold buttocks closed for ~5 minutes after administration
Level of sedation, respiratory rate, heart rate, blood pressure, oxygen saturation (ie, pulse oximetry)
Drug Interactions
AtorvaSTATin: May increase the serum concentration of Midazolam. Risk C: Monitor therapy
Avoid combination
Itraconazole: May increase the serum concentration of Midazolam. Management: Oral midazolam is contraindicated.
Use intravenous midazolam with great caution in patients receiving itraconazole, employing reduced initial doses
whenever possible and monitoring closely for enhanced and prolonged effects. Risk X: Avoid combination
Ketoconazole (Systemic): May increase the serum concentration of Midazolam. Risk X: Avoid combination
Macrolide Antibiotics: May increase the serum concentration of Midazolam. Management: Consider an alternative less
likely to interact. Azithromycin is likely a lower-risk macrolide, and benzodiazepines less dependent on CYP3A
metabolism (e.g., lorazepam, oxazepam) are similarly less likely to interact. Exceptions: Azithromycin (Systemic);
Fidaxomicin; Roxithromycin; Spiramycin.Risk D: Consider therapy modification
concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents
duration of each drug. Risk D: Consider therapy modification
Propofol: Midazolam may increase the serum concentration of Propofol. Propofol may increase the serum concentration
of Midazolam. Risk C: Monitor therapy
Protease Inhibitors: May increase the serum concentration of Midazolam. Management: Oral midazolam
contraindicated with all protease inhibitors. IV midazolam contraindicated with fosamprenavir and nelfinavir;
other protease inhibitors recommend caution, close monitoring, and consideration of lower IV midazolam doses
with concurrent use. Risk X: Avoid combination
Onset of action: IM: Sedation: Children: Within 5 minutes; Adults: ~15 minutes; IV: 3 to 5 minutes; Oral: 10 to 20
minutes; Intranasal: Children: 5.55 ± 2.22 minutes (Lee-Kim 2004); Adults: Within 5 minutes
Peak effect: IM: Children: 15 to 30 minutes; Adults: 30 to 60 minutes; IV: 3 to 5 minutes; Intranasal: Children: 10 minutes
(al-Rakaf 2001)
Dura tion: IM: Up to 6 hours; Mean: 2 hours; Intranasal: Children: 23.1 minutes (Chiaretti 2011); IV: Single dose: <2
hours (dose-dependent) (Fragen 1997)
Absorption: IM: Rapid, complete; Oral, Intranasal: Rapid (Lee-Kim 2004)
Distribution: Widely distributed in body including CSF; Vd:
Preterm infants (n=24; GA: 26 to 34 weeks; PNA: 3 to 11 days): Median: 1.1 L/kg (range: 0.4 to 4.2 L/kg) (de Wildt
2001)
Infants and Children 6 months to 16 years: 1.24 to 2.02 L/kg
Adults: 1 to 3.1 L/kg; increased in females, elderly, and obesity
Protein binding: ~97%, primarily albumin; in patients with cirrhosis, protein binding is reduced with a free fraction of
~5% (Trouvin 1988)
Metabolism: Extensively hepatic CYP3A4; 60% to 70% of biotransformed midazolam is the active metabolite 1-hydroxy-
midazolam (or alpha-hydroxymidazolam)
Bioavailability: Oral: 40% to 50% (Kanto 1985), ~36% (children); IM: >90%; Intranasal: Children: ~60%; Rectal: Children:
~40% to 65% (mean: 52%) (Clausen 1988)
Prolonged in cirrhosis, congestive heart failure, obesity, renal failure, and elderly. Note: In patients with renal
failure, reduced elimination of active hydroxylated metabolites leads to drug accumulation and prolonged
sedation.
Preterm infants (n=24; GA: 26 to 34 weeks; PNA: 3 to 11 days): Median: 6.3 hours (range: 2.6 to 17.7 hours) (de
Wildt 2001)
Neonates: 4 to 12 hours; seriously ill neonates: 6.5 to 12 hours
Children: IV: 2.9 to 4.5 hours; Syrup: 2.2 to 6.8 hours

Adults: 3 hours (range: 1.8 to 6.8 hours)
Time to peak, serum: IM: 0.5 to 1 hour; Oral: 0.17 to 2.65 hours
Excretion: IV: Urine (primarily as metabolites); Oral: Urine (~90% within 24 hours; primarily [60% to 70%] as glucuronide
conjugates of the hydroxylated metabolites; <0.03% as unchanged drug); feces (~2% to 10% over 5 days) (Kanto
1985; Smith 1981)
Clearance:
Preterm infants (n=24; GA: 26 to 34 weeks; PNA: 3 to 11 days): Median: 1.8 mL/minute/kg (range: 0.7 to 6.7
mL/minute/kg) (de Wildt 2001)
Neonates <39 weeks GA: 1.17 mL/minute/kg
Neonates >39 weeks GA: 1.84 mL/minute/kg
Seriously ill neonates: 1.2 to 2 mL/minute/kg
Infants >3 months: 9.1 mL/minute/kg
Children >1 year: 3.2 to 13.3 mL/minute/kg
Healthy adults: 4.2 to 9 mL/minute/kg
Adults with acute renal failure: 1.9 mL/minute/kg
Renal function impairment: Elimination half-life is prolonged and clearance is reduced.
Hepatic function impairment: Cmax and bioavailability were 43% and 100% higher, respectively following oral
administration. Clearance was reduced 50%, half-life increased 2.5-fold, and Vd increased by 20% following IV
administration.
Geriatric: Plasma half-life was ~2-fold higher, mean Vdincreased consistently between 15% to 100%, and mean clearance
decreased ~25%.
Heart failure: Following oral administration (7.5 mg), half-life increased 43%. Two-fold increase in the elimination half-
life, a 25% decrease in the plasma clearance and a 40% increase in Vd following parenteral administration.
Obesity: Mean half-life is prolonged (5.9 hours) and Vdincreased ~50%.
Adverse Reactions
Cardiovascular: Hypotension (children)
Central nervous system: Drowsiness, drug dependence (physical and psychological dependence with prolonged use),
headache, myoclonus (preterm infants), seizure-like activity (children), severe sedation
Gastrointestinal: Hiccups (more common in adults), nausea, vomiting
Local: Injection site reaction (severity less than diazepam), pain at injection site (severity less than diazepam)
Ophthalmic: Nystagmus (children)
Respiratory: Apnea (children), bradypnea, cough, decreased tidal volume
Miscellaneous: Paradoxical reaction (children)
Rare but important or life-threatening: Acidic taste, agitation, amnesia, bigeminy, bradycardia, bronchospasm,
confusion, delirium (emergence), dyspnea, euphoria, hallucination, hyperventilation, laryngospasm, sialorrhea,
skin rash, tachycardia, ventricular premature contractions, wheezing
MILRINONA
Dosing: Neonatal
Hemodynamic support (eg, septic shock, cardiogenic shock, acute decompensated heart failure): Limited data
available: Note: Dosing should be individualized and titrated to effect due to interpatient variability in milrinone
clearance, with or without low cardiac output syndrome or acute kidney injury (Bailey 2004; Garcia Guerra 2013;
Gist 2015; Vogt 2014):
Term neonates: IV: Continuous IV infusion: 0.25 to 0.75 mcg/kg/minute; titrate to effect (Eichenwald 2017).
Loading doses have been reported in the literature. One study used a loading dose of 50 mcg/kg
administered over 15 minutes, followed by a continuous infusion in 10 neonates (median age: 5 days; age
range: 3 to 27 days old) with low cardiac output after cardiac surgery (Chang 1995). Loading doses,
although, have been associated with hypotension and some experts recommend eliminating the loading
dose to reduce the risk of hypotension, especially in patients with renal dysfunction (Eichenwald 2017;
MacDonald 2016).
Low cardiac output syndrome (LCOS) following CHD corrective surgery, prevention: Limited data available: Term
neonates: IV: Loading dose: 25 or 75 mcg/kg administered over 60 minutes followed by a continuous IV infusion
of 0.25 or 0.75 mcg/kg/minute (Hoffman 2003). Dosing based on a double-blind, placebo-controlled trial which
randomized 227 postoperative cardiac surgery patients (age range: 2 days to 6.9 years, median: 3 months) at high
risk for LCOS to low-dose milrinone (loading dose: 25 mcg/kg, continuous infusion: 0.25 mcg/kg/minute), high-
dose milrinone (loading dose: 75 mcg/kg, continuous infusion: 0.75 mcg/kg/minute), or placebo; results showed
patients in the high-dose milrinone group had a 64% relative risk reduction for the development of LCOS
compared to placebo; the low-dose milrinone group had a statistically insignificant trend toward reducing the
development of LCOS (Hoffman 2003).
Persistent pulmonary hypertension of the newborn (PPHN), adjunct treatment for patients with poor nitric oxide
response: Note: Administer in combination with nitric oxide. Limited data available: Preterm and term neonates:
Continuous IV infusion: Initial: 0.3 to 0.5 mcg/kg/minute; titrate as needed; maximum rate: 1 mcg/kg/minute;
dosing based on a total of 27 patients (GA ≥26 weeks) from 2 retrospective reviews and a prospective open-label
study (James 2015; McNamara 2006; McNamara 2013); most patients did not receive a loading dose; the
prospective, open-label study (n=11; GA: ≥34 weeks; weight: ≥1.5 kg) did administer a loading dose of 50 mcg/kg
over 60 minutes (McNamara 2013).
Dosing: Pediatric
Hemodynamic support (eg, acute decompensated heart failure, cardiogenic shock, septic shock): Limited data
available; optimal dosing not established: Note: Dosing should be individualized and titrated to effect due to
interpatient variability in clearance, with or without low cardiac output syndrome or acute kidney injury (Bailey
2004; Garcia Guerra 2013; Gist 2015; Vogt 2014):
Infants, Children, and Adolescents: IV, Intraosseous: Loading dose (optional): 50 mcg/kg administered over 10 to
60 minutes followed by a continuous IV or intraosseous infusion; infusion dose range: 0.25 to 0.75
mcg/kg/minute; titrate dose to effect (PALS [Kleinman 2010]). Due to the risk of hypotension, some centers
do not utilize a loading dose (ACCM [Davis 2017]).
Low cardiac output syndrome (LCOS) following CHD corrective surgery, prevention: Limited data available: Infants and
Children: IV: Loading dose: 25 or 75 mcg/kg administered over 60 minutes followed by a continuous IV infusion of
0.25 or 0.75 mcg/kg/minute (Hoffman 2003). Dosing based on a double-blind, placebo-controlled trial which
randomized 227 postoperative cardiac surgery patients (age range: 2 days to 6.9 years, median: 3 months) at high
risk for LCOS to low-dose milrinone (loading dose: 25 mcg/kg, continuous infusion: 0.25 mcg/kg/minute), high-
dose milrinone (loading dose: 75 mcg/kg, continuous infusion: 0.75 mcg/kg/minute), and placebo; results showed
patients in the high-dose milrinone group had a 64% relative risk reduction for the development of LCOS
compared to placebo; the low-dose milrinone group had a statistically insignificant trend toward reducing the
development of LCOS (Hoffman 2003).
Infants, Children and Adolescents: Specific recommendations for dosing adjustments in pediatric patients are lacking.
Milrinone clearance is significantly reduced and other pharmacokinetic parameters (eg volume of distribution) have
shown a high degree of interpatient variability in pediatric patients with acute kidney injury; doses should be
individualized and titration based upon hemodynamic and clinical response rather than an algorithmic approach based
upon dose adjustment for estimated creatinine clearance (Gist 2015, Vogt 2014).
• Arrhythmias: Ventricular arrhythmias, including nonsustained ventricular tachycardia and supraventricular

arrhythmias, have been reported. Observe closely for arrhythmias in this very high-risk patient population;
sudden cardiac death has been observed. Due to the prolonged half-life as compared to other inotropic
agents, ventricular or atrial arrhythmias may persist even after discontinuation of milrinone especially in
patients with renal dysfunction (Cox 2013; Leier 1998). Ensure that ventricular rate is controlled in atrial
fibrillation/flutter before initiating; may increase ventricular response rate. In heart transplant candidates,
institute appropriate measures to protect patient against risks of sudden cardiac death (Brozena 2004).
• Hypotension: Hypotension may occur. Monitor blood pressure closely. Hypotension may be prolonged
especially in patients with renal dysfunction (Cox 2013; Leier 1998). Vigorous diuresis may contribute to
hypotension; cautious administration of fluids may be required to prevent hypotension. Omitting the bolus
dose may decrease the risk of hypotension (Baruch 2001; Cuffe 2002). If hypotension occurs, consider dose
reduction or temporary discontinuation.
• Cardiovascular disease: Avoid use in patients with severe obstructive aortic or pulmonic valvular disease in lieu
of surgical relief of the obstruction; may aggravate outflow tract obstruction in hypertrophic
cardiomyopathy with outflow tract obstruction.

use and throughout therapy to minimize the risk of arrhythmias.
• Renal impairment: Use with caution in patients with renal impairment; reduction in infusion rate recommended.
Hypotension may be prolonged in patients with renal dysfunction (Cox 2013; Leier 1998).
• Appropriate use: A facility for immediate treatment of potential cardiac events, including life-threatening
ventricular arrhythmias, must be available. Safe and effective use beyond 48 hours (prolonged use) has not
been demonstrated. An increased risk of death and hospitalization has been observed with prolonged use
in NYHA Class III/IV heart failure patients. Sudden cardiac death has been reported with prolonged use.
Continuous electrocardiographic monitoring is recommended.
IV, Intraosseous:
Loading dose: Prepare loading doses using the vial formulation only (not the premixed bag). Dilute in 1/2NS, NS, or
D5W if necessary for small doses or longer infusion times; in adults, diluting to 10 to 20 mL for ease of
administration has been recommended.
Continuous IV infusion: Dilute with 1/2NS, NS, or D5W; usual concentration: ≤200 mcg/mL; 250 mcg/mL in NS has
been used (Barton 1996). Note: Some pediatric centers use a concentration as high as 800 mcg/mL (Murray
2014; Sinclair-Pingel 2006).
IV, Intraosseous:
Loading dose: Administer undiluted or diluted by slow IV push over at least 10 minutes; to minimize hypotension,
slower infusion rates up to 60 minutes may also be used (PALS [Kleinman 2010]) or the loading dose may
be divided into two or more doses and each dose is administered over 10 minutes if blood pressure
remains within an acceptable range (ACCM [Davis 2017]).
Continuous IV or Intraosseous infusion: Administer as a continuous IV infusion with the use of an infusion pump
or syringe pump or an intraosseous infusion until IV access can be obtained in pediatric patients (PALS
[Kleinman 2010]). Avoid extravasation; administration into a large vein may help prevent the possibility of
extravasation; some suggest central-line administration is preferred, especially in neonates; administration
into an umbilical arterial catheter is not recommended (Eichenwald 2017).
Blood pressure, heart rate, ECG; platelet count, electrolytes (especially potassium and magnesium) and fluid status,
renal function; infusion site
If pulmonary artery catheter is in place, monitor cardiac index, stroke volume, systemic vascular resistance, pulmonary
capillary wedge pressure and pulmonary vascular resistance.
Consult individual institutional policies and procedures.
Drug Interactions
NO
Onset of action: IV: 5 to 15 minutes
Distribution: Vd beta:
Infants (after cardiac surgery): 0.9 ± 0.4 L/kg (Ramamoorthy 1998)
Children (after cardiac surgery): 0.7 ± 0.2 L/kg (Ramamoorthy 1998)
Adults:
After cardiac surgery: 0.3 ± 0.1 L/kg (Ramamoorthy 1998)
Heart failure (with single injection): 0.38 L/kg
Heart failure (with infusion): 0.45 L/kg
Protein binding, plasma: ~70%
Metabolism: Hepatic (minor); majority is not metabolized (Rocci 1987)
Infants (after cardiac surgery): 3.15 ± 2 hours (Ramamoorthy 1998)
Children (after cardiac surgery): 1.86 ± 2 hours (Ramamoorthy 1998)
Adults:
Heart failure: 2.3 to 2.4 hours; renal impairment prolongs half-life (Rocci 1987)
Severe heart failure undergoing continuous venovenous hemofiltration (CVVH): 20.1 ± 3.3 hours (Taniguchi
2000)
Excretion: Urine (83% as unchanged drug; 12% as 0-glucuronide metabolite); active tubular secretion is a major
elimination pathway for milrinone (Rocci 1987)
Clearance:
Infants (after cardiac surgery): 3.8 ± 1 mL/kg/minute (Ramamoorthy 1998)
Children (after cardiac surgery): 5.9 ± 2 mL/kg/minute (Ramamoorthy 1998)
Children (with septic shock): 10.6 ± 5.3 mL/kg/minute (Lindsay 1998)
Adults:
After cardiac surgery: 2 ± 0.7 mL/kg/minute (Ramamoorthy 1998)
Heart failure: 2.2 to 2.3 mL/kg/minute
Adverse Reactions
Cardiovascular: Angina pectoris, chest pain, hypotension, supraventricular cardiac arrhythmia, ventricular arrhythmia
(nonsustained ventricular tachycardia, ventricular ectopy, ventricular fibrillation, ventricular tachycardia)
Rare but important or life-threatening: Anaphylaxis, atrial fibrillation, bronchospasm, hepatic insufficiency, hypokalemia,
injection site reaction, myocardial infarction, skin rash, thrombocytopenia, torsades de pointes, tremor
MONTELUKAST
Dosing: Pediatric
Note: Patients with both asthma and allergic rhinitis should take only 1 dose in the evening.
Allergic rhinitis:
Perennial: Oral:
Infants ≥6 months and Children <6 years: 4 mg once daily
Children ≥6 years and Adolescents <15 years: 5 mg once daily
Adolescents ≥15 years: 10 mg once daily
Seasonal: Oral:
Children 2 to 5 years: 4 mg once daily
Children ≥6 years and Adolescents <15 years: 5 mg once daily

Adolescents ≥15 years: 10 mg once daily
Asthma, maintenance therapy: Oral:
12 months to 5 years: 4 mg once daily in the evening
6 to 14 years: 5 mg once daily in the evening
≥15 years: 10 mg once daily in the evening
Asthma, acute exacerbation, adjunct therapy: Limited data available: Children 2 to 5 years: Oral: 4 mg as a single
dose; in a double-blind, placebo-controlled trial of 52 children with acute asthma exacerbation, a single
dose of montelukast (4 mg) with concomitant short-acting beta2-agonist (salbutamol) showed lower
respiratory rate and improved pulmonary indices compared to placebo (Harmanci 2006)
Exercise-induced bronchospasm, prevention: Note:Additional doses should not be administered within 24 hours.
Daily administration to prevent exercise-induced bronchospasm has not been evaluated. Patients receiving
montelukast for another indication should not take an additional dose to prevent exercise-induced
bronchoconstriction. Oral:
Children ≥6 years and Adolescents <15 years: 5 mg at least 2 hours prior to exercise
Adolescents ≥15 years: Tablet: 10 mg at least 2 hours prior to exercise
Urticaria (nonsteroidal antiinflammatory drug-induced): Oral: Adolescents ≥15 years: 10 mg once daily (Pacor
2001)
No adjustment necessary.
Mild to moderate impairment: No dosage adjustment necessary.
Severe impairment: There are no dosage adjustments provided in the manufacturer's labeling; has not been
studied.
Contraindications
Hypersensitivity to montelukast or any component of the formulation
• Eosinophilia and vasculitis: In rare cases, patients may present with systemic eosinophilia, sometimes presenting
with clinical features of vasculitis consistent with eosinophilic granulomatosis with polyangiitis (formerly
known as Churg-Strauss), a condition which is often treated with systemic corticosteroid therapy. Health
care providers should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac
complications, and/or neuropathy presenting in their patients. A causal association between montelukast
and these underlying conditions has not been established.
• Neuropsychiatric events: Postmarketing reports of behavioral changes (eg, abnormal dreams, agitation,
aggression, anxiety, attention deficit, depression, disorientation, hallucinations, hostility, insomnia,
irritability, memory disturbances, restlessness, sleep disturbance, suicide ideation/behavior, and tremor)
have been noted in pediatric, adolescent, and adult patients. In a retrospective analysis performed by
Merck, serious behavior-related events were rare (Philip 2009a); assess patients for behavioral changes.
Patients should be instructed to notify the prescriber if behavioral changes occur.
Disease related concerns:
• Acute asthma/bronchospasm: Not FDA approved for use in the reversal of bronchospasm in acute asthma
attacks, including status asthmaticus. Some studies, however, support its use as adjunctive therapy (Cylly
2003; Ferreira 2001; Harmancik 2006). Appropriate rescue medication should be available. Montelukast
treatment should continue during acute asthma exacerbation.
• Aspirin-sensitive asthmatics: Montelukast will not interrupt bronchoconstrictor response to aspirin or other
NSAIDs. Patients with known aspirin sensitivity should continue to avoid these agents.
• Corticosteroids: When inhaled or systemic corticosteroid reduction is considered in patients initiating or

receiving montelukast, appropriate clinical monitoring and a gradual dose reduction of the steroid are
recommended.
Oral: When treating asthma, administer dose in the evening. Patients with allergic rhinitis may individualize
administration time (morning or evening). Patients with both asthma and allergic rhinitis should take their dose in
the evening. May administer without regard to food or meals.
Granules: May be administered directly into the mouth, dissolved in 5 mL of cold or room temperature baby formula or
breast milk, or mixed with a spoonful of cold or room temperature applesauce, carrots, rice, and ice cream; do
not add to any other liquids or foods; administer within 15 minutes of opening the packet; liquids may be taken
subsequent to administration.
Some products may contain phenylalanine.
Monitor asthma symptoms, FEV1, peak flow and/or other pulmonary function tests, mood or behavior changes,
including suicidal thinking/behavior
Drug Interactions
Gemfibrozil: May increase the serum concentration of Montelukast. Risk C: Monitor therapy
Duration: >24 hours
Absorption: Rapid
Distribution: Vd: 8 to 11 L
Protein binding, plasma: >99%
Metabolism: Extensively hepatic via CYP3A4, 2C8, and 2C9
Bioavailability: Tablet: 10 mg, Mean: 64%; Chewable tablet: 5 mg: 73% (63% when administered with a standard meal)
Half-life elimination: 2.7 to 5.5 hours; Mild-to-moderate hepatic impairment: 7.4 hours
Time to peak: Tablet: 10 mg: 3 to 4 hours (fasting); Chewable tablet: 4 mg (children 2 to 5 years): 2 hours (fasting);
Chewable tablet 5 mg: 2 to 2.5 hours (fasting); Granules: 2.3 ± 1 hours (fasting) and 6.4 ± 2.9 hours (with high-fat
meal)
Excretion: Feces (86%); urine (<0.2%)
Hepatic function impairment: Following a single 10 mg dose, AUC increased 41% and half-life was prolonged to 7.4 hours
in patients with mild-to-moderate hepatic impairment and cirrhosis. Patients with severe hepatic impairment or
hepatitis have not been evaluated.
Pediatric: In children 6 to 23 months of age, the systemic exposure to montelukast is higher than in adults.
Geriatric: Plasma half-life is slightly longer in elderly patients.
Adverse Reactions
Central nervous system: Dizziness (adolescents and adults), fatigue (adolescents and adults), headache (children and
adolescents)
Dermatologic: Atopic dermatitis (children), dermatitis (children), eczema (children), skin infection (children), skin rash,
urticaria (children)
Gastrointestinal: Abdominal pain (children), diarrhea (children and adolescents), dyspepsia, gastroenteritis, nausea
(children and adolescents), toothache (adolescents and adults), tooth infection (children)
Genitourinary: Pyuria (adolescents and adults)

Hepatic: Increased serum alanine aminotransferase (adolescents and adults), increased serum aspartate
aminotransferase (adolescents and adults)
Infection: Influenza (children and adolescents), varicella zoster infection (children), viral infection (children and
adolescents)
Neuromuscular & skeletal: Asthenia (adolescents and adults)
Ophthalmic: Conjunctivitis (children), myopia (children)
Otic: Otalgia (children), otitis (children and adolescents), otitis media (children and adolescents)
Respiratory: Acute bronchitis (children), cough, epistaxis (adolescents and adults), laryngitis (children and adolescents),
nasal congestion (adolescents and adults), pharyngitis (children), pneumonia (children), rhinitis (infective;
children), rhinorrhea (children), sinus headache (adolescents and adults), sinusitis, upper respiratory tract
infection
Miscellaneous: Fever, trauma (adolescents and adults)
Rare but important or life-threatening: Abnormal dreams, aggressive behavior, agitation, anaphylaxis, angioedema,
anxiety, arthralgia, behavioral changes, bleeding tendency disorder, bruise, depression, diarrhea, disorientation,
drowsiness, edema, eosinophilia (systemic), eosinophilic granulomatosis with polyangiitis, eosinophilic
pneumonitis, epistaxis, erythema multiforme, erythema nodosum, hallucination, hepatic eosinophilic infiltration,
hepatitis (mixed pattern, hepatocellular, and cholestatic), hostility, hypersensitivity reaction, hypoesthesia,
insomnia, irritability, lack of concentration, memory impairment, mood changes, muscle cramps, myalgia, nausea,
obsessive compulsive disorder, palpitations, pancreatitis, paresthesia, pruritus, restlessness, seizure,
somnambulism, Stevens-Johnson syndrome, stuttering, suicidal ideation, suicidal tendencies, thrombocytopenia,
tic disorder, toxic epidermal necrolysis, tremor, urinary incontinence, urticaria, vasculitis, vomiting
MORFINA
Dosing: Neonatal
Doses should be titrated to appropriate effect; when changing routes of administration in chronically treated patients,
please note that oral doses are approximately one-half as effective as parenteral dose; Note: Use preservative-free
formulation:
Analgesia: Note: Neonates may be more susceptible to respiratory depression; consider frequent or continuous
electronic monitoring (eg, pulse oximetry) and be in a setting that permits rapid management of respiratory insufficiency
(American Pain Society 2016; Berde 2002).
Oral: 0.08 mg/kg/dose every 4 to 6 hours (APA 2012)
IM, IV (preferred), SubQ: Initial: 0.05 to 0.1 mg/kg/dose; usual frequency every 4 to 6 hours, although some neonates
may require every 8 hour dosing; titrate carefully to effect; maximum dose: 0.1 mg/kg/dose (Anand 2001; Hegenbarth
2008)
Continuous IV infusion: Initial: 0.01 mg/kg/hour (10 mcg/kg/hour); titrate carefully to effect; maximum: 0.03
mg/kg/hour (30 mcg/kg/hour) (Anand 2001); some have suggested a lower usual maximum infusion rate of 0.015 to
0.02 mg/kg/hour (15 to 20 mcg/kg/hour) due to decreased elimination, increased CNS sensitivity, and adverse effects;
Note: Some centers may use slightly higher doses, especially in neonates who develop tolerance.
Endotracheal intubation, nonemergent: IM, IV: 0.05 to 0.1 mg/kg; allow at least 5 minutes for onset of analgesia (Kumar
2010)
Neonatal abstinence syndrome: Limited data available: Note: The lowest concentration of the commercially available
oral solution (2 mg/mL) should be utilized if possible; if doses are too small to accurately measure then a dilution of 0.4
mg/mL may be utilized (see Extemporaneous Preparations for dilution details). Oral: Initial: 0.04 mg/kg/dose every 3 to
4 hours; increase by 0.04 mg/kg/dose if symptoms are not controlled; maximum dose: 0.2 mg/kg/dose (Hudak 2012);
dose and weaning schedule should be individualized based on signs and symptoms of withdrawal and/or withdrawal
scores; once withdrawal symptoms are controlled, maintain dose for 48 to 72 hours; then taper dose usually by 10% to
20% every 2 to 7 days (Burgos 2009; Hudak 2012).
Dosing: Pediatric
Doses should be titrated to appropriate effect; use lower doses in opioid naive patients; when changing routes of
administration in chronically treated patients, please note that oral doses are approximately one-half as effective as
parenteral dose.
Acute pain, moderate to severe: Note: Repeated SubQ administration causes local tissue irritation, pain, and induration.
The use of IM injections is no longer recommended, especially for repeated administration due to painful
administration, variable absorption, and lag time to peak effect; other routes are more reliable and less painful
(American Pain Society 2016).
Infants ≤6 months, nonventilated: Note: Infants <3 months of age are more susceptible to respiratory depression; lower
doses are recommended; consider frequent or continuous electronic monitoring (eg, pulse oximetry) and be in a setting
that permits rapid management of respiratory insufficiency (American Pain Society 2016; Berde 2002).
Oral: Oral solution (2 mg/mL or 4 mg/mL): 0.08 to 0.1 mg/kg/dose every 3 to 4 hours (American Pain Society 2008; Berde
2002).
IV or SubQ: 0.025 to 0.03 mg/kg/dose every 2 to 4 hours (American Pain Society 2008; Berde 2002).
Infants ≤6 months, ventilated: Note: Infants <3 months are more susceptible to respiratory depression. Patients should
have continuous electronic monitoring (eg, pulse oximetry) and be in a setting that permits rapid management of
respiratory insufficiency.
IV; intermittent dosing: Infants ≥3 months: Initial: 0.05 mg/kg/dose every 2 to 4 hours; dosing based on experience in
postoperative cardiothoracic patients (Penk 2018).
Continuous IV infusion: Initial: 0.008 to 0.02 mg/kg/hour (8 to 20 mcg/kg/hour); titrate carefully to effect (Berde 2002;
Lynn 1998); reported dose range following titration: 0.015 to 0.04 mg/kg/hour (15 to 40 mcg/kg/hour); dosing based on
studies in postoperative patients, most commonly following cardiac surgery (Koren 1985; Lynn 1998; Penk 2018;
Valkenburg 2016). Lower initial doses have been reported in infants following cardiac surgery compared to non-cardiac
surgical infants (Lynn 1998); infants with Down Syndrome have been shown to have similar morphine requirements
postoperatively as patients without following cardiac surgery (Goot 2018; Valkenburg 2016).
Infants >6 months, Children, and Adolescents:
Oral: Immediate-release tablets, oral solution (2 mg/mL or 4 mg/mL):
Patient weight <50 kg: 0.2 to 0.5 mg/kg/dose every 3 to 4 hours as needed; some experts have recommended an initial
dose of 0.3 mg/kg for severe pain; usual initial maximum dose: 15 to 20 mg (American Pain Society 2008; APA 2012;
Berde 2002).
Patient weight ≥50 kg: 15 to 20 mg every 3 to 4 hours as needed (American Pain Society 2008; Berde 2002).
IM, IV, or SubQ; intermittent dosing:
Patient weight <50 kg: Opioid naïve: Initial: 0.05 mg/kg/dose; usual maximum initial dose: 1 to 2 mg/dose; higher doses
may be required if pain not adequately controlled or if patient is opioid tolerant; usual range: 0.1 to 0.2 mg/kg/dose
every 2 to 4 hours as needed; use lower doses in opioid naïve patients; usual maximum dose: Infants: 2 mg/dose;
Children 1 to 6 years: 4 mg/dose; Children 7 to 12 years: 8 mg/dose; Adolescents: 10 mg/dose.
Patient weight ≥50 kg: Initial: 2 to 5 mg every 2 to 4 hours as needed; Use lower end of the dosing range in opioid naïve
patients; higher doses have been recommended (5 to 8 mg every 2 to 4 hours as needed) and may be needed in tolerant
patients (Berde 2002; Kliegman 2011).
Continuous IV infusion, SubQ continuous infusion: Note: Patients should have continuous electronic monitoring (eg,
pulse oximetry) and be in a setting that permits rapid management of respiratory insufficiency (American Pain Society
2016; Berde 2002).
Patient weight <50 kg: Initial: 0.01 mg/kg/hour (10 mcg/kg/hour); titrate carefully to effect; dosage range: 0.01 to 0.04
mg/kg/hour (10 to 40 mcg/kg/hour) (APA 2012; Friedrichsdorf 2007; Golianu 2000).
Patient weight ≥50 kg: 1.5 mg/hour (Berde 2002).
Conversion from intermittent IV morphine: Administer the patient's total daily IV morphine dose over 24 hours as a
continuous infusion; titrate dose to appropriate effect.
Epidural: Astramorph/PF, Duramorph: Limited data available: Note: Must use preservative-free formulation:
Intermittent: Infants, Children, and Adolescents: 0.015 to 0.05 mg/kg (15 to 50 mcg/kg) (APA 2012; Henneberg 1993); a
trial evaluating pain relief in pediatric patients after abdominal surgery (n=76; age: Newborn to 13 years; median age: 12
months) administered epidural morphine every 8 hours in combination with bupivacaine during the immediate postop
period; most children achieved good pain relief with this regimen (Henneberg 1993). Maximum dose: 0.1 mg/kg (100
mcg/kg) or 5 mg/24 hours.
Continuous epidural infusion: Infants >6 months, Children, and Adolescents: 0.001 to 0.005 mg/kg/hour (1 to 5
mcg/kg/hour) (Suresh 2012).
Analgesia for minor procedures/sedation: Infants, Children, and Adolescents: IV: 0.05 to 0.1 mg/kg/dose; administer 5
minutes before the procedure; maximum dose: 4 mg; may repeat dose in 5 minutes if necessary (Cramton 2012; Zeltzer
1990).
Chronic pain: Note: Patients taking opioids chronically may become tolerant and require doses higher than the usual
dosage range to maintain the desired effect. Tolerance can be managed by appropriate dose titration. There is no
optimal or maximal dose for morphine in chronic pain. The appropriate dose is one that relieves pain throughout its
dosing interval without causing unmanageable side effects. Consider total daily dose, potency, prior opioid use, degree
of opioid experience and tolerance, conversion from previous opioid (including opioid formulation), patient's general
condition, concurrent medications, and type and severity of pain during prescribing process.
Oral: Extended-/controlled-release preparations: A patient's morphine requirement should be established using

immediate-release formulations. Conversion to long acting products may be considered when chronic, continuous
treatment is required. Higher dosages should be reserved for use only in opioid-tolerant patients.
Capsules, extended release (Avinza): Adolescents ≥18 years: Daily dose administered once daily (for best results,
administer at same time each day).
Opioid-naive: Initial: 30 mg once daily; adjust in increments ≤30 mg daily every 4 days.
Capsules, extended release (Kadian): Adolescents ≥18 years: Note: Not intended for use as an initial opioid in the
management of pain; use immediate release formulations before initiation. Total daily oral morphine dose may be
either administered once daily or in 2 divided doses daily (every 12 hours). The first dose of Kadian may be taken with
the last dose of the immediate release morphine.
Tablets, controlled release (MS Contin): Children and Adolescent able to swallow tablets whole: Usually not used as an
initial opioid in the management of pain; use immediate release formulations to titrate dose. Total daily morphine dose
may be administered in 2 divided doses daily (every 12 hours) or in 3 divided doses daily (every 8 hours).
Weight-directed dosing: 0.3 to 0.6 mg/kg/dose every 12 hours (Berde 1990).
Alternate dosing; fixed dosing (Berde 2002):
Patient weight 20 to <35 kg: 10 to 15 mg every 8 to 12 hours; Note: 10 mg strength not available in US.
Patient weight 35 to <50 kg: 15 to 30 mg every 8 to 12 hours.
Patient weight ≥50 kg: 30 to 45 mg every 8 to 12 hours.
Discontinuation of extended-release formulations: In general, gradually titrate dose downward (eg, every 2 to 4 days).
Do not discontinue abruptly.
Conversion from other oral morphine formulations to extended-release formulations:
Avinza: Adolescents ≥18 years: Total daily morphine dose administered once daily. The first dose of Avinza may be taken
with the last dose of the immediate-release morphine. Maximum daily dose: 1,600 mg/day due to fumaric acid content.
Kadian: Adolescents ≥18 years: Total daily oral morphine dose may be either administered once daily or in 2 divided
doses daily (every 12 hours).
MS Contin: Children and Adolescents: Total daily oral morphine dose may be administered either in 2 divided doses daily
(every 12 hours) or in 3 divided doses (every 8 hours).
Conversion from parenteral morphine or other opioids to controlled/extended release formulations: Substantial
interpatient variability exists in relative potency. Therefore, it is safer to underestimate a patient's daily oral morphine
requirement and provide breakthrough pain relief with immediate-release morphine than to overestimate
requirements. Consider the parenteral to oral morphine ratio or other oral or parenteral opioids to oral morphine
conversions.
Continuous IV infusion, SubQ continuous infusion: Children and Adolescents: 0.01 to 0.04 mg/kg/hour (10 to 40
mcg/kg/hour) (APA 2012; Friedrichsdorf 2007; Golianu 2000); opioid-tolerate patients may require higher doses; in a
small study of terminal pediatric oncology patients (n=8; age range: 3 to 16 years), the median required dose was 0.04 to
0.07 mg/kg/hour (40 to 70 mcg/kg/hour); range: 0.025 to 2.6 mg/kg/hour (Miser 1980); another study evaluating
subcutaneous continuous infusion in children with cancer (n=17; age range: 22 months to 22 years) had similar findings;
median dose: 0.06 mg/kg/hour (60 mcg/kg/hour); range: 0.025 to 1.79 mg/kg/hour (Miser 1983).
Conversion from intermittent IV morphine: Administer the patient's total daily IV morphine dose over 24 hours as a
continuous infusion; titrate dose to appropriate effect.
Sickle cell disease, acute crisis; opioid naïve patients (APS 1999; NHLBI 2014): Note: Individualize dose; titrate to effect;
Infants ≥6 months, Children, and Adolescents:
Patient weight <50 kg: Initial: IV: 0.1 to 0.15 mg/kg every 2 to 4 hours; maximum dose: 7.5 mg/dose.
Patient weight ≥50 kg: Initial: IV: 5 to 10 mg every 2 to 4 hours.
Tetralogy of fallot, hypercyanotic spell (infundibular spasm): Infants and Children: Limited data available: IM, IV, SubQ:
0.1 mg/kg has been used to decrease ventilatory drive and systemic venous return (Hegenbarth 2008).
Palliative care, dyspnea management: Limited data available: Children and Adolescents:
Inhalation (nebulization; preservative-free injection): Dose should be individualized and is dependent upon patient's
previous or current systemic opioid exposure; doses not intended to provide analgesic activity; current systemic
analgesia should be continued: Initial dose: Equivalent to patient's 4-hour systemic morphine requirement (eg, IV or oral
dose); titrate to effect (Golianu 2000); every 4 to 6 hour administration has been suggested (Cohen 2002). In the only
pediatric case report (end-stage CF, age: 10 years, weight: 20 kg), an initial dose of 2.5 mg was used and final dose was
10 mg every 4 to 6 hours (Cohen 2002); from experience in adult patients, an initial dose of 5 mg has been used and
reported range 2.5 to 30 mg administered up to every 4 hours (Ferraresi 2005; Shirk 2006).
Continuous IV or SubQ infusion (when oral ineffective): Initial: 0.005 mg/kg/hour (5 mcg/kg/hour); titrate for comfort
(Garcia-Salido 2015); dosing based on palliative management of terminal infants with spinal muscular atrophy (type 1);
intermittent IV maximum doses of 0.4 mg/kg have been reported to control symptoms of dyspnea and pain (di Pede
2018).
Oral: 0.1 mg/kg/dose every 4 hours as needed (Garcia-Salido 2015); titrate for comfort; dosing based on palliative
management of terminal infants with spinal muscular atrophy (type 1); maximum doses of 0.4 mg/kg have been
reported to control symptoms of dyspnea and pain (di Pede 2018).

Infants, Children and Adolescents: According to the manufacturers' labeling, no specific dosage adjustments are
provided (all formulations). In general, the manufacturers recommend starting cautiously with lower doses; titrating
slowly while carefully monitoring for side effects. However, the choice of an alternate opioid may be prudent in patients
with baseline renal impairment or rapidly changing renal function especially since other analgesics may be safer and
reduced initial morphine dosing may result in suboptimal analgesia. Although clearance of morphine is similar to
patients with normal renal function, morphine glucuronide metabolites (M3G [inactive as an analgesic; may contribute
to CNS stimulation] and M6G [active analgesic]) accumulate in renal impairment resulting in increased sensitivity;
patients may experience severe and prolonged respiratory depression which may even be delayed (Lugo 2002; Niscola
2010).

Infants, Children and Adolescents: There are no dosage adjustments provided in manufacturer's labeling.
Pharmacokinetics are unchanged in mild liver disease; substantial extrahepatic metabolism may occur. In adults with
cirrhosis, increases in half-life and AUC suggest dosage adjustment required.
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned
about performing tasks which require mental alertness (eg, operating machinery or driving). Some dosage forms may be
contraindicated in patients with severe CNS depression.
• Constipation: May cause constipation which may be problematic in patients with unstable angina and patients post-
myocardial infarction. Consider preventive measures (eg, stool softener, increased fiber) to reduce the potential for
constipation.
• Hypotension: May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in
patients with hypovolemia, cardiovascular disease (including acute MI), circulatory shock, or drugs that may exaggerate
hypotensive effects (including phenothiazines or general anesthetics). Monitor for symptoms of hypotension following
initiation or dose titration. Avoid use in patients with circulatory shock. Some dosage forms may be contraindicated in
patients with cardiac arrhythmias or heart failure due to chronic lung disease.
• Phenanthrene hypersensitivity: Use with caution in patients with hypersensitivity reactions to other phenanthrene
derivative opioid agonists (codeine, hydrocodone, hydromorphone, levorphanol, oxycodone, oxymorphone).
• Respiratory depression: [US Boxed Warning]: Serious, life-threatening, or fatal respiratory depression may occur.
Monitor closely for respiratory depression, especially during initiation or dose escalation. Swallow morphine ER
formulations whole (or may sprinkle the contents of the capsule on applesauce and swallow without chewing); crushing,
chewing, or dissolving the ER formulations can cause rapid release and absorption of a potentially fatal dose of
morphine. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of
opioids.
• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.
• Adrenocortical insufficiency: Use with caution in patients with adrenal insufficiency, including Addison disease. Long-
term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction, infertility, mood disorders,
and osteoporosis (Brennan 2013).
• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction or acute pancreatitis; opioids may
cause constriction of sphincter of Oddi.
• CNS depression/coma: Avoid use in patients with impaired consciousness or coma, as these patients are susceptible to
intracranial effects of CO2 retention.
• Delirium tremens: Use with caution in patients with delirium tremens. Some dosage forms may be contraindicated in
patients with delirium tremens.
• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial
pressure (ICP); exaggerated elevation of ICP may occur. Some dosage forms may be contraindicated in patients with
increased intracranial or cerebrospinal pressure, head injuries, or brain tumor.
• Hepatic impairment: Use with caution in patients with severe hepatic impairment.
• Mental health conditions: Use opioids with caution for chronic pain in patients with mental health conditions (eg,
depression, anxiety disorders, post-traumatic stress disorder) due to increased risk for opioid use disorder and overdose;
more frequent monitoring is recommended (Dowell [CDC 2016]).
• Obesity: Use with caution in patients who are morbidly obese.
• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture.
• Psychosis: Use with caution in patients with toxic psychosis.
• Respiratory disease: Use with caution and monitor for respiratory depression in patients with significant chronic
obstructive pulmonary disease or cor pulmonale and patients having a substantially decreased respiratory reserve,
hypoxia, hypercarbia, or preexisting respiratory depression, particularly when initiating therapy and titrating therapy;
critical respiratory depression may occur, even at therapeutic dosages. Consider the use of alternative nonopioid
analgesics in these patients.
• Sleep-disordered breathing: Use opioids with caution for chronic pain and titrate dosage cautiously in patients with
risk factors for sleep-disordered breathing, including HF and obesity. Avoid opioids in patients with moderate to severe
sleep-disordered breathing (Dowell [CDC 2016]).
• Seizure disorders: Use with caution in patients with seizure disorders; may cause or exacerbate preexisting seizures.
Some dosage forms may be contraindicated in patients with seizure disorder.
• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.
• Benzodiazepines or other CNS depressants: [US Boxed Warning]: Concomitant use of opioids with benzodiazepines or
other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death.
Reserve concomitant prescribing of morphine and benzodiazepines or other CNS depressants for use in patients for
whom alternative treatment options are inadequate. Limit dosage and durations to the minimum required and follow
patients for signs and symptoms of respiratory depression and sedation. Some dosage forms may be contraindicated in
patients with acute alcoholism.
• Ethanol use: Extended-release capsules: [US Boxed Warning]: Patients should not consume alcoholic beverages or
medication containing ethanol while taking ER capsules; ethanol may increase morphine plasma levels, resulting in a
potentially fatal overdose.
information.
• Cachectic or debilitated patients: Use with caution in cachectic or debilitated patients; there is a greater potential for
critical respiratory depression, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in
these patients.
• Neonates: Neonatal withdrawal syndrome: [US Boxed Warning]: Prolonged maternal use of opioids during pregnancy
can cause neonatal withdrawal syndrome in the newborn, which may be life-threatening if not recognized and treated
according to protocols developed by neonatology experts. If prolonged opioid therapy is required in a pregnant woman,
ensure treatment is available and warn patient of risk to the neonate. Signs and symptoms include irritability,
hyperactivity, abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Onset,
duration, and severity depend on the drug used, duration of use, maternal dose, and rate of drug elimination by the
newborn.
• Pediatric: Infants <3 months of age, especially if premature, are more susceptible to respiratory depression and/or
apnea; use with caution and generally in reduced doses in this age group (APS 2008).

Prolonged use of any morphine product during pregnancy can result in neonatal opioid withdrawal syndrome, which
may be life-threatening if not recognized and treated, and requires management according to protocols developed by
neonatology experts.
For postoperative tonsillectomy (with/without adenoidectomy) pain management in pediatric patients, morphine has
been shown to have a higher risk of adverse effects compared to other analgesics without additional analgesic benefit;
patient-specific risk factors for these adverse events are not fully defined (Biesiade 2014; Jimenez 2012; Kelly 2015;
Ragjavendran 2010; Sadhasivam 2012). Data is preliminary and large-scale population-based generalizations and
recommendations for practice have not been made. However, racial differences in adverse effects have been observed.
A statistically significant higher incidence of adverse effects (pruritus, emesis) was reported in Latino children and
adolescents following perioperative morphine administration than the comparative non-Latino Caucasian cohort
(Jimenez 2012). In another trial, Caucasian children and adolescents receiving peri/postoperative morphine showed a
higher incidence of postoperative pruritus and emesis than African-American patients (Sadhasivam 2012). The observed
risk for respiratory depression between racial groups has been variable, with some data showing no racial difference in
risk between Latino and non-Latino Caucasians or between Caucasians and African-American patients, while other data
shows a higher risk in African-American pediatric patients compared to Caucasians (Biesiada 2014; Jimenez 2012;
Sadhasivam 2012). Regardless of race, an overall higher and clinically significant incidence of respiratory depression has
been observed in patients with sleep disturbances requiring tonsillectomy procedure (eg, obstructive sleep apnea); a
lower initial dose has been suggested in these patients (Ragjavendran 2010). Current guidelines recommend that
children and adolescents receive intravenous dexamethasone intraoperatively and effective therapy for postoperative
tonsillectomy pain; NSAIDs (except ketorolac) can be used safely (AAO-HNS [Baugh 2011]).

Parenteral:
IV push/intermittent infusion: May dilute to a final concentration of 0.5 to 5 mg/mL
Continuous IV infusion: Dilute in D5W, D10W, or NS to a usual final concentration of 0.1 to 1 mg/mL; more concentrated
solutions may be used in patients requiring fluid restriction or high doses (Murray 2014; Sinclair-Pingel 2006);
concentrations >5 mg/mL are rarely needed (Gahart 2014). ISMP and Vermont Oxford Network recommend a standard
concentration of 0.1 mg/mL for neonates (ISMP 2011).
Epidural and intrathecal: Use only preservative-free injections. Dilution may be required; determined by the individual
patient's dosage requirements and the characteristics of the continuous microinfusion device; filter through ≤5 micron
microfilter before injecting into microinfusion device
Oral: Administer with food
Immediate release: Oral solution: Available in multiple strengths, including a concentrated oral solution (20 mg/mL).
Precautions should be taken to avoid confusion between the different concentrations; prescriptions should have the
concentration specified as well as the dose clearly represented as milligram (mg) of morphine, not volume (mL). The
enclosed calibrated oral syringe should always be used to administer the concentrated oral solution to ensure the dose
is measured and administered accurately. The concentrated oral solution (20 mg/mL) should only be used in opioid-
tolerant patients (adults taking ≥60 mg/day of morphine or equivalent for ≥1 week).
Extended/controlled release products: Do not chew, crush, break, or dissolve extended and controlled release products;
swallow whole. Avinza and Kadian capsules may be opened and contents sprinkled on a small amount of applesauce and
eaten immediately without chewing; rinse mouth with water and swallow to ensure all beads have been ingested; do
not chew, crush, or dissolve beads or pellets from capsule as it can result in a rapid release and absorption of a
potentially fatal dose of morphine. Kadian capsules may be opened and contents sprinkled into ~10 mL of water, then
flushed while swirling through a prewetted 16-French gastrostomy tube fitted with a funnel at the port end; flush with
water to transfer all pellets and flush the tube; do not attempt to administer via NG tube. Do not administer Avinza with
alcohol.
Parenteral: Note: Solutions for injection should be visually inspected for particulate matter and discoloration prior to
administration. Do not use if contains a precipitate or is darker in color than pale yellow or discolored in any other way.
IV push: Administer undiluted or diluted solution over 4 to 5 minutes (Gahart 2014); rapid IV administration may
increase adverse effects
Intermittent IV infusion: Further dilute and administer over 15 to 30 minutes
Continuous IV infusion: Administer as a continuous infusion via an infusion pump.
Epidural and intrathecal: Use only preservative-free injections. In pediatric patients, limited data is available; for adults,
Infumorph was developed for use in continuous microinfusion devices only; it may require dilution before use, as
determined by the individual patient's dosage requirements and the characteristics of the continuous microinfusion
device; not recommended for single dose IV, IM, or SubQ administration; filter through ≤5 micron microfilter before
injecting into microinfusion device. Astramorph/PF may be administered as a continuous infusion via the epidural route
only. Duramorph is not for use in continuous microinfusion devices.
Inhalation: Limited data available; utilize preservative free parenteral morphine and further dilute prior to
administration (Cohen 2002; Ferraresi 2005; Shirk 2006)
Respiratory rate; oxygen saturation; mental status; blood pressure; heart rate; pain relief; signs of misuse, abuse, and
addiction; level of sedation; signs or symptoms of hypogonadism or hypoadrenalism with long term use (Brennan 2013)
Chronic pain (long-term therapy outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or
medication-assisted treatment for opioid use disorder): Evaluate benefits/risks of opioid therapy within 1 to 4 weeks of
treatment initiation and with dose increases. Re-evaluate benefits/risks every 3 months during therapy or more
frequently in patients at increased risk of overdose or opioid use disorder. Urine drug testing is recommended prior to
initiation and with consideration for re-checking at least yearly (includes controlled prescription medications and illicit
drugs of abuse). State prescription drug monitoring program (PDMP) data should be reviewed by clinicians prior to
initiation and periodically during therapy (frequency ranging from every prescription to every 3 months) (Dowell [CDC
2016]).
Astramorph/PF, Duramorph, Infumorph: Patients should be observed in a fully equipped and staffed environment for at
least 24 hours following initiation, and as appropriate for the first several days after catheter implantation. Naloxone
injection should be immediately available. Patient should remain in this environment for at least 24 hours following the
initial dose. For patients receiving Infumorph via microinfusion device, patient may be observed, as appropriate, for the
first several days after catheter implantation.
Alternative monitoring recommendations (Bujedo 2012): Epidural: Note: All patients receiving neuraxial opioids should
be monitored for adequate ventilation (eg, respiratory rate, depth of respiration [without disturbing patient]),
oxygenation (eg, pulse oximetry when appropriate), and level of consciousness.
Single dose: Monitor patient for a minimum of 24 hours after administration with a frequency of at least once per hour
for the first 12 hours after administration, followed by at least once every 2 hours for the next 12 hours (ie, from 12 to
24 hours after administration). After 24 hours, frequency dictated by overall clinical condition and concurrent
medications.
Continuous infusion or patient controlled epidural analgesia (PCEA): Monitor patient during the entire duration of the
infusion with a frequency of at least once per hour for the first 12 hours, followed by at least once every 2 hours for the
next 12 hours (ie, from 12 to 24 hours after administration). After 24 hours, monitor at least once every 4 hours. After
discontinuation of infusion or PCEA, frequency dictated by overall clinical condition and concurrent medications.
Note: Also refer to institution specific protocols as appropriate
Drug Interactions
Amphetamines: May enhance the analgesic effect of Opioid Agonists. Risk C: Monitor therapy
Anticholinergic Agents: May enhance the adverse/toxic effect of Opioid Agonists. Specifically, the risk for constipation
and urinary retention may be increased with this combination. Risk C: Monitor therapy
Antiplatelet Agents (P2Y12 Inhibitors): Morphine (Systemic) may diminish the antiplatelet effect of Antiplatelet Agents
(P2Y12 Inhibitors). Morphine (Systemic) may decrease the serum concentration of Antiplatelet Agents (P2Y12
Inhibitors). Management: Consider alternative anti-ischemic/analgesic therapies (eg, beta-blockers, nitroglycerin) in
patients with acute coronary syndromes treated with a P2Y12 inhibitor when possible. The risks associated with other
opioids are unknown. Exceptions: Cangrelor. Risk D: Consider therapy modification
Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Risk C:
Monitor therapy
CNS Depressants: May enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of
opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if
alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider
Desmopressin: Opioid Agonists may enhance the adverse/toxic effect of Desmopressin. Risk C: Monitor therapy
Diuretics: Opioid Agonists may enhance the adverse/toxic effect of Diuretics. Opioid Agonists may diminish the
therapeutic effect of Diuretics. Risk C: Monitor therapy
Gabapentin: May enhance the CNS depressant effect of Morphine (Systemic). Morphine (Systemic) may increase the
serum concentration of Gabapentin. Risk C: Monitor therapy
Gastrointestinal Agents (Prokinetic): Opioid Agonists may diminish the therapeutic effect of Gastrointestinal Agents
(Prokinetic). Risk C: Monitor therapy
therapy
concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only
be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug.
Risk D: Consider therapy modification
Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor
therapy
RifAMPin: May decrease the serum concentration of Morphine (Systemic). Risk C: Monitor therapy
Serotonin Modulators: Opioid Agonists may enhance the serotonergic effect of Serotonin Modulators. This could result
in serotonin syndrome. Exceptions: Nicergoline. Risk C: Monitor therapy
Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to
combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate
with alcohol or sedative hypnotics is contraindicated. Risk D: Consider therapy modification
Succinylcholine: May enhance the bradycardic effect of Opioid Agonists. Risk C: Monitor therapy
Test Interactions
Some quinolones may produce a false-positive urine screening result for opioids using commercially-available
immunoassay kits. This has been demonstrated most consistently for levofloxacin and ofloxacin, but other quinolones
have shown cross-reactivity in certain assay kits. Confirmation of positive opioid screens by more specific methods
should be considered.

Onset of action (patient dependent; dosing must be individualized): Oral (immediate release): ~30 minutes; IV: 5 to 10
minutes
Duration (patient dependent; dosing must be individualized): Pain relief:
Immediate-release formulations (tablet, oral solution, injection): 3 to 5 hours
Extended-release capsule and tablet: 8 to 24 hours (formulation dependent)
Epidural or intrathecal: Single dose: Up to 24 hours (Bujedo 2012)
Suppository: 3 to 7 hours
Absorption: Variable
Distribution: Distributes to skeletal muscle, liver, kidneys, lungs, intestinal tract, spleen and brain; Vd:
Cancer patients (children age: 1.7 to 18.7 years): Median: 5.2 L/kg; a significantly higher Vd was observed in children <11
years (median: 7.1 L/kg) versus >11 years (median: 4.7 L/kg) (Hunt 1999)
Adults: 1 to 6 L/kg; binds to opioid receptors in the CNS and periphery (eg, GI tract)
Protein binding: Premature Infants: <20%; Adults: 20% to 35%
Metabolism: Hepatic via conjugation with glucuronic acid primarily to morphine-6-glucuronide (M6G) (active analgesic)
morphine-3-glucuronide (M3G) (inactive as analgesic; may contribute to CNS stimulation [Lugo 2002]); minor
metabolites include morphine-3-6-diglucuronide; other minor metabolites include normorphine (active) and morphine
3-ethereal sulfate
Bioavailability: Oral: 17% to 33% (first-pass effect limits oral bioavailability); Nebulization: 5.5 ± 3.2% (Masood 1996)
Preterm: 10 to 20 hours
Neonates: 7.6 hours (range: 4.5 to 13.3 hours)
Infants 1 to 3 months: Median: 6.2 hours (range: 5 to 10 hours) (McRorie 1992)
Infants 3 to 6 months: Median: 4.5 hours (range: 3.8 to 7.3 hours) (McRorie 1992)
Infants 6 months to Children 2.5 years: Median: 2.9 hours (range: 1.4 to 7.8 hours) (McRorie 1992)
Preschool Children: 1 to 2 hours
Children with sickle cell disease (age: 6 to 19 years): ~1.3 hours (Dampier 1995)
Adults: Immediate-release forms: 2 to 4 hours; Avinza: ~24 hours; Kadian: 11 to 13 hours
Time to peak:
Plasma:
Tablets, oral solution, epidural: 1 hour
Extended release tablets: 3 to 4 hours; Avinza: 30 minutes (maintained for 24 hours); Kadian: ~10 hours
Suppository: 20 to 60 minutes
SubQ: 50 to 90 minutes
IM: 30 to 60 minutes
IV: 20 minutes
Cerebrospinal fluid: After an oral dose of controlled release morphine concentrations peak at 8 hours for both normal
and reduced renal function; morphine-6-glucuronide (active analgesic) and morphine-3-glucuronide distribution into the
CNS may be delayed peaking at 12 hours in patients with normal renal function or up to 24 hours in patients with ESRD
(peak level of morphine-6-glucuronide is ~15 times higher than patients with normal renal function) (D'Honneur 1994).
Excretion: Urine (primarily as morphine-3-glucuronide, neonates: 3% to 15%; adults: ~2% to 12% excreted unchanged);
feces (~7% to 10%). It has been suggested that accumulation of morphine-6-glucuronide might cause toxicity with renal
insufficiency. All of the metabolites (ie, morphine-3-glucuronide, morphine-6-glucuronide, and normorphine) have been
suggested as possible causes of neurotoxicity (eg, myoclonus).
Clearance: Note: In pediatric patients, adult values are reached by 6 months to 2.5 years of age (McRorie 1992)
Preterm: 0.5 to 3 mL/minute/kg
Neonates 1 to 7 days: Median: 5.5 mL/minute/kg (range: 3.2 to 8.4 mL/minute/kg) (McRorie 1992)
Neonates 8 to 30 days: Median: 7.4 mL/minute/kg (range: 3.4 to 13.8 mL/minute/kg) (McRorie 1992)
Infants 1 to 3 months: Median: 10.5 mL/minute/kg (range: 9.8 to 20.1 mL/minute/kg) (McRorie 1992)
Infants 3 to 6 months: Median: 13.9 mL/minute/kg (range: 8.3 to 24.1 mL/minute/kg) (McRorie 1992)
Infants 6 months to Children 2.5 years: Median: 21.7 mL/minute/kg (range: 5.8 to 28.6 mL/minute/kg) (McRorie 1992)
Preschool Children: 20 to 40 mL/minute/kg
Cancer patients (Children age 1.7 to 18.7 years): Median: 23.1 mL/minute/kg; a significantly higher clearance was
observed in children <11 years (median: 37.4 mL/minute/kg) versus >11 years (median: 21.9 mL/minute/kg) (Hunt 1999)
Children with sickle cell disease (age: 6 to 19 years): ~36 mL/minute/kg (range: 6 to 59 mL/minute/kg) (Dampier 1995)
Adults: 20 to 30 mL/minute/kg
Adverse Reactions
Cardiovascular: Atrial fibrillation (oral), bradycardia (oral, rectal), chest pain (oral), circulatory depression (oral, IV),
edema (oral, rectal), facial flushing (oral, rectal), flushing (oral), hypertension (oral), hypotension (oral), orthostatic
hypotension (IM, IV), palpitations (oral, rectal), peripheral edema, peripheral vascular insufficiency (IV), phlebitis (IV),
presyncope (oral, rectal), shock, syncope (oral, rectal), tachycardia (oral), vasodilatation (oral)
Central nervous system: Abnormal dreams (oral), abnormal gait (oral), abnormality in thinking (oral), agitation (oral,
rectal), altered mental status (IV), amnesia (oral), anxiety, apathy (oral), ataxia (oral), chills (oral), coma (oral), confusion,
decreased cough reflex, delirium (oral), depression (oral), disorientation (oral, rectal), disruption of body temperature
regulation (IV, epidural, intrathecal), dizziness, drowsiness (oral), dysphoria, dyssynergia (oral), euphoria, fear (IV),
feeling abnormal (oral), hallucination (oral), headache, hypoesthesia (oral), increased catecholamines (IV, epidural,
intrathecal), increased intracranial pressure (oral), insomnia (oral, rectal), lack of concentration (oral), lethargy (oral),
malaise (oral), mood changes (oral), myoclonus, nervousness (oral), pain (oral), paradoxical central nervous system
stimulation (IV, epidural, intrathecal), paresthesia (oral), sedation (oral, rectal), seizure, slurred speech (oral), toxic
psychosis (IM, IV, epidural, intrathecal), vertigo (oral), voice disorder (oral), withdrawal syndrome (oral)
Dermatologic: Decubitus ulcer (oral), diaphoresis (oral, rectal), hemorrhagic urticaria (IV, rectal), pallor (oral), pruritus,
skin rash (oral, rectal), urticaria, xeroderma (oral)
Endocrine & metabolic: Amenorrhea (oral), antidiuretic effect (oral, rectal), decreased libido (oral, rectal), gynecomastia
(oral), hyponatremia (oral), increased thirst (oral), SIADH (oral), weight loss (oral)
Gastrointestinal: Abdominal pain (oral), anorexia (oral, rectal), biliary colic (oral), biliary tract spasm (rectal),
constipation, decreased appetite (IV), delayed gastric emptying (oral), diarrhea, dysgeusia (oral), dyspepsia (oral),
dysphagia (oral), gastric atony (oral), gastroenteritis (oral), gastroesophageal reflux disease (oral), gastrointestinal
hypermotility (IV; in patients with chronic ulcerative colitis), hiccups (oral), nausea, rectal disease (oral), toxic megacolon
(IV; patients with chronic ulcerative colitis), vomiting, xerostomia (oral, rectal)
Genitourinary: Dysuria (oral), ejaculatory disorder (oral), erectile dysfunction (IV), hypogonadism (oral), impotence
(oral), oliguria, ureteral spasm (IV), urinary hesitancy (oral, rectal), urinary retention, urine abnormality (oral)
Hematologic & oncologic: Anemia (oral), granuloma (IV, epidural, intrathecal), leukopenia (oral), thrombocytopenia
(oral)
Hepatic: Increased liver enzymes (oral)
Hypersensitivity: Anaphylactoid reaction (IM)
Local: Erythema at injection site (IV), induration at injection site (SC), local irritation (IV, epidural, intrathecal), local
swelling (IV, intrathecal, epidural; genital swelling in males following infusion device implant surgery), pain at injection
site (SC), residual mass at injection site (inflammatory; IV, epidural, intrathecal)
Neuromuscular & skeletal: Arthralgia (oral), back pain (oral), bone pain (oral), decreased bone mineral density (oral),
foot-drop (oral), laryngospasm (oral), muscle rigidity (oral), muscle spasm (IV, epidural, intrathecal; myoclonic spasm of
lower extremities), muscle twitching (oral), tremor (oral), vesicle sphincter spasm (IV), weakness (oral, rectal)
Ophthalmic: Amblyopia (oral), blurred vision (oral), conjunctivitis (oral), diplopia (oral), eye pain (oral), miosis (oral, IV),
nystagmus (oral), visual disturbance (oral, rectal)
Respiratory: Apnea (oral, IV), asthma (oral), atelectasis (oral), dyspnea, flu-like symptoms (oral), hypoventilation, hypoxia
(oral), pulmonary edema (oral; includes noncardiogenic), respiratory depression (IV, epidural, intrathecal), respiratory
insufficiency (oral), rhinitis (oral)
NITROGLICERINA
Dosing: Neonatal
Vasodilation; perioperative, congenital heart defect repair: Limited data available: Continuous IV infusion: Initial: 0.25 to
0.5 mcg/kg/minute; titrate by 0.5 to 1 mcg/kg/minute every 3 to 5 minutes as needed; usual dose: 1 to 3
mcg/kg/minute; usual maximum dose: 5 mcg/kg/minute. In one clinical study of 16 pediatric patients <24 months of age
(median: 4.4 months, range: 3 days to 23.7 months), a median dose of 1.8 mcg/kg/minute (range: 0.5 to 4
mcg/kg/minute) was reported following cardiac surgery with bypass (Williams 1994); another trial describes a fixed dose
of 1 mcg/kg/minute administered to 15 neonates (mean: 8 days of age) after cardiac surgery in conjunction with
dopamine (Laitinen 1999)
Extravasation (sympathomimetic vasopressors), treatment (alternative to phentolamine): Very limited data available;
dosing regimens highly variable: Topical: 2% ointment: 4 mm/kg applied as a thin ribbon to the affected areas; after 8
hours if no improvement, the dose may be repeated at the site; dosing based on a case series in four premature
neonates (GA: 24 to 31 weeks; at time of treatment: weight: 670 to 1,565 g; PNA: 4 to 40 days) (Wong 1992). A case
report in a premature neonate (GA: 34 weeks; weight: 1,800 g) describes a higher dose of a 1-inch strip (total dose)
applied to the affected sites (ankle and wrist) (Denkler 1989); however, this is greater than the usual initial adult dose
(1/2 inch) for angina; hypotension may occur; carefully monitor blood pressure (Reynolds 2014). Note: Minimal data
available from clinical trials/case reports; however, use is described in neonatal extravasation treatment protocols
(Restieaux 2013; Sawatzky-Dickson 2006; Thigpen 2007).
Dosing: Pediatric
Note: Continuous IV infusion dosing units vary by age (mcg/kg/minute or mcg/minute); extra precautions should be
taken. Tolerance to the hemodynamic and antianginal effects can develop within 24 to 48 hours of continuous use.
Nitrate-free interval (10 to 12 hours/day) is recommended to avoid tolerance development; gradually decrease dose in
patients receiving nitroglycerin for prolonged periods to avoid withdrawal reaction.
Heart failure; cardiogenic shock: Limited data available:
Infants and Children: Continuous IV infusion: Initial: 0.25 to 0.5 mcg/kg/minute; titrate by 1 mcg/kg/minute every 15 to
20 minutes as needed; faster titration may be necessary in some patients; in adolescents, titration every 3 to 5 minutes
has been suggested; usual dose range: 1 to 5 mcg/kg/minute; usual maximum dose: 10 mcg/kg/minute (AHA
[Chameides 2011]; Artman 1987; Ilbawi 1985; Park 2014); doses up to 20 mcg/kg/minute may be used (Friedman 1985)
Adolescents: Continuous IV infusion: Initial: 5 to 10 mcg/minute; titrate every 3 to 5 minutes as needed to maximum
rate of 200 mcg/minute (AHA [Chameides 2011]; Park 2014)
Extravasation (sympathomimetic vasopressors), treatment (alternative to phentolamine): Very limited data available;
dosing based on experience in neonatal patients; optimal dosing has not been established: Infants, Children, and
Adolescents: Topical: 2% ointment: 4 mm/kg applied as a thin ribbon to the affected areas; after 8 hours if no
improvement, the dose may be repeated at the affected site (Wong 1992). The maximum reported dose is application of
a 1-inch strip to the affected site in a neonate (Denkler 1989); however, this is greater than the usual initial adult dose
(1/2 inch) for angina; hypotension may occur; carefully monitor blood pressure (Reynolds 2014). Note: Minimal data
available from clinical trials/case reports; however, use has been described in reviews of extravasation treatment
(Reynolds 2014; Treadwell 2012).


Contraindications
Hypersensitivity to nitroglycerin, other nitrates or nitrites, or any component of the formulation (includes adhesives for
transdermal product); concurrent use with phosphodiesterase-5 (PDE-5) inhibitors (avanafil, sildenafil, tadalafil, or
vardenafil); concurrent use with soluble guanylate cyclase (sGC) stimulators (eg, riociguat).
Additional contraindications for IV product: Hypersensitivity to corn or corn products (solutions containing dextrose);
constrictive pericarditis; increased intracranial pressure; pericardial tamponade; restrictive cardiomyopathy;
uncorrected hypovolemia
• Headache: Dose-related headaches may occur, especially during initial dosing.
• Hypotension/bradycardia: Severe hypotension and shock may occur (even with small doses); paradoxical bradycardia
and increased angina pectoris may accompany hypotension. Orthostatic hypotension may also occur; ethanol may
accentuate this. Use with caution in volume depletion, preexisting hypotension, constrictive pericarditis, aortic or mitral
stenosis, and extreme caution with inferior wall MI and suspected right ventricular involvement. According to the
ACCF/AHA, avoid use in patients with severe hypotension (SBP <90 mm Hg or ≥30 mm Hg below baseline), marked
bradycardia or tachycardia, and right ventricular MI (ACCF/AHA [O'Gara 2013]).
• Increased intracranial pressure: Nitroglycerin may precipitate or aggravate increased intracranial pressure and
subsequently may worsen clinical outcomes in patients with neurologic injury (eg, intracranial hemorrhage, traumatic
brain injury) (Rangel-Castilla 2008). Some products are contraindicated in patients with increased intracranial pressure.
• Hypertrophic cardiomyopathy (HCM): Avoid use in patients with HCM with outflow tract obstruction; nitrates may
reduce preload, exacerbating obstruction and cause hypotension or syncope and/or worsening of heart failure
(ACCF/AHA [Gersh, 2011]).
information.
• Tolerance: May occur; cross tolerance to other nitro compounds have been reported. Appropriate dosing is needed to
minimize tolerance development.

Parenteral: Continuous IV infusion: Dilute in D5W or NS to 50 to 100 mcg/mL; maximum concentration not to exceed
400 mcg/mL; prepare in glass bottles, EXCEL or PAB containers (adsorption occurs to soft plastic [eg, PVC]).
Parenteral: Continuous IV infusion: Administer via infusion pump. Adsorption occurs to soft plastic (eg, PVC); special
administration sets intended for nitroglycerin (nonpolyvinyl chloride) must be used
Blood pressure, heart rate (continuously with IV use)
Drug Interactions
Anticholinergic Agents: May decrease the absorption of Nitroglycerin. Specifically, anticholinergic agents may decrease
the dissolution of sublingual nitroglycerin tablets, possibly impairing or slowing nitroglycerin absorption. Risk C: Monitor
therapy
Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive
effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapy
Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Risk C:
Monitor therapy
Dapsone (Topical): May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Risk C: Monitor
therapy
Heparin: Nitroglycerin may diminish the anticoagulant effect of Heparin. Nitroglycerin may decrease the serum
concentration of Heparin. Risk C: Monitor therapy
Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-
Containing Products. Risk C: Monitor therapy
Local Anesthetics: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Local Anesthetics.
Specifically, the risk for methemoglobinemia may be increased. Risk C: Monitor therapy
therapy
Phosphodiesterase 5 Inhibitors: May enhance the vasodilatory effect of Vasodilators (Organic Nitrates). Risk X: Avoid
combination
Test Interactions
IV formulation: Due to propylene glycol content, triglyceride assays dependent on glycerol oxidase may be falsely
elevated.
Storage and Stability

Extended-release capsules: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from
moisture.
IV solution: Store nitroglycerin premixed with dextrose at 25°C (77°F); brief exposure up to 40°C (104°F) does not
adversely affect the product. Protect from light until time of use. Avoid excessive heat; protect from freezing.
Nitroglycerin diluted in D5W or NS in glass containers is physically and chemically stable for 48 hours at room
temperature and 7 days under refrigeration. In D5W or NS in EXCEL/PAB containers it is physically and chemically stable
for 24 hours at room temperature.

Onset of action: IV: Immediate
Peak effect: IV: Immediate
Duration: IV: 3 to 5 minutes
Distribution: Vd: ~3 L/kg
Protein binding: 60%
Metabolism: Extensive first-pass effect; metabolized hepatically to glycerol di- and mononitrate metabolites via liver
reductase enzyme; subsequent metabolism to glycerol and organic nitrate; nonhepatic metabolism via red blood cells
and vascular walls also occurs
Half-life elimination: ~1 to 4 minutes
Excretion: Urine (as inactive metabolites)
Adverse Reactions
Cardiovascular: Bradycardia, exacerbation of angina pectoris, flushing, hypotension, orthostatic hypotension, peripheral
edema (lingual spray), syncope
Central nervous system: Dizziness, headache (more common with patch, ointment), paresthesia
Dermatologic: Diaphoresis
Gastrointestinal: Abdominal pain (lingual spray), vomiting
Neuromuscular & skeletal: Weakness (all sublingual forms)
Respiratory: Dyspnea, pharyngitis (lingual spray), rhinitis (lingual spray)
Miscellaneous: Drug tolerance
NORADRENALINA
Dosing: Neonatal
Septic shock, refractory: Limited data available: Continuous IV infusion: Usual initial dose: 0.05 to 0.1 mcg/kg/minute,
titrate to desired effect; usual range: 0.1 to 2 mcg/kg/minute; based on experience in pediatric patients during
cardiopulmonary arrest (Fuhrman 2011; PALS [Kleinman 2010]); in a prospective observational study of 22 term
neonates (GA: 39.1 ± 1.7 weeks; birth weight: 3.11 ± 0.78 kg), norepinephrine was initiated at 0.2 to 0.5
mcg/kg/minute and titrated every 30 minutes until desired effect (target normalized blood pressure); the majority
of subjects (n=15) responded to a mean dose of 0.5 ± 0.4 mcg/kg/minute; reported range: 0.2 to 7.1
mcg/kg/minute; the study also suggests that norepinephrine may improve organ perfusion and function as
indicated by increased urine output and decrease in serum lactate concentrations (Tourneux 2008a).
Circulatory failure (pulmonary hypertension, persistent [PPHN] induced); refractory: Very limited data available: GA
>35 weeks: Continuous IV infusion: Initial: 0.5 mcg/kg/minute, titrate every 30 minutes until desired effect (target
mean systemic arterial pressure); in reported experience, most neonates required doses ≤1 mcg/kg/minute.
Dosing based on a prospective observational study of 18 neonates with PPHN induced circulatory failure despite
adequate hydration (GA: 37 ± 3 weeks; birth weight: 2.8 ± 0.7 kg) also receiving nitric oxide; results showed
normalization of systemic arterial pressure with no changes in ventilator rate or pressures, postductal oxygen
saturations improved from 89% ± 2% to 95% ± 4% (p < 0.05) with a decreased oxygen requirement from 51% ±
20% to 41% ± 20% (p < 0.01); reported maximum infusion rate: 3.3 mcg/kg/minute in three subjects (Tourneux
2008b); based on experience in pediatric patients during cardiopulmonary arrest the usual initial dose is 0.05 to
0.1 mcg/kg/minute; usual range: 0.1 to 2 mcg/k/minute (Fuhrman 2011; PALS [Kleinman 2010])
Dosing: Pediatric
Hypotension/shock: Infants, Children, and Adolescents: Continuous IV infusion: Initial: 0.05 to 0.1 mcg/kg/minute,
titrate to desired effect; usual maximum dose: 2 mcg/kg/minute (Fuhrman 2011; PALS [Kleinman 2010]; Park
2014). A retrospective, descriptive study in pediatric patients (n=144; median age: 25 months; IQR: 9 to 83
months) receiving norepinephrine for septic shock reported the mean initial dose as 0.5 ± 0.4 mcg/kg/minute up
to a maximum mean dose of 2.5 ± 2.2 mcg/kg/minute; the maximum individual reported rate: 10.5
mcg/kg/minute (Lampin 2012).
Contraindications
Hypotension from hypovolemia except as an emergency measure to maintain coronary and cerebral perfusion until
volume could be replaced; mesenteric or peripheral vascular thrombosis unless it is a lifesaving procedure; during
anesthesia with cyclopropane (not available in US) or halothane (not available in US) anesthesia
Documentation of allergenic cross-reactivity for vasopressors is limited. However, because of similarities in chemical
structure and/or pharmacologic actions, the possibility of cross-sensitivity can not be ruled out with certainty
• Extravasation: Vesicant; ensure proper needle or catheter placement prior to and during infusion. Avoid
extravasation; infuse into a large vein if possible. Avoid infusion into leg veins. Monitor IV site closely. [US
Boxed Warning]: If extravasation occurs, infiltrate the area with diluted phentolamine (5 to 10 mg in
saline) with a fine hypodermic needle. Phentolamine should be administered as soon as possible after
extravasation is noted to prevent sloughing /necrosis.
• Hypoxia/hypercarbia: Use in patients with profound hypoxia or hypercarbia may produce ventricular
tachycardia or fibrillation; use with extreme caution.
• Sodium metabisulfite: Product may contain sodium metabisulfite; use caution in patients with asthma or a
sulfite allergy.
• Administration: Administer infusions into a large vein, particularly an antecubital vein; some clinicians have
indicated that the femoral vein is also an acceptable route. Avoid catheter tie-in technique, if possible.
Avoid leg veins in elderly patients or in those suffering from occlusive disorders (eg, atherosclerosis,
arteriosclerosis, diabetic endarteritis, Buerger disease). Gangrene has been reported in a lower extremity
when infusions were given in an ankle vein.
• Appropriate use: Assure adequate circulatory volume to minimize need for vasoconstrictors. Avoid
hypertension; monitor blood pressure closely and adjust infusion rate.
Continuous IV infusion: Dilute with D5W, D5NS, or NS; dilution in NS is not recommended by the manufacturer;
however, stability in NS has been demonstrated (Tremblay 2008). Concentrations ranging from 4 to 16 mcg/mL are
typically used in clinical practice (Phillips 2011). ISMP and Vermont Oxford Network recommend a standard
concentration of 16 mcg/mL for neonates (ISMP 2011).
Continuous IV infusion: Administer as a continuous infusion via an infusion pump. Central line administration is
preferred; extravasation may cause severe ischemic necrosis. Do not administer sodium bicarbonate (or any alkaline
solution) through an IV line containing norepinephrine; inactivation of norepinephrine may occur.
(do NOT flush the line); remove needle/cannula; elevate extremity. Initiate phentolamine (or alternative) antidote (see
Management of Drug Extravasations for more details). Apply dry warm compresses (Hurst 2004).
Drug Interactions
Alpha1-Blockers: May diminish the vasoconstricting effect of Alpha-/Beta-Agonists. Similarly, Alpha-/Beta-Agonists may
antagonize Alpha1-Blocker vasodilation. Risk C: Monitor therapy

Serotonin/Norepinephrine Reuptake Inhibitors may enhance the vasopressor effect of Alpha-/Beta-Agonists. Risk
Tricyclic Antidepressants: May enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Management:
Avoid, if possible, the use of direct-acting alpha-/beta-agonists in patients receiving tricyclic antidepressants. If
combined, monitor for evidence of increased pressor effects and consider reductions in initial dosages of the
alpha-/beta-agonist. Risk D: Consider therapy modification

Onset of action: Very rapid acting
Duration: Vasopressor: 1 to 2 minutes
Metabolism: Via catechol-o-methyltransferase (COMT) and monoamine oxidase (MAO)
Excretion: Urine (as inactive metabolites)
Adverse Reactions
Cardiovascular: Bradycardia, cardiac arrhythmia, cardiomyopathy (stress), peripheral vascular insufficiency
Central nervous system: Anxiety, transient headache
Rare but important or life-threatening: Peripheral gangrene, peripheral ischemia (digital [Daroca-Pérez 2017])
OCTREOTIDE
Dosing: Neonatal
Note: All neonatal dosing based on use of the immediate-release injection solution. Dosing is presented in multiple
formats (eg, mcg/kg/hour, mcg/kg/day, mcg/kg/dose); use extra precaution.
Chylothorax, acquired (eg, postoperative): Limited data available: Dosing based on several case series/reports;
randomized, controlled trials are lacking; efficacy results variable; optimal dose not established (Church 2017):
GA ≥35 weeks: Continuous IV infusion: Usual initial dose: 1 to 2 mcg/kg/hour, titrate to clinical response; reported
median maximum dose: 4 mcg/kg/hour; reported range 0.5 to 15 mcg/kg/hour (Bellini 2018; Landis 2013;
Moreira-Pinto 2011). Other protocols have initiated and maintained the infusion at fixed rate of 3
mcg/kg/hour (Yeh 2013). In trials, the reported median range duration of therapy was 7 to 9.5 days (range:
4 to 41 days) (Bellini 2018; Mery 2014; Yeh 2013)
Chylothorax, congenital: Limited data available; efficacy results variable; optimal dose not established: Note:Due to a
high incidence of NEC when used in premature neonates and questionable benefit, octreotide should not be used
as an initial management and avoided altogether if possible (Church 2017).
GA ≥28 weeks: Continuous IV infusion: Usual initial dose: 0.5 to 2 mcg/kg/hour, titrate to clinical response;
reported median maximum dose: 10 mcg/kg/hour; reported range: 1 to 20 mcg/kg/hour; median duration
of therapy: 9 days (range: 4 to 47 days); dosing based on several case reports; randomized, controlled trials
are lacking; congenital chylothorax tends to require higher doses and a longer duration of therapy
compared to acquired chylothorax (Bellini 2018; Das 2010).
Congenital hyperinsulinism (persistent hyperinsulinemic hypoglycemia of infancy): Limited data available: Note:Not
first-line therapy (diazoxide suggested for initial management); NEC has been observed in neonates being treated
with octreotide for congenital hyperinsulinemia (Laje 2010; McMahon 2017).
Dosing should be individualized to patient response to achieve and maintain target serum glucose concentrations
(typically >70 mg/dL); usually used in combination with a dextrose infusion when therapy first initiated.
Tachyphylaxis may develop with prolonged therapy requiring dosing adjustment or alternate therapy (Shah
2017; Sperling 2014).
SubQ:
Intermittent SubQ: Initial: 5 mcg/kg/day in divided doses every 6 to 8 hours; titrate to response, increments
of 5 mcg/kg/day have been used; usual reported effective range: 5 to 25 mcg/kg/day in divided
doses; maximum daily dose: 35 mcg/kg/day (Demirbilek 2017; Shah 2017; Sperling 2014; Yorifuji
2017).
Continuous SubQ infusion: Term neonate: Initial: 5 mcg/kg/day delivered over 24 hours; titrate to
response, 5 mcg/kg/day increments have been used; usual reported effective range: 5 to 25
mcg/kg/day; maximum daily dose: 35 mcg/kg/day (Demirbilek 2017; Hosokawa 2017; Shah 2017;
Sperling 2014; Yorifuji 2017).
Dosing: Pediatric
Note: Unless otherwise specified, all pediatric dosing based on use of the immediate-release injection solution (non-
long-acting). Dosing is presented in multiple formats (eg, mcg/kg/hour, mcg/kg/day, mcg/kg/dose); use extra
precaution.
Chylothorax, acquired (eg, postoperative): Limited data available; efficacy results variable; optimal dose not established
(Church 2017): Infants and Children: Continuous IV infusion: Reported range: 1 to 4 mcg/kg/hour; in one report,
octreotide was initiated and maintained at fixed rate of 3 mcg/kg/hour; other reports describe initiation of
therapy at the lower end of a dosing range and titration; usual duration of therapy: 7 days (Landvoigt 2006; Mery
2014; Yeh 2013).
Diarrhea: Very limited data available; reported dosing highly variable: Note: In pediatric patients, octreotide has been
used to manage refractory cases of diarrhea due to multiple etiologies including GVHD, chemotherapy induced,
and congenital secretory syndromes; use has been described in a small trial, several case reports and by some
centers. A dose-response relationship has not been established. SubQ administration is the usual route; however,
the IV route has been used in some cases (Al-Hussaini 2012; Beckman 2000; Couper 1989; Jaros 1988; Pai 2011).
Intermittent SubQ: Usual initial dose: 1 to 10 mcg/kg/dose every 8 to 12 hours; doses should begin at the
low end of the range and be titrated to effect; reported range: 1 to 49 mcg/kg/day (Al-Hussaini 2012;
Beckman 2000; Couper 1989; Jaros 1988; Pai 2011); a higher dose of 60 mcg/kg/day has been
reported (Al-Hussaini 2012). In adults, a maximum dose of 500 mcg/dose has been recommended
for GVHD (ASCO [Benson 2004]).
Continuous IV infusion: Note: Typically IV infusion reserved for patients failing intermittent dosing: Initial: 1
mcg/kg/hour (Beckman 2000); some patients may require titration; doses up to 49 mcg/kg/day have
been reported (Pai 2011).
Esophageal varices; gastrointestinal bleed: Limited data available: Infants, Children, and Adolescents: IV: Initial: 1 to 2
mcg/kg bolus followed by 1 to 2 mcg/kg/hourcontinuous IV infusion; titrate infusion rate to response; taper dose
by 50% every 12 hours when no active bleeding occurs for 24 hours; may discontinue when dose is 25% of initial
dose (Al-Hussaini 2012; Eroglu 2004).
Hyperinsulinemic hypoglycemia: Limited data available: Note: Not first-line therapy (diazoxide suggested for initial
management) (Shah 2017). Dosing should be individualized to patient response to achieve and maintain target
serum glucose concentrations (typically >70 mg/dL) (Sperling 2014).
Daily dosing: Infants, Children, and Adolescents: SubQ:
Intermittent SubQ: Initial: 5 mcg/kg/day in divided doses every 6 to 8 hours; titrate to response, 5
mcg/kg/day increments have been used; usual reported effective range: 5 to 25 mcg/kg/day in
divided doses; maximum daily dose: 35 mcg/kg/day (Demirbilek 2017; Shah 2017).
Continuous SubQ infusion: Initial: 5 mcg/kg/day delivered over 24 hours; titrate to response, 5 mcg/kg/day
increments have been used; usual reported effective range: 5 to 25 mcg/kg/day; maximum daily
dose: 35 mcg/kg/day(Demirbilek 2017; Hosokawa 2017; Shah 2017).
Monthly dosing: Long-acting depot formulation; conversion from SubQ (daily) to IM (monthly): Very limited data
available:
Note: Not for initial management; for administration by a health care professional; in pediatric trials, initial
doses (7) were administered in an inpatient facility. Due to the delayed onset of therapeutic levels
with the long-acting IM formulation, overlap with SubQ octreotide therapy (intermittent or
continuous infusion) along with IM therapy is necessary:
Children and Adolescents: Long-acting formulation (Sandostatin LAR): IM: Calculate patient's cumulative
31-day SubQ dose, which will equal the monthly IM dose; administer this dose every 4 weeks.
Continue with SubQ octreotide therapy for 2 months after starting IM long-acting formulation (first 2
IM depot doses) then discontinue prior at the time of the third IM dose; monitor patient closely for
hypoglycemia while receiving both IM (long-acting) and SubQ octreotide (Le Quan Sang 2012; Shah
2017).
Hypothalamic obesity (from cranial insult): Limited data available; efficacy results variable: Children ≥8 years of age and
Adolescents: SubQ: Initial: 5 mcg/kg/day divided into 3 daily doses; dose may be increased bimonthly at 5
mcg/kg/day increments to a maximum of 15 mcg/kg/day divided into 3 daily doses; dosing based on small trials
which showed insulin suppression, decreased caloric intake, and BMI stabilization or decrease; trials were limited
to a 6 month duration; long-term effects are unknown (Lustig 1999; Lustig 2003; Lustig 2011).
Sulfonylurea overdose: Limited data available: Dosing in pediatric patients based on experience in adult patients;
pediatric-specific reports are sparse (Glatstein 2010; Howland 2011). Infants, Children, and Adolescents: SubQ: 1
to 1.25 mcg/kg/dose every 6 hours; repeat as needed based upon blood glucose concentrations (Howland 2011);
children generally need only a single dose (Dougherty 2013). Note: Although octreotide use is strongly advocated
as a first-line therapy, indications and dosing for octreotide are not firmly established (Glatstein 2012).
There are no pediatric specific recommendations; clearance is decreased by 50% in adult patients with severe renal
failure requiring dialysis; based on experience in adult patients, consider dosing adjustment.

There are no dosage adjustments provided in the manufacturer’s labeling. Half-life is prolonged and total body clearance
is decreased in adult patients with cirrhosis and fatty liver disease; based on experience in adult patients, use with
caution, dosing adjustment suggested.
• Abnormal Schillings test: Chronic treatment has been associated with abnormal Schillings test; monitor vitamin
B12 levels.
• Cholelithiasis: May impair gallbladder function (inhibits gallbladder contractility and decreases bile secretion);
monitor patients for cholelithiasis. Cholelithiasis and complications of cholelithiasis (eg, cholecystitis,
cholangitis, pancreatitis) requiring cholecystectomy have been reported; discontinue and treat
appropriately if suspected. The incidence of gallbladder stone or biliary sludge increases with a duration of
therapy of ≥12 months. Prophylactic cholecystectomy is recommended in patients with GI or pancreatic
neuroendocrine tumors undergoing abdominal surgery if octreotide treatment is planned (Oberg 2004).
• Glucose regulation: Somatostatin analogs may affect glucose regulation. In type I diabetes, severe hypoglycemia
may occur; in type II diabetes or patients without diabetes, hyperglycemia may occur. Insulin and other
hypoglycemic medication requirements may change. Octreotide may worsen hypoglycemia in patients with
insulinomas; use with caution.
• Local reactions: Mild to moderate injection-site pain (usually lasting 1 hour) may occur with the depot
formulation.
• Hypothyroidism: Suppresses secretion of TSH; monitor for hypothyroidism.
• Pancreatitis: May alter absorption of dietary fats; monitor for pancreatitis.
• Cardiovascular disease: Use with caution in patients with heart failure or concomitant medications that alter
heart rate or rhythm; bradycardia, conduction abnormalities, and arrhythmia have been observed in
acromegalic and carcinoid syndrome patients. Cardiovascular medication requirements may change.
• Excessive fluid loss: May reduce excessive fluid loss in patients with conditions that cause such a loss; periodic
monitoring for elevations in zinc levels is recommended in such patients that are maintained on total
parenteral nutrition (TPN).
• Hepatic impairment: Use caution in patients with hepatic impairment; dosage adjustment may be required in
patients with established cirrhosis.
• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment may be required in
patients receiving dialysis.

• QTc-prolonging agents: Octreotide may enhance the adverse/toxic effects of other QTc-prolonging agents.
• Depot formulation: Do not use depot formulation for the treatment of sulfonylurea-induced hypoglycemia
(Dougherty 2010).
• Vehicle used in depot injection (polylactide-co-glycolide microspheres): Has rarely been associated with retinal
artery occlusion in patients with abnormal arteriovenous anastomosis (eg, patent foramen ovale).
• Elderly: Dosage adjustment may be necessary; significant increases in elimination half-life have been observed
in older adults.
• Females: Therapy may restore fertility; females of childbearing potential should use adequate contraception.
• Pediatric: Postmarketing cases of serious and fatal events, including hypoxia and necrotizing enterocolitis (NEC),
have been reported with octreotide use in children (usually with serious underlying conditions), particularly
in children <2 years of age. In studies with octreotide depot, the incidence of cholelithiasis in children is
higher than the reported incidences for adults and efficacy was not demonstrated.
• Radiolabeled diagnostic evaluations: Therapy with immediate release octreotide (solution) should be withheld
24 hours prior to administration of radiolabeled somatostatin analogs; the IM (depot) formulation should
be withheld at least 2 months before administration of radiolabeled somatostatin analogs (Oberg 2004).
Serious and some fatal adverse effects have been reported in pediatric patients including NEC, hypoxia, and pancreatitis,
and during administration of IV doses bradycardia has been reported; most severe adverse events or death were
observed in neonates, infants, and children <2 years of age; direct causality with octreotide was not established due to
complex patient comorbidities (Church 2017; FDA 2007; Testoni 2015). Use in neonates, including term and preterm,
should be done with extreme caution and reserved for refractory cases; consider avoiding use if patient has other risk
factors for NEC (Testoni 2015).
Parenteral:
IV infusion: Dilute Sandostatin injection in 50 to 200 mL NS or D5W

IM: Sandostatin LAR: Allow Sandostatin LAR Depot vial and provided diluent-filled syringe to reach room
temperature slowly (approximately 30 to 60 minutes). Reconstitute with provided diluent; see detailed
mixing instructions included with the product. Administer immediately after preparation.
Parenteral: Only Sandostatin injection may be administered IV and SubQ; Sandostatin LAR Depot may only be
administered IM
SubQ: Use the concentration with smallest volume to deliver dose to reduce injection site pain; rotate injection site; may
bring to room temperature prior to injection
IV infusion: Dilute Sandostatin injection and infuse over 15 to 30 minutes or over 24 hours as a continuous infusion; in
emergency situations, may be administered undiluted by direct IV push over 3 minutes; allow solution to come to
room temperature before administration
IM: Administer into gluteal area only; avoid deltoid injections due to significant pain and discomfort at injection site
Schedule injections between meals to decrease GI effects. May alter absorption of dietary fats.
Neonatal, Pediatric: In addition to indication-specific therapeutic endpoints, patient should also be monitored for signs
of NEC (neonates), vital signs (HR, RR, BP, O2sat; particularly during IV administration), serum electrolytes and
glucose; baseline and periodic ultrasound (cholelithiasis); growth parameters
Chronic therapy: Growth parameters; thyroid function (baseline and periodic), vitamin B12 level, blood glucose, glycemic
control and antidiabetic regimen (patients with diabetes mellitus), cardiac function (heart rate, ECG), zinc level
(patients with excessive fluid loss maintained on TPN)
Adult: Indication specific:
Acromegaly: Growth hormone, somatomedin C (IGF-1)
Carcinoid: Urinary 5-hydroxyindole acetic acid (5-HIAA), plasma serotonin and plasma substance P
VIPomas: Vasoactive intestinal peptide (VIP)
Reference Range
Vasoactive intestinal peptide (VIP): Adult: <75 ng/L; levels vary considerably between laboratories
Drug Interactions
Monitor therapy
CycloSPORINE (Systemic): Somatostatin Analogs may decrease the serum concentration of CycloSPORINE
(Systemic). Risk D: Consider therapy modification
Monitor therapy
Food Interactions
Octreotide may alter absorption of dietary fats. Management: Administer injections between meals to decrease GI
effects.
Duration: SubQ: 6 to 12 hours; when using Sandostatin LAR Depot formulation, steady-state levels are achieved after 3
injections (3 months of therapy)
Absorption: SubQ: Rapid and complete; IM (depot formulation): Released slowly (via microsphere degradation in the
muscle)
Distribution: Vd: 14 L (21.6 ± 8.5 L in acromegaly)
Protein binding: 65%, primarily to lipoprotein (41% in acromegaly)
Metabolism: Extensively hepatic
Bioavailability: SubQ: 100%; IM: 60% to 63% of SubQ dose
Half-life elimination: 1.7 to 1.9 hours; Increased in elderly patients; Cirrhosis: Up to 3.7 hours; Fatty liver disease: Up to
3.4 hours; Renal impairment: Up to 3.1 hours
Time to peak, plasma: SubQ: 0.4 hours (0.7 hours acromegaly); IM: 1 hour
Excretion: Urine (32% as unchanged drug)
Clearance: Adults: 10 L/hour; Adults with acromegaly: 18 L/hour
Renal function impairment: Elimination and clearance are prolonged; clearance may be reduced by about 50% in
patients with severe renal failure.
Hepatic function impairment: Patients with liver cirrhosis showed prolonged elimination of the drug with t½increasing
and clearance decreasing.
Geriatric: There is a 46% increase in the half-life of the drug, and a 26% decrease in clearance.
Adverse Reactions
Adverse reactions vary by route of administration and dosage form. Frequency of cardiac, endocrine, and
gastrointestinal adverse reactions was generally higher in patients with acromegaly.
Cardiovascular: Cardiac arrhythmia, cardiac conduction disturbance, edema, flushing, hypertension, pulmonary
embolism, sinus bradycardia
Central nervous system: Cerebrovascular disease, depression, dizziness, fatigue, headache, malignant hyperthermia,
pain
Dermatologic: Alopecia, pruritus, skin rash
Endocrine & metabolic: Goiter, hyperglycemia, hypoglycemia, hypothyroidism
Gastrointestinal: Abdominal distention, abdominal distress, abdominal pain, abnormal stools, biliary obstruction (duct
dilatation), cholelithiasis (length of therapy dependent), constipation, diarrhea, dyspepsia, fecal discoloration,
flatulence, gallbladder sludge (length of therapy dependent), loose stools, malabsorption (fat), nausea,
steatorrhea, tenesmus, upper abdominal pain, vomiting
Genitourinary: Pollakiuria, urinary tract infection
Hematologic & oncologic: Anemia, bruise, rectal hemorrhage
Hepatic: Ascites
Immunologic: Antibody development (to octreotide; no efficacy change)
Infection: Cold symptoms
Local: Hematoma at injection site, pain at injection site
Neuromuscular & skeletal: Arthralgia, arthropathy, asthenia, back pain, musculoskeletal pain, myalgia, tremor
Ophthalmic: Blurred vision, visual disturbance
Respiratory: Epistaxis, flu-like symptoms, pleural effusion, sinusitis, upper respiratory tract infection
Rare, postmarketing, and/or case reports: Abdominal swelling, acute myocardial infarction, adrenocortical insufficiency,
amenorrhea, amnesia, anaphylactic shock, aneurysm, anxiety, aphasia, appendicitis, arterial thrombosis (arm),
arthritis, atrial fibrillation, basal cell carcinoma of skin, Bell's palsy, biliary obstruction, breast carcinoma, cardiac
failure, cellulitis, chest pain, cholangitis (ascending), cholecystitis, cholestatic hepatitis, cyanocobalamin
deficiency, deafness, decreased libido, diabetes insipidus, diabetes mellitus, dyspnea, facial edema, galactorrhea
not associated with childbirth, gastrointestinal hemorrhage, gastrointestinal ulcer, glaucoma, gynecomastia,
hematuria, hemiparesis, hemorrhoids, hepatitis, hypersensitivity reaction, increased creatine phosphokinase in
blood specimen, increased intraocular pressure, increased liver enzymes, increased serum creatinine, infrequent
uterine bleeding, intestinal obstruction, intracranial hemorrhage, iron deficiency, ischemia, jaundice, joint
effusion, liver steatosis, menstrual disease (polymenorrhea), migraine, nephrolithiasis, neuritis, nodule
(pulmonary), nonimmune anaphylaxis, orthostatic hypotension, otalgia, palpitations, pancreatitis, pancytopenia,
paranoid ideation, paresis, petechia, pituitary apoplexy, pneumonia, pneumothorax (aggravated), polyp
(gallbladder), prolonged QT interval on ECG, pulmonary hypertension, Raynaud’s disease, renal failure syndrome,
renal insufficiency, scotoma, seizure, status asthmaticus, suicidal tendencies, syncope, tachycardia,
thrombocytopenia, thrombophlebitis, thrombosis (including retinal vein), urticaria, vaginitis, vertigo, visual field
defect, weight loss
PARACETAMOL
Dosing: Pediatric
Note: In 2011, McNeil Consumer Healthcare reduced the maximum daily doses and increased the dosing interval on the
labeling of some of their acetaminophen OTC products used in older pediatric patients (usually children ≥12 years and
adolescents) and adults in an attempt to protect consumers from inadvertent overdoses. For example, the maximum
daily dose of Extra Strength Tylenol OTC and Regular Strength Tylenol OTC were decreased to 3,000 mg/day and 3,250
mg/day respectively, and the dosing interval for Extra Strength Tylenol OTC was increased. Health care professionals
may still prescribe or recommend the 4 g adult daily maximum to patients ≥12 years of age (but are advised to use their
own discretion and clinical judgment) (McNeil Consumer Healthcare 2014).
Pain (mild to moderate) or fever: Note: Limit acetaminophen dose from all sources (prescription and OTC);
maximum daily dose of acetaminophen should be limited to ≤75 mg/kg/day in ≤5 divided doses and not to
exceed 4,000 mg/day for most products although some formulations suggest lower maximum daily dosing
(see dosing information for further detail):
Oral: Note: With OTC use, should not exceed recommended treatment duration unless directed by health
care provider; for fever: 3 days (all ages); pain (excluding sore throat): Children ≥12 years and
Adolescents: 10 days, children: 5 days, or infants: 3 days; sore throat in children: 2 days
Weight-directed dosing: Infants, Children, and Adolescents: 10 to 15 mg/kg/dose every 4 to 6 hours

as needed (American Pain Society 2008; Kliegman 2011; Sullivan 2011); do not exceed 5 doses
in 24 hours; maximum daily dose: 75 mg/kg/day not to exceed 4,000 mg/day
Fixed dosing:
Oral suspension, chewable tablets: Infants and Children <12 years: Consult specific product
formulations for appropriate age groups. See table; use of weight to select dose is
preferred; if weight is not available, then use age; doses may be repeated every 4
hours; maximum: 5 doses/day
Acetaminophen Dosing (Oral)
Weight (preferred)A Dosage

Age
kg Lbs
(mg)
Acetaminophen Dosing (Oral)
Weight (preferred)A Dosage

Age
kg Lbs
(mg)
AManufacturer’s recommendations are based on weight in pounds (OTC labeling); weight in kg listed here is derived
from pounds and rounded; kg weight listed also is adjusted to allow for continuous weight ranges in kg. OTC labeling
instructs consumer to consult with physician for dosing instructions in infants and children under 2 years of age.
2.7 to 5.3 6 to 11 0 to 3 mo 40
5.4 to 8.1 12 to 17 4 to 11 mo 80
8.2 to 10.8 18 to 23 1 to 2 y 120
10.9 to 16.3 24 to 35 2 to 3 y 160
16.4 to 21.7 36 to 47 4 to 5 y 240
21.8 to 27.2 48 to 59 6 to 8 y 320
27.3 to 32.6 60 to 71 9 to 10 y 400
32.7 to 43.2 72 to 95 11 y 480
Immediate release solid dosage formulations: Note: Actual OTC dosing recommendations may
vary by product and/or manufacturer:
Children 6 to 11 years: 325 mg every 4 to 6 hours; maximum daily dose: 1,625

mg/day; Note: Do not use more than 5 days unless directed by a physician
Regular strength: 650 mg every 4 to 6 hours; maximum daily dose: 3,250

mg/day unless directed by a physician; under physician supervision daily
doses ≤4,000 mg may be used
Extra strength: 1,000 mg every 6 hours; maximum daily dose: 3,000

mg/day unless directed by a physician; under physician supervision daily
doses ≤4,000 mg may be used
Extended release: Children ≥12 years and Adolescents: 1,300 mg every 8 hours; maximum
daily dose: 3,900 mg/day
IV:
Infants and Children <2 years:
Manufacturer’s labeling: Fever: 15 mg/kg/dose every 6 hours; maximum daily dose: 60

mg/kg/day
Alternate dosing: Limited data available: Pain and fever: 7.5 to 15 mg/kg/dose every 6 hours;
maximum daily dose: 60 mg/kg/day (Wilson-Smith 2009)
<50 kg: 15 mg/kg/dose every 6 hours or12.5 mg/kg/dose every 4 hours; maximum single dose:
15 mg/kg up to 750 mg; maximum daily dose: 75 mg/kg/day not to exceed 3,750
mg/day
≥50 kg: 1,000 mg every 6 hours or 650 mg every 4 hours; maximum single dose: 1,000 mg;
Rectal:
Weight-directed dosing: Limited data available: Infants and Children <12 years: 10 to 20 mg/kg/dose
every 4 to 6 hours as needed;do not exceed 5 doses in 24 hours(Kliegman 2011; Vernon
1979); maximum daily dose: 75 mg/kg/day
Fixed dosing:
Infants 6 to 11 months: 80 mg every 6 hours; maximum daily dose: 320 mg/day
Infants and Children 12 to 36 months: 80 mg every 4 to 6 hours; maximum daily dose: 400
mg/day
Children >3 to 6 years: 120 mg every 4 to 6 hours; maximum daily dose: 600 mg/day
Children >6 up to 12 years: 325 mg every 4 to 6 hours; maximum daily dose: 1,625 mg/day
Children ≥12 years and Adolescents: 650 mg every 4 to 6 hours; maximum daily dose: 3,900
mg/day
Pain; peri-/postoperative management; adjunct to opioid therapy:
IV:
Infants and Children <2 years: Limited data available: 7.5 to 15 mg/kg/dose every 6 hours; maximum
daily dose: 60 mg/kg/day (Wilson-Smith, 2009)
<50 kg: 15 mg/kg/dose every 6 hours or12.5 mg/kg/dose every 4 hours; maximum single dose:
15 mg/kg up to 750 mg; maximum daily dose: 75 mg/kg/day not to exceed 3,750
mg/day
≥50 kg: 1,000 mg every 6 hours or 650 mg every 4 hours; maximum single dose: 1,000 mg;
Rectal: Limited data available: Children and Adolescents:
Loading dose: 40 mg/kg for 1 dose, in most trials, the dose was administered postoperatively
(Birmingham 2001; Capici 2008; Hahn 2000; Mireskandari 2011; Prins 2008; Riad 2007;
Viitanen 2003); a maximum dose of 1,000 mg was most frequently reported. However, in one
trial evaluating 24 older pediatric patients (all patients ≥25 kg; mean age: ~13 years), the data
suggested that a dose of 1,000 mg does not produce therapeutic serum concentrations (target
for study: >10 mcg/mL) compared to a 40 mg/kg dose (up to~ 2,000 mg); the resultant
Cmax was: 7.8 mcg/mL (1,000 mg dose group) vs 15.9 mcg/mL (40 mg/kg dose
group). Note: Therapeutic serum concentrations for analgesia have not been well-established
(Howell 2003).
Maintenance dose: 20 to 25 mg/kg/dose every 6 hours as needed for 2 to 3 days has been suggested
if further pain control is needed postoperatively; maximum daily dose: 100 mg/kg/day;
therapy longer than 5 days has not been evaluated (Birmingham 2001; Hahn 2000; Prins
2008).
Note: In the majority of trials, suppositories were not divided due to unequal distribution of drug
within suppository; doses were rounded to the nearest mg amount using 1 or 2 suppositories
of available product strengths.
IV: Children ≥2 years and Adolescents: CrCl ≤30 mL/minute: Use with caution; consider decreasing daily dose and
extending dosing interval
Oral (Aronoff 2007):
GFR ≥10 mL/minute/1.73 m2: No adjustment required
GFR <10 mL/minute/1.73 m2: Administer every 8 hours
Intermittent hemodialysis or peritoneal dialysis: Administer every 8 hours
CRRT: No adjustments necessary
Use with caution. Limited, low-dose therapy is usually well-tolerated in hepatic disease/cirrhosis; however, cases of
hepatotoxicity at daily acetaminophen dosages <4,000 mg/day have been reported. Avoid chronic use in hepatic
impairment.
Contraindications
Injection: Hypersensitivity to acetaminophen or any component of the formulation; severe hepatic impairment or severe
active liver disease
OTC labeling: When used for self-medication, do not use with other drug products containing acetaminophen or if
allergic to acetaminophen or any of the inactive ingredients
• Hepatotoxicity: Injection: Acetaminophen has been associated with acute liver failure, at times resulting in
liver transplant and death. Hepatotoxicity is usually associated with excessive acetaminophen intake and
often involves more than one product that contains acetaminophen. Do not exceed the maximum
recommended daily dose (>4 g daily in adults). In addition, chronic daily dosing may also result in liver
damage in some patients.
• Skin reactions: Serious and potentially fatal skin reactions, including acute generalized exanthematous
pustulosis (AGEP), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) have occurred
rarely with acetaminophen use. Discontinue therapy at the first appearance of skin rash.
• Ethanol use: Use with caution in patients with alcoholic liver disease; consuming ≥3 alcoholic drinks/day may
increase the risk of liver damage.
• G6PD deficiency: Use with caution in patients with known G6PD deficiency.
• Hepatic impairment: Use with caution in patients with hepatic impairment or active liver disease; use of the IV
formulation is contraindicated in patients with severe hepatic impairment or severe active liver disease.
• Hypovolemia: Use the IV formulation with caution in patients with severe hypovolemia (eg, due to dehydration
or blood loss).
• Malnutrition: Use with caution in patients with chronic malnutrition.
• Renal impairment: Use with caution in patients with severe renal impairment; consider dosing adjustments.
• Aspartame: Some products may contain aspartame, which is metabolized to phenylalanine and must be avoided
(or used with caution) in patients with phenylketonuria.
• Dosage limit: Limit acetaminophen dose from all sources (prescription, OTC, combination products) and all
routes of administration (IV, oral, rectal) to <4 g/day (adults).
Prophylactic use of acetaminophen to reduce fever and discomfort associated vaccination is not recommended by the
Advisory Committee on Immunization Practices (ACIP). Additionally, the ACIP does not recommend prophylactic
acetaminophen to reduce risk of febrile seizure in infants and children with or without a history of febrile seizures.
Antipyretics have not been shown to prevent febrile seizures (NCIRD/ACIP 2011). One study reported that routine
prophylactic administration of acetaminophen to prevent fever prior to vaccination decreased the immune response of
some vaccines; in the trial evaluating 459 infants (including 226 who received acetaminophen), antibody geometric
mean concentrations (GMCs) for targeted vaccine immune response markers were lower in significantly more infants in
the acetaminophen group compared with control. Before the booster dose, children who received prophylactic
acetaminophen had lower antibody GMCs for all vaccine serotypes than children in the control group; this effect
persisted after boosting even in the absence of additional acetaminophen doses. The clinical significance of this
reduction in immune response has not been established (Prymula 2009). Antipyretics may be used to treat fever or
discomfort following vaccination (NCIRD/ACIP 2011).
including hyperosmolality, lactic acidosis, seizures and respiratory depression; use caution (AAP, 1997; Shehab, 2009).
Parenteral: Injectable solution may be administered directly from the vial without further dilution. Use within 6 hours of
opening vial or transferring to another container. Discard any unused portion; single-use vials only.
Doses <1,000 mg (<50 kg): Withdraw appropriate dose from vial and transfer to a separate sterile container (eg,
glass bottle, plastic IV container, syringe) for administration. Small volume pediatric doses (up to 600 mg
[60 mL]) may be placed in a syringe.
Doses of 1,000 mg (≥50 kg): Insert vented IV set through vial stopper.
Oral: Administer with food to decrease GI upset; shake drops and suspension well before use; do not crush or chew
extended release products
Parenteral: For IV infusion only. May administer undiluted over 15 minutes. Use within 6 hours of opening vial or
transferring to another container. Discard any unused portion; single-use vials only.
Rectal: Remove wrapper; insert suppository well up into the rectum.
Drug Interactions
Barbiturates: May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2)
increase the risk of liver damage. Exceptions: Amobarbital; Butabarbital; Butalbital; Methohexital; PENTobarbital;
Secobarbital; Thiopental. Risk C: Monitor therapy
CarBAMazepine: May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen;
and 2) increase the risk of liver damage. Risk C: Monitor therapy
Dapsone (Topical): May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Risk C: Monitor
therapy
Fosphenytoin-Phenytoin: May decrease the serum concentration of Acetaminophen. Specifically, serum concentrations
of acetaminophen may be decreased (leading to decreased efficacy), but the formation of the toxic N-acetyl-p-
benzoquinone imine (NAPQI) metabolite may be increased (leading to increased hepatotoxicity). Risk C: Monitor
therapy
Isoniazid: May enhance the adverse/toxic effect of Acetaminophen. Risk C: Monitor therapy
Phenylephrine (Systemic): Acetaminophen may increase the serum concentration of Phenylephrine (Systemic). Risk C:
Monitor therapy
Probenecid: May increase the serum concentration of Acetaminophen. Probenecid may also limit the formation of at
least one major non-toxic metabolite, possibly increasing the potential for formation of the toxic NAPQI
metabolite. Risk D: Consider therapy modification
Vitamin K Antagonists (eg, warfarin): Acetaminophen may enhance the anticoagulant effect of Vitamin K Antagonists.
This appears most likely with daily acetaminophen doses exceeding 1.3 or 2 g/day for multiple consecutive
days. Risk C: Monitor therapy
Adverse Reactions
Oral, Rectal:
Endocrine & metabolic: Decreased serum bicarbonate, decreased serum calcium, decreased serum sodium,
hyperchloremia, hyperuricemia, increased serum glucose
Genitourinary: Nephrotoxicity (with chronic overdose)
Hematologic & oncologic: Anemia, leukopenia, neutropenia, pancytopenia
Hepatic: Increased serum alkaline phosphatase, increased serum bilirubin
Hypersensitivity: Hypersensitivity reaction (rare)
Renal: Hyperammonemia, renal disease (analgesic)
IV:
Cardiovascular: Hypertension, hypotension, peripheral edema (adults), tachycardia
Central nervous system: Agitation (neonates, infants, children, and adolescents), anxiety (adults), fatigue (adults),
headache (more common in adults), insomnia (adults), trismus (adults)
Dermatologic: Pruritus (neonates, infants, children, and adolescents), skin rash
Endocrine & metabolic: Hypervolemia, hypoalbuminemia (neonates, infants, children, and adolescents),
hypokalemia, hypomagnesemia (neonates, infants, children, and adolescents), hypophosphatemia
(neonates, infants, children, and adolescents)
Gastrointestinal: Abdominal pain, constipation (neonates, infants, children, and adolescents), diarrhea (neonates,
infants, children, and adolescents), nausea (more common in adults), vomiting (more common in adults)
Genitourinary: Oliguria (neonates, infants, children, and adolescents)
Hematologic & oncologic: Anemia

Hepatic: Increased serum transaminases
Neuromuscular & skeletal: Limb pain, muscle spasm
Ophthalmic: Periorbital edema
Respiratory: Abnormal breath sounds (adults), atelectasis (neonates, infants, children, and adolescents), dyspnea
(adults), hypoxia, pleural effusion (neonates, infants, children, and adolescents), pulmonary edema
(neonates, infants, children, and adolescents), stridor (adults), wheezing (adults)
Miscellaneous: Fever (neonates, infants, children, and adolescents)
Rare but important or life-threatening: Anaphylaxis, hypersensitivity reaction
PENICILLIN G BENZATHINE
Dosing: Neonatal
Syphilis, congenital: IM: 50,000 units/kg as a single dose (Red Book, 2012)
Dosing: Pediatric
Group A streptococcal upper respiratory infection(Gerber, 2009): Infants, Children, and Adolescents: IM:
Rheumatic fever, primary prevention:
≤27 kg: 600,000 units as a single dose
>27 kg: 1.2 million units as a single dose
Rheumatic fever, secondary prevention: Note:Duration of secondary rheumatic fever prophylaxis varies:
Rheumatic fever with carditis and residual heart disease: 10 years or until 40 years of age (whichever
is longer), sometimes lifelong prophylaxis; rheumatic fever with carditis but no residual heart
disease: 10 years or until 21 years of age (whichever is longer); rheumatic fever without carditis: 5
years or until 21 years of age (whichever is longer)
≤27 kg: 600,000 units every 3-4 weeks
>27 kg: 1.2 million units every 3-4 weeks
Syphilis: (CDC, 2010; Red Book, 2012): Infants, Children, and Adolescents: IM
Primary, Secondary, or Early Latent (<1 year duration): 50,000 units/kg once; maximum dose: 2.4 million
units
Late Latent or Latent with unknown duration: 50,000 units/kg once weekly for 3 doses; maximum dose: 2.4
million units
There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.
Contraindications
Hypersensitivity to penicillin(s) or any component of the formulation
• Hypersensitivity reactions: Serious and occasionally severe or fatal hypersensitivity (anaphylactic) reactions have
been reported in patients on penicillin therapy, especially with a history of beta-lactam hypersensitivity
(including cephalosporins), history of sensitivity to multiple allergens, or previous IgE-mediated reactions
(eg, anaphylaxis, angioedema, urticaria). Serious anaphylactic reactions require immediate emergency
treatment with epinephrine, oxygen, intravenous steroids and airway management (including intubation)
as indicated.
treatment.
• Syphilis/neurosyphilis use: CDC and AAP do not currently recommend the use of penicillin G benzathine for the
initial treatment regimen for congenital syphilis or neurosyphilis due to reported treatment failures and
lack of published clinical data on its efficacy (CDC [Workowski 2015]).
• Appropriate administration: [US Boxed Warning]: Not for intravenous use; cardiopulmonary arrest and death
have occurred from inadvertent IV administration. Administer by deep IM injection only. Quadriceps
femoris fibrosis and atrophy have been reported after repeated IM injections of penicillin preparations into
the anterolateral thigh. Injection into or near an artery or nerve could result in severe neurovascular
damage or permanent neurological damage.
• Appropriate use: Use only for treatment of infections due to penicillin G sensitive gram positive organisms, few
gram-negative organisms such as Neisseria gonorrhoeae, and some anaerobes and spirochetes. Use only
for infections susceptible to the low and very prolonged serum concentrations of benzathine penicillin G.
• Prolonged use: Extended duration of therapy or use associated with high serum concentrations (eg, in renal
insufficiency) may be associated with an increased risk for some adverse reactions (neutropenia, hemolytic
anemia, serum sickness).
Injection into or near a nerve may result in permanent neurovascular and neurological damage, gangrene requiring
amputation of proximal portions of extremities, necrosis, and sloughing at the injection site. These effects have most
often occurred in infants and small children. Avoid repeated IM injections into the anterolateral thigh in neonates and
infants since quadriceps femoris fibrosis and atrophy may occur.
IM: Administer undiluted as deep IM injection in the upper outer quadrant of the buttock (adolescents) or into the
midlateral aspect of the thigh (neonates, infants, and children); do not give IV, intra-arterially or SubQ; inadvertent IV
administration has resulted in thrombosis, severe neurovascular damage, cardiac arrest, and death
CBC, urinalysis, culture, renal function tests, stool frequency
Drug Interactions
Methotrexate: Penicillins may increase the serum concentration of Methotrexate. Risk C: Monitor therapy
Mycophenolate: Penicillins may decrease serum concentrations of the active metabolite(s) of Mycophenolate. This
effect appears to be the result of impaired enterohepatic recirculation. Risk C: Monitor therapy
Probenecid: May increase the serum concentration of Penicillins. Management: Avoid the routine use of penicillins and
probenecid, but this combination may be used advantageously in select cases with careful monitoring. Monitor
for toxic effects of penicillins if probenecid is initiated or the dose is increased. Risk D: Consider therapy
modification
Vitamin K Antagonists (eg, warfarin): Penicillins may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C:
Monitor therapy
Test Interactions
Positive Coombs' [direct], false-positive urinary and/or serum proteins; false-positive or negative urinary glucose using
Clinitest®
Duration: 1 to 4 weeks (dose dependent); larger doses result in more sustained levels
Absorption: IM: Slow
Distribution: Minimal concentrations attained in CSF with inflamed or uninflamed meninges; highest levels in the kidney;
lesser amounts in liver, skin, intestines
Protein Binding: ~60%
Time to peak, serum: Within 12 to 24 hours; serum levels are usually detectable for 1 to 4 weeks depending on the dose;
larger doses result in more sustained levels rather than higher levels
Excretion: Excreted by renal tubular excretion; penicillin G is detected in urine for up to 12 weeks after a single IM
injection; renal clearance is delayed in neonates, young infants, and patients with impaired renal function
Adverse Reactions
Cardiovascular: Cerebrovascular accident, hypotension, palpitations, syncope, tachycardia, vasodilatation, vasospasm,

vasodepressor syncope
Central nervous system: Anxiety, coma, confusion, dizziness, drowsiness, euphoria, fatigue, headache, localized warm
feeling, nervousness, neurologic abnormality (neurogenic bladder), numbness, pain, seizure, transverse myelitis
Dermatologic: Diaphoresis, gangrene of skin or other tissue, pallor, skin mottling, skin ulceration at injection site
Gastrointestinal: Bloody stools, intestinal necrosis, nausea, vomiting
Genitourinary: Hematuria, impotence, priapism, proteinuria
Hematologic & oncologic: Local hemorrhage (at injection site), lymphadenopathy
Hepatic: Increased serum AST
Immunologic: Jarisch-Herxheimer reaction
Local: Abscess at injection site, atrophy at injection site, bruising at injection site, cellulitis at injection site, localized
edema (at injection site), inflammation at injection site, injection site reaction (neurovascular damage), pain at
injection site, residual mass at injection site, tissue necrosis at injection site
Neuromuscular & skeletal: Arthropathy, exacerbation of arthritis, periosteal disease (periostitis), rhabdomyolysis,
tremor, weakness
Ophthalmic: Blindness, blurred vision
Renal: Increased blood urea nitrogen, increased serum creatinine, myoglobinuria, renal failure
Respiratory: Cyanosis
ROCURONIO
Dosing: Neonatal
Note: Dose to effect; doses will vary due to interpatient variability. Dosing also dependent on anesthetic technique and
age of patient. In general, the onset of effect is shortened and duration is prolonged as the dose increases. The time to
maximum nerve block is longest in neonates.
Tracheal intubation, surgical:
Initial: IV: 0.45 to 0.6 mg/kg
Maintenance for continued surgical relaxation:
Intermittent IV dosing: 0.075 to 0.15 mg/kg; dosing interval as determined by monitoring
Continuous IV infusion: 7 to 10 mcg/kg/minute (0.42 to 0.6 mg/kg/hour)
Tracheal intubation, nonemergent: IV: 0.6 to 1.2 mg/kg (Kumar 2010)
Dosing adjustment in renal impairment: No dosage adjustment necessary; duration of neuromuscular blockade may vary
in patients with renal impairment.
Dosing adjustment in hepatic impairment: There are no dosage adjustments provided in the manufacturer's labeling;
however, dosage reductions may be necessary in patients with liver disease; duration of neuromuscular blockade may
be prolonged due to increased volume of distribution.
Dosing: Pediatric
Note: Dose to effect; doses will vary due to interpatient variability. Dosing also dependent on anesthetic technique and
age of patient. In general, the onset of effect is shortened and duration is prolonged as the dose increases. The time to
maximum nerve block is shortest in infants 1 to 3 months; the duration of relaxation is shortest in children 2 to 11 years
and longest in infants. The manufacturer recommends dosing based on actual body weight in all obese patients;
however, some have recommended dosing based on ideal body weight (IBW) in obese patients (Playfor 2007).
Rapid sequence intubation: Children and Adolescents: IV: 0.9 to 1.2 mg/kg; Note: Lower doses of 0.6 mg/kg have been
reported in the literature; however, some studies found this dosing resulted in prolonged time to onset, shortened
duration of neuromuscular blockade and less favorable intubating conditions (Cheng 2002; Fuchs-Buder 1996; Mazurek
1998; Naguib 1997)
Tracheal intubation, surgical: Infants, Children, and Adolescents: Note: Inhaled anesthetic agents prolong the duration of
action of rocuronium; use lower end of the dosing range; dosing interval guided by monitoring with a peripheral nerve
stimulator.
Initial:
IV: 0.45 to 0.6 mg/kg
IM (Kaplan 1999): Limited data available: Note: Due to the prolonged time to onset in some patients, IM dosing may not
be ideal for rapid sequence intubation for the general population and should be reserved to clinical scenarios when
alternative agents are not appropriate.
Infants ≥3 months: 1 mg/kg administered as a single dose

Children 1 to 6 years: 1.8 mg/kg administered as a single dose
Maintenance for continued surgical relaxation:
Intermittent IV dosing: Infants, Children, and Adolescents: 0.075 to 0.15 mg/kg; repeat as needed
Continuous IV infusion: Infants, Children, and Adolescents: 7 to 12 mcg/kg/minute (0.42 to 0.72 mg/kg/hour); the
manufacturer recommends using the lower end of the dosing range for infants and the upper end for children >2 to ≤11
years of age; higher doses have been reported with prolonged infusions (Tobias 1996)

Infants, Children, and Adolescents: No dosage adjustment necessary; duration of neuromuscular blockade may vary in
patients with renal impairment.

Infants, Children, and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling; however,
dosage reductions may be necessary in patients with liver disease; duration of neuromuscular blockade may be
prolonged due to increased volume of distribution. When rapid sequence intubation is required in adult patients with
ascites, a dose on the higher end of the dosage range may be necessary to achieve adequate neuromuscular blockade.
• Anaphylactoid/hypersensitivity reactions: Have been reported; immediate treatment (including epinephrine 1 mg/mL)
for anaphylactoid and/or hypersensitivity reactions should be available during use.
• Neuromuscular cross-sensitivity: Cross-sensitivity with other neuromuscular-blocking agents may occur; use is
contraindicated in patients with previous anaphylactic reactions to other neuromuscular blockers.
• Prolonged paralysis: Some patients may experience prolonged recovery of neuromuscular function after
administration (especially after prolonged use). Patients should be adequately recovered prior to extubation. Other
factors associated with prolonged recovery should be considered (eg, corticosteroid use, patient condition).
• Burn injury: Resistance may occur in burn patients (≥20% of total body surface area), usually several days after the
injury, and may persist for several months after wound healing (Han 2009).
• Cardiovascular disease: Use with caution in patients with cardiovascular disease (eg, heart failure); onset of action may
be delayed and duration of action may be prolonged.
• Conditions that may antagonize neuromuscular blockade (decreased paralysis): Respiratory alkalosis, hypercalcemia,
demyelinating lesions, peripheral neuropathies, denervation, and muscle trauma may result in antagonism of
neuromuscular blockade (ACCM/SCCM/ASHP [Murray 2002]; Greenberg 2013; Miller 2010; Naguib 2002).
• Conditions that may potentiate neuromuscular blockade (increased paralysis): Electrolyte abnormalities (eg, severe
hypocalcemia, severe hypokalemia, hypermagnesemia), cachexia, neuromuscular diseases, metabolic acidosis,
respiratory acidosis, Eaton-Lambert syndrome, and myasthenia gravis may result in potentiation of neuromuscular
blockade (Greenberg 2013; Miller 2010; Naguib 2002).
• Hepatic impairment: Use with caution in patients with hepatic impairment; clinical duration may be prolonged.
• Pulmonary hypertension: Use with caution in patients with pulmonary hypertension; use may increase pulmonary
vascular resistance worsening symptoms of right heart failure.
• Respiratory disease: Use with caution in patients with respiratory disease.
• Valvular heart disease: Use with caution in patients with valvular heart disease; use may increase pulmonary vascular
resistance.
information.
• Immobilized patients: Resistance may occur in patients who are immobilized.
• Pediatric: Not recommended by the manufacturer for rapid sequence intubation in pediatric patients; however, it has
been used successfully in clinical trials for this indication (Cheng 2002; Fuchs-Buder 1996; Mazurek 1998; Naguib 1997).
• Appropriate use: Maintenance of an adequate airway and respiratory support is critical. Tolerance to rocuronium may
develop. All patients should receive eye care including liberal use of lubricating drops, gel, or ointment and eyelids
should remain closed during continuous neuromuscular blockade to protect against damage to the cornea (ulceration
and drying).
• Experienced personnel: Should be administered by adequately trained individuals familiar with its use.
• Extravasation: If extravasation occurs, local irritation may ensue; discontinue administration immediately and restart in
another vein.

Continuous IV infusion: Dilute with NS, D5W, D5NS or LR to a final concentration of 0.5 to 5 mg/mL; use within 24 hours
of preparation
Parenteral:
IM: Administer undiluted by rapid IM injection into the deltoid muscle (Kaplan 1999; Reynolds 1996)
IV: May be administered undiluted by rapid IV injection; or further diluted and infused as a continuous IV infusion
Drug Interactions
Acetylcholinesterase Inhibitors: May diminish the neuromuscular-blocking effect of Neuromuscular-Blocking Agents
(Nondepolarizing). Risk C: Monitor therapy
Aminoglycosides: May enhance the respiratory depressant effect of Neuromuscular-Blocking Agents. Risk C: Monitor
therapy
Calcium Channel Blockers: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents
CarBAMazepine: May decrease the serum concentration of Neuromuscular-Blocking Agents (Nondepolarizing). Risk C:
Monitor therapy
Cardiac Glycosides: Neuromuscular-Blocking Agents may enhance the arrhythmogenic effect of Cardiac Glycosides. Risk
C: Monitor therapy
Clindamycin (Topical): May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Risk C:
Monitor therapy
Colistimethate: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Risk D: Consider
Corticosteroids (Systemic): Neuromuscular-Blocking Agents (Nondepolarizing) may enhance the adverse neuromuscular
effect of Corticosteroids (Systemic). Increased muscle weakness, possibly progressing to polyneuropathies and
myopathies, may occur. Risk D: Consider therapy modification
CycloSPORINE (Systemic): May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Risk C:
Monitor therapy
Fosphenytoin-Phenytoin: May diminish the neuromuscular-blocking effect of Neuromuscular-Blocking Agents

(Nondepolarizing). Fosphenytoin-Phenytoin may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking
Agents (Nondepolarizing). Fosphenytoin-Phenytoin may decrease the serum concentration of Neuromuscular-Blocking
Agents (Nondepolarizing). Risk C: Monitor therapy
Inhalational Anesthetics: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents

Ketorolac (Systemic): May enhance the adverse/toxic effect of Neuromuscular-Blocking Agents (Nondepolarizing).
Specifically, episodes of apnea have been reported in patients using this combination. Risk C: Monitor therapy
Lincosamide Antibiotics: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Risk C:
Monitor therapy
Local Anesthetics: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Exceptions:
Benzocaine; Benzydamine; Cocaine (Topical); Dibucaine; Dyclonine; Ethyl Chloride; Hexylresorcinol; Lidocaine
(Ophthalmic); Lidocaine (Topical); Pramoxine; Proparacaine; Tetracaine (Ophthalmic); Tetracaine (Topical). Risk C:
Monitor therapy
Loop Diuretics: May diminish the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Loop Diuretics may
enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Risk C: Monitor therapy
Magnesium Salts: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Risk C: Monitor
therapy
Polymyxin B: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Risk D: Consider
QuiNIDine: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Risk C: Monitor therapy
QuiNINE: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Risk X: Avoid combination
Spironolactone: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing).

Risk C: Monitor therapy
Tetracyclines: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Risk C: Monitor
therapy
Thiazide and Thiazide-Like Diuretics: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents
Vancomycin: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Risk C: Monitor
therapy

Store unopened/undiluted vials under refrigeration at 2°C to 8°C (36°F to 46°F); do not freeze. When stored at room
temperature (25°C [77°F]), it is stable for 60 days; once opened, use within 30 days. Dilutions up to 5 mg/mL in 0.9%
sodium chloride, dextrose 5% in water, 5% dextrose in sodium chloride 0.9%, or lactated Ringer's are stable for up to 24
hours at room temperature.

Onset of action:
Infants ≥3 months and Children: 30 seconds to 1 minute
Adults: Good intubation conditions within 1 to 2 minutes (depending on dose administered); maximum neuromuscular
blockade within 4 minutes
Duration:
Infants: 3 to 12 months: 40 minutes
Children: 1 to 12 years: 26 to 30 minutes
Adults: ~30 minutes (with standard doses, increases with higher doses and inhalational anesthetic agents); hypothermia
may prolong the duration of action
Distribution: Vd:
Children: 0.21 to 0.3 L/kg
Adults: 0.22 to 0.26 L/kg
Hepatic dysfunction: 0.53 L/kg
Renal dysfunction: 0.34 L/kg
Protein binding: ~30%

Metabolism: Minimally hepatic; 17-desacetylrocuronium (5% to 10% activity of parent drug)
Alpha elimination: 1 to 2 minutes
Beta elimination:
Infants 3 to 12 months: 1.3 ± 0.5 hours
Children 1 to <3 years: 1.1 ± 0.7 hours
Children 3 to <8 years: 0.8 ± 0.3 hours
Adults: 1.4 to 2.4 hours
Hepatic impairment: 4.3 hours
Renal impairment: 2.4 hours
Excretion: Feces (31%); urine (26%) (Proost 2000)
Clearance: Pediatric patients:
Infants 3 to <12 months: 0.35 L/kg/hour
Children 1 to <3 years: 0.32 L/kg/hour
Children 3 to <8 years: 0.44 L/kg/hour

Renal function impairment: Patients with renal failure have clinical durations that are similar to but somewhat more
variable than what is expected in patients with normal renal function.
Hepatic function impairment: Patients with clinically significant hepatic impairment had moderately prolonged clinical
duration; patients with cirrhosis had increased Vd, prolonged plasma half-life, and >2.5 times the recovery time
compared to patients with normal hepatic function.
Adverse Reactions
Cardiovascular: Hypertension, increased peripheral vascular resistance, tachycardia (more common in children),
transient hypotension
Rare but important or life-threatening: Anaphylactoid reaction, asthma, cardiac arrhythmia, ECG abnormality, hiccups,
injection site edema, nausea, vomiting
SUCCINILCOLINA
Dosing: Neonatal
Note: Because of the risk of adverse effects, including malignant hyperthermia and cardiac arrhythmias, surgical or long-
term paralytic use (ie, continuous IV infusion) is not recommended (Coté 2013; Fisher 1999).
Endotracheal intubation: Note: To reduce the risk of bradycardia or asystole, premedication with atropine
recommended prior to IV succinylcholine doses (AAP [Hegenbarth 2008]; Choong 2010; Coté 2013; Ghanta 2007; Lemyre
2009).
Emergent (eg, rapid sequence intubation):
IM: 4 to 5 mg/kg; pharmacokinetic data suggests that neonates typically require higher mg/kg doses than older pediatric
patients (AAP [Hegenbarth 2008]; Cote 2013)
IV: 2 to 3 mg/kg (AAP [Hegenbarth 2008]; Cote 2013)
Nonemergent: Limited data available:
IM: 2 mg/kg/dose; reserved for situations of no IV access (AAP [Kumar 2010])
IV: 2 mg/kg/dose (Choong 2010; Ghanta 2007; Lemyre 2009); one trial allowed repeat doses of 1 mg/kg every 3 to 5
minutes if inadequate response (failed intubation attempt) up to a total maximum dose of 4 mg/kg (ie, 2 additional
doses) (Ghanta 2007)
Dosing: Pediatric
Note: Dose to effect; doses will vary due to interpatient variability. Use carefully and/or consider dose reduction in
patients with reduced plasma cholinesterase activity due to genetic abnormalities of plasma cholinesterase or when
associated with other conditions (eg, electrolyte abnormalities, neuromuscular disease); prolonged neuromuscular
blockade may occur. Initial dose of succinylcholine must be increased when nondepolarizing agent pretreatment used
because of the antagonism between succinylcholine and nondepolarizing neuromuscular-blocking agents (Miller 2010).
Because of the risk of adverse effects including malignant hyperthermia and cardiac arrhythmias, surgical or long-term
paralytic use (ie, continuous IV infusion) is not recommended (Coté 2013; Fisher 1999).
Endotracheal intubation; emergent (eg, rapid sequence intubation): Note: To reduce the risk of bradycardia or asystole,
premedication with atropine recommended prior to IV succinylcholine doses (AAP [Hegenbarth 2008]; Coté 2013)
Infants, Children, and Adolescents: Note: In obese patients, pediatric patient data (age range: 9 to 15 years) suggest
dosing based on use total body weight (Rose 2000).
IM:
Infants <6 months: Limited data available: 4 to 5 mg/kg; pharmacokinetic data suggests that young infants typically
require doses on the higher end of this range (AAP [Hegenbarth 2008]; Coté 2013)
Infants ≥6 months and Children: 4 mg/kg; maximum dose: 150 mg/dose (AAP [Hegenbarth 2008]; Lui 1981)
Adolescents: 3 to 4 mg/kg; maximum dose: 150 mg/dose
IV:
Manufacturer's labeling:
Infants ≤6 months: 2 to 3 mg/kg/dose

Infants >6 months and Children ≤2 years: 1 to 2 mg/kg/dose
Children >2 years and Adolescents: 1 mg/kg/dose
Alternate dosing: Limited data available:
Infants: 2 to 3 mg/kg/dose (AAP [Hegenbarth 2008]; Coté 2013)
Children: 1 to 2 mg/kg/dose (AAP [Hegenbarth 2008]; Ballow 2012; Coté 2013)
Adolescents: 1 to 1.5 mg/kg/dose (Ballow 2012; Sluga 2005; Weiss 1997)


• Anaphylaxis: Severe anaphylactic reactions (some life-threatening and fatal) have been reported; immediate treatment
(including epinephrine 1 mg/mL) for anaphylactoid and/or hypersensitivity reactions should be available during use. Use
caution in patients with previous anaphylactic reactions to other neuromuscular blocking agents.
• Bradycardia: Risk of bradycardia may be increased with second dose and may occur more in children. Occurrence may
be reduced by pretreating with anticholinergic agents (eg, atropine).
• Increased intraocular pressure (IOP): May increase IOP; avoid use in patients in which an increase in IOP is undesirable
(eg, narrow-angle glaucoma, penetrating eye injuries).
• Intracranial pressure: May cause a transient increase in intracranial pressure (adequate anesthetic induction prior to
administration of succinylcholine will minimize this effect).
• Intragastric pressure: May increase intragastric pressure, which could result in regurgitation and possible aspiration of
stomach contents.
• Malignant hyperthermia: Use may be associated with acute onset of malignant hyperthermia; risk may be increased
with concomitant administration of volatile anesthetics.
• Neuromuscular cross-sensitivity: Cross-sensitivity with other neuromuscular-blocking agents may occur; use extreme
caution in patients with previous anaphylactic reactions to other neuromuscular-blocking agents.
• Vagal tone: May increase vagal tone.
• Burn injury: Use with caution in patients with extensive or severe burns; risk of hyperkalemia is increased following
injury. Onset of time and duration of risk are variable, but risk is generally greatest 7 to 10 days after injury. Resistance
may occur in burn patients (≥20% of total body surface area), usually several days after the injury, and may persist for
several months after wound healing (Han 2009).
demyelinating lesions, peripheral neuropathies, denervation, muscle trauma, and diabetes mellitus may result in
antagonism of neuromuscular blockade (ACCM/SCCM/ASHP [Murray 2002]; Greenberg 2013; Miller 2010; Naguib 2002).
hypocalcemia, severe hypokalemia, hypermagnesemia), neuromuscular diseases, metabolic acidosis, respiratory
acidosis, Eaton-Lambert syndrome, and myasthenia gravis may result in potentiation of neuromuscular blockade
(Greenberg 2013; Miller 2010; Naguib 2002).
• Fractures/muscle spasm: Use with caution in patients with fractures or muscle spasm; initial muscle fasciculations may
cause additional trauma.
• Hyperkalemia: Use with extreme caution in patients with pre-existing hyperkalemia. Severe hyperkalemia may develop
in patients with chronic abdominal infections, burn injuries, multiple trauma/crush injuries, extensive denervation of
skeletal muscle, upper motor neuron injury, subarachnoid hemorrhage, or conditions which cause degeneration of the
central and peripheral nervous system.
• Plasma pseudocholinesterase disorders: Metabolized by plasma cholinesterase; use with caution (if at all) in patients
suspected of being homozygous for the atypical plasma cholinesterase gene. Plasma cholinesterase activity may also be
reduced by burns, anemia, decompensated heart disease, infections, malignant tumors, myxedema, pregnancy, severe
hepatic or renal dysfunction, peptic ulcer, and certain medications and chemicals.
information.
• Elderly: Use with caution in the elderly, effects and duration are more variable.
• Pediatric: [US Boxed Warning]: Use caution in children and adolescents. Acute rhabdomyolysis with hyperkalemia,
ventricular arrhythmias and cardiac arrest have been reported (rarely) in children with undiagnosed skeletal muscle
myopathy (eg, Duchenne muscular dystrophy); occurs soon after administration and requires immediate treatment of
hyperkalemia. Prolonged resuscitation may be required. Use in children should be reserved for emergency intubation
when immediate airway control is necessary (eg, laryngospasm, difficult airway, full stomach), or IM use when a suitable
vein is inaccessible.
• Appropriate use: Maintenance of an adequate airway and respiratory support is critical. All patients should receive eye
care including liberal use of lubricating drops, gel, or ointment and eyelids should remain closed during continuous
neuromuscular blockade to protect against damage to the cornea (ulceration and dryness).
• Experienced personnel: Should be administered by adequately trained individuals familiar with its use.
• Risk of medication errors: Accidental administration may be fatal. Confirm proper selection of intended product, store
vial so the cap and ferrule are intact and the possibility of selecting the wrong product is minimized, and ensure that the
intended dose is clearly labeled and communicated, when applicable.
In children and adolescents, rare reports of acute rhabdomyolysis with hyperkalemia followed by ventricular
dysrhythmias, cardiac arrest, and death have been reported in children with undiagnosed skeletal muscle myopathy,
most frequently Duchenne muscular dystrophy. This syndrome presents as peaked T-waves and sudden cardiac arrest
within minutes after the administration of succinylcholine. Bradycardia and rarely asystole have been reported; higher
incidence in children, particularly those receiving doses >1.5 mg/kg, and following repeat dosing in both children and
adults. Also, if sudden cardiac arrest occurs immediately after administration of succinylcholine, consider hyperkalemia
as potential etiology and manage accordingly. In neonates, some experts consider hyperkalemia a contraindication for
use (AAP [Kumar 2010]).
Parenteral:
IM: Injection should be made deeply. Use only when IV access is not available.
IV: May be administered undiluted by rapid IV injection.
Monitor cardiac, blood pressure, and oxygenation during administration; temperature, serum potassium and calcium,
assisted ventilator status; neuromuscular function with a peripheral nerve stimulator
Drug Interactions
Acetylcholinesterase Inhibitors: May increase the serum concentration of Succinylcholine. Management: Consider
alternatives to this combination due to a risk of prolonged neuromuscular blockade. Risk D: Consider therapy
modification
therapy
C: Monitor therapy
Monitor therapy
Cyclophosphamide: May increase the serum concentration of Succinylcholine. Management: Consider alternatives to
succinylcholine in patients who have received cyclophosphamide in the past 10 days, or reduced succinylcholine doses (a
serum pseudocholinesterase assay may help inform this reduction) with close monitoring. Risk D: Consider therapy
modification
Monitor therapy
Monitor therapy
Monitor therapy
therapy
Sertraline: May increase the serum concentration of Succinylcholine. Risk C: Monitor therapy
therapy
therapy

Manufacturer recommends refrigeration at 2°C to 8°C (36°F to 46°F) and may be stored at room temperature for 14
days; however, additional testing has demonstrated stability for ≤6 months unrefrigerated (25°C) (Ross, 1988; Roy,
2008). Stability in polypropylene syringes (20 mg/mL) at room temperature (25°C) is 45 days (Storms, 2003).

Onset of action: Dependent on route, age, and dose; data suggest faster onset with higher doses (Coté 2013):
IM: Infants and Children: 3 to 4 minutes (Liu 1981); Adults: 2 to 3 minutes
IV:
Neonates and Infants: ~30 seconds (range: 19 to 40 seconds [dose: 2 to 4 mg/kg]) (Meakin 1990)
Children and Adolescents: 35 to 55 seconds (Coté 2013); Dose-specific: 40 seconds (dose: 1.5 to 2 mg/kg); 50 seconds
(dose: 1 mg/kg) (Coté 2013)
Adults: Flaccid paralysis: <60 seconds
Duration: Dependent on route, age, and dose; hypothermia may prolong the duration of action
IM: 10 to 30 minutes; Observed to be shorter in infants than children
IV: ~4 to 6 minutes; Faster recovery rate in infants and children compared to adults (Fisher 1975)
Distribution: Vd higher in neonates and infants due to larger ECF volume; higher IV doses necessary
Metabolism: Rapidly hydrolyzed by plasma pseudocholinesterase to inactive metabolites

Excretion: Urine (~10% excreted unchanged)
Adverse Reactions
Cardiovascular: Bradycardia (higher with second dose; more frequent in children), cardiac arrhythmia, hypertension,
hypotension, malignant hyperthermia, tachycardia
Endocrine & metabolic: Hyperkalemia
Gastrointestinal: Sialorrhea
Neuromuscular & skeletal: Fasciculations, jaw tightness, myalgia (postoperative), rhabdomyolysis (with possible
myoglobinuric acute renal failure)
Ophthalmic: Increased intraocular pressure
Respiratory: Apnea, respiratory depression (prolonged)
Rare but important or life-threatening: Abnormal bone growth (myositis ossificans; prolonged use), myopathy (acute
quadriplegic myopathy syndrome; prolonged use)
SULFATO FERROSO
Dosing: Neonatal
Note: Multiple concentrations of ferrous sulfate oral liquid exist; close attention must be paid to the concentration
when ordering and administering ferrous sulfate; incorrect selection or substitution of one ferrous sulfate liquid for
another without proper dosage volume adjustment may result in serious over- or underdosing.
Note: Doses expressed in terms of elemental iron; ferrous sulfate contains ~20% elemental iron; ferrous sulfate
exsiccated (dried) contains ~30% elemental iron
Iron deficiency; prevention in neonates fed human milk:Oral:
Preterm (<37 weeks gestational age): 2 mg/kg/day divided every 12 to 24 hours; begin at 4 to 8 weeks PNA
(maximum dose: 15 mg/day) (AAP [Baker 2010]; WHO 2001)
Full-term: In healthy, term infants, that are full or partially breastfed, AAP does not recommend routine additional
supplementation of iron be considered until at least 4 to 6 months of age, if at all (AAP [Baker 2010];
Schanler 2011)
Iron deficiency anemia; treatment: Oral: 3 to 6 mg/kg/day in 3 divided doses (ASPEN Pediatric Nutrition Support Core
Curriculum [Corkins 2015]; Rao 2009)
Supplementation during epoetin use: Limited data available; dosing regimens variable: Usual dose: 6 mg/kg/day in 2 to
3 divided doses; usual range: 3 to 8 mg/kg/day although higher doses (up to 12 mg/kg/day) have been used in
some protocols (Kleinman 2009; Meyer 1996; Rao 2009)
Dosing: Pediatric
Note: Multiple concentrations of ferrous sulfate oral liquid exist; close attention must be paid to the concentration
when ordering and administering ferrous sulfate; incorrect selection or substitution of one ferrous sulfate liquid for
another without proper dosage volume adjustment may result in serious over- or underdosing.
Note: Doses expressed in terms of elemental iron; Ferrous sulfate contains ~20% elemental iron; ferrous sulfate
exsiccated (dried) contains ~30% elemental iron
Iron deficiency anemia; prevention: Oral:
Infants ≥4 months (receiving human milk as only nutritional source or >50% as source of nutrition without iron
fortified food): 1 mg iron/kg/day (Baker 2010); Note: In healthy, term infants, AAP does not recommend
routine additional supplementation of iron be considered until at least 4 to 6 months of age if breastfed
(full or partial) (Baker 2010; Schanler 2011)
Infants ≥6 months and Children <2 years in areas where anemia prevalence is >40%: 10 to 12.5 mg daily for 3
consecutive months in a year (WHO 2016b)
Children 2 years to <5 years in areas where anemia prevalence is >40%: 30 mg daily for 3 consecutive months in a
year (WHO 2016b)
Children ≥5 to 12 years in areas where anemia prevalence is >40%: 30 to 60 mg daily for 3 consecutive months in
a year (WHO 2016b)
Adolescent menstruating females (nonpregnant females of reproductive potential) in areas where anemia
prevalence is >40%: 30 to 60 mg daily for 3 consecutive months in a year (WHO 2016a)
Treatment of iron deficiency: Infants, Children, and Adolescents: 3 to 6 mg/kg/day in 3 divided doses; suggested
maximum daily dose: 200 mg/day (ASPEN Pediatric Nutrition Support Core Curriculum [Corkins 2015]; Kliegman
2016)
Contraindications
Hypersensitivity to iron salts or any component of the formulation; hemochromatosis, hemolytic anemia
• Gastrointestinal disease: Avoid in patients with peptic ulcer, enteritis, or ulcerative colitis.

• Blood transfusion recipients: Avoid in patients receiving frequent blood transfusions.
• Elderly: Anemia in the elderly is often caused by “anemia of chronic disease” or associated with inflammation
rather than blood loss. Iron stores are usually normal or increased, with a serum ferritin >50 ng/mL and a
decreased total iron binding capacity. Hence, the “anemia of chronic disease” is not secondary to iron
deficiency but the inability of the reticuloendothelial system to reclaim available iron stores.
• Pediatric: Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under
6 years of age. Keep this product out of the reach of children. In case of accidental overdose call the poison
control center immediately.
• Premature infants: Avoid use in premature infants until the vitamin E stores, deficient at birth, are replenished.
• Oral iron formulations: Immediate release oral iron products are preferred for treatment of iron deficiency
anemia; enteric coated and slow/sustained release preparations are not desired due to poor absorption
(Hershko 2014; Liu 2012).
• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity
reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products
containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995).
Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in
premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984).
(AAP 1997; Zar 2007).
• Duration of therapy: Administration of iron for >6 months should be avoided except in patients with continuous
bleeding or menorrhagia.
Consider all iron sources when evaluating the dose of iron, including combination products, infant formulas, and liquid
nutritional supplements. Some liquid preparations may temporarily stain the teeth.
including hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Shehab 2009).
Oral: Do not chew or crush extended release preparations; administer with water or juice between meals for maximum
absorption; may administer with food if GI upset occurs; do not administer with milk or milk products
May be administered with food to prevent irritation; however, not with cereals, dietary fiber, tea, coffee, eggs, or milk.
Ferrous sulfate contains ~20% elemental iron (ie, 325 mg ferrous sulfate is equivalent to 65 mg elemental iron); ferrous
sulfate exsiccated (dried) contains ~30% elemental iron.
Dietary sources of iron include beans, cereal (enriched), clams, beef, lentils, liver, oysters, shrimp, and turkey. Foods that
enhance dietary absorption of iron include broccoli, grapefruit, orange juice, peppers, and strawberries. Foods
that decrease dietary absorption of iron include coffee, dairy products, soy products, spinach, and tea.
Dietary reference intake (IOM 2001): Note: Dosage expressed in terms of elemental iron; ferrous sulfate contains ~20%
elemental iron; ferrous sulfate exsiccated (dried) contains ~30% elemental iron.
0 to 6 months: 0.27 mg daily (adequate intake)
7 to 12 months: 11 mg daily
1 to 3 years: 7 mg daily
14 to 18 years: Males: 11 mg daily; Females: 15 mg daily; Pregnant females: 27 mg daily; Lactating females: 10 mg
daily
19 to 50 years: Males: 8 mg daily; Females: 18 mg daily; Pregnant females: 27 mg daily; Lactating females: 9 mg
daily
≥50 years: 8 mg daily
Serum iron, total iron binding capacity, reticulocyte count, hemoglobin, ferritin
Reference Range
Serum iron: 22-184 mcg/dL
Total iron binding capacity:

Infants: 100-400 mcg/dL
Children and Adults: 250-400 mcg/dL
Drug Interactions
Antacids: May decrease the absorption of Iron Salts. Risk D: Consider therapy modification
Cefdinir: Iron Salts may decrease the serum concentration of Cefdinir. Red-appearing, non-bloody stools may also
develop due to the formation of an insoluble iron-cefdinir complex. Management: Avoid concurrent cefdinir and
oral iron when possible. Separating doses by several hours may minimize interaction. Iron-containing infant
formulas do not appear to interact with cefdinir. Risk D: Consider therapy modification
Ferric Hydroxide Polymaltose Complex: May decrease the serum concentration of Iron Salts. Specifically, the absorption
of oral iron salts may be reduced. Management: Do not administer intravenous (IV) ferric hydroxide polymaltose
complex with other oral iron salts. Therapy with oral iron salts should begin 1 week after the last dose of IV ferric
hydroxide polymaltose complex. Risk D: Consider therapy modification
Levothyroxine: Iron Salts may decrease the serum concentration of Levothyroxine. Management: Separate oral
administration of iron salts and levothyroxine by at least 4 hours. Separation of doses is not required with
parenterally administered iron salts or levothyroxine.Risk D: Consider therapy modification
PenicillAMINE: Polyvalent Cation Containing Products may decrease the serum concentration of PenicillAMINE.
Management: Separate the administration of penicillamine and oral polyvalent cation containing products by at
least 1 hour. Risk D: Consider therapy modification
Proton Pump Inhibitors: May decrease the absorption of Iron Salts. Risk C: Monitor therapy
Quinolones: Iron Salts may decrease the serum concentration of Quinolones. Management: Give oral quinolones at least
several hours before (4 h for moxi- and sparfloxacin, 2 h for others) or after (8 h for moxi-, 6 h for cipro/dela-, 4 h
for lome-, 3 h for gemi-, and 2 h for levo-, nor-, oflox-, pefloxacin, or nalidixic acid) oral iron
salts Exceptions: LevoFLOXacin (Oral Inhalation). Risk D: Consider therapy modification
Tetracyclines: May decrease the absorption of Iron Salts. Iron Salts may decrease the serum concentration of
Tetracyclines. Exceptions: Eravacycline. Risk D: Consider therapy modification
Food Interactions
Cereals, dietary fiber, tea, coffee, eggs, and milk may decrease absorption.
Test Interactions
False-positive for blood in stool by the guaiac test
Onset of action: Hematologic response: Oral: ~3 to 10 days
Peak effect: Reticulocytosis: 5 to 10 days; hemoglobin increases within 2 to 4 weeks

Absorption: Iron is absorbed in the duodenum and upper jejunum; in persons with normal serum iron stores, 10% of an
oral dose is absorbed; this is increased to 20% to 30% in persons with inadequate iron stores. Food and
achlorhydria will decrease absorption
Protein binding: To transferrin
Excretion: Urine, sweat, sloughing of the intestinal mucosa, and menses
Adverse Reactions
Gastrointestinal: Abdominal pain (Tolkien 2015), constipation (Tolkien 2015), darkening of stools (Tolkien 2015),
diarrhea (Tolkien 2015), flatulence (Tolkien 2015), heartburn (Tolkien 2015), nausea (Tolkien 2015), vomiting
(Tolkien 2015)
Rare but important or life-threatening: Abdominal discomfort (Tolkien 2015)
Breast-Feeding Considerations
Iron is present in breast milk (IOM 2001).
Maternal iron requirements are increased in breastfeeding women (IOM 2001). Breast milk levels of iron are maintained
in females with mild to moderate iron deficiency anemia (IDA), but concentrations decrease if IDA is severe (El-
Farrash 2012; Kumar 2008).
Maternal use of ferrous sulfate increases the iron content of breast milk (Marin 2012). Adverse events were not
observed in breastfeeding infants following maternal use of ferrous sulfate in supplemental doses (Baykan 2006).
Ferrous sulfate has been evaluated in multiple studies for the treatment of postpartum IDA (Markova 2015). The
World Health Organization considers ferrous salts used for anemia to be compatible with breastfeeding (WHO
2002). All postpartum women at risk of gestational anemia (regardless of breastfeeding status) may be given oral
iron with or without folic acid for 6 to 12 weeks postpartum to reduce the risk of anemia (WHO 2016c).
Additional Information
When treating iron deficiency anemias, treat for 3-4 months after hemoglobin/hematocrit return to normal in order to
replenish total body stores.
Elemental Iron Content of Iron Salts
Approximate
Elemental Iron Content
Iron Salt Equivalent Doses
(% of salt form)
(mg of iron salt)
Ferrous fumarate 33 197
Ferrous gluconate 11.6 560
Ferrous sulfate 20 324
Ferrous sulfate, exsiccated 30 217
VANCOMYCIN
Dosing: Pediatric
Initial dosage recommendations presented, serum concentrations should be monitored and adjusted
accordingly. Note: Doses require adjustment in renal impairment. Consider single-dose administration with serum
concentration monitoring rather than scheduled dosing in patients with urine output <1 mL/kg/hour or if serum
creatinine significantly increases from baseline (eg, doubles).
General dosing, susceptible infection: Infants, Children, and Adolescents: IV: 45 to 60 mg/kg/day divided every 6 to 8
hours; dose and frequency should be individualized based on serum concentrations (Red Book [AAP 2018]). Note: Every
6 hour dosing recommended as initial dosage regimen if targeting trough serum concentrations >10 mcg/mL (Benner
2009; Frymoyer 2009) in patients with normal renal function. Close monitoring of serum concentrations and assurance
of adequate hydration status is recommended; utilize local antibiogram and protocols for further guidance.
Bacteremia [S. aureus (methicillin-resistant)]: Infants, Children, and Adolescents: IV: 15 mg/kg/dose every 6 hours for 2
to 6 weeks depending on severity (IDSA [Liu 2011])
Bone and joint infection:
Osteomyelitis (S. aureus [methicillin-resistant]): Infants, Children, and Adolescents: IV: 15 mg/kg/dose every 6 hours for
a minimum of 4 to 6 weeks (IDSA [Liu 2011])
Septic arthritis (S. aureus [methicillin-resistant]): Infants, Children, and Adolescents: IV: 15 mg/kg/dose every 6 hours for
minimum of 3 to 4 weeks (IDSA [Liu 2011])
C. difficile infection:
Manufacturer's labeling: Infants, Children, and Adolescents: Oral: 40 mg/kg/day divided every 6 to 8 hours for 7 to 10
days; maximum daily dose: 2,000 mg/day
Guideline recommendations:
Non-severe infection, initial or first recurrence: Children and Adolescents: Oral: 10 mg/kg/dose 4 times daily for 10 days;
maximum dose: 125 mg/dose (IDSA/SHEA [McDonald 2018])
Severe/fulminant infection, initial: Children and Adolescents:
Oral: 10 mg/kg/dose 4 times daily for 10 days; maximum dose: 500 mg/dose; may consider adding IV metronidazole in
critically ill patients (IDSA/SHEA [McDonald 2018]). If patient is unable to tolerate oral therapy, may use nasogastric
administration (ASID [Trubiano 2016]).
Rectal: Note: Consider use when ileus is present. Limited data available: Rectal enema: 500 mg in 100 mL NS; dose
volume is determined by age (IDSA/SHEA [McDonald 2018]); the optimal doses have not been established in pediatric
patients; suggested volumes for children: 1 to 3 years: 50 mL; 4 to 9 years: 75 mL; >10 years: 100 mL (ASID [Trubiano
2016]); administer 4 times daily with or without IV metronidazole (IDSA/SHEA [McDonald 2018])
Second or subsequent recurrence: Children and Adolescents: Pulsed-tapered regimen: Oral: 10 mg/kg/dose 4 times daily
for 10 to 14 days; then 10 mg/kg/dose twice daily for 7 days, then 10 mg/kg/dose once daily for 7 days, then 10
mg/kg/dose every 2 or 3 days for 2 to 8 weeks; maximum dose: 125 mg/dose (IDSA/SHEA [McDonald 2018])
CNS infection:
Brain abscess, subdural empyema, spinal epidural abscess [S. aureus (methicillin-resistant)]: Infants, Children, and
Adolescents: IV: 15 mg/kg/dose every 6 hours for 4 to 6 weeks (some experts combine with rifampin) (IDSA [Liu 2011])
Meningitis: Infants, Children, and Adolescents: IV: 15 mg/kg/dose every 6 hours; Note: Maintain trough serum
concentrations of 15 to 20 mcg/mL (IDSA [Tunkel 2004]; IDSA [Tunkel 2017])
S. aureus (methicillin-resistant): Infants, Children, and Adolescents: IV: 15 mg/kg/dose every 6 hours for 2 weeks (some
experts combine with rifampin) (IDSA [Liu 2011])
VP-shunt infection, ventriculitis: Limited data available: Infants, Children, and Adolescents:
Intrathecal/intraventricular (use a preservative-free preparation): 5 to 20 mg/day; usual dose: 10 or 20 mg/day (IDSA
[Tunkel 2004]; IDSA [Tunkel 2017]); due to the smaller CSF volume in infants, some guidelines recommend decreasing
the infant dose (IDSA [Tunkel 2017])
Endocarditis, treatment:
Empiric therapy/culture negative: Children and Adolescents: IV 60 mg/kg/day divided every 6 hours; maximum daily
dose: 2,000 mg/day; use in combination with other antibiotics for at least 4 weeks; longer duration may be required if
prosthetic material is present; dosage should be adjusted to target trough serum concentrations of 10 to 15 mcg/mL;
higher trough concentrations (15 to 20 mcg/mL) may be needed if there is a lack of response or if a resistant organism
(MIC >1 mcg/mL) is identified (AHA [Baltimore 2015])
Streptococcus (including enterococcus): Children and Adolescents: IV: 40 mg/kg/day divided every 8 to 12 hours for at
least 4 to 6 weeks; a longer duration and additional antibiotics may be required depending on organism and presence of
prosthetic material; dosage should be adjusted to target trough serum concentrations of 10 to 15 mcg/mL; higher
trough concentrations (15 to 20 mcg/mL) may be needed for resistant organisms (MIC >1 mcg/mL) or if there is a lack of
response (AHA [Baltimore 2015])
S. aureus:
Non-methicillin resistant: Children and Adolescents: IV: 40 mg/kg/day divided every 8 to 12 hours for at least 4 to 6
weeks; a longer duration and additional antibiotics may be required depending on organism and presence of prosthetic
material; dosage should be adjusted to target trough serum concentrations of 10 to 15 mcg/mL; higher trough
concentrations (15 to 20 mcg/mL) may be needed for resistant organisms (MIC >1 mcg/mL) or if there is a lack of
response (AHA [Baltimore 2015])
Methicillin-resistant:
AHA Guidelines: Children and Adolescents: IV: 40 mg/kg/daydivided every 8 to 12 hours for at least 6 weeks; maximum
daily dose: 2,000 mg/day; a longer duration may be required depending on the presence of prosthetic material; dosage
should be adjusted to target trough serum concentrations of 15 to 20 mcg/mL (AHA [Baltimore 2015])
IDSA Guidelines: Infants, Children, and Adolescents: IV: 60 mg/kg/daydivided every 6 hours (IDSA [Liu 2011])
Enterocolitis (S. aureus): Infants, Children, and Adolescents: Oral: 40 mg/kg/day divided every 6 to 8 hours for 7 to 10
days; maximum daily dose: 2,000 mg/day
Intra-abdominal infection, complicated (MRSA):Infants, Children, and Adolescents: IV: 40 mg/kg/day divided every 6 to 8
hours (IDSA [Solomkin 2010])
Peritonitis (peritoneal dialysis) (ISPD [Warady 2012]):
Prophylaxis: Infants, Children, and Adolescents:
Touch contamination of PD line (if known MRSA colonization): Intraperitoneal: 25 mg per liter
High-risk gastrointestinal procedures: Note:Use should be reserved for patients at high risk for MRSA: IV: 10 mg/kg
administered 60 to 90 minutes before procedure; maximum dose: 1,000 mg
Treatment: Infants, Children, and Adolescents:
Intermittent: Intraperitoneal: Initial dose: 30 mg/kg in the long dwell; subsequent doses: 15 mg/kg/dose every 3 to 5
days during the long dwell; Note: Increased clearance may occur in patients with residual renal function; subsequent
doses should be based on serum concentration obtained 2 to 4 days after the previous dose; redosing should occur
when serum concentration <15 mcg/mL.
Continuous: Intraperitoneal: Loading dose: 1,000 mg per liter of dialysate; maintenance dose: 25 mg per liter
Pneumonia:
Community-acquired pneumonia (CAP): Infants >3 months, Children, and Adolescents: IV: 40 to 60 mg/kg/day every 6 to
8 hours; dosing to achieve AUC/MIC >400 has been recommended for treating moderate to severe MRSA infections
(IDSA/PIDS [Bradley 2011])
Alternate dosing: S. aureus (methicillin-resistant): Infants, Children, and Adolescents: IV: 60 mg/kg/day divided every 6
hours for 7 to 21 days depending on severity (IDSA [Liu 2011])
Health care-associated pneumonia (HAP), S. aureus(methicillin-resistant): Infants, Children, and Adolescents: IV: 60
mg/kg/day divided every 6 hours for 7 to 21 days depending on severity (IDSA [Liu 2011])
Septic thrombosis of cavernous or dural venous sinus [S. aureus (methicillin-resistant)]: Infants, Children, and
Adolescents: IV: 15 mg/kg/dose every 6 hours for 4 to 6 weeks (some experts combine with rifampin) (IDSA [Liu 2011])
Skin and skin structure infections, complicated: [MRSA or S. aureus (methicillin sensitive) in penicillin allergic
patients]: Infants, Children, and Adolescents (IDSA [Stevens 2014]):
Non-necrotizing infection: IV: 10 mg/kg/dose every 6 hours
Necrotizing infection: IV: 15 mg/kg/dose every 6 hours. Continue until further debridement is not necessary, patient has
clinically improved, and patient is afebrile for 48 to 72 hours.
Alternate dosing: S. aureus (methicillin-resistant): Infants, Children, and Adolescents: IV: 60 mg/kg/day divided every 6
hours for 7 to 14 days (IDSA [Liu 2011])
Surgical (perioperative) prophylaxis: Infants, Children, and Adolescents: IV: 15 mg/kg/dose within 120 minutes prior to
surgical incision. May be administered in combination with other antibiotics depending upon the surgical procedure
(ASHP/IDSA/SIS/SHEA [Bratzler 2013]).
Oral: There are no dosage adjustments provided in manufacturer's labeling; however, dosage adjustment unlikely due to
low systemic absorption.
IV: Note: Vancomycin levels should be monitored in patients with any renal impairment:
Infants, Children, and Adolescents: The following adjustments have been recommended (Aronoff 2007): Note: Renally
adjusted dose recommendations are based on doses of 10 mg/kg/dose every 6 hours or 15 mg/kg/dose every 8 hours:
GFR 10 to 29 mL/minute/1.73 m2: 10 mg/kg/dose every 18 to 24 hours
GFR <10 mL/minute/1.73 m2: 10 mg/kg/dose; redose based on serum concentrations
Intermittent hemodialysis: 10 mg/kg/dose; redose based on serum concentrations
Peritoneal dialysis (PD): 10 mg/kg/dose; redose based on serum concentrations
Continuous renal replacement therapy (CRRT): 10 mg/kg/dose every 12 to 24 hours; monitor serum concentrations
IV: There are no dosage adjustments provided in the manufacturer's labeling; however, degrees of hepatic dysfunction
do not affect the pharmacokinetics of vancomycin (Marti 1996).
• Extravasation and thrombophlebitis: IV vancomycin is an irritant; ensure proper needle or catheter placement prior to
and during infusion; avoid extravasation. Pain, tenderness, and necrosis may occur with extravasation. If
thrombophlebitis occurs, slow infusion rates, dilute solution (eg, 2.5 to 5 g/L) and rotate infusion sites.
• Nephrotoxicity: May cause nephrotoxicity although limited data suggest direct causal relationship; usual risk factors
include preexisting renal impairment, concomitant nephrotoxic medications, advanced age, dehydration, critically-ill
patients, patients with rapidly changing renal function, higher vancomycin serum levels, prolonged exposure, and
concomitant piperacillin/tazobactam administration. If multiple sequential (≥2) serum creatinine concentrations
demonstrate an increase of 0.5 mg/dL or ≥50% increase from baseline (whichever is greater) in the absence of an
alternative explanation, the patient should be identified as having vancomycin-induced nephrotoxicity (ASHP/IDSA/SIDP
[Rybak 2009]). Discontinue treatment if signs of nephrotoxicity occur; renal damage is usually reversible. Nephrotoxicity
has been reported following treatment with oral vancomycin (typically in patients >65 years of age).
• Neutropenia: Prolonged therapy and use of concomitant drugs that cause neutropenia may increase the risk; monitor
leukocyte counts periodically in these patients. Prompt reversal of neutropenia is expected after discontinuation of
therapy.
• Ototoxicity: Ototoxicity is rarely associated with monotherapy. Ototoxicity manifests as tinnitus, hearing loss,
dizziness, or vertigo. It has been most frequently reported in older patients, patients receiving excessive doses, those
who have underlying hearing loss, or those receiving concomitant ototoxic drugs (eg, aminoglycosides). Serial auditory
function testing may be helpful to minimize risk. Ototoxicity may be transient or permanent; discontinue treatment if
signs of ototoxicity occur.
• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile infection (CDI); CDI
has been observed >2 months postantibiotic treatment.
• Inflammatory bowel disease: Clinically significant serum concentrations have been reported in patients with
inflammatory disorders of the intestinal mucosa who have taken oral vancomycin (multiple doses) for the treatment
of C. difficile-associated diarrhea. Although use may be warranted, the risk for adverse reactions may be higher in this
situation; consider monitoring serum trough concentrations, especially with renal insufficiency, severe colitis, and
concurrent enteral vancomycin administration (IDSA/SHEA [McDonald 2018]; Pettit 2015).
• Pregnancy: [US Boxed Warning]: The formulation of vancomycin injection containing the excipients, polyethylene
glycol (PEG 400) and N-acetyl D-alanine (NADA), is not recommended for use during pregnancy. PEG 400 and NADA have
caused fetal malformations in animal reproduction studies. If use of vancomycin is needed during pregnancy, use other
available formulations of vancomycin.
• Renal impairment: Use with caution in patients with renal impairment or those receiving other nephrotoxic or ototoxic
drugs; dosage modification required (especially in elderly patients). Accumulation may occur after multiple oral doses of
vancomycin in patients with renal impairment; consider monitoring trough concentrations in this circumstance.
information.
• Appropriate use: Oral vancomycin is only indicated for the treatment of CDI or enterocolitis due to S. aureus and is not
effective for systemic infections; parenteral vancomycin is not effective for the treatment of enterocolitis. Prescribing
vancomycin in the absence of a proven or strongly suspected bacterial infection or prophylactic indication is unlikely to
provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
• Infusion reactions: Rapid IV administration (eg, over <60 minutes) may result in hypotension, flushing, erythema,
urticaria, pruritus, wheezing, dyspnea, and, rarely, cardiac arrest. Reactions usually cease promptly after infusion is
stopped. Frequency of infusion reactions may increase with concomitant administration of anesthetics. If used in
conjunction with anesthesia, complete the vancomycin infusion prior to anesthesia induction.
• Intraocular administration (off-label route): Hemorrhagic occlusive retinal vasculitis (HORV), including permanent
visual loss, has been reported in patients receiving intracameral or intravitreal administration of vancomycin during or
after cataract surgery. Safety and efficacy of intraocularly administered vancomycin has not been established;
vancomycin is not indicated for prophylaxis of endophthalmitis.
• Intraperitoneal administration (off-label route): Use caution when administering intraperitoneally (IP); in some
continuous ambulatory peritoneal dialysis (CAPD) patients, chemical peritonitis (cloudy dialysate, fever, severe
abdominal pain) has occurred. Symptoms are self-limited and usually clear after vancomycin discontinuation.
Parenteral: Reconstitute vials with SWFI to a final concentration of 50 mg/mL (see manufacturer's labeling for specific
details). Further dilute the reconstituted solution in a compatible diluent (eg, D5W, NS) to a final concentration ≤5
mg/mL. In fluid restricted patients, a concentration of 10 mg/mL may be used, but the risk of infusion reactions
increases.
Intrathecal/intraventricular: Dilute to 1 to 5 mg/mL concentration in preservative free NS for administration into the CSF
(Al-Jeraisy 2004; Pfausler 1997); concentrations as high as 10 mg/mL have been reported in adults (Cook 2009)
Parenteral: Administer intermittent IV infusion over 60 minutes. Red man syndrome may occur if the infusion is too
rapid. It is not an allergic reaction, but may be characterized by hypotension and/or a maculopapular rash appearing on
the face, neck, trunk, and/or upper extremities; if this should occur, slow the infusion rate to administer dose over 90 to
120 minutes (Healy 1990; Szymusiak-Mutnick 1996) and increase the dilution volume; the reaction usually dissipates in
30 to 60 minutes; administration of antihistamines just before the infusion may also prevent or minimize this reaction.
Irritant; ensure proper needle or catheter placement prior to and during infusion. Avoid extravasation. If extravasation
(do NOT flush the line); remove needle/cannula; elevate extremity. Information varies regarding the use of dry cold or
dry warm compresses (Hurst 2004; Reynolds 2014); however, dry warm compresses may be of benefit in increasing local
blood flow to enhance drug removal from the extravasation site. Intradermal hyaluronidase may be considered for
refractory cases (Reynolds 2014).
Intrathecal/Intraventricular: Administer as diluted solution (1 to 10 mg/mL) (Al-Jeraisy 2004; Cook 2009; Pfausler 1997)
Reference Range
Measure trough serum concentrations to assess efficacy. Peak concentrations may be helpful in the setting of atypical
pharmacokinetic profile. Trough serum concentration typically obtained at steady state (ie, prior to the fourth dose).
Target trough serum concentration may vary depending on organism, MIC, source of infection, and/or other patient
factors (ASHP/IDSA/SIDP [Rybak 2009]); utilize local antibiogram and protocols for further guidance.
15 to 20 mcg/mL: For organisms with an MIC ≥1 mcg/mL to meet the target AUC/MIC of ≥400 in non-neonatal patients
(see Note). The American Thoracic Society (ATS) guidelines for hospital-acquired pneumonia and the Infectious Disease
Society of America (IDSA) meningitis guidelines also recommend trough concentrations of 15 to 20 mcg/mL.
Recommended to improve penetration and improve clinical outcomes for complicated infections (eg, bacteremia,
endocarditis, osteomyelitis) caused by S. aureus (ASHP/IDSA/SIDP [Rybak 2009]; IDSA [Liu 2011]).
10 to 15 mcg/mL: Current recommendation for all other infections with an organism with an MIC <1 mcg/mL. In
neonates, for confirmed or highly suspected MRSA infection, initial target trough concentration of ~10 mcg/mL is
suggested to achieve an AUC24 >400 for organisms with MIC ≤1 mcg/mL (Frymoyer 2014; Stockmann 2015)
Note: Although AUC/MIC is the preferred pharmacokinetic-pharmacodynamic parameter used to determine clinical
effectiveness, trough serum concentrations may be used as a surrogate marker for AUC and are recommended as the
most accurate and practical method of vancomycin monitoring (ASHP/IDSA/SIDP [Rybak 2009]; IDSA [Liu 2011]).
Drug Interactions
Aminoglycosides: Vancomycin may enhance the nephrotoxic effect of Aminoglycosides. Risk C: Monitor therapy
Monitor therapy
Colistimethate: Vancomycin may enhance the nephrotoxic effect of Colistimethate. Risk D: Consider therapy
modification
Neuromuscular-Blocking Agents: Vancomycin may enhance the neuromuscular-blocking effect of Neuromuscular-
Nonsteroidal Anti-Inflammatory Agents: May increase the serum concentration of Vancomycin. Risk C: Monitor therapy
Piperacillin: May enhance the nephrotoxic effect of Vancomycin. Risk C: Monitor therapy
Adverse Reactions
Injection:
Cardiovascular: Hypotension (accompanied by flushing), local phlebitis
Central nervous system: Chills, drug fever
Hematologic & oncologic: Eosinophilia, neutropenia (reversible)
Hypersensitivity: Flushing of face and neck (Red man syndrome; may be infusion related)
Rare but important or life-threatening: DRESS syndrome (drug rash with eosinophilia and systemic symptoms),
ototoxicity (rare; use of other ototoxic agents may increase risk), renal failure (limited data suggesting direct
relationship), Stevens-Johnson syndrome, thrombocytopenia, vasculitis
VASOPRESINA
Dosing: Neonatal
Cardiac surgery (complex procedure; eg, Norwood; arterial switch); post-bypass: Limited data available: Continuous IV
infusion: Mean reported dose range: 0.3 to 0.5 milliunits/kg/minute, titrated to hemodynamic goals (Alten 2012; Burton
2011). Dosing based on experience in 37 neonates (n=19 in vasopressin group) which showed a mean infusion rate: 0.3
milliunits/kg/minute (range: 0.08 to 1 milliunit/kg/minute) was associated with decreased catecholamine use and
significant reduction in fluid resuscitation during first 24 hours after surgery compared to the control group (Alten 2012);
a retrospective report of 28 neonates with refractory hemodynamic instability after Norwood palliation showed
improvement in urine output, SBP, and pH markers with vasopressin at a mean infusion rate of 0.5 milliunits/kg/minute
(Burton 2011). Note: Hyponatremia reported frequently; monitor serum Na (Alten 2012; Davalos 2013).
Hypotension (initial therapy): Very limited data available (Rios 2014): ELBW neonates (GA ≤30 weeks): Continuous IV
infusion: Reported range: 0.17 to 0.67 milliunits/kg/minute (0.01 to 0.04 units/kg/hour); dosing initiated at low end of
range and titrated at 20 minute intervals in 0.17 milliunits/kg/minute (0.01 units/kg/hour) increments. Dosing based on
a prospective, randomized, double-blind trial comparing vasopressin and dopamine as initial therapy in 20 hypotensive
ELBW neonates (vasopressin treatment group, n=10; mean GA: 25.7 weeks; PNA: <24 hours; mean birth weight: 640 g)
with a control group of 50 normotensive ELBW neonates; primary efficacy outcomes were similar in both treatment
groups; other findings showed that subjects in the vasopressin group received significantly fewer surfactant doses and
had a lower mean PaCO2; and unlike the dopamine group, tachycardia was not observed in the vasopressin group (Rios
2015).
Persistent pulmonary hypertension of the newborn (PPHN), refractory: Very limited data available: GA ≥37 weeks:
Continuous IV infusion: Initial: 0.1 milliunits/kg/minute, increase in 0.1 milliunits/kg/minute increments every hour as
needed for clinical response to a maximum dose of 1.2 milliunits/kg/minute; dosing based on a case series in 10
neonates (GA ≥37 weeks; birth weight ≥2.2 kg) which showed significant improvement in oxygenation index, blood
pressure, and urine output and a reduction in iNO dose (Mohamed 2014)
Shock; vasodilatory with refractory hypotension unresponsive to fluid resuscitation and exogenous catecholamines:
Limited data available; dosing regimens and efficacy results variable: Continuous IV infusion: 0.17 to 10
milliunits/kg/minute (0.01 to 0.6 units/kg/hour) have been used; doses were initiated at the lower end of the range and
titrated to effect in most studies. Dosing based on retrospective reviews and case reports that have shown increases in
arterial blood pressure and urine output and also allowed for dosage reductions of additional vasopressors (Bidegain
2010; Brierley 2009; Choong 2008; Ikegami 2010; Meyer 2008).
Dosing: Pediatric
Diabetes insipidus: Note: Highly variable dosage; titrate dosage based upon serum and urine sodium and osmolality in
addition to fluid balance and urine output. Children and Adolescents: IM, SubQ: 2.5 to 10 units 2 to 4 times daily
(Kliegman 2007)
Central diabetes insipidus: Limited data available: Infants, Children, and Adolescents: Continuous IV infusion: Initial: 0.5
milliunits/kg/hour; titrate upward in 0.5 milliunits/kg/hour increments at approximately 10-minute intervals to target
urine output (suggested output target: <2 mL/kg/hour) (Sperling 2014; Wise-Faberowski 2004); infusion rates up to 10
milliunits/kg/hour have been reported (Alharfi 2013). Note: Use in conjunction with fluid therapy, monitor urine output
and specific gravity, serum and urine electrolytes (primarily Na), and plasma osmolality.
Cadaveric organ donations (hormone replacement therapy): Limited data available (Nakagawa/NATCO Guidelines 2008):
Infants, Children, and Adolescents: Continuous IV infusion: Initial: 0.5 to 1 milliunits/kg/hour; titrate dose to maintain
targeted urine output. In a retrospective case-controlled study (n=34, age: 8.2 ± 6.2 years), a mean dose of 41
milliunits/kg/hour was reported with a range of 0.2 milliunits/kg/hour to 150 milliunits/kg/hour (Katz 2000).
GI hemorrhage: Limited data available: Children and Adolescents: Continuous IV infusion: Initial: 2 to 5
milliunits/kg/minute; titrate dose as needed; maximum dose: 10 milliunits/kg/minute (Kliegman 2007, Tuggle 1988);
usual adult dosing range is 0.2 to 0.4 units/minute up to a maximum rate of 0.8 units/minute (AASLD [Garcia-Tsao
2007]). Note: Higher doses have not been associated with greater efficacy but have been associated with increased risk
of complications (Tuggle 1988).
Pulseless arrest, ventricular fibrillation, ventricular tachycardia: Limited data available: Infants, Children, and
Adolescents: IV: 0.4 units/kg as a single dose after traditional resuscitation methods and at least two doses of
epinephrine have been administered. Note: Due to insufficient evidence, no formal recommendations for or against the
routine use of vasopressin during pediatric cardiac arrest are provided (Duncan 2009; Mann 2002; PALS 2010).
Vasodilatory shock with hypotension unresponsive to fluid resuscitation and exogenous catecholamines: Limited data
available; efficacy results have varied (SCCM [Dellinger 2013]): Infants, Children, and Adolescents: Continuous IV
infusion: 0.17 to 8 milliunits/kg/minute (0.01 to 0.48 units/kg/hour) has been used; dosing based on retrospective
reviews and case reports that have shown increases in arterial blood pressure and urine output and also allowed for
dosage reductions of additional vasopressors (Brierley 2009; Choong 2008; Meyer 2008). The only double-blind,
placebo-controlled trial (n=65, age: 3 to 14 years) evaluated a dose of 0.5 to 2 milliunits/kg/minute (0.03 to 0.12
units/kg/hour) at multiple centers and found no significant difference in the time to reach hemodynamic stability and a
trend toward increased mortality in the vasopressin group was noted. Based on these findings, the authors did not
recommend routine use of vasopressin (Choong 2009). Note: Abrupt discontinuation of infusion may result in
hypotension; to discontinue, gradually taper infusion.


Contraindications
Hypersensitivity to vasopressin or any component of the formulation; hypersensitivity to chlorobutanol (Vasostrict 10
mL vial only); uncorrected chronic nephritis with nitrogen retention (Pitressin Synthetic only)
• Extravasation: Vesicant; ensure proper needle or catheter placement prior to and during infusion. Extravasation may
lead to severe vasoconstriction and localized tissue necrosis; also, gangrene of extremities, tongue, and ischemic colitis.
Avoid extravasation.
• Water intoxication: May cause water intoxication; early signs include drowsiness, listlessness, and headache; these
should be recognized to prevent coma and seizures.
• Asthma: Use with caution in patients with asthma.
• Cardiovascular disease: Use with caution in patients with cardiovascular disease, including arteriosclerosis; may
worsen cardiac output.
• Goiter: Use with caution in patients with a goiter with cardiac complications.
• Migraine: Use with caution in patients with a history of migraines.
• Renal impairment: Use with caution in patients with renal disease.
• Seizures: Use with caution in patients with a history of seizure disorder.
• Vascular disease: Use with caution in patients with vascular disease.

May cause hyponatremia; frequency not well-defined in pediatric patients and may vary based on indication. In young
pediatric patients (mean age: 5.2 months; including neonates) who received a vasopressin infusion for hemodynamic
instability following complex cardiac surgery, the observed incidence of hyponatremia (defined as serum Na <135
mEq/L) was statistically higher in the vasopressin group than the control (48% vs 17%, p=0.004) and the decrease in
serum sodium concentration was significantly greater (9.9 mEq/L vs 7.5 mEq/L, p=0.009); it was also observed that the
decrease in the serum Na was more rapid in the vasopressin group (Davalos 2013). With other uses in pediatric patients,
hyponatremia has not been characterized; monitor fluid balance, serum Na and urine output closely.
Parenteral: Continuous IV infusion: Dilute in NS or D5W to a final concentration of 0.1 to 1 unit/mL. Use of a diluted
solution (0.04 units/mL) was described in a pediatric clinical trial that utilized lower dosing (eg, 0.0005 units/kg/hour)
(Wise-Faberowski 2004).
Parenteral:
IM, SubQ: Administer without further dilution.
Continuous IV infusion: Dilute prior to administration. Infusion through central line is strongly recommended.
(do NOT flush the line); remove needle/cannula; elevate extremity. Initiate phentolamine (or alternative antidote) (see
Management of Drug Extravasations for more details).
Specific monitoring determined by indication and may include: Blood pressure, heart rate, fluid intake and output, urine
specific gravity, urine and serum osmolality; serum and urine sodium: Hemoglobin and hematocrit (GI bleeding). Consult
individual institutional policies and procedures.
Reference Range
Vasopressin concentration:
Basal: <4 pg/mL
Water deprivation: 10 pg/mL
Shock: 100 to 1,000 pg/mL (biphasic response)

None known.
Drug Interactions
There are no known significant interactions.

Store intact vials between 2°C and 8°C (36°F and 46°F). Do not freeze.
Vasostrict: May also remove intact vials from refrigeration and store at 20°C to 25°C (68°F to 77°F) for up to 12 months
or manufacturer expiration date, whichever is earlier (indicate date of removal on the vial or note the manufacturer
expiration date, whichever is earlier). After initial entry into the 10 mL vial, opened vial must be refrigerated; discard 30
days after first puncture. Discard unused diluted solution (in D5W or NS) after 18 hours at room temperature or 24
hours under refrigeration.

Onset of action:
Nasal: 1 hour
IV: Vasopressor effect: Rapid with peak effect occurring within 15 minutes of initiation of continuous IV infusion
Duration: Nasal: 3 to 8 hours; IM, SubQ: Antidiuretic: 2 to 8 hours; IV: Vasopressor effect: Within 20 minutes after IV
infusion terminated
Absorption: None from GI tract, destroyed by trypsin in GI tract, must be administered parenterally
Metabolism: Hepatic, renal (inactive metabolites)
Half-life elimination: IM, IV, SubQ: 10 to 20 minutes (apparent half-life: ≤10 minutes)
Excretion: Nasal: Urine; SubQ: Urine (5% as unchanged drug) after 4 hours; IV: Urine (~6% as unchanged drug)
Adverse Reactions
Cardiovascular: Angina pectoris, atrial fibrillation, bradycardia, cardiac arrest, cardiac arrhythmia, ischemic heart disease,
limb ischemia (distal), localized blanching, low cardiac output, myocardial infarction, right heart failure, shock,
vasoconstriction (peripheral)
Central nervous system: Headache (pounding), vertigo
Dermatologic: Circumoral pallor, diaphoresis, gangrene of skin or other tissues, skin lesion (ischemic), urticaria
Endocrine & metabolic: Hyponatremia, hypovolemic shock, water intoxication
Gastrointestinal: Abdominal cramps, flatulence, mesenteric ischemia, nausea, vomiting
Hematologic & oncologic: Decreased platelet count, hemorrhage (intractable)
Hepatic: Increased serum bilirubin
Neuromuscular & skeletal: Tremor
Renal: Renal insufficiency
Respiratory: Bronchoconstriction
VECURONIO
Dosing: Neonatal
Paralysis/skeletal muscle relaxation: Limited data available:
Intermittent IV: 0.1 mg/kg/dose (Kumar 2010); maintenance: 0.03 to 0.15 mg/kg/dose every 1 to 2 hours as needed
(Costarino 1987)
Continuous IV infusion: Initial: 1.7 mcg/kg/minute (0.1 mg/kg/hour) (Fitzpatrick 1991; Reich 2004); titrate until desired
neuromuscular blockade is achieved; some investigators have suggested adjusting rates in 25% to 100% increments
(Reich 2004); doses ranging from 1.2 to 3 mcg/kg/minute (0.07 to 0.18 mg/kg/hour) have been reported (Fitzpatrick
1991)
Dosing: Pediatric
Note: Dose to effect; doses will vary due to interpatient variability. Dosing in obese patients should be calculated using
ideal body weight (Playfor 2007).
Paralysis/skeletal muscle relaxation:
Manufacturer's labeling: Surgical relaxation, tracheal intubation: Infants >7 weeks, Children, and Adolescents: IV: 0.08 to
0.1 mg/kg; Note: If intubation is performed using succinylcholine, the initial dose of vecuronium may be reduced to 0.04
to 0.06 mg/kg with inhalation anesthesia and 0.05 to 0.06 mg/kg with balanced anesthesia. Children 1 to 10 years may
require slightly higher initial doses and more frequent supplementation.
Alternate dosing (Martin 1999; Playfor 2007):
Infants:
IV: 0.08 to 0.1 mg/kg/dose; repeat as needed
Continuous IV infusion: 0.8 to 1.7 mcg/kg/minute (0.05 to 0.1 mg/kg/hour)
Children and Adolescents:
IV: 0.08 to 0.1 mg/kg/dose; repeat as needed
Continuous IV infusion: 0.8 to 2.5 mcg/kg/minute (0.05 to 0.15 mg/kg/hour)

There are no dosage adjustments provided in manufacturer’s labeling. However, patients with renal impairment do not
experience clinically significant prolongation of neuromuscular blockade with vecuronium; however, in patients who are
anephric, the clinical duration is prolonged.

There are no dosage adjustments provided in manufacturer's labeling; however, dose reductions may be necessary in
patients with liver disease.
• Anaphylaxis: Severe anaphylactic reactions have been reported with vecuronium use; some life-threatening and fatal.
Appropriate emergency treatment (including epinephrine 1 mg/mL) should be immediately available during use. Use
caution in patients with previous anaphylactic reactions to other neuromuscular-blocking agents.
• Prolonged paralysis: Some patients may experience delayed recovery of neuromuscular function after administration
(especially after prolonged use). Other factors associated with delayed recovery should be considered (eg, corticosteroid
use, disease-related conditions).
• Burn injury: Resistance may occur in burn patients (≥20% of total body surface area), usually several days after the
injury, and may persist for several months after wound healing (Han 2009).
demyelinating lesions, peripheral neuropathies, denervation, and muscle trauma may result in antagonism of
neuromuscular blockade (ACCM/SCCM/ASHP [Murray 2002]; Greenberg 2013; Miller 2010; Naguib 2002).
hypocalcemia, severe hypokalemia, hypermagnesemia), neuromuscular diseases, metabolic acidosis, respiratory
acidosis, Eaton-Lambert syndrome, and myasthenia gravis may result in potentiation of neuromuscular blockade
(Greenberg 2013; Miller 2010; Naguib 2002).
• Hepatic impairment: Use with caution in patients with hepatic impairment; clinical duration may be prolonged.
• Renal impairment: In general, patients with renal impairment do not experience clinically significant prolongation of
neuromuscular blockade with vecuronium; however, in patients who are anephric, the clinical duration may be
prolonged.
• Respiratory disease: Use with caution in patients with underlying respiratory disease.
• Immobilized patients: Resistance may occur in patients who are immobilized.
• Pediatric: Children 1-10 years of age may require slightly higher initial doses and slightly more frequent
supplementation.
• Appropriate use: Maintenance of an adequate airway and respiratory support is critical. All patients should receive eye
care including liberal use of lubricating drops, gel, or ointment and eyelids should remain closed during continuous
neuromuscular blockade to protect against damage to the cornea (ulceration and drying).

Parenteral:
IV bolus: Reconstitute with provided diluent or compatible solution for injection to final concentration of 1 mg/mL; for
neonatal use, reconstitute with SWFI instead of provided diluent (contains benzyl alcohol).
Continuous IV infusion: Further dilute reconstituted vial in a compatible solution (eg, D5W, NS) for IV infusion; the
manufacturer suggests a final concentration range of 0.1 to 0.2 mg/mL; however, concentrations as high as 1 mg/mL
have been reported (Murray 2014; Phillips 2011; Sinclair-Pingel 2006 ).
Parenteral:
IV bolus: Administer undiluted (reconstituted solution at 1 mg/mL) by rapid direct injection
Continuous IV infusion: Administer via an infusion pump at a concentration not to exceed 1 mg/mL
Assisted ventilation status, heart rate, blood pressure, peripheral nerve stimulator measuring twitch response
Drug Interactions
Acetylcholinesterase Inhibitors: May diminish the neuromuscular-blocking effect of Neuromuscular-Blocking Agents
therapy
Calcium Channel Blockers: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents
CarBAMazepine: May decrease the serum concentration of Vecuronium. Risk C: Monitor therapy
C: Monitor therapy
Monitor therapy
Corticosteroids (Systemic): Neuromuscular-Blocking Agents (Nondepolarizing) may enhance the adverse neuromuscular
effect of Corticosteroids (Systemic). Increased muscle weakness, possibly progressing to polyneuropathies and
myopathies, may occur. Risk D: Consider therapy modification
Monitor therapy
Fosphenytoin-Phenytoin: May diminish the neuromuscular-blocking effect of Neuromuscular-Blocking Agents

(Nondepolarizing). Fosphenytoin-Phenytoin may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking
Agents (Nondepolarizing). Fosphenytoin-Phenytoin may decrease the serum concentration of Neuromuscular-Blocking
Agents (Nondepolarizing). Risk C: Monitor therapy
Inhalational Anesthetics: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents

Ketorolac (Systemic): May enhance the adverse/toxic effect of Neuromuscular-Blocking Agents (Nondepolarizing).
Specifically, episodes of apnea have been reported in patients using this combination. Risk C: Monitor therapy
Monitor therapy
Monitor therapy
therapy
MetroNIDAZOLE (Systemic): May enhance the neuromuscular-blocking effect of Vecuronium. Risk C: Monitor therapy
Piperacillin: May enhance the neuromuscular-blocking effect of Vecuronium. Risk C: Monitor therapy
Polymyxin B: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Risk D: Consider
Spironolactone: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing).

Risk C: Monitor therapy
therapy
Thiazide and Thiazide-Like Diuretics: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents
therapy

Onset of action:
Good intubation conditions: Within 2.5 to 3 minutes
Maximum neuromuscular blockade: Within 3 to 5 minutes
Duration: Under balanced anesthesia (time to recovery to 25% of control): 25 to 40 minutes; recovery 95% complete ~45
to 65 minutes after injection of intubating dose; hypothermia may prolong the duration of action
Distribution: Vd: 0.3 to 0.4 L/kg
Metabolism: Active metabolite: 3-desacetyl vecuronium (1/2 the activity of parent drug)
Half-life, elimination:
Infants: 65 minutes
Children: 41 minutes
Healthy adult surgical patients and renal failure patients undergoing transplant surgery: 65 to 75 minutes; Late
pregnancy: 35 to 40 minutes
Half-life, distribution: Adults: 4 minutes
Excretion: Primarily feces (40% to 75%); urine (30% as unchanged drug and metabolites); the rate of elimination is
appreciably reduced with hepatic dysfunction but not with renal dysfunction
Adverse Reactions
Rare but important or life-threatening: Bradycardia, circulatory shock, edema, flushing, hypersensitivity reaction
(including erythema, hypotension, tachycardia, urticaria), pruritus, skin rash

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ACETILCISTEINA

Loading dose: 140 mg/kg; maximum dose: 15 g/dose

Preparation for Administration: Pediatric

General dosing, severe, susceptible infections: Infants, Children, and Adolescents:

Meningitis (Tunkel 2004):

Infants and Children: IV: 20 to 30 mg/kg/daydivided every 8 hours

Adolescents: IV: 15 mg/kg/day divided every 8 hours

VP-shunt infection, ventriculitis: Limited data available: Intraventricular/intrathecal (use a preservative-

Cystic fibrosis, pulmonary infection: Infants, Children, and Adolescents:

Traditional dosing: IV, IM: 10 mg/kg/dose every 8 hours (Wallace 1993)

Mycobacterium, avium complex infection (MAC), treatment: HIV-exposed/-positive:

Infants, Children, and Adolescents ≤14 years:

Twice-weekly regimen: IM, IV: 25 to 30 mg/kg/dose administered twice weekly as part of a

Adolescents ≥15 years: Independent of HIV status:

Dosing: Renal Impairment: Pediatri

Peritoneal dialĺlysis (PD): 5 mg/kg/dose; redose as indicated by serum concentrations9

Hypersensitivity to amikacin, other aminoglycosides, or any component of the formulation

Concerns related to adverse effects:

• Hypersensitivity: Cross-sensitivity to other aminoglycosides may occur.

• Hypocalcemia: Use with caution in patients with hypocalcemia.

Concurrent drug therapy issues:

Dosage form specific issues:

Warnings: Additional Pediatric Considerations

Preparation for Administration: Adult

IM: Administer IM injection in large muscle mass.

IV: Infuse over 30 to 60 minutes.

• Treatment course >5 days

• Patients with decreased or changing renal function

• Patients with poor therapeutic response

• Neonates and Infants <3 months of age

• Atypical body constituency (obesity, expanded extracellular fluid volume)

• Patients on hemodialysis or chronic ambulatory peritoneal dialysis

• Signs of nephrotoxicity or ototoxicity

• Concomitant use of other nephrotoxic agents

Life-threatening infections: 25 to 40 mcg/mL

Serious infections: 20 to 25 mcg/mL

Urinary tract infections: 15 to 20 mcg/mL

Pharmacodynamics/Kinetics (Adult data unless noted)

Oral: Poorly absorbed

Half-life elimination (renal function and age dependent):

Children: 1.6 to 2.5 hours

Adolescents: 1.5 ± 1 hour

Excretion: Urine (94% to 98% unchanged)

Pharmacodynamics/Kinetics: Additional Considerations

Renal function impairment: Clearance is decreased in renal impairment.

Central nervous system: Neurotoxicity

Otic: Auditory ototoxicity, vestibular ototoxicity

Rare but important or life-threatening: Dyspnea, eosinophilia, hypersensitivity reaction

Mild to moderate infection:

Group A Streptococcus: IV: 200 mg/kg/day divided every 6 hours.

Dental or oral procedures or respiratory tract procedures (eg, tonsillectomy, adenoidectomy):Infants,

Dosing: Renal Impairment: Pediatric

GFR 30 to 50 mL/minute/1.73 m2: 35 to 50 mg/kg/dose every 6 hours

GFR 10 to 29 mL/minute/1.73 m2: 35 to 50 mg/kg/dose every 8 to 12 hours

GFR <10 mL/minute/1.73 m2: 35 to 50 mg/kg/dose every 12 hours

Intermittent hemodialysis: 35 to 50 mg/kg/dose every 12 hours

Peritoneal dialysis (PD): 35 to 50 mg/kg/dose every 12 hours

Continuous renal replacement therapy (CRRT): 35 to 50 mg/kg/dose every 6 hours

Dosing: Hepatic Impairment: Pediatric

Concerns related to adverse effects:

• Hypersensitivity/anaphylactoid reactions: Serious and occasionally severe or fatal hypersensitivity

• Superinfection: Prolonged use may result in fungal or bacterial superinfection,

Warnings: Additional Pediatric Considerations