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.705,706 Patients also should be warned to avoid consuming alcoholic beverages while taking antihistamines, since alcohol may potentiate these CNS effects.169,350,390,407,509,705,706 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 α-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 a 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 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 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 Overdosage of doxylamine has been reported in children.705,706 Manifestations of doxylamine overdosage in children have included coma, generalized tonic-clonic (grand mal) seizures, cardiorespiratory arrest, and death.705,706 Children appear to be at high risk for cardiorespiratory arrest secondary to doxylamine overdosage.705,706 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 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
Antihistamines 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 For additional information, see the individual monographs in 4:00.
Doxylamine succinate in fixed combination with pyridoxine hydrochloride is intended for use in the management of nausea and vomiting of pregnancy.705,706,710 Historically, there was considerable controversy regarding the teratogenic potential, if any, of doxylamine succinate;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, FDA concluded that it is unlikely that doxylamine succinate is teratogenic.350 In addition, FDA states that the removal of products containing doxylamine succinate that previously were commercially available for the management of nausea and vomiting of pregnancy was not for reasons of safety or effectiveness.709 Numerous epidemiologic studies (including cohort studies, case-control studies, and meta-analyses) have been performed to investigate possible teratogenic effects of doxylamine succinate in fixed combination with pyridoxine hydrochloride in pregnant women and have found no evidence of an increased risk of fetal malformations.705,706,711,712
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. Adverse effects (e.g., excitement, irritability, and sedation) have been reported in infants presumably exposed to antihistamines (e.g., doxylamine) through human milk.705,706 Infants with apnea or other respiratory syndromes may be particularly vulnerable to the sedative effects of antihistamines (e.g., doxylamine).705,706
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. The manufacturer of doxylamine in fixed combination with pyridoxine states that this preparation should not be used in nursing women.705,706
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.705,706 The manufacturer of doxylamine in fixed combination with pyridoxine hydrochloride states that the drug is contraindicated in patients receiving MAO inhibitors.705,706
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 astemizole or terfenadine was commercially available in the US,456,659,660 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. 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, and Nizatidine 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 | |
SECOND GENERATION ANTIHISTAMINES
acrivastine | fexofenadine |
astemizolea | levocetirizine |
cetirizine | loratadine |
desloratadine | terfenadinea |
ano longer commercially available in the US
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
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.)
OTHERS
astemizolea | fexofenadine |
azatadinea | loratadine |
cyproheptadine | phenindamine |
desloratadine | terfenadinea |
ano longer commercially available in the US
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