4:00 Antihistamine Drugs

Antihistamines General Statement

Introduction

 Antihistamines, which inhibit the effects of histamine at H1 receptors, have been classified as
first generation (i.e., relatively sedating) or second generation (i.e., relatively nonsedating).

Uses

Antihistamines are most often used to provide symptomatic relief of allergic symptoms caused
by histamine release. The drugs are not curative and merely provide palliative therapy.
Antihistamines are used only as adjunctive therapy to epinephrine and other standard measures
in the treatment of anaphylactic reactions and laryngeal edema after the acute manifestations
have been controlled. Individual patients vary in their response to antihistamines. A specific
antihistamine that provides dramatic relief without adverse effects to one patient may produce
intolerable adverse effects in another patient. Trial of various antihistamines may be necessary to
determine which drug will provide relief while causing minimal adverse effects.

 Nasal Allergies and the Common Cold

Antihistamines are most beneficial in the management of nasal allergies. Seasonal allergic
rhinitis (e.g., hay fever) and perennial (nonseasonal) allergic rhinitis are benefited more than
perennial nonallergic (vasomotor) rhinitis. Orally administered antihistamines generally provide
symptomatic relief of rhinorrhea, sneezing, oronasopharyngeal irritation or itching, lacrimation,
and red, irritated, or itching eyes associated with the early response to histamine.100, 149, 168, 169,
170, 487, 494, 509
The drugs generally are not effective in relieving symptoms of nasal obstruction,
which are characteristic of the late allergic reaction,100, 170, 487 although limited data indicate that
cetirizine and levocetirizine may relieve some symptoms of late allergic reactions.581, 681, 682
Antihistamines (e.g., azelastine) also may be administered intranasally for the symptomatic relief
of seasonal allergic rhinitis.526, 527, 528 (See Uses in Azelastine 52:02.) In comparative studies,
intranasal azelastine was more effective than placebo and at least as effective as oral
antihistamines (e.g., cetirizine, terfenadine [no longer commercially available in the US]) or
intranasal corticosteroids in relieving allergic rhinitis.529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539
However, unlike intranasal corticosteroids, azelastine does not appear to exhibit local histologic
anti-inflammatory activity;529, 530 therefore, beneficial effects on nasal obstruction appear to
result principally from antihistaminic and/or other activity.530, 531, 535

Chronic nasal congestion and headache caused by edema of the paranasal sinus mucosa are often
refractory to antihistamine therapy. In the treatment of hay fever, antihistamines are more likely
to be beneficial when therapy is initiated at the beginning of the hay fever season when pollen
counts are low (e.g., before pollination begins) and if used regularly during the pollen season.
Antihistamines are less likely to be effective when pollen counts are high, when pollen exposure
is prolonged, and when nasal congestion is prominent.149, 151, 168
Although antihistamines frequently are used for symptomatic relief in the common cold,
evidence of effectiveness remains to be clearly established.100, 129, 130, 398, 401, 402, 467, 487, 494, 525, 540,
564, 565
Antihistamines cannot prevent, cure, or shorten the course of the common cold,100, 129, 130,
398, 400, 402
but may provide some symptomatic relief.130, 169, 390, 392, 400, 401, 519, 540, 564, 565
Conventional (prototypical, first generation) antihistamines (e.g., those with anticholinergic
activity) are considered effective in relieving rhinorrhea and sneezing associated with the
common cold,130, 169, 390, 392, 400, 540, 564 but evidence of efficacy in relieving oronasopharyngeal
itching, lacrimation, or itching eyes associated with this condition currently is lacking.169
Nonsedating (second generation) antihistamines do not appear to be effective in relieving
rhinorrhea, suggesting that histamine is not a principal mediator of this manifestation.519, 524, 564
The extent to which histamine contributes to other manifestations of the common cold currently
is unclear, but pathogenesis of the full constellation of symptoms that constitute the common
cold appears to be complex, involving a number of mediators and neurologic mechanisms.519, 520,
521, 522, 523

Routine, prolonged administration of fixed combinations containing antihistamines, nasal

decongestants, anticholinergics, analgesic-antipyretics, caffeine, antitussives, and/or expectorants
has been questioned.100, 390 Single-ingredient products generally are safer than combination
products,100 while also facilitating dosage adjustment.100, 390 There is no evidence that
combinations containing 2 or more antihistamines are more effective than one antihistamine or
that combinations of subtherapeutic doses of 2 or more antihistamines are more effective than
therapeutic doses of one antihistamine.100, 390, 397, 398 Oral antihistamine combinations containing
an analgesic-antipyretic and/or nasal decongestant; an antitussive and nasal decongestant; an
analgesic-antipyretic, antitussive, and nasal decongestant; or an antitussive may be rational if
each ingredient has demonstrated clinical effectiveness and is present in therapeutic dosage.100,
390, 397, 398, 399
Selective use of such combinations can provide a convenient and rational approach
for relief of concurrent symptoms (e.g., rhinorrhea, nasal congestion, cough), which often are
present in allergic rhinitis and other conditions (e.g., common cold), by allowing the patient to
use a single combination rather than multiple single-entity preparations.100, 390, 398, 487
Combination preparations generally should be used only when symptoms amenable to each
ingredient are present concurrently.100, 390, 398 Combinations containing an antihistamine and an
expectorant, anticholinergic agent, or bronchodilator are not considered rational.100, 390

Although cough and cold preparations that contain antihistamines, nasal decongestants, cough
suppressants, and/or expectorants commonly were used in pediatric patients younger than 2 years
of age, systematic reviews of controlled trials have concluded that nonprescription (over-the-
counter, OTC) cough and cold preparations are no more effective than placebo in reducing acute
cough and other symptoms of upper respiratory tract infection in these patients.693 Furthermore,
adverse events, including deaths, have been (and continue to be) reported in pediatric patients
younger than 2 years of age receiving these preparations.693 (See Cautions: Pediatric
Precautions.)

 Other Allergic Conditions

Antihistamines are often effective in the treatment of allergic dermatoses and other dermatoses
associated with histamine release, but effectiveness varies with the causative agent and
symptoms may return when the drug is stopped. Antihistamines have been used in the
symptomatic treatment of chronic idiopathic urticaria;176, 177, 178, 179, 509, 567, 568, 569, 570, 571, 572, 573,
669, 670, 683, 684
occasionally, patients who do not experience adequate relief with an antihistamine
(H1-receptor antagonist) alone may benefit from the addition of an H2-receptor antagonist.176, 177,
178, 179
However, in one study, the addition of an H2-receptor antagonist did not provide a
substantial increase in response (as determined by reduction in whealing).175 Some
antihistamines also may symptomatically relieve pruritus accompanying atopic dermatitis,
contact dermatitis, pruritus ani or vulvae, and insect bites. Some evidence suggests that first
generation antihistamines such as hydroxyzine and diphenhydramine may be more effective than
second generation antihistamines (e.g., terfenadine [no longer commercially available in the US],
loratadine) for the relief of pruritus associated with certain allergic dermatoses (e.g., atopic
dermatitis), but additional study is needed to elucidate further the relative efficacy of these drugs
as antipruritics.487, 495, 496 Antihistamines also may be used in the treatment of dermatographism.
Patients with dermatographism or other urticarial conditions who do not experience adequate
relief with anantihistamine (H1-receptor antagonist) alone may benefit from the addition of an
H2-receptor antagonist to enhance relief of pruritus and wheal formation.173, 174, 321, 487

Antihistamines are useful in the management of allergic conjunctivitis caused by foods or

inhaled allergens. Allergic or hypersensitivity reactions to penicillin, streptomycin,
sulfonamides, and other drugs may be amenable to antihistamine therapy. Pruritus and urticaria
accompanying these conditions usually are temporarily relieved; edema is more resistant and
serum sickness is not benefited.

Symptoms of mild transfusion reactions not caused by ABO incompatibility or pyrogens may be
alleviated by antihistamines. The drugs should not be added to blood being transfused.
Antihistamines may be administered prophylactically to patients with a history of transfusion
reactions, but the drugs should not be given routinely to patients receiving blood. Antihistamines
also may be useful to prevent sequelae following desensitization procedures and allergic
reactions to radiographic contrast media. It must be kept in mind that prophylactic use of
antihistamines may mask incipient signs of allergic reactions, and the patient's hypersensitivity
may not be recognized until a serious reaction occurs.

Although epinephrine is the initial drug of choice for patients with anaphylactic or anaphylactoid
reactions, antihistamines are useful in the ancillary treatment of pruritus, urticaria, angioedema,
and bronchospasm associated with these reactions.487, 492, 493 Concurrent use of H1- and H2-
receptor antagonists appears to reduce the adverse effects of histamine on the peripheral
vasculature and myocardium during anaphylaxis.487, 492

 Asthma
Antihistamines may provide some benefit in certain asthmatic patients, but the drugs usually are
not effective in treating bronchial asthma per se and should not be used in the treatment of severe
acute asthma attacks. In addition, antihistamines are not included in the usual recommended
regimens for the management of asthma, including long-term control of the disease.566
Antihistamine and decongestant combinations may provide symptomatic relief (e.g., of rhinitis)
in patients with chronic rhinitis and persistent asthma, but the drugs have not been shown to have
a protective effect on lower airways; other agents (e.g., inhaled corticosteroids) are for protective
effects on lower airways.566 In general, patients with predictable seasonal asthma should receive
long-term anti-inflammatory therapy (e.g., inhaled corticosteroids, mast-cell stabilizers), initiated
prior to the anticipated onset of exposure to allergens and continued throughout the season.566
The drugs may be used with caution to treat hay fever or other airway disorder with a histamine-
mediated component in patients with such disorders and asthma. Although some clinicians
believe that the anticholinergic effects (e.g., reduction of nasal secretions) of some of these drugs
may cause thickening of bronchial secretions resulting in further airway obstruction in
asthmatics, especially those with status asthmaticus, most experts consider complete avoidance
of currently available antihistamines in asthmatics unjustified.467, 481, 484, 487 (See Cautions:
Precautions and Contraindications.)

 Motion Sickness and Vertigo

Some antihistamines (e.g., dimenhydrinate, diphenhydramine, meclizine, promethazine) are
useful for the prevention and treatment of nausea, vomiting, and/or vertigo associated with
motion sickness328, 341, 342, 343, 344, 345, 346, 347, 348 and they are considered the drugs of choice for
the management of this condition.341, 342, 345, 346, 347 For additional information on the use of
antihistamines for the management of motion sickness, see Dimenhydrinate and see Meclizine
Hydrochloride in 56:22.08. Dimenhydrinate and meclizine have also been used in the
symptomatic treatment of vertigo associated with diseases affecting the vestibular system (e.g.,
labyrinthitis, Meniere's disease). Nonphenothiazine antihistamines are less effective than the
phenothiazines in controlling nausea and vomiting not related to vestibular stimulation.

 Chemotherapy-induced Nausea and Vomiting

Some antihistamines (e.g., diphenhydramine) may be useful as adjunctive antiemetic agents to
prevent chemotherapy-induced nausea and vomitingb; however, the American Society of Clinical
Oncology currently does not recommend that antihistamines be used alone as antiemetic agents
in patients receiving chemotherapy.680

 Insomnia
Some antihistamines, especially the ethanolamines such as diphenhydramine and doxylamine,
are used for their sedative effects as nighttime sleep aids.197, 407, 408 The US Food and Drug
Administration (FDA) states that diphenhydramine currently is the only antihistamine
commercially available in the US that has been shown to be both safe and effective for self-
medication as a nighttime sleep aid.407 In individuals who experience occasional sleeplessness or
those who have difficulty falling asleep, diphenhydramine (administered as either the citrate or
hydrochloride salt) is more effective than placebo in reducing sleep onset (i.e., time to fall
asleep) and increasing the depth and quality of sleep.197, 407 Although the safety and efficacy of
doxylamine as a nighttime sleep aid have not been fully established,197, 407 the FDA states that,
pending further accumulation of data, doxylamine-containing nighttime sleep aids that have been
approved for this use may continue to be marketed in the US.407 Some proprietary sleep aids also
may continue to contain pyrilamine despite a lack of substantial evidence of safety and efficacy
for use of this antihistamine as a nighttime sleep aid;197, 407 however, many such preparations
have been or are likely to be reformulated with other antihistamines (e.g., diphenhydramine).407

 Other Systemic Uses

Some antihistamines such as diphenhydramine have been used effectively as antitussives.
Diphenhydramine also may be useful in the management of tremor early in the course of
parkinsonian syndrome673, 674, 675 and in the management of drug-induced extrapyramidal
reactions.676
 Topical and Other Local Uses
Diphenhydramine and tripelennamine (no longer commercially available in the US;
extemporaneous formulation would be necessary) are used topically for temporary relief of
pruritus and pain associated with various skin conditions including minor burns, sunburn, minor
cuts or scrapes, insect bites, or minor skin irritations.196, 349 The drugs may provide effective
localized antipruritic activity when applied topically if pruritus and discomfort are histamine
mediated; the weak local anesthetic action of the drugs also may contribute to the overall
effect.349 However, many clinicians suggest that topical diphenhydramine not be used on large
areas of the body or more often than directed,672 since increased percutaneous absorption of the
drug may occur that can result in systemic adverse effects and toxicity.556, 557 (See Acute
Toxicity: Manifestations.) Topical diphenhydramine also should not be used for self-medication
in the management of varicella (chickenpox) or measles without first consulting a clinician.672

Some antihistamines also have been used for their topical or local anesthetic effects in
ophthalmic, urologic, proctologic, gastroscopic, otolaryngologic, and dental procedures.
However, topical use of antihistamines generally is discouraged because sensitivity reactions
(e.g., sensitization, hypersensitivity) may result.11, 44, 50, 149, 151, 345, 355, 356, 357, 358, 359, 368, 379, 380,
436
(See Cautions: Sensitivity Reactions.) In addition, use of certain antihistamines (e.g.,
diphenhydramine) for local anesthesia via local infiltration also is discouraged because of the
risk of local tissue necrosis.411, 437 If the drugs are used topically as antipruritics, therapy
generally should be short-term (i.e., for no longer than 7 days) because of the increasing risk of
sensitivity reactions from prolonged or repeated use.349 Antihistamines are more effective,
especially if pruritus is generalized, and are less likely to cause sensitivity reactions when the
drugs are administered systemically rather than applied topically.349

Dosage and Administration

 Administration
Antihistamines usually are administered orally. Although some of these drugs may be given IV,
IM, or subcutaneously, most antihistamines are not administered parenterally because they
frequently cause local irritation. Some antihistamines also may be administered topically196, 349
or intranasally.526, 527, 528 Topical use of antihistamines generally is discouraged since sensitivity
reactions (e.g., sensitization, hypersensitivity) may result.11, 44, 50, 149, 151, 345, 355, 356, 357, 358, 359, 368,
379, 380
In addition, topical preparations containing diphenhydramine should not be used more
often than directed for any condition, applied on large areas of the body, or used concomitantly
with other preparations containing diphenhydramine, including those used orally,672 since
increased serum concentrations of diphenhydramine may occur that can result in CNS
toxicity.556, 575, 576 (See Acute Toxicity: Manifestations.) Topical diphenhydramine also should
not be used for self-medication in the management of varicella (chickenpox) or measles without
first consulting a clinician.672

 Dosage
Dosage of antihistamines should be individualized according to the patient's response and
tolerance.

Cautions
Adverse effects, which vary in incidence and severity with the individual drug, are caused by all
antihistamines, although serious toxicity rarely occurs. Individual patients vary in their
susceptibility to the adverse effects of these drugs, and such effects may disappear despite
continued therapy. Geriatric patients may be particularly susceptible to dizziness, sedation, and
hypotension. Most mild reactions may be relieved by a reduction in dosage or changing to
another antihistamine.

Severe cardiovascular effects, including prolongation of the QT interval, arrhythmias, cardiac

effects, hypotension, palpitations, syncope, dizziness and/or death have been reported in patients
receiving astemizole (no longer commercially available in the US) or terfenadine (no longer
commercially available in the US).413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 431, 434, 443, 444, 445, 446,
447, 448, 449, 466, 476, 514
These cardiotoxic effects usually were associated with higher than
recommended dosages and/or increased plasma concentrations of the drugs and their active
metabolites.413, 414, 416, 417, 419, 421, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 448, 449, 453, 454, 455, 456, 457,
458, 459, 461, 462, 463, 464, 465, 466, 476, 512, 514

 CNS Effects
CNS depression is common with usual dosage of antihistamines, especially with the
ethanolamine derivatives. Sedation, ranging from mild drowsiness to deep sleep, occurs most
frequently; however, in the treatment of allergies, this effect may be therapeutically useful.
Dizziness, lassitude, disturbed coordination, and muscular weakness may also occur. In some
patients, the sedative effects disappear spontaneously after the antihistamine has been
administered for 2-3 days. Individuals who perform potentially hazardous tasks requiring mental
alertness or physical coordination (e.g., operating machinery, driving a motor vehicle) should be
warned about possible drowsiness, dizziness, or weakness. Patients also should be warned to
avoid consuming alcoholic beverages while taking antihistamines, since alcohol may potentiate
these CNS effects.169, 350, 390, 407, 509 In addition, patients already receiving other CNS depressants
(e.g., sedatives, tranquilizers) should be warned not to undertake self-medication with an
antihistamine without first consulting their clinician.350, 407, 491 Patients using diphenhydramine or
doxylamine for self-medication should be warned that the drugs may cause marked
drowsiness.100, 169, 197, 350, 390 Acrivastine, desloratadine, fexofenadine, loratadine, and, possibly,
cetirizine and levocetirizine appear to cause fewer adverse CNS effects, including effects on
psychomotor performance and reactivity, than other currently available (first generation)
antihistamines and therefore commonly have been referred to as relatively "nonsedating" or
second generation antihistamines.154, 155, 156, 159, 165, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 404,
405, 406, 459, 470, 471, 472, 473, 495, 496, 497, 498, 499, 516, 517, 509, 695
However, while most second generation
antihistamines do not appear to potentiate the effects of CNS depressants, including alcohol,161,
192, 404, 405, 406, 497, 498, 499
acrivastine, cetirizine, and levocetirizine may potentiate such effects,
although less prominently than first generation antihistamines.494, 498, 499, 509, 685

Some patients, especially children, receiving antihistamines may experience paradoxical

excitement characterized by restlessness, insomnia, tremors, euphoria, nervousness, delirium,
palpitation, and even seizures. There have been several reports of toxic psychosis in children
who received concomitant oral and topical diphenhydramine for relief of pruritus associated with
varicella (chickenpox), poison ivy, or sunburn.556, 557, 575, 576 (See Acute Toxicity:
Manifestations.) In addition, central anticholinergic syndrome characterized by hallucinations,
agitation, and confusion occurred in several children receiving usual or excessive dosages of
cyproheptadine.662 Patients should be warned that phenindamine may be particularly likely to
occasionally cause insomnia and nervousness in some individuals.100, 169, 350 Antihistamines also
may precipitate epileptiform seizures in patients with focal lesions of the cerebral cortex, and the
drugs should be administered with caution in patients with seizure disorders.

An acute dystonic reaction, which consisted of trismus, difficulty in swallowing, dysarthria,

rigidity, and motor incoordination, and was accompanied by mental confusion and tremors, was
reported in at least 1 patient receiving IV diphenhydramine.409

 GI and Hepatic Effects

Adverse GI effects of antihistamines include epigastric distress, anorexia, nausea, vomiting,
diarrhea, or constipation. GI symptoms may be decreased by administering the drug with meals
or with milk. Cholestasis,392, 393, 395 hepatitis,392, 393, 394 hepatic failure,391 hepatic function
abnormality,391 and jaundice391, 392, 393, 394, 395, 396 have been reported rarely in patients receiving
antihistamines (e.g., cyproheptadine, terfenadine).

 Sensitivity Reactions
Antihistamines can cause sensitivity reactions (e.g., sensitization, hypersensitivity) following
topical application11, 44, 50, 149, 151, 345, 349, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 368, 369, 370, 379, 380 or
systemic administration,50, 149, 151, 345, 360, 361, 364, 369, 370, 379, 381, 382, 383, 388, 436 but such reactions
are more likely following topical use of the drugs,149, 151, 345, 349, 355, 356, 361, 364, 369, 370, 379
especially ethylenediamine derivatives.44, 50, 355, 356, 361, 362, 379, 380 Antihistamines can act as
haptens349 and cause IgE-mediated (type I) hypersensitivity reactions349, 369, 381, 383, 388 or T cell-
mediated (type IV) sensitization reactions.44, 50, 149, 349, 355, 356, 359, 360, 361, 362, 379 Type I reactions
appear to occur rarely, but type IV reactions occur more frequently, particularly following
topical application of the drugs.149, 349, 355, 356, 361, 363, 364, 369, 379, 381, 383 Sensitization following
topical use of antihistamines results in allergic contact dermatitis, which may be manifested as
eczema, pruritus, and inflammation, at the site of application.44, 50, 349, 355, 356, 359, 360, 361, 362, 363,
364, 368, 379, 380
Once local sensitization to an antihistamine occurs, the dermatitis can recur
following subsequent topical or systemic exposure to the drug44, 50, 355, 360, 361, 364, 379 or a
chemically related drug (including local anesthetics).44, 50, 355, 356, 360, 361, 364, 379 Photosensitivity
(principally photoallergic dermatitis) reactions, which may be manifested as eczema, pruritus,
papular rash, and erythema on exposed skin, also have occurred following topical365, 366 or
systemic administration365, 367, 509 of antihistamines, and cross-sensitivity with chemically related
drugs can occur.367

 Cardiovascular Effects
Although antihistamines exhibit anticholinergic and local anesthetic effects, including quinidine-
like effects on cardiac conduction, and certain drugs have been investigated for potential
antiarrhythmic activity, adverse cardiovascular effects are uncommon and usually limited to
overdosage situations. When adverse cardiac effects have occurred, they generally were
characteristic anticholinergic and/or local anesthetic (quinidine-like) effects such as tachycardia,
palpitation, ECG changes (e.g., widened QRS), and arrhythmias (e.g., extrasystole, heart block).
Other cardiovascular effects reported with antihistamines include hypotension and hypertension;
in some cases, hypotension may result in part from -adrenergic blocking activity of the
antihistamine.
Serious cardiac effects, including prolongation of the QT interval corrected for rate (QTc), ST-U
abnormalities, arrhythmias (e.g., ventricular tachycardia, atypical ventricular tachycardia
[torsades de pointes], ventricular fibrillation, heart block), arrest, hypotension, palpitations,
syncope, dizziness, and/or death (secondary to ventricular tachyarrhythmia), have been reported
rarely in patients receiving terfenadine413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 431, 434, 443, 444, 445,
446, 447, 448, 449, 466, 476, 514
or astemizole.424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 448, 449, 453, 456, 457,
458, 459, 460, 461, 462, 463, 507, 512
Astemizole and terfenadine are no longer commercially available in
the US.456, 659, 660 These cardiotoxic effects usually were associated with higher than
recommended dosages and/or increased plasma concentrations of the drugs and their active
metabolites,413, 414, 416, 417, 419, 421, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 448, 449, 453, 459, 461, 466, 476,
514
although serious cardiac effects also have been reported occasionally at usual astemizole or
terfenadine dosages.413, 414, 417, 418, 424, 433, 448, 449, 456, 459, 461, 476, 512 While patients with impaired
liver function and, possibly, geriatric patients may have been at particular risk of accumulation of
these antihistamines and associated cardiotoxic effects,413, 417, 418, 419, 422, 424, 433, 447, 448, 449, 456, 459,
466, 476, 512
these effects have been reported rarely in apparently healthy individuals with no
associated risk factors.413, 414, 417, 418, 476

Patients who were receiving concomitant therapy with an azole (including imidazole derivative
[e.g., ketoconazole] and triazole derivative [e.g., itraconazole]) antifungal, a macrolide (e.g.,
clarithromycin, erythromycin, troleandomycin) anti-infective, mibefradil (no longer
commercially available in the US), quinine, or grapefruit juice also appeared to be at substantial
risk of such toxicity, probably secondary to interference with metabolism of the antihistamine.413,
415, 416, 417, 418, 419, 420, 421, 423, 443, 444, 445, 446, 447, 448, 449, 455, 456, 457, 458, 459, 460, 466, 475, 476, 477, 479, 480,
487, 490, 507, 511, 512, 513, 515, 518, 542, 543, 544
In addition, concomitant use of terfenadine or astemizole
with most human immunodeficiency virus (HIV) protease inhibitors, quinupristin and
dalfopristin, zileuton, or serotonin-reuptake inhibitors has not been recommended since HIV
protease inhibitors, quinupristin and dalfopristin, zileuton, and serotonin-reuptake inhibitors have
been associated with increased plasma concentrations of these antihistamines and potentially
serious and/or life-threatening adverse effects could have occurred as a result of these drugs'
effects on the metabolism of astemizole or terfenadine.413, 518, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554,
574, 664

The potential for similar drug interactions and cardiac effects with loratadine remains to be
elucidated more fully.470, 505, 506 However, acrivastine and loratadine have not been shown to
prolong the QT interval when administered alone.487 Prolongation of the QTc interval has been
reported in a limited number of healthy adults receiving desloratadine dosages of 45 mg daily (9
times the recommended daily dosage) for 10 days; however, the manufacturer states that no
clinically relevant adverse events were reported.670

The manufacturer of cetirizine states that no clinically important prolongation of the QTc interval
has been reported in healthy adult men receiving cetirizine during controlled clinical studies.509
The manufacturer of levocetirizine (the R enantiomer of cetirizine) states that no clinically
important prolongation of the QTc interval has been reported following administration of a single
dose of levocetirizine.685 The effects of multiple-dose administration are not known, but
levocetirizine is not expected to have clinically important effects on the QTc interval based on
results of QTc studies with cetirizine and the lack of reports of QTc interval prolongation during
postmarketing surveillance of that drug.685 The manufacturer of cetirizine also states that
concomitant administration of the antihistamine with drugs known to inhibit cytochrome P-450
microsomal enzymes (e.g., azithromycin, erythromycin, ketoconazole) has not been associated
with clinically important changes in ECG parameters (e.g., QTc intervals) and that no clinically
important interactions have been reported in patients receiving cetirizine concomitantly with
azithromycin, erythromycin, or ketoconazole.509, 580, 584

The manufacturer of fexofenadine states that no statistically significant mean increases in the
QTc interval have been reported in healthy adults or patients with seasonal allergic rhinitis
receiving fexofenadine hydrochloride dosages up to 400 mg twice daily (for 6 days) or 60-240
mg twice daily (for 2 weeks), respectively, during controlled clinical studies.516, 517

The mechanism of the cardiotoxic effects of astemizole and terfenadine has not been fully
understood,417, 425, 426, 461, 462, 466, 476 and it appeared to be contrary to what would have been
expected from studies on cardiac histamine H1-receptors;426, 439, 463, 464, 465 the possibility that H3-
receptors (mediating a regulatory feedback mechanism) may have been involved had been
suggested.426 Limited evidence from animal models using terfenadine has suggested that the
cardiotoxic effects of the drug may have resulted at least in part from blockade of the potassium
channel involved in repolarization of cardiac cells (i.e., blockade of the delayed rectifier
potassium current IK).455, 462, 476, 514, 516 Unlike other antihistamines, anticholinergic and/or local
anesthetic effects appeared to be unlikely causes of the cardiac effects of these 2 second
generation (relatively "nonsedating") antihistamines.426

It has been recommended that usual dosages of terfenadine (i.e., 60 mg twice daily) and
astemizole (i.e., 10 mg daily) not be exceeded because of the risk of potentially life-threatening
cardiotoxic effects.413, 417, 419, 430, 433, 448, 449, 459, 476 Because of this risk, patients were advised not
to temporarily increase (e.g., double) the prescribed dosage in an attempt to accelerate or
improve symptomatic relief provided by these drugs.413, 419, 424, 433, 448, 449, 459, 476

Patients with hepatic impairment, geriatric patients, those receiving drugs or who had underlying
conditions that might have prolonged the QT interval, and those who were receiving drugs that
could have produced electrolyte abnormalities such as hypokalemia or hypomagnesemia may
have been at increased risk of cardiac arrhythmias during terfenadine or astemizole therapy.413,
419, 424, 433, 448, 449, 459, 466, 475, 476, 477
Therefore, administration of these antihistamines was not
recommended in such patients.413, 419, 424, 433, 448, 449, 459, 476, 477 Terfenadine or astemizole also
should not have been used in patients receiving a macrolide (e.g., clarithromycin, erythromycin,
troleandomycin) anti-infective, an azole antifungal (including imidazole [e.g., itraconazole] and
triazole [e.g., itraconazole] derivatives), or mibefradil; in addition, use of these antihistamines in
patients receiving any other drug (e.g., quinine, most HIV protease inhibitors, serotonin-reuptake
inhibitors, zileuton) that potentially could inhibit their metabolism was not recommended.413, 416,
417, 418, 419, 447, 448, 449, 455, 459, 466, 475, 476, 490, 508, 513, 514, 518, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 574
It
also has been recommended that astemizole or terfenadine not be taken with grapefruit juice.413,
512
Concomitant administration of astemizole with therapeutic doses of quinine was
contraindicated.511, 512, 513, 514

 Other Adverse Effects

Adverse anticholinergic effects of antihistamines include dryness of mouth, nose, and throat;
dysuria; urinary retention; impotence; vertigo; visual disturbances; blurred vision; diplopia;
tinnitus; acute labyrinthitis; insomnia; tremors; nervousness; irritability; and facial dyskinesia.
Tightness of the chest, thickening of bronchial secretions, wheezing, nasal stuffiness, sweating,
chills, early menses, toxic psychosis, headache, faintness, and paresthesia have occurred.

Rarely, agranulocytosis, hemolytic anemia, leukopenia, thrombocytopenia, and pancytopenia

have been reported in patients receiving some antihistamines. Increased appetite and/or weight
gain also occurred in patients receiving antihistamines (cyproheptadine).

 Precautions and Contraindications

Antihistamines having substantial anticholinergic activity (usually conventional [prototypical,
first generation] including ethanolamines) should be administered with caution, if at all, in
patients with angle-closure glaucoma, prostatic hypertrophy (which may result in difficulty in
urination), stenosing peptic ulcer, pyloroduodenal obstruction, or bladder neck obstruction.
Because it was suggested that the anticholinergic effect of antihistamines might reduce the
volume and cause thickening of bronchial secretions and thus result in obstruction of respiratory
passages, it had been recommended that the drugs be used with caution and only under the
direction of a clinician in patients with asthma or chronic obstructive pulmonary disease if
clearance of bronchial secretions was a problem.169, 467, 487 While some clinicians100, 481, 482 and
manufacturers320, 391, 411, 484, 487 continue to warn against use of the drugs in patients with asthma
because of potential effects of anticholinergic activity on the volume and fluidity of bronchial
secretions, most experts467, 486, 500 and clinicians382, 481, 482, 484, 487 believe that there currently is
little, if any, direct evidence of antihistamine-induced exacerbation of asthma secondary to
bronchial drying nor substantiation for avoiding use of currently available antihistamines in
asthmatic patients.467, 481, 500 Antihistamines usually should not be used, unless under the
direction of a clinician, in patients who have a breathing problem (e.g., emphysema, chronic
bronchitis),467, 485, 486 and these drugs generally should not be used in asthmatics who previously
experienced a serious antihistamine-induced adverse bronchopulmonary effect.467, 481 467, 481 In
addition, antihistamines should be used with caution in patients with increased intraocular
pressure, hyperthyroidism, cardiovascular disease, or hypertension. The drugs are
contraindicated in patients with asthmatic attacks. For self-medication, cough preparations
containing an antihistamine (e.g., diphenhydramine) should not be used for persistent or chronic
cough or breathing problems such as those occurring with smoking, asthma, chronic bronchitis,
or emphysema, or for cough accompanied by excessive phlegm, unless directed by a clinician.501
A persistent cough may be indicative of a serious condition.501 If cough persists for more than
one week, is recurrent, or is accompanied by fever, rash, or persistent headache, a clinician
should be consulted.501

Patients should be advised that CNS depression (e.g., drowsiness) is common with first
generation antihistamines, even at usual dosages and particularly with ethanolamine derivatives.
(See Cautions: CNS Effects.) In addition, patients should be warned that additive CNS
depression may occur when first generation antihistamines or possibly, cetirizine or
levocetirizine is administered concomitantly with other CNS depressants, including alcohol.685
(See Drug Interactions: CNS Depressants.) Patients receiving acrivastine, a second generation
antihistamine, also should be warned of the possibility of such effects.494, 498, 499

Diphenhydramine toxicity (e.g., dilated pupils, facial flushing, hallucinations, ataxic gait, urinary
retention) has been reported in pediatric patients following topical application of
diphenhydramine to large areas of the body (often areas with broken skin) or following
concomitant use of topical and oral preparations containing diphenhydramine.556 (See Acute
Toxicity: Manifestations.) Therefore, the US Food and Drug Administration (FDA) and many
clinicians warn that oral diphenhydramine should not be used concomitantly with any other
preparations containing the drug, including those used topically.556, 672 (See Cautions, in
Diphenhydramine 4:04.) In addition, topical preparations containing diphenhydramine should
not be used more often than directed for any condition, applied on large areas of the body, or
used concomitantly with other preparations containing diphenhydramine, including those used
orally,672 since increased serum concentrations of diphenhydramine may occur that can result in
CNS toxicity.556, 557, 575, 576 (See Acute Toxicity: Manifestations.) Patients should be advised to
consult a clinician prior to use of topical diphenhydramine for the management of varicella
(chickenpox) or measles.672

Although diphenhydramine appears to have low abuse potential, several children, adolescents,
and at least one adult with chronic hematologic and antineoplastic diseases have exhibited drug-
seeking behavior and anticholinergic effects after chronic intermittent rapid IV administration of
the drug.661

While astemizole and terfenadine were commercially available in the US, individuals receiving
these second generation antihistamines were warned that patients with hepatic impairment (e.g.,
cirrhosis, hepatitis); geriatric patients; those who were concomitantly receiving an azole-
derivative anti-infective (e.g., fluconazole, itraconazole, ketoconazole, metronidazole,
miconazole), a macrolide antibiotic (e.g., clarithromycin, erythromycin, troleandomycin),
mibefradil (no longer commercially available in the US), or other potent inhibitors of the
cytochrome P-450 isoenzyme (CYP3A) (including most HIV protease inhibitors, quinupristin
and dalfopristin, zileuton, or serotonin-reuptake inhibitors) responsible for the metabolism of
astemizole or terfenadine (see Drug Interactions); those who were having underlying conditions
that might prolong the QT interval corrected for rate (QTc) (e.g., hypokalemia, hypomagnesemia,
bradycardia, congenital QT syndrome); those who were receiving drugs that might prolong the
QTc interval (e.g., certain antiarrhythmic agents, bepridil hydrochloride, certain psychotropic
agents, probucol [no longer commercially available in the US], cisapride, sparfloxacin,
pentamidine); or those who were receiving drugs (e.g., diuretics) that could produce electrolyte
abnormalities, such as hypokalemia or hypomagnesemia, may have experienced prolongation of
the QTc interval and may have been at increased risk of cardiac arrhythmias (e.g., ventricular
tachycardia, atypical ventricular tachycardia [torsades de pointes], ventricular fibrillation) when
they were receiving recommended dosages of astemizole or terfenadine.416, 434, 457, 458, 466, 475, 476,
477, 478, 512, 515, 594, 595, 596, 597, 605, 606, 607, 615, 643, 645, 646, 658, 664
Therefore, administration of
astemizole or terfenadine was not recommended in such patients.434, 477, 512, 594, 597, 605, 606, 643, 664

In addition, astemizole or terfenadine was contraindicated in patients with disease states (e.g.,
severe hepatic impairment) or receiving concomitant therapy (e.g., itraconazole, ketoconazole,
clarithromycin, erythromycin, troleandomycin, mibefradil) known to impair metabolism of the
antihistamine.419, 443, 477, 510, 512, 594, 596, 597, 605, 606, 607, 634 Astemizole also was contraindicated in
patients receiving concomitant therapy with quinine.512

For additional cautions, contraindications, and drug interactions with the phenothiazine
derivatives, see the Phenothiazines General Statement 28:16.08.24.
 Pediatric Precautions
Antihistamines should not be administered to premature or full-term neonates. Young children
may be more susceptible than adults to the toxic effects of antihistamines.307, 308 (See Acute
Toxicity.) Adults responsible for the supervision of a child receiving an antihistamine should be
warned that children may be at increased risk for experiencing CNS stimulant effects with
antihistamines.100, 169, 307 (See Cautions: CNS Effects.) Although the relationship and possible
mechanism(s) have not been elucidated,203, 204, 205, 206, 207 respiratory depression, sleep apnea, and
sudden infant death syndrome (SIDS) have occurred in a number of infants and young children
who were receiving usual dosages of phenothiazine-derivative antihistamines (i.e., promethazine,
trimeprazine [no longer commercially available in the US]).202, 203, 206, 207 (See Cautions:
Pediatric Precautions, in Promethazine 4:04.) In addition, death has been reported in children
younger than 2 years of age receiving carbinoxamine-containing preparations696, 697 or cough and
cold preparations containing an antihistamine with or without other agents (e.g., cough
suppressants, expectorants, nasal decongestants).693 (See Uses: Regulations Governing
Carbinoxamine-containing Preparations, in Carbinoxamine Maleate 4:04 and also see Cautions:
Pediatric Precautions, in Pseudoephedrine Hydrochloride 12:12.12.)

In a report published by the US Centers for Disease Control and Prevention (CDC), cough and
cold preparations containing carbinoxamine, pseudoephedrine, acetaminophen, and/or
dextromethorphan were determined by medical examiners or coroners to be the underlying cause
of death in 3 infants 6 months of age or younger during 2005.693, 694 The actual cause of death
might have been overdosage of one drug, interaction of different drugs, an underlying medical
condition, or a combination of drugs and underlying medical conditions.693 In addition, an
estimated 1519 children younger than 2 years of age were treated in emergency departments in
the US during 2004-2005 for adverse events, including overdoses, associated with cold and
cough preparations.693

The dosages at which cold and cough preparations can cause illness or death in pediatric patients
younger than 2 years of age are not known, and there are no specific dosage recommendations
(i.e., approved by the US Food and Drug Administration [FDA]) for the symptomatic treatment
of cold and cough for patients in this age group.693 Because of the absence of dosage
recommendations, limited published evidence of effectiveness, and risks for toxicity (including
fatal overdosage).693, 694 FDA stated that nonprescription cough and cold preparations should not
be used in children younger than 2 years of age;699 the agency continues to assess safety and
efficacy of these preparations in older children.702, 704 Meanwhile, because children 2-3 years
of age also are at increased risk of overdosage and toxicity, some manufacturers of oral
nonprescription cough and cold preparations recently have agreed to voluntarily revise the
product labeling to state that such preparations should not be used in children younger than 4
years of age.701, 702, 703, 704 Because FDA does not typically request removal of products
with previous labeling from pharmacy shelves during a voluntary label change, some
preparations will have the new recommendation ("do not use in children younger than 4 years of
age"), while others will have the previous recommendation ("do not use in children younger than
2 years of age").702, 704 FDA recommends that parents and caregivers adhere to the dosage
instructions and warnings on the product labeling that accompanies the preparation if
administering to children and consult with their clinician about any concerns.701, 702, 703
Clinicians should ask caregivers about use of nonprescription cough and cold preparations to
avoid overdosage.693
Because antihistamines may cause drowsiness that can be potentiated by other CNS depressants
(e.g., sedatives, tranquilizers), an antihistamine should be used in children receiving one of these
drugs only under the direction of a clinician.350 Antihistamines should not be used in children
who have a breathing problem (e.g., chronic bronchitis) or glaucoma unless otherwise directed
by a clinician.485 It also has been recommended that antihistamines not be used in children with
asthma, liver disease, or seizure disorder unless under the direction of a clinician.390 For
additional information, see the individual monographs in 4:00.

Acute toxicity has been reported in pediatric patients following topical application of
diphenhydramine to large areas of the body (often areas with broken skin) or following
concomitant use of topical and oral preparations containing diphenhydramine.556 (See Cautions:
Precautions and Contraindications, and also see Acute Toxicity.)

While it is desirable to avoid the use of alcohol-containing antihistamine preparations in children

because of potential toxicity,100, 390, 403 inclusion of alcohol in some preparations may be a
pharmaceutical necessity (e.g., as a solvent) and therefore complete avoidance of such
preparations may not be possible.390, 403 According to a final rule issued in 1995 by the US Food
and Drug Administration (FDA), over-the-counter (OTC) oral preparations intended for use in
children younger than 6 years of age, children 6-11 years of age, or children 12 years of age and
older may contain up to 0.5, 5, or 10% alcohol, respectively.678, 679

 Pregnancy and Lactation

Pregnancy
Safe use of antihistamines during pregnancy has not been established; therefore, the drugs should
not be used in women who are or may become pregnant unless the potential benefits justify the
possible risks to the fetus. Some manufacturers caution that antihistamines should not be used
during the third trimester because of the risk of severe reactions (e.g., seizures) to the drugs in
neonates and premature infants.143, 320 There is considerable controversy regarding the
teratogenic potential, if any, of doxylamine;169, 268, 269, 270, 271, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282,
283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 350
however,
after evaluating extensive data and information concerning the possible teratogenicity of the
drug, the FDA concluded that it is unlikely that doxylamine is teratogenic.350 FDA recognizes,
however, that despite the large number of pregnancies evaluated to date the possibility that
doxylamine may be weakly teratogenic cannot be excluded.350 For additional information, see the
individual monographs in 4:00.

Lactation
Most manufacturers state that antihistamines should not be administered to nursing women, since
the drugs may inhibit lactation and small amounts appear to be distributed into milk. Because of
the potential for serious adverse reactions (e.g., CNS effects) to antihistamines in nursing infants,
a decision should be made whether to discontinue nursing or antihistamines, taking into account
the importance of the drugs to the woman.

Drug Interactions

 CNS Depressants
Additive CNS depression may occur when antihistamines are administered concomitantly with
other CNS depressants including barbiturates, tranquilizers, and alcohol. If antihistamines are
used concomitantly with other depressant drugs, caution should be used to avoid overdosage.
Patients should be advised to avoid alcoholic beverages during antihistamine therapy.350, 407, 585,
586
Patients already receiving another CNS depressant (e.g., sedatives, tranquilizers) should not
undertake self-medication with an antihistamine without first consulting a physician.350, 407, 585,
586
Unlike first generation antihistamines, most second generation antihistamines (e.g.,
astemizole [no longer commercially available in the US], loratadine, terfenadine [no longer
commercially available in the US]) do not appear to potentiate the sedative effects of CNS
depressants;161, 192, 404, 405, 406, 456, 497, 498, 499, 659, 660 however, acrivastine, cetirizine, and
levocetirizine, which also have been classified as second generation antihistamines, may
potentiate such effects, although less prominently than first generation antihistamines.494, 498, 499,
509, 685

It also should be considered that monoamine oxidase (MAO) inhibitors may prolong and
intensify some anticholinergic effects (e.g., dryness) of antihistamines.

 Epinephrine
Phenothiazine-type antihistamines (e.g., methdilazine [no longer commercially available in the
US], promethazine, trimeprazine [no longer commercially available in the US]) may block and
reverse the vasopressor effect of epinephrine. If patients receiving phenothiazines require a
vasopressor agent, norepinephrine or phenylephrine should be used; epinephrine should not be
used.

 Drugs and Foods Affecting Hepatic Microsomal Enzymes

Concomitant administration of astemizole or terfenadine with drugs that can inhibit the
metabolism of these antihistamines has resulted in accumulation of potentially cardiotoxic
concentrations of astemizole or terfenadine and/or their active metabolites.413, 416, 417, 418, 419, 447,
448, 449, 454, 456, 457, 458, 459, 460, 466, 477, 508
(See Cautions: Cardiovascular Effects.) Both human and
animal data have indicated that associated cardiotoxic effects resulted principally from
accumulation of unchanged astemizole (and its main metabolite desmethylastemizole) or
unchanged terfenadine.466, 476, 477, 478, 512, 541, 596, 597, 605, 606, 607, 615, 616, 617, 638

Serious, potentially life-threatening cardiac effects have occurred when astemizole or terfenadine
was used concomitantly with certain azole antifungal (including imidazole derivative [e.g.,
ketoconazole] and triazole derivative [e.g., itraconazole]) or macrolide (e.g., clarithromycin,
erythromycin, troleandomycin) anti-infectives, mibefradil (no longer commercially available in
the US), or quinine sulfate (a single dose of 430 mg), probably secondary to inhibition of
metabolism of the antihistamine by these drugs.413, 415, 416, 417, 418, 419, 420, 421, 423, 443, 444, 445, 446, 447,
448, 449, 454, 455, 456, 457, 458, 459, 460, 466, 475, 476, 477, 490, 508, 511, 512, 513, 514, 515
Therefore, while
456, 659, 660
astemizole or terfenadine was commercially available in the US, concomitant therapy
with these or other known inhibitors of astemizole or terfenadine metabolism was
contraindicated.416, 418, 419, 447, 448, 449, 477, 512, 594, 596, 597, 605, 606, 607, 643 No clinically adverse effects
or changes in the QTc intervals were reported after concomitant administration of erythromycin
or ketoconazole with fexofenadine, the active metabolite of terfenadine.516, 517 The increased
safety profile of fexofenadine compared with the parent drug, terfenadine, may result from the
lack of fexofenadine-induced cardiotoxicity in addition to only minimal metabolism of
fexofenadine in the liver by the cytochrome P-450 microsomal enzyme system.514, 516, 517

Concomitant use of terfenadine or astemizole with other chemically related azole-derivative anti-
infective (e.g., fluconazole, miconazole, metronidazole), most human immunodeficiency virus
(HIV) protease inhibitors, quinupristin and dalfopristin, zileuton, or serotonin-reuptake inhibitors
has not been recommended since these drugs may have increased plasma concentrations of
terfenadine and/or astemizole and potentially serious and/or life-threatening adverse effects
could have occurred.413, 518, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 574, 664

Grapefruit juice also may have inhibited metabolism of terfenadine.413, 514, 518, 541, 544, 555
Increased oral bioavailability of unchanged terfenadine observed with concomitant
administration of the drug and grapefruit juice has been associated with prolongation of the QT
interval averaging 3.3% (range: -1.6 to 9.5%);541 mean QT interval corrected for rate (QTc)
increased by 4-14 msec compared with administration of terfenadine with water.413, 514, 518, 541,
544, 555
Therefore, it has been recommended that astemizole or terfenadine not be taken
concomitantly with grapefruit juice.512, 596, 607

Ketoconazole and Other Azole Antifungal Agents

Prolongation of the QT interval and QT interval corrected for rate (QTc) and, rarely, serious
cardiovascular effects, including arrhythmias (e.g., ventricular tachycardia, atypical ventricular
tachycardia [torsades de pointes, ventricular fibrillation]), cardiac arrest, palpitations,
hypotension, dizziness, syncope, and death, have been reported in patients receiving
recommended dosages of astemizole or terfenadine concomitantly with ketoconazole.416, 418, 419,
420, 434, 443, 458, 475, 476, 512, 515, 594, 595, 596, 597, 598, 599, 605, 606, 607, 643
Ketoconazole has markedly
inhibited the metabolism of astemizole or terfenadine, probably via inhibition of the cytochrome
P-450 microsomal enzyme system, which resulted in increased plasma concentrations of
unchanged astemizole (and its principal metabolite desmethylastemizole) or unchanged
terfenadine; clearance of the active carboxylic acid metabolite of terfenadine also may have been
reduced.434, 458, 475, 476, 477, 512, 597, 598, 605, 643 Increased plasma concentrations of unchanged
astemizole (and its principal metabolite desmethylastemizole) or unchanged terfenadine has been
associated with prolongation of the QT and QTc intervals.416, 419, 420, 443, 458, 475, 476, 477, 512, 594, 597,
599, 605, 643
Similar alterations in astemizole or terfenadine pharmacokinetics and adverse cardiac
effects (prolongation of the QTc interval, cardiac arrest, and ventricular arrhythmias [e.g.,
torsades de pointes]) have been reported in patients receiving the antihistamine concomitantly
with itraconazole.457, 477, 478, 490, 512, 594, 596, 605, 607, 612 Therefore, while commercially available in
the US,456, 659, 660 astemizole and terfenadine were contraindicated in patients receiving
ketoconazole or itraconazole.418, 457, 458, 477, 512, 515, 594, 605, 643 In addition, it has been
recommended that astemizole and terfenadine also not be used in patients receiving drugs that
are structurally related to these antifungals (e.g., triazoles such as fluconazole, imidazoles such
as miconazole, nitroimidazoles such as metronidazole).512, 594, 596, 597, 607

Increased plasma concentrations of loratadine and its active metabolite desloratadine

(descarboethoxyloratadine) also have been reported in controlled clinical studies in healthy men
receiving 10 mg of loratadine once daily concomitantly with ketoconazole dosages of 200 mg
every 12 hours.470, 502 In these studies, area under the plasma concentration-time curve (AUC) of
loratadine increased by 307% following concomitant administration with ketoconazole while
AUC of desloratadine increased by 73% following concomitant administration with
ketoconazole.470, 502 However, no clinically important changes, as measured by ECG and
laboratory evaluations, vital signs, and adverse effects, were reported after concomitant
administration of ketoconazole with loratadine.470 In addition, no changes in QTc intervals,
sedation, or syncope were reported in these individuals.470, 502 Plasma concentrations of
ketoconazole appeared to be unchanged in individuals receiving loratadine concomitantly.470 In
addition, increased plasma concentrations of loratadine (AUC increased by 180%) and
desloratadine (AUC increased by 56%) have been reported in a limited number of individuals
receiving a single 20-mg dose of loratadine concomitantly with a ketoconazole dosage of 200 mg
twice daily.488, 502 However, no changes in QTc intervals were reported 2, 6, and 24 hours after
concomitant administration of the drugs.488, 502 Adverse effects were similar in individuals
receiving loratadine alone compared with those receiving loratadine concomitantly with
ketoconazole.488, 502

Increased plasma concentrations of desloratadine and 3-hydroxydesloratadine have been reported

in a controlled clinical study in healthy individuals receiving 7.5 mg of desloratadine once daily
concomitantly with ketoconazole dosages of 200 mg every 12 hours for 10 days.670 In this study,
AUC of desloratadine or 3-hydroxydesloratadine increased by 39 or 72%, respectively, while
peak plasma concentrations increased by 45 or 43%, respectively, following concomitant
administration with ketoconazole.670 However, no clinically important changes, as measured by
ECG and laboratory evaluations, vital signs, and adverse effects, were reported after concomitant
administration of ketoconazole with desloratadine.670

The manufacturer of cetirizine states that no clinically important drug interactions have been
reported in patients receiving cetirizine concomitantly with ketoconazole.509

Increased plasma concentrations of fexofenadine have been reported in 2 studies in healthy

individuals receiving 120 mg of fexofenadine twice daily concomitantly with ketoconazole 400
mg once daily.516 In these studies, AUC of fexofenadine increased by 164% following
concomitant administration with ketoconazole while peak plasma concentrations of fexofenadine
increased by 135%.516 However, no clinically important adverse effects or changes in the QTc
intervals were reported after concomitant administration of ketoconazole with fexofenadine.516,
517

Macrolides
Erythromycin and clarithromycin have altered the metabolism of astemizole or terfenadine.419,
434, 443, 445, 466, 477, 507, 512, 515, 594, 596, 597, 606, 607, 613, 643
In some individuals, concomitant
administration of erythromycin with astemizole or terfenadine has resulted in increased plasma
concentrations of unchanged astemizole (and its principal metabolite desmethylastemizole) or
unchanged terfenadine (and its active carboxylic metabolite fexofenadine).512, 596, 606, 607
Prolongation of the QTc, ST-U abnormalities, and ventricular tachycardia, including torsades de
pointes, have been reported in some patients receiving astemizole or terfenadine concomitantly
with erythromycin or the structurally related macrolides clarithromycin, troleandomycin, or
josamycin.416, 434, 445, 446, 447, 448, 449, 466, 476, 507, 512, 594, 596, 597, 606, 607, 655 Cardiac arrest and death
have occurred in patients receiving erythromycin concomitantly with astemizole or
terfenadine.510, 512, 606 Therefore, while commercially available in the US,456, 659, 660 astemizole or
terfenadine was contraindicated in patients receiving clarithromycin, erythromycin, or
troleandomycin.416, 418, 446, 448, 449, 477, 512, 515, 582, 594, 606, 613, 655

Limited data have suggested that azithromycin606, 607, 608, 610, 611, 632 and dirithromycin606, 609, 633
did not appear to alter the metabolism of terfenadine.593, 606, 608, 609, 610, 611, 633

Increased plasma concentrations of loratadine and its active metabolite desloratadine have been
reported in controlled clinical studies in healthy men receiving 10 mg of loratadine once daily
concomitantly with erythromycin dosages of 500 mg every 8 hours for 10 days.470, 502, 503 In
these studies, AUC of loratadine increased by 40% following concomitant administration with
erythromycin, while AUC of desloratadine increased by 46%.470, 502, 503 However, no clinically
important changes, as measured by ECG and laboratory evaluations, vital signs, and adverse
effects, were reported after concomitant administration of erythromycin with loratadine.470, 503 In
addition, no changes in QTc intervals, sedation, or syncope were reported in these individuals.470,
502, 503
Although the clinical importance has not been established, decreased plasma
concentrations of erythromycin (AUC decreased by 15-18%) have been reported in these patients
receiving loratadine concomitantly.470, 503

Increased plasma concentrations of loratadine and desloratadine also have been reported in a
controlled drug interaction study in healthy men receiving 10 mg of loratadine every 24 hours
concomitantly with clarithromycin dosages of 500 mg every 12 hours for 10 days.663 In this
study, peak steady-state plasma concentrations and AUC of loratadine increased by 36 and 76%,
respectively, following concomitant administration with clarithromycin for 10 days while peak
steady-state plasma concentrations and AUC of desloratadine increased by 69 and 49%,
respectively, compared with administration of loratadine alone.663 Although mean maximum QTc
interval was modestly increased (by less than 3% and not exceeding 439 msec) when loratadine
was administered concomitantly with clarithromycin, such increase was similar to that observed
when loratadine was administered alone and probably was not clinically important.663 The
pharmacokinetics of clarithromycin were not affected by concomitant loratadine.663

Increased plasma concentrations of desloratadine and 3-hydroxydesloratadine have been reported

in a controlled clinical study in healthy individuals receiving 7.5 mg of desloratadine once daily
concomitantly with erythromycin dosages of 500 mg every 8 hours for 10 days.670 In this study,
AUC of desloratadine or 3-hydroxydesloratadine increased by 14 or 40%, respectively, while
peak plasma concentrations increased by 24 or 43%, respectively, following concomitant
administration with erythromycin.670 In another study in healthy individuals receiving 5 mg of
desloratadine once daily concomitantly with azithromycin (500 mg followed by 250 mg once
daily for 4 days), AUC of desloratadine or 3-hydroxydesloratadine increased by 5 or 4%,
respectively, while peak plasma concentrations increased by 15%.670 However, no clinically
important changes, as measured by ECG and laboratory evaluations, vital signs, and adverse
effects, were reported after concomitant administration of erythromycin or azithromycin with
desloratadine.670

The manufacturer of cetirizine states that no clinically important drug interactions have been
reported in patients receiving cetirizine concomitantly with azithromycin or erythromycin.509
Increased plasma concentrations of fexofenadine have been reported in 2 studies in healthy
individuals receiving 120 mg of fexofenadine twice daily concomitantly with erythromycin
dosages of 500 mg every 8 hours.516 In these studies, AUC of fexofenadine increased by 109%
following concomitant administration with erythromycin, while peak plasma concentrations of
fexofenadine increased by 82%.516 However, no clinically important adverse effects or changes
in the QTc intervals were reported after concomitant administration of erythromycin with
fexofenadine.516, 517

HIV Protease Inhibitors

In vitro, ritonavir has been shown to inhibit the metabolism of terfenadine, but the clinical
importance of this in vitro finding is not known.596, 607 Several manufacturers of HIV protease
inhibitors and some clinicians state that specific in vivo pharmacokinetic drug interaction studies
between these antihistamines and HIV protease inhibitors currently are not available.545, 546, 547,
548, 549, 554
Concomitant use of astemizole or terfenadine with HIV protease inhibitors (e.g.,
indinavir, nelfinavir, ritonavir, saquinavir) has not been recommended,512, 582, 596, 607 because of
the theoretical risk that the HIV protease inhibitor could produce substantially increased plasma
concentrations of unchanged astemizole or terfenadine resulting in potentially serious and/or life-
threatening adverse effects.512, 545, 546, 547, 548, 549, 554 The manufacturers of indinavir and ritonavir
state that concomitant use of either drug with astemizole or terfenadine is contraindicated
because such use may precipitate potentially life-threatening adverse effects.656, 657

Serotonin-reuptake Inhibitors
In vitro, fluvoxamine, nefazodone, or sertraline and/or their metabolites have been shown to
inhibit metabolism of terfenadine probably secondary to inhibition of the cytochrome P-450
(CYP34A) enzyme system, but the clinical importance of these in vitro findings is not known.553,
596, 607, 641
Concomitant administration of astemizole or terfenadine and any of the serotonin-
reuptake inhibitors (i.e., fluoxetine, fluvoxamine, nefazodone, paroxetine, sertraline) has not
been recommended since substantially increased plasma concentrations of unchanged astemizole
or terfenadine could occur resulting in an increased risk of serious adverse cardiac effects.512, 553,
582, 596, 607
The manufacturer of fluvoxamine and some clinicians state that concomitant use of the
antidepressant with terfenadine or astemizole is contraindicated.551, 552 However, at least one
manufacturer (i.e., of sertraline) states that in vivo drug interaction studies with sertraline and
terfenadine have failed to confirm any important alteration in plasma terfenadine concentrations
by the antidepressant and that a clinically important interaction is unlikely.647

Increased plasma concentrations of desloratadine and 3-hydroxydesloratadine have been reported

in a controlled clinical study in healthy individuals who were pretreated with fluoxetine for 23
days prior to receiving 5 mg of desloratadine once daily concomitantly with fluoxetine 20 mg
once daily for 7 days.670 In this study, peak plasma concentrations of desloratadine or 3-
hydroxydesloratadine increased by 15 or 17%, respectively, while AUC of 3-
hydroxydesloratadine increased by 13%, following concomitant administration with
fluoxetine.670 However, no clinically important changes, as measured by ECG and laboratory
evaluations, vital signs, and adverse effects, were reported after concomitant administration of
fluoxetine with desloratadine.670

Zileuton
Increased plasma concentrations of terfenadine have been reported in one study in healthy
individuals receiving 60 mg of terfenadine every 12 hours concomitantly with zileuton dosages
of 600 mg every 6 hours for 7 days.574, 596, 607 In this study, AUC and peak plasma concentrations
of terfenadine increased by about 35%, resulting from a 22% decrease in the clearance of
unchanged terfenadine.574, 596, 607 Although no adverse cardiac effects (e.g., substantial changes
in QTc intervals) were reported in these individuals, concomitant administration of astemizole or
terfenadine with zileuton is not recommended since pharmacokinetics of the antihistamines may
be impaired resulting in an increased risk of serious adverse cardiac effects.512, 574, 582, 596, 607

Quinine and Chemically Related Drugs

There has been some evidence indicating that quinine may alter the pharmacokinetics of
astemizole.511, 512, 614 Quinine is extensively metabolized in the liver; however, only limited
information exists about the specific cytochrome P-450 microsomal isoenzymes responsible for
the drug's metabolism.615 Increased plasma concentrations of astemizole and
desmethylastemizole were reported in a study in healthy men receiving 10 mg of astemizole
orally once daily for 24 days and 20 mg of quinine sulfate every 4 hours for 4 consecutive doses
on the 22nd day and then a single 430-mg dose on the 24th day of the study.614 In this study,
slight increases in the maximum plasma concentration and AUC of astemizole were associated
with concomitant administration of the 20-mg doses of quinine sulfate; however, no clinically or
statistically significant changes in QT interval were observed.614 Maximum plasma
concentrations and AUCs of astemizole and desmethylastemizole increased threefold following
concomitant administration of the antihistamine and the 430-mg dose of quinine sulfate; these
increases were associated with increases in the QT interval.614 Therefore, the manufacturer of
astemizole has stated that concomitant administration of astemizole and therapeutic doses (i.e.,
more than 80 mg daily) of quinine sulfate were contraindicated.512

Although increases in plasma concentrations of astemizole and its desmethyl metabolite also
may occur in patients receiving the antihistamine concomitantly with food products containing
quinine (e.g., tonic water), such increases are small and not associated with clinically or
statistically significant prolongation of the QT interval when consumption is limited to
approximately 1 L (32 oz) of tonic water a day (about 80 mg of quinine sulfate).614 Since
consumption of larger daily amounts of quinine in tonic water may be associated with risk in
patients receiving astemizole, patients who consume large amounts of tonic water daily may
wish to consult their clinician.593

Histamine H2-Receptor Antagonists and Xanthine Derivatives

The manufacturer of terfenadine has stated that detectable plasma concentrations of unchanged
terfenadine were not present and mean pharmacokinetic parameters (e.g., AUC, elimination half-
life, peak plasma concentration) for the carboxylic acid metabolite fexofenadine did not appear
to be affected in a study in which a single dose of terfenadine was given to individuals receiving
multiple doses of cimetidine.443, 597, 604 Other data also suggest that an interaction between the
drugs seems unlikely.593 While the potential for such a drug interaction has not been established,
cardiotoxic effects also occurred following a terfenadine overdosage in at least one patient who
was receiving cimetidine.597 In addition, torsades de pointes and prolongation of QT interval
were reported in a patient receiving terfenadine 60 mg twice daily concomitantly with cimetidine
400 mg twice daily, and some clinicians state that concomitant use of terfenadine and cimetidine
is not recommended.642, 644
Increased plasma concentrations of loratadine and its active metabolite desloratadine have been
reported in controlled clinical studies in healthy men receiving 10 mg of loratadine once daily
concomitantly with cimetidine dosages of 300 mg 4 times daily (every 6 hours) for 10 days.470,
502, 503
In these studies, AUC of loratadine increased by 103% following concomitant
administration with cimetidine, while AUC of descarboethoxyloratadine increased by 6%
following concomitant administration with cimetidine.470, 502, 503 However, no clinically
important changes, as measured by ECG and laboratory evaluations, vital signs, and adverse
effects, were reported after concomitant administration of cimetidine with loratadine.470, 503 In
addition, no changes in QTc intervals, sedation, or syncope were reported in these individuals.470,
502, 503
Plasma concentrations of cimetidine appeared to be unchanged in individuals receiving
loratadine concomitantly.470

Increased plasma concentrations of desloratadine have been reported in a controlled clinical

study in healthy individuals receiving 5 mg of the drug once daily concomitantly with cimetidine
(600 mg every 12 hours for 14 days under steady-state conditions).670 In this study, peak plasma
concentrations and AUC of desloratadine increased by 12 and 19%, respectively, following
concomitant administration with cimetidine.670 However, no clinically important changes, as
measured by ECG and laboratory evaluations, vital signs, and adverse effects, were reported
after concomitant administration of cimetidine with desloratadine.670

Other Drugs
To date, the number of patients receiving loratadine concomitantly with ranitidine or
theophylline has been too small to rule out a possible drug interaction between loratadine and
such drugs and therefore, the manufacturers have recommended that loratadine be used with
caution in patients receiving them.488

Grapefruit Juice
Concomitant oral administration of grapefruit juice with terfenadine has been reported to
increase bioavailability of terfenadine.541, 542, 544, 555, 596, 607, 616, 617, 643, 649 This increased
bioavailability of terfenadine was associated with prolongation of the QT interval averaging
3.3% (range: -1.6 to 9.5%); mean QTc intervals increased by 4-14 msec compared with
administration of terfenadine with water.541, 544, 555, 596, 607, 615 The interaction between grapefruit
juice and terfenadine bioavailability appears to result from inhibition, probably prehepatic,541, 544,
555, 574, 616, 619, 620, 621, 622, 623, 624, 636, 637
of the cytochrome P-450 enzyme system by some
constituent(s) in the juice.541, 544, 574, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 636, 637
Patients have been discouraged to ingest grapefruit juice concomitantly with terfenadine;541, 542
in addition, concomitant administration of astemizole with grapefruit juice has not been
recommended since substantially increased plasma concentrations of unchanged astemizole also
could occur resulting in an increased risk of serious adverse cardiac effects.512, 582

Concomitant oral administration of grapefruit juice with desloratadine does not appear to alter
bioavailability of the drug.671

Laboratory Test Interferences

Antihistamines may suppress inhalation-challenge testing with histamine or antigen as well as

the wheal and flare reactions to antigen skin testing.309, 310, 311, 312, 313, 314, 315, 316, 317 Considerable
interindividual variation in the extent and duration of suppression has been reported, depending
on the antigen and test technique, antihistamine and dosage regimen, time since the last dose, and
individual response to testing.309, 311, 312, 316, 317 In one study, usual oral dosages of
chlorpheniramine or diphenhydramine suppressed the wheal response for about 2 days after the
last dose, promethazine or tripelennamine suppressed whealing for about 3 days, and
hydroxyzine suppressed whealing for about 4 days.309 Combined use of an H1- and H2-antagonist
appears to have a synergistic suppressive effect on immediate and late cutaneous reactions to
skin test antigens.316, 317 Whenever possible, antihistamines should be discontinued about 4 days
prior to skin testing procedures since they may prevent otherwise positive reactions to dermal
reactivity indicators. Some evidence suggests that loratadine or terfenadine should be
discontinued at least 7 days prior to such testing and that the results of such tests should be
interpreted with caution even if testing were performed 4-6 weeks after astemizole
discontinuance.487

In one study, topical application of an antihistamine (i.e., 2% pyrilamine maleate cream) to the
skin test site 10 minutes after antigen testing decreased pruritus but did not suppress wheal or
flare 10 minutes after application.318

Acute Toxicity

 Manifestations
Although antihistamines have relatively high therapeutic indexes, overdosage may result in
death, especially in infants and children. There have been several reports of toxicity, often
occurring within 24-48 hours of repeated topical application of diphenhydramine, in children
with pruritus associated with varicella (chickenpox), poison ivy, or sunburn.556, 557 Such toxicity
included toxic psychosis (sometimes mimicking varicella encephalitis) and occurred in children
who received oral and topical diphenhydramine concomitantly.556, 557, 575, 576 The toxicity usually
was associated with increased (60-1900 ng/mL) serum concentration of diphenhydramine.556, 557
Topical diphenhydramine usually was applied to large areas of the body and usually was
contained in Caladryl, a commercially available lotion containing 1% diphenhydramine and 8%
calamine; such combination is no longer commercially available in the US since Caladryl has
been reformulated by the manufacturer to contain pramoxine hydrochloride with calamine or
zinc acetate.563 In general, overdosage of diphenhydramine may cause CNS stimulation and/or
depression; in young children, CNS stimulation is dominant. Symptoms of antihistamine toxicity
in children may resemble atropine overdosage and include fixed dilated pupils, abnormal eye
movements, flushed face, dry mouth, urinary retention, fever, excitation, hallucinations,
disorientation, delusions, agitation, bizarre behavior, confusion, jitteriness, restlessness,
irritability, hyperactivity, delirium, twitching, tiredness, abnormal tongue movement, unsteady
gait, trembling extremities, slurred speech, ataxia, incoordination, athetosis, tonic-clonic
seizures, and postictal depression. Children recovered gradually from these adverse CNS effects,
usually within 24-48 hours following removal of the topical preparation and discontinuance of
all diphenhydramine-containing preparations.556, 557

Overdosage in adults usually causes CNS depression with drowsiness or coma which may be
followed by excitement, seizures, and finally postictal depression. In children and adults,
cerebral edema and upper nephron nephrosis, a deepening coma, tachycardia, QRS widening,
heart block, cardiorespiratory collapse/arrest,391 cardiogenic shock, and death may occur. The
risk of cardiotoxicity has been particularly likely with astemizole and terfenadine;413, 417, 419, 430,
433, 448, 449, 459, 461, 487
however, these 2 antihistamines are no longer commercially available in the
US.456, 659, 660 (See Cautions: Cardiovascular Effects.) Symptoms of overdosage occur within 30
minutes to 2 hours after ingestion; death may occur within 18 hours. Toxic effects may persist
for prolonged (e.g., several days) periods after acute overdosage of antihistamines (e.g.,
astemizole) with long elimination half-lives. Rhabdomyolysis (evidenced by myoglobinuria) has
been associated with overdosage of doxylamine.410 Acute toxicity has been reported following
topical overdosage of diphenhydramine451, 452 or tripelennamine213 (no longer commercially
available in the US) in children.

 Treatment
Treatment of acute antihistamine overdosage consists of symptomatic and supportive therapy
including artificial respiration, if necessary. If the patient is conscious, has not lost the gag reflex,
and is not having seizures, emesis should be induced; however, the manufacturer of trimeprazine
(no longer commercially available in the US) stated that emesis should not be induced because
dystonic reaction of the head and neck may cause aspiration of gastric contents. The
manufacturer of carbinoxamine maleate also states that emesis should not be induced; activated
charcoal should be administered and gastric lavage should be considered following ingestion of a
potentially life-threatening amount of carbinoxamine maleate.677

While phenothiazine-type antihistamines may exhibit an antiemetic effect, ipecac syrup still may
be effective in oral poisonings with these agents if given early (usually within 1 hour) before
toxic or antiemetic effects appear. For additional information about induction of emesis for acute
poisonings, see Ipecac 56:20. If emesis cannot be induced, gastric lavage and administration of
activated charcoal are indicated; an endotracheal tube with cuff inflated should be in place to
prevent aspiration of gastric contents. Saline cathartics (e.g., magnesium sulfate) may be
administered.

Vasopressor agents, such as norepinephrine or phenylephrine, may be administered if necessary.

Epinephrine should not be used, especially with phenothiazine overdosage, because epinephrine
may lower the blood pressure further. Analeptic agents should not be used since they may cause
seizures. Physostigmine may be useful to counteract the CNS anticholinergic effects of
antihistamine intoxication. Diazepam can be given IV in the management of seizures that do not
respond to physostigmine. Hyperthermia may be treated with cold packs or sponging with tepid
water; sponging with alcohol should not be used.

If hypotension and/or cardiac arrhythmias occur (reported mainly with overdosage of astemizole
or terfenadine), appropriate therapy should be instituted.592, 593, 594 Antiarrhythmic agents that can
prolong the QT interval (e.g., class 1A agents) should be avoided in treating overdosage-
associated arrhythmias in which prolongation of the QTc interval is a manifestation.416, 594, 597, 600,
601
While arrhythmias may resolve spontaneously following discontinuance of the
antihistamine,416, 420 when necessary, therapy for ventricular tachyarrhythmias with associated
QT prolongation (e.g., torsades de pointes) can include temporary atrial or ventricular pacing, IV
magnesium sulfate, IV isoproterenol, and/or DC cardioversion (for initial management of
sustained, symptomatic runs).416, 421, 423, 600, 601, 602, 603

Pharmacology
Histamine is a physiologically active, endogenous substance (autacoid) that binds to and
activates histamine H1- and H2-receptors at various sites in the body.149, 150, 151, 371, 389, 487 H3-
receptors, which may be involved in feedback control of histamine synthesis and release, also
have been described.371, 372, 373, 374, 375 The principal pharmacologic effects of histamine involve
the cardiovascular system, extravascular smooth muscle (e.g., bronchial tree), and exocrine
glands (e.g., stimulation of salivary, gastric, lacrimal, and bronchial secretions).149, 150, 151, 371, 378,
389
Histamine also can stimulate some nerve endings and thus causes pruritus.149 Characteristic
cardiovascular effects of histamine include direct and indirect microvascular dilation,
hypotension, tachycardia, and flushing (involving H1- and H2-receptors) and increased vascular
permeability (thought to principally involve H1-receptors). Intracutaneous injection of histamine
produces a "triple response" of local reddening, a bright halo or flare, and wheal formation.149,
150, 151, 371, 376
In allergic conditions, histamine and other substances (e.g., leukotrienes,
prostaglandins, kinins, serotonin, platelet-activating factor) are secreted from mast cells,
basophils, and other cells in response to antigenic stimulation.149, 150, 152, 153, 172, 371, 378 Histamine
binds to and activates specific receptors in the nose, eyes, respiratory tract, and skin, causing
characteristic allergic signs and symptoms.100, 149, 150, 152, 153

The term antihistamine has historically been used to describe drugs that act as H1-receptor
antagonists.149, 150 Although drugs that antagonize H2-receptors also are commercially available
(e.g., cimetidine, famotidine, nizatidine, ranitidine), these drugs generally are not referred to as
antihistamines but rather as H2-receptor antagonists.149, 150 Antihistamines competitively
antagonize most of the smooth muscle stimulating actions of histamine on the H1-receptors of the
GI tract, uterus, large blood vessels, and bronchial muscle. Contraction of the sphincter of Oddi
and bile duct may be mediated in part by H1-receptors, and opiate-induced contraction of biliary
smooth muscle has been antagonized by antihistamines.377 The drugs only are feebly antagonistic
to bronchospasm induced by antigen-antibody reactions. Antihistamines also effectively
antagonize the action of histamine that results in increased capillary permeability and the
formation of edema. H1-receptor antagonists also suppress flare and pruritus that accompany the
endogenous release of histamine. Antihistamines appear to act by blocking H1-receptor sites,
thereby preventing the action of histamine on the cell; they do not chemically inactivate or
physiologically antagonize histamine nor do they prevent the release of histamine.
Antihistamines do not block the stimulating effect of histamine on gastric acid secretion, which
is mediated by H2-receptors of the parietal cells. For information on the effects of H2-receptor
antagonists, see Cimetidine 56:28.12, Famotidine 56:28.12, Nizatidine 56:28.12, and
Ranitidine 56:28.12.

The basic ethylamine group common to antihistamines also is common to anticholinergics,

ganglionic and adrenergic blocking agents, local anesthetics, and antispasmodics; antihistamines
therefore may be expected to exhibit some of the activities of these other classes of drugs. Some
antihistamines also demonstrate a quinidine-like effect on myocardial conduction, and they may
enhance the pressor action of norepinephrine. The antiemetic and antimotion-sickness actions of
some antihistamines appear to result, at least in part, from their central anticholinergic and CNS
depressant properties. The effects of diphenhydramine on parkinsonian syndrome and drug-
induced extrapyramidal reactions are also apparently related to its central anticholinergic effects.

Although the antipruritic effect of systemically administered or locally applied antihistamines in

conditions associated with histamine-induced pruritus appears to result from a peripheral
antihistaminic effect and possibly a local anesthetic effect,149, 171, 349 the sedative effect of
systemically administered antihistamines also appears to contribute to their antipruritic
activity.11, 171 The drugs are more effective antipruritics when administered systemically than
when applied topically, especially when pruritus is generalized.349 Because pruritus can involve
mediators other than histamine, the antipruritic efficacy of antihistamines is not routine.349

Pharmacokinetics

Limited information is available on the pharmacokinetics of most antihistamines.

 Absorption
Antihistamines generally are well absorbed following oral or parenteral administration, but
various salts may differ in activity and toxicity because of differences in solubility or absorption.
The least soluble antihistamines are often the least toxic and may have a slow onset but
prolonged duration of action. Following oral administration of antihistamines, symptomatic relief
of allergic reactions usually begins within 15-30 minutes and usually is maximal within 1 hour.
The duration of action is variable but symptoms usually are relieved for 3-6 hours after oral
administration of most antihistamines. There may be some decrease in effectiveness with
prolonged use of these drugs, although a substantial degree of tolerance to the antihistaminic
effects generally does not occur. However, tolerance to the sedative effects may occur.

Some antihistamines (e.g., astemizole [no longer commercially available in the US], cetirizine,
desloratadine, loratadine) exhibit a slower onset of action and/or prolonged duration of effect.
Following single- and multiple-dose administration, the long-acting antihistamine loratadine
exhibits antihistaminic effects beginning within 1-3 hours, reaching a maximum at 8-10 hours,
and lasting in excess of 24 hours.470 Following single- and multiple-dose administration of a 5-
mg dose of desloratadine, the antihistaminic effect of the drug is apparent within 1 hour and lasts
for 24 hours.670 Following oral administration of a single 10-mg dose of cetirizine hydrochloride
in healthy individuals, the antihistaminic effect of the drug is apparent within 20-60 minutes and
lasts for at least 24 hours.509 Following oral administration of a 5-mg dose of levocetirizine
dihydrochloride in patients with allergic rhinitis, the antihistaminic effect of the drug is apparent
within 1 hour and lasts for at least 24 hours. 685

Topically applied antihistamines generally do not readily penetrate intact skin, especially when
salts of the drugs are used.349 However, percutaneous absorption can occur,213, 214, 215, 319, 349, 556
especially when the stratum corneum is disrupted,349, 556 and rarely may result in systemic effects
and toxicity.44, 319, 349, 356, 556

 Distribution
The distribution of most antihistamines has not been fully characterized. Those compounds that
have been studied show highest concentrations in the lungs and lower concentrations in spleen,
kidneys, brain, muscle, and skin. Protein binding of these agents ranges from 50-99%.

Unlike other currently available antihistamines, second generation (also referred to as relatively
"nonsedating") antihistamines such as acrivastine, astemizole, cetirizine, desloratadine,
fexofenadine, levocetirizine, loratadine, and terfenadine (no longer commercially available in the
US) appear to distribute poorly or not appreciably into the CNS at usual dosages.154, 155, 156, 157,
158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 404, 405, 406, 470, 471, 472, 473, 474, 487, 495, 496, 497, 498, 516, 669, 670, 695
It
is thought that this lack of CNS distribution results principally from the inability of these agents
to cross the tightly fused outer membranes of endothelial cells lining the brain capillaries.487, 498
Cetirizine, because of its substantial polarity, also does not readily cross the blood-brain
barrier;509, 583, 584 however, some data indicate that the drug may cause more somnolence than
other second generation antihistamines.583 Levocetirizine also is considered mildly sedating.695

Small amounts of the drugs appear to be distributed into milk.

 Elimination
The metabolic fate of most antihistamines is not clearly established. The drugs usually appear to
be extensively metabolized, mainly in the liver. Some second generation antihistamines (e.g.,
astemizole, loratadine, terfenadine) are metabolized principally by the cytochrome P-450
microsomal enzyme system, mainly by the isoenzyme 3A4 (CYP3A4), although other
isoenzymes, including CYP1A2 and CYP2D6, also may be involved.156, 157, 161, 477, 512, 587, 588, 589,
590, 591, 594, 596, 597, 607, 635, 650, 651, 652, 653, 654
Desloratadine also is extensively metabolized;
however, the enzyme(s) responsible for metabolism of the drug has not been identified.670 Other
second generation antihistamines (e.g., cetirizine, fexofenadine, levocetirizine) appear to be only
minimally metabolized in the liver.509, 575, 576, 648, 685

Metabolism of some antihistamines that are extensively metabolized in the liver (e.g.,
astemizole, terfenadine) may be substantially reduced in patients with hepatic impairment and
possibly in geriatric patients.413, 417, 418, 419, 422, 424, 433, 447, 448, 449, 456, 459, 466, 476, 512 In addition,
metabolism also may be substantially reduced in patients concomitantly receiving foods (e.g.,
grapefruit juice)512, 541, 542, 543, 544, 555, 596, 607, 616, 617 or drugs (e.g., certain azole-derivative anti-
infective agents, including fluconazole, itraconazole, ketoconazole, metronidazole, and
miconazole; certain macrolide antibiotics, including clarithromycin, erythromycin, and
troleandomycin; mibefradil [no longer commercially available in the US]; possibly certain
human immunodeficiency virus [HIV] protease inhibitors, including indinavir, nelfinavir,
ritonavir, and saquinavir; possibly some serotonin-reuptake inhibitors, including fluoxetine,
fluvoxamine, nefazodone, paroxetine, and sertraline; zileuton; quinine) that affect the hepatic
microsomal enzyme system.418, 419, 420, 443, 444, 445, 446, 455, 475, 476, 477, 478, 512, 547, 548, 549, 554, 574, 594,
596, 597, 598, 605, 606, 607, 615, 639
Decreased metabolism may result in accumulation of potentially
toxic concentrations of the unchanged antihistamines that may be associated with serious adverse
cardiac effects.418, 419, 422, 443, 447, 448, 449, 476, 512, 594, 596, 597, 607 (See Cautions: Cardiovascular
Effects and see Drug Interactions.)

Many antihistamines are excreted in urine as inactive metabolites within 24 hours; however,
some antihistamines (e.g., terfenadine, desloratadine, loratadine, astemizole, acrivastine) have
active H1-antagonist metabolites. Negligible amounts of most antihistamines are excreted
unchanged in urine; however, cetirizine and levocetirizine are excreted in urine mainly as
unchanged drug.577, 578, 579, 583, 685, 686

Chemistry

Antihistamines (histamine H1-receptor antagonists) competitively inhibit most of the

pharmacologic actions of histamine.
Antihistamines have been classified chemically and also have been classified according to their
propensity to cause sedation, with relatively sedating antihistamines (i.e., conventional,
prototypical antihistamines) being classified as first generation and relatively "nonsedating"
antihistamines (e.g., acrivastine, astemizole [no longer commercially available in the US],
desloratadine, fexofenadine, loratadine, terfenadine [no longer commercially available in the
US]) being classified as second generation.435, 471, 487, 495, 496, 497, 498, 516 Cetirizine also is
considered a second generation antihistamine; however, some data indicate that it causes more
sedation than other second generation antihistamines.583 Levocetirizine, the active R enantiomer
of cetirizine, is considered a mildly sedating antihistamine695 and has been found to be slightly
more sedating than desloratadine.687

FIRST GENERATION ANTIHISTAMINES

azatadine* diphenhydramine brompheniramine doxylamine carbinoxamine hydroxyzine

chlorpheniramine meclizine clemastine promethazine cyproheptadine triprolidine
dimenhydrinate

* no longer commercially available in the US

SECOND GENERATION ANTIHISTAMINES

acrivastine fexofenadine astemizole* levocetirizine cetirizine loratadine desloratadine

terfenadine*

Most antihistamines are substituted ethylamines. In general, these molecules consist of 3

portions: R1 = nucleus, X = a linkage such as nitrogen, oxygen, or carbon, and the ethylamine
group. Antihistamines can be depicted by a general formula:

R1 is composed of aromatic and/or heterocyclic groups, which may be separated from X by a

methylene group. Hydrogenation of the rings in the R1 portion of the molecule decreases
antihistamine activity. Usually, activity of an antihistamine is increased by substitution of a
halogen atom in the para position of the phenyl or benzyl group of R1. For maximum activity,
the terminal nitrogen of the ethylamine group should be a tertiary amine with methyl groups or a
small cyclic moiety in R2 and R3. In optically active compounds, the dextro isomer (e.g.,
dexchlorpheniramine, dexbrompheniramine) usually is more active than the levo isomer.

Antihistamines can be classified on the basis of X substitution as follows:

ETHYLENEDIAMINE DERIVATIVES

antazoline pyrilamine methapyrilene tripelennamine

This group of antihistamines has nitrogen in the X position. Ethylenediamine derivatives have
relatively weak CNS effects; however, drowsiness may occur in some patients. Adverse GI
effects are common with this group of antihistamines.

ETHANOLAMINE DERIVATIVES (AMINOALKYL ETHERS)

bromodiphenhydramine* diphenhydramine carbinoxamine diphenylpyraline clemastine

doxylamine dimenhydrinate phenyltoloxamine

This group of antihistamines, which has oxygen in the X position, has substantial atropine-like
activity. Drugs in this group commonly cause CNS depression; with usual doses, drowsiness
occurs in about 50% of patients who receive ethanolamine derivative antihistamines. The
incidence of adverse GI effects with these antihistamines is relatively low. Dimenhydrinate (see
56:22.08) and diphenhydramine also are used as antiemetics.

ALKYLAMINES (PROPYLAMINE DERIVATIVES)

acrivastine dimethindene brompheniramine pheniramine chlorpheniramine pyrrobutamine

dexbrompheniramine triprolidine dexchlorpheniramine

These antihistamines contain a carbon atom in the X position. Alkylamines cause less drowsiness
and more CNS stimulation than the other antihistamines and thus are suitable for daytime use.

PHENOTHIAZINE DERIVATIVES

promethazine

In this group of antihistamines, nitrogen, as part of a phenothiazine nucleus, is in the X position.

Most phenothiazines are used principally as antipsychotics (see 28:16.08); however, some are
useful as antihistamines, antipruritics, and antiemetics.

PIPERAZINE DERIVATIVES

cetirizine levocetirizine hydroxyzine meclizine

In this group, nitrogen, as part of a piperazine nucleus, is in the X position. Meclizine is used in
the treatment of motion sickness. (See 56:22.08.) Hydroxyzine is used as a tranquilizer, sedative,
antipruritic, and antiemetic. (See 28:24.92.)

* no longer commercially available in the US

OTHERS

astemizole * fexofenadine azatadine * loratadine cyproheptadine phenindamine desloratadine

terfenadine *

Related Monographs
For further information on chemistry and stability, pharmacokinetics, uses, and dosage and
administration of antihistamines available as single entities, see the individual monographs in
4:00.

AHFS Drug Information.  Copyright, 1959-2008, Selected Revisions November 2008.

American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda,
Maryland 20814.

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Copyright © 2008 by the American Society of Health-System Pharmacists, Inc. All rights
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