ORIGINAL ARTICLE
Digoxin: Clinical Highlights
A Review of Digoxin and Its Use in Contemporary Medicine
Michael Ehle, PharmD, BCPS,* Chandni Patel, PharmD,* and Robert P. Giugliano, MD, SM
Abstract: Digoxin is the oldest cardiac medication used in contemporary
medicine. With a complex pharmacokinetic profile and narrow therapeutic
index, its use in managing patients with atrial arrhythmias or heart failure can
present a challenge to todays clinicians. Digoxin dosing based on patient-
specific factors such as age, lean body weight, and renal function will allow
practitioners to minimize drug toxicity while maintaining clinical effi-
cacy. The ability to recognize digoxin overdose, which can manifest in
both the acute and chronic settings, helps guide the appropriate dosing of
digoxin immune globulins to reverse toxicity. Understanding this unique
medication is essential for clinicians to ensure digoxin is used safely and
effectively in practice.
Key Words: atrial fibrillation, digoxin, heart failure, therapeutic drug
monitoring, toxicity
(Crit Pathways in Cardiol 2011;10: 9398)
U se of cardiac glycosides dates as far back as the ancient
Egyptians, and digoxin is the oldest cardiac medication pres-
ently used in medical practice. However, despite its long history in
medicine, use of digoxin has fallen out of favor.1 Its unique mech-
anism of action, complicated pharmacokinetic properties, narrow
therapeutic index, and extensive toxicity profile make it a medica-
tion that requires individualized dosing based on multiple patient-
specific factors. This article will focus on the important clinical
aspects of digoxin and will highlight its use in contemporary
medicine.
MECHANISM OF ACTION
Digoxin is a unique medication with pharmacological effects
resulting in hemodynamic, sympatholytic, and electrophysiologic
changes. Its primary mechanism action is inhibition of the Na-K
ATPase pump, thereby promoting Na-Ca exchange, which
results in an influx of intracellular Ca and increased myocardial
contraction. Second, digoxin has parasympathomimetic actions.
These manifest clinically by increasing vagal tone to the sinoatrial
(SA) and atrioventricular (AV) nodes, resulting in decreased heart
rate and slowed AV-nodal conduction.1,2
PHARMACOKINETICS
Digoxin is available in multiple formulations, each differing
slightly in bioavailability (oral PO tablets 70%, elixir 80%, cap-
sules 90%, and intravenous IV 100%) (Table 1). It is 20% to 25%
bound to plasma proteins and has a large volume of distribution of
4 to 7 L/kg. The initial onset of action is seen within 15 to 30
minutes when administered IV, and 30 minutes to 2 hours when
From the Departments of *Pharmacy and Cardiovascular Medicine, Brigham and
Womens Hospital, Boston, MA.
Reprints: Robert Giugliano, MD, SM, TIMI Study Office, 350 Longwood Ave-
nue, 1st Floor Offices, Boston, MA 02115. E-mail: rgiugliano@partners.org.
Copyright 2011 by Lippincott Williams & Wilkins
ISSN: 1535-282X/11/1002-0093
DOI: 10.1097/HPC.0b013e318221e7dd
Critical Pathways in Cardiology Volume 10, Number 2, June 2011
given orally. Peak effect of IV and oral digoxin is seen in 1 to 4
hours and 2 to 6 hours, respectively. Metabolism of digoxin is not
dependent on the cytochrome-P450 (CYP-450) system, but rather
hydrolysis, oxidation, and conjugation in the liver; it is excreted
50% to 70% unchanged in the urine and is not removed by hemo-
dialysis. Digoxin exhibits first-order kinetics, meaning a 50% reduc-
tion in the dose results in a 50% reduction in the steady-state serum
digoxin concentration (SDC). The half-life and time to steady-state
varies by patient and is dependent on the renal function. In patients
with normal renal function, the half-life ranges from 1.5 to 2 days.
This is prolonged anywhere from 3.5 to 5 days in patients with
moderate to severe renal dysfunction. Patients with normal renal
function reach steady state in 5 to 7 days after initiation of therapy,
whereas it may take up to 15 to 20 days in patients with impaired
renal function.3
FOOD AND DRUG ADMINISTRATION-APPROVED
INDICATIONS
Digoxin is approved by the US Food and Drug Administra-
tion to control ventricular response in patients with chronic atrial
fibrillation (AF), and is the only oral agent with positive inotropic
effects approved for the management of mild to moderate heart
failure.3 In managing patients with a left ventricular ejection fraction
(LVEF) 40%, the current Heart Failure Society of America guide-
lines recommend digoxin as adjunct treatment to therapies that have
proven mortality benefit, such as ACE inhibitors (ACE-I) and
-blockers4 (Table 2).
PATIENT-SPECIFIC DOSING CONSIDERATIONS
Both loading and maintenance doses for digoxin are depen-
dent on several patient-specific factors including lean body weight,
age, renal function, and concomitant medications. Each of these will
vary patient to patient, but all should be taken into consideration to
determine an optimal digoxin regimen.
Digoxin is distributed largely into tissue and therefore the
lean body weight of a patient plays a key role in determining
appropriate dosing. In patients with a low lean body weight, SDC
may be elevated compared with their higher lean body weight
counterparts, as there is less tissue for the drug to distribute.1,3
Patients with a low lean body weight often require decreased doses
of digoxin as compared with patients with higher lean body weight
and visa versa.
Renal excretion is responsible for 50% to 70% of digoxin
clearance. Patients with decreased renal function will begin to
accumulate the drug if not dosed appropriately, increasing the risk of
digoxin toxicity.1 Lower loading and maintenance doses must be
used in patients with renal dysfunction.
Increased age is often associated with a decrease in muscle
mass resulting in a low lean body weight. Elderly patients may also
have decreased renal function, which could slow the rate of digoxin
clearance from the body. As such, digoxin should be used cautiously
in this patient population with close follow-up and dose adjustment
as required.1,3 Lower loading and maintenance doses must be
considered in elderly patients taking digoxin.
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Ehle et al Critical Pathways in Cardiology Volume 10, Number 2, June 2011

LOADING DOSE AND MAINTENANCE DOSE

TABLE 1. Digoxin Pharmacokinetics
REGIMENS
Bioavailability Injection: 100% Capsule: 90% Digoxins variable pharmacokinetic profile requires initial
Oral elixir: 80% dosing to differ based on clinical indication. In patients presenting in
Oral tablet: 70% AF with rapid ventricular response who require digoxin for rate
Onset of action Injection: 530 min Oral: 0.52 h control, a loading dose is needed to reach adequate and effective
Peak effect Injection: 14 h Oral: 26 h
drug levels; a maintenance dose regimen will then follow. For
management in patients with heart failure a loading dose is not
Metabolism Undergoes hydrolysis, oxidation, and
necessary and a maintenance dose can be initiated immediately.1,4
conjugation
Metabolism not dependant on CYP-450 system
DOSING FOR CONTROL OF VENTRICULAR
Excretion First order kinetics
RESPONSE IN PATIENTS WITH AF
Urine: 50%70% unchanged
To achieve adequate response and avoid toxicity, prescribers
Not removed by dialysis must account for the patient-specific characteristics mentioned pre-
Half-life Healthy adult patients: 1.52 d viously. In elderly patients, patients with renal insufficiency, or
Anuric adult patients: 3.55 d those with low body weight, lower loading doses must be consid-
Time to steady state Healthy adult patients: 57 d ered. Likewise, a higher loading dose may be necessary in younger,
Anuric adult patients: prolonged to 1520 d higher body weight individuals with normal renal function. Typi-
cally, a dose of 0.5 to 1.0 mg may be administered either IV or PO
in 3 divided doses at 6 to 8 hours intervals, with a max recom-
mended loading dose of 1.0 mg. Clinical response should be as-
TABLE 2. HFSA Guideline Recommendations for Use of sessed before administration of the next dose. An example of a 1.0
Digoxin mg oral or IV loading dose is as follows:
Recommendation Strength of Evidence* Initial 0.5 mg 1 assess clinical response in 6 to 8 hours;
Digoxin should be considered for patients NYHA class II-III A Additional 0.25 mg 1 assess clinical response in 6 to 8
with left ventricular systolic dysfunction NYHA class IV B hours;
(LVEF 40%) who have signs or Final 0.25 mg 1 to complete the total loading dose of 1.0 mg.
symptoms of heart failure while receiving
standard therapy, including ACE-I and Maintenance doses should be initiated based on age, lean
B-blockers body weight, and renal function, titrated to the lowest possible dose
The dose of digoxin, which should be based C to maintain clinical effect, and/or an SDC of 0.8 to 2 ng/mL. Current
on lean body mass, renal function, and guidelines recommend against high digoxin doses (0.25 mg daily)
concomitant medications, should be 0.125 for rate control in patients with AF.4
mg daily in the majority of patients and
the serum digoxin level should be 1.0 DOSING FOR PATIENTS WITH MILD TO MODERATE
ng/mL
HEART FAILURE
Adequate control of the ventricular response B
to atrial fibrillation in patients with heart
Loading doses are not required when managing heart failure.
failure is recommended In this patient population, digoxin is used for its positive inotropic
effects and neurohormonal modulation and should be initiated at a
High doses of digoxin (maintenance doses C
0.25 mg daily) for the purpose of rate maintenance dose dependent on age, lean body mass, and renal
control are not recommended function.4 Elderly patients or those with renal dysfunction should be
Patients taking amiodarone therapy and A
dosed cautiously with a starting regimen of 0.125 mg daily; hemo-
digoxin or warfarin generally have their dialysis patients may only require a dose of 0.0625 mg daily or less.
maintenance doses of many commonly In contrast to patients with AF, digoxin doses for patients with heart
used agents, such as digoxin, warfarin, failure should be titrated to achieve an SDC of 0.5 to 0.9 ng/mL.5,6
and statins, reduced when amiodarone is
initiated and then carefully monitored for KEY CLINICAL TRIALS WITH DIGOXIN IN THE
the possibility of adverse drug
interactions. Adjustment in doses of these MANAGEMENT OF HEART FAILURE
drugs and laboratory assessment of drug In 1993, 2 trials were published shedding light on outcomes
activity or serum concentration after associated with withdrawing digoxin therapy in patients with heart
initiation of amiodarone is recommended failure. The RADIANCE trial7 was a 12-week double-blind placebo
*Level of evidence A: data derived from multiple randomized clinical trials or
control study evaluating 178 patients with New York Heart Asso-
meta-analyses. Level of evidence B: data derived from a single randomized trial or ciation (NYHA) class II or III heart failure and an LVEF of 35%.
nonrandomized studies. Level of evidence C: only consensus opinion of experts, case Patients were in normal sinus rhythm and maintained on digoxin,
studies, or standard-of-care. diuretics, and ACE-Is. In all, 85 patients were randomized to
continue digoxin and 93 patients were switched to placebo; other
medical therapy for heart failure remained the same. The
PROVED trial8 was designed similarly to RADIANCE; however,
In patients with coronary ischemia, digoxin should be initi- patients enrolled were maintained only on a regimen of digoxin
ated at a lower dose (eg, reduction by 25%50%). Myocardial and diuretics. In all, 46 patients were withdrawn from digoxin
ischemia may lead to increased tissue sensitivity to digoxin as it can therapy and the remaining 42 patients continued on treatment.
inhibit the Na-K ATPase pump, the result of which is an The results of these 2 trials mirrored one another. In
elevation in SDC.3 RADIANCE, the relative risk of worsening heart failure in the

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Critical Pathways in Cardiology Volume 10, Number 2, June 2011
placebo group compared with the digoxin group was 5.9, and 23
patients switched to placebo were withdrawn from the study for
worsening heart failure compared with 4 who were continued on
digoxin (P 0.001). Measures of functional capacity deteriorated
(P 0.033 for maximal exercise tolerance, P 0.01 for submaxi-
mal exercise endurance, and P 0.019 for NYHA class), and there
was a decrease in reported quality of life scores (P 0.04) and
ejection fraction (EF) (P 0.001) in patients who discontinued
digoxin. An increase in heart rate (P 0.001) and body weight
(P 0.001) was also noted in the placebo group.7 The results of
PROVED revealed a worsening in maximal exercise capacity
(P 0.003) and an increase in treatment failures in patients
withdrawn from digoxin therapy (39% placebo, 19% digoxin, P
0.039); time to treatment failure was also decreased in the
placebo arm (P 0.037). Patients continuing digoxin maintained
a lower body weight (P 0.044) and heart rate (P 0.003), and
had higher LVEF (P 0.016) at 3 months.8
Although these are small trials of short duration, both support
continuing digoxin therapy in patients with heart failure who are
already prescribed diuretics alone or in combination with an ACE-I.
It is important to note that neither of these trials was designed to
provide an answer as to how digoxin may affect the survival of
patients with heart failure.
The DIG trial evaluated mortality in patients in normal sinus
rhythm who had reduced (EF 45%, DIG-Main9) or preserved
systolic function (EF 45%, DIG-Ancillary10). In all, 7788 patients
were enrolled, 6800 of which had an EF 45%. Patients received 4
different daily doses of digoxin or matching placebo (0.125 mg, 0.25
mg, 0.375 mg, 0.5 mg) based on age, sex, weight, and serum
creatinine. Beta-blockers were not widely recommended for heart
failure; most patients were treated with an ACE-Is and diuretics. The
primary outcome was all-cause mortality. Secondary outcomes in-
cluded cardiovascular death, death from congestive heart failure,
and hospitalization due to heart failure. The authors concluded that
digoxin use had no effect on mortality when compared with placebo,
but did find a 6% reduction in hospitalization rates in patients with
an EF 45%.9 In the 988 patients with an EF 45% included in the
DIG-Ancillary trial, digoxin had no effect on mortality and all-cause
or cardiovascular hospitalizations.10
SDCS IN PATIENTS WITH HEART FAILURE
Digoxin contains a narrow therapeutic index, and even still
some patients may experience toxicity when within that range.3
Previously SDCs of 0.8 to 2 ng/mL were accepted despite the
indication, however reanalysis the DIG trial has suggested otherwise
in regards to the use of digoxin in the management of heart failure.
Rathore et al11 conducted a post hoc analysis of the DIG trial
looking 3782 men with an EF 45% who were split into 3 groups
based on SDC, group 1 (0.5 0.8 ng/mL), group 2 (0.9 1.1 ng/mL),
and group 3 (1.2 ng/mL). Group 1 with the lowest SDC had an
absolute 6.3% reduction in mortality compared with placebo. Group
2 had no difference in mortality when compared with placebo, and
group 3 with the highest SDC had an 11.8% absolute increase in
mortality risk compared with placebo. The authors concluded that in
men with an EF 45%, optimal management with digoxin should
target an SDC 0.5 to 0.8 ng/mL.
Ahmed et al5 conducted a post hoc analysis of 5549 patients
from the DIG trial focusing on SDC. The authors found that patients
with an SDC of 0.5 to 0.9 ng/mL at 1 month had a statistically
significant 23% reduction in all-cause mortality compared with
those with an SDC of 1 ng/mL. This in addition to a 38% relative
risk reduction (9.8% absolute risk reduction) consistent with the
original study in regards to heart failure hospitalizations. There are
no prospective randomized trials looking at SDC and outcomes in
2011 Lippincott Williams & Wilkins
Digoxin
patients with heart failure, and clinicians must remember that these
data are the result of post hoc analysis. It is unknown if targeting a
lower SDC in this patient population truly improves survival;
however, the data available supports targeting a lower SDC of 0.5 to
0.9 ng/mL in patients with heart failure.
APPROPRIATE TIMES TO OBTAIN SDCS
With a time to steady state ranging from 5 to 20 days
dependent on the patient, obtaining an SDC that truly correlates to
the clinical picture can be challenging. In the instance of AF where
rapid digitalization with a loading dose may be required, therapy
should be guided on clinical response. Measurement of an SDC
immediately (ie, within 48 hours) following a loading dose will bare
no relevance to the global clinical picture, but instead represents a
snapshot in time which could be misleading and result in inappro-
priate management. A true steady-state SDC can be obtained after 3
to 4 half lives. In patients with normal renal function drawing an
SDC after 5 to 7 days of maintenance therapy will correlate to an
accurate steady-state level. In patients with impaired renal function,
obtaining an SDC roughly 2 to 3 weeks of maintenance therapy will
reflect a true steady-state level. Understanding the kinetic properties
of the drug will allow clinicians to better manage their patients and
avoid over or under dosing of digoxin.
CLINICAL ADVERSE EFFECTS OF DIGOXIN AND
RECOGNIZING TOXICITY
Digoxin has many adverse reactions and affects multiple
organ systems (Table 3). Signs and symptoms of toxicity are often
similar to digoxin adverse effects though more severe and acute.
They can be present regardless of the SDC, however are documented
to occur more frequently at an SDC 2 ng/mL.12 In clinical
practice, often the first and most commonly seen signs of toxicity
which precede cardiac effects include somnolence and loss of
appetite, occurring in up to 80% of patients. Cardiac toxicity
typically peaks 3 to 6 hours after an overdose and may persist for 24
hours or greater, and neurologic or visual effects can remain once
cardiac effects have dissipated.3,12 Clinicians should also be cogni-
zant of hyperkalemia, a sign of serious digoxin toxicity brought
about by Na-K ATPase blockade throughout the body producing
a leak of potassium from the intracellular into extracellular space.12
DRUG INTERACTIONS AND CLINICAL
MANAGEMENT
Although metabolism of digoxin is not dependent on the
CYP-450 system, the potential for drug interactions still remains
(Table 4). Concomitant administration with several medications can
cause rapid, clinically significant increases in SDC and increased
risk of toxicity. Digoxin is a substrate and inhibitor of p-glycopro-
tein, a transmembrane glycoprotein, which serves as an ATP-
dependent efflux pump for a variety of chemicals in the body.
Several p-glycoprotein interactions exist with digoxin and include
medications that are often times prescribed together for the treat-
ment of AF.13
Current ACC/AHA/ESC guidelines6 give nondihydropyri-
dine calcium channel blockers, such as diltiazem or verapamil, a
class Ib recommendation as a first-line therapy for rate control in the
treatment of paroxysmal or permanent AF. IV digoxin or amioda-
rone hold a class Ib recommendation to control heart rate in patients
with AF and heart failure.6 A combination of rate controlling agents
is often required to effectively manage patients in AF, creating the
potential for digoxin drug interactions which require attention and
dose adjustment. Both amiodarone and verapamil are potent inhib-
itors of p-glycoprotein. Concomitant use of digoxin and verapamil
can increase digoxin levels by 50% to 70% after just 1 week as a
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Ehle et al Critical Pathways in Cardiology Volume 10, Number 2, June 2011

TABLE 3. Adverse Effects and Signs/Symptoms of Toxicity

Present as Adverse Effects
Adverse Effects Clinical Toxicity and in Toxic Situations
Cardiac Palpitations Arrhythmias (multiple rhythms may be seen in a single patient)
AV dissociation Ventricular fibrillation
Accelerated junctional rhythm Cardiac arrest
PR prolongation
ST segment depression
CNS Somnolence Visual disturbances: Flashing lights, halos, color
disturbances (green-yellow patterns)
Dizziness Hallucinations
Headache Acute fatigue
Confusion Hazy or blurred vision
Electrolyte abnormalities Hyperkalemia
Gastrointestinal Anorexia
Nausea
Vomiting
Abdominal pain
Diarrhea

TABLE 4. Digoxin Drug Interactions

Pharmacokinetic
Drugs that increase digoxin serum concentrations
Amiodarone Dronedarone Protease inhibitors Tetracyclines
Alprazolam Itraconazole Quinidine Verapamil
Atorvastatin Macrolides Ranolazine
Cyclosporine NSAIDs Simvastatin
Diphenoxylate Propafenone Spironolactone

Drugs that may decrease digoxin serum concentrations

Antacids Penicillamine Sulfasalazine
Cholestyramine/colestipol Phenytoin Thyroid hormone
Neomycin Rifampin
Pharmacodynamic Interaction/Effect
Concomitant drug
Beta blockers May result in advanced or complete heart block
IV calcium Rapid administration of IV Ca may produce arrhythmias
Nondihydropyridine CCB May result in advanced or complete heart block
Succinylcholine Arrhythmia
Sympathomimetics Arrhythmia
Thiazide or loop diuretics Electrolyte disturbances may lead to arrhythmia
CCB indicates calcium channel blocker; Ca, calcium; IV, intravenous.

result of a 27% decrease in total body digoxin clearance.14 Digoxin
dose reductions are required and levels should be monitored closely.
Coadministration with amiodarone can cause digoxin levels to
increase by 70% within 24 hours.15 Careful attention must be paid
when these drugs are administered in combination, and half the
usual digoxin dose should be used initially following SDCs closely
to avoid toxicity.3,15 Like amiodarone, digoxin also interacts with
dronedarone, potentiating its electrophysiologic effects (ie, de-
creased AV-node conduction). Additionally, dronedarone has been
shown to increase digoxin levels 2.5 fold when the 2 are adminis-
tered together as a result of dronedarones P-glycoprotein inhibition.
If combination therapy with dronedarone and digoxin is absolutely
necessary, the dose of digoxin should be halved upon initiation of
dronedarone and digoxin levels should be monitored closely; dis-
continuation of digoxin should be considered if possible.16 Several
other medications may increase SDCs due to p-glycoprotein inhibi-
tion, which include: antihyperlipidemics (atorvastatin and simvasta-
tin), antiarrhythmic agents (propafenone and quinidine), immuno-
suppressive medications (cyclosporine), and protease inhibitors to
treat HIV (daunavir, saquinavir, and ritonavir).
Use of p-glycoprotein inducers such as rifampin, neomycin,
and penicillamine will cause an increase in the hepatic metabolism
of digoxin and result in decreased SDCs. Digoxin levels should be
closely monitored within 3 to 5 days of initiating rifampin and
digoxin doses should be adjusted accordingly to maintain an appro-
priate SDC dependent on the indication.3

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Critical Pathways in Cardiology Volume 10, Number 2, June 2011 Digoxin

CONTRAINDICATIONS AND PRECAUTIONS
Digoxin is contraindicated in patients with ventricular fibril-
lation and should be avoided in patients with an accessory bypass
tract such as Wolff-Parkinson-White Syndrome due to the risk of
ventricular fibrillation. Caution should be taken in patients with slow
SA and AV nodal conduction since digoxin prolongs the PR inter-
val, which could lead to complete heart block. Patients with elec-
trolyte disturbances (hypokalemia and hypomagnesemia) exhibit
increased myocardial sensitivity to digoxin, therefore normal serum
concentrations of these electrolytes are desired. Calcium concentra-
tions should also be within range as hypercalcemia can increase
digoxins effects on myocardial contractility and excitability.3
Patients with heart failure and preserved ventricular function
are more susceptible to toxicity. Digoxin should be avoided in the
setting on an acute MI since an increase in oxygen demand can lead
to ischemia. Patients with Beriberi heart disease should initially
receive supplemental thiamine in order for digoxin to be effective.3
Digoxin should be used with extreme caution, if at all, in patients
with cardiac amyloidosis. The drug can become bound extracellu-
larly by amyloid fibrils and cause severe hypersensitivity and tox-
icity in this patient population.17
DIGOXIN IMMUNE GLOBULIN
Digoxin-specific antibody (Fab) fragments are safe and
highly effective in treating severe digitalis poisoning. They are
derived and purified from IgG antidigoxin antibodies of immunized
sheep. The Fab fragments bind to free digoxin forming a digoxin-
immune fragment complex, which is renally excreted, resulting in a
decrease in SDC. There are 2 commercially available formulations:
Digibind and DigiFab. Both formulations are equivalent and can be
used interchangeably, with each vial binding to 0.5 mg of digoxin.
Both have similar pharmacokinetic properties, but it is important to
note that the half life is significantly longer in patients with renal
impairment.18,19
Dosing is variable, based on the amount of digoxin ingested
(Fig. 1). In an acute overdose of a known amount of digoxin, the
dose of Fab fragment can be calculated based on total body load
ingested and the approximate bioavailability of digoxin (Fig. 1,
Table 5). As an example, given a patient presenting with signs of
digoxin toxicity after acutely ingesting twenty-five 0.25 mg cap-
sules, the dose of Fab in vials is as follows:
25 capsules 0.25 mg 0.8*
10 vials
0.5 mg digoxin bound per vial)
*0.8 approximate bioavailability of oral digoxin.
When an unknown amount of digoxin is ingested acutely, an
Fab dose of 10 vials may be administered, followed by an additional
10 vials as required with close monitoring; for life-threatening
symptoms 20 vials may be given initially. For patients taking

Patient presents with

clinical signs of
digoxin toxicity

Acute Ingestion Chronic Ingestion

Known Amount Unknown Amount Known SDC Unknown SDC

Dose (in vials) = 10 vials, repeat if need

and monitor Dose (in vials) =
mg ingested x 0.8*
0.5 mg bound per vial Life threatening (SDC) x (wt in kg) 6 vials
100
OR as outlined in Table 5
symptoms: 20 vials

*0.8 = approximate bioavailability of oral digoxin

FIGURE 1. Dosing of digoxin Fab to treat digoxin toxicity. To determine the appropriate dose of digoxin Fab in cases of toxic-
ity, first classify the overdose as either acute or chronic. Then, use an estimate of the amount of excess dose in the setting of
an acute ingestion. For chronic ingestions, a serum digoxin concentration is helpful to guide the dose of digoxin Fab.

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Ehle et al Critical Pathways in Cardiology Volume 10, Number 2, June 2011
TABLE 5. Approximate Fab Dosing for Acute Ingestion
No. Digoxin Tablets or
Capsules Ingested Dose of DigiFab No. Vials
25 10
50 20
75 30
100 40
150 60
200 80
digoxin chronically who present with signs of toxicity and a known
SDC, the Fab dose can be calculated using the SDC and the patients
body weight in kilograms; chronic ingestion with an unknown SDC
can be treated with an Fab dose of 6 vials.18,19 As an example, a
70-kg patient chronically taking digoxin presents with an SDC of
11.7 ng/mL. The dose of Fab in vials is as follows:
11.7 ng/mL 70 kg 6. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for
8 vials
100
SUMMARY
Digoxin is a complex medication that has numerous limita-
tions, but can be safely and effectively used when administered at
appropriate doses and adequately monitored. In patients with heart
failure, a goal concentration of 0.5 to 0.9 ng/mL will optimally
inhibit the Na K ATPase pump resulting in positive inotropic
effects. These patients do not need a loading dose and can be
immediately initiated on maintenance therapy. In AF, digoxin slows
AV nodal conduction resulting in negative chronotropic effects. A
loading dose between 0.5 to 1.0 mg and maintenance doses of 0.25
mg daily should be calculated based on patient-specific consider-
ations such as age, renal function, body weight, and concomitant
medications. The dose can be titrated to a goal concentration of 0.8
to 2 ng/mL or desired clinical response.
Digoxin has variable pharmacokinetics and concentrations
should be closely monitored in the elderly population, patients with
impaired renal function, and patients with low lean body weight.
Levels should be obtained based on individual clinical picture and
can be drawn at steady state in 5 to 20 days depending on renal
function. Digoxin is metabolized in the liver independent of the
CYP-450 system and excreted in the urine. Drug interactions with
the P-glycoprotein drug efflux system are common and dose adjust-
ments may be necessary. The first signs of toxicity include somno-
lence and loss of appetite, with more serious toxicities usually
occurring when SCDs reach greater than 2 ng/mL. If clinically
warranted, digoxin immune globulin can be effectively used to
reverse toxic effects of digoxin. Although digoxin has many limi-
tations including a narrow therapeutic index and variable pharma-
cokinetic profile, it can be effective and safely administered when
98 | www.critpathcardio.com
dosed correctly with appropriate monitoring based on patient-spe-
cific factors.
DISCLOSURES
Nothing to declare.
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14. Product Information. Verapamil 2007. Corona, CA: Watson Laboratories;
2007.
15. Product Information. Amiodarone 2009. Hawthorne, NY: Taro Pharmaceu-
ticals; 2009.
16. Prescribing Information: Multaq (dronedarone) 2009. Bridgewater, NJ:
Sanofi-aventis; 2009.
17. Hassan W, Al-Sergani H, Mourad W, et al. Amyloid heart disease: new
frontiers and insights in pathophysology, diagnosis, and management. Tex
Heart Inst J. 2005;32:178 184.
18. Prescribing Information: Digibind (digoxin immune Fab) 2003. Research
Triangle Park, NC: GlaxoSmithKline; 2003.
19. Prescribing Information: Digifab (digoxin immune Fab) 2005. Brentwood,
TN: Protherics Inc; 2005.
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