Diphenhydramine shares the toxic potentials of other antihistamines, and the usual precautions of antihistamine therapy should be observed.
When diphenhydramine is used in fixed combination with other agents (e.g., analgesic-antipyretics, nasal decongestants), the usual cautions, precautions, and contraindications associated with these agents must be considered in addition to those associated with diphenhydramine.
Local necrosis has occurred with subcutaneous or intradermal administration of parenteral diphenhydramine.
Diphenhydramine toxicity (e.g., dilated pupils, flushed face, 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 the drug. 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. In December 2002, the FDA issued a final rule requiring that a warning statement regarding such concomitant use be added to all OTC oral antiemetic, antihistamine, antitussive, and nighttime sleep aid preparations containing diphenhydramine.
Diphenhydramine hydrochloride topical solution contains a flammable vehicle, and the solution should not be exposed to an open flame or ignited materials (e.g., a lighted cigarette). Because of the potential for increased systemic exposure and subsequent toxicity, many clinicians state that 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 the drug, including those used orally, since increased serum concentrations of diphenhydramine may occur that can result in systemic toxicity. Patients should be advised to consult a clinician prior to use of topical diphenhydramine for the management of varicella (chickenpox) or measles.
Commercially available formulations of diphenhydramine may contain sodium bisulfite, a sulfite that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.
Although diphenhydramine appears to have low abuse potential and a favorable adverse effect profile, several children, adolescents, and young adults with chronic hematologic and neoplastic diseases have exhibited drug-seeking behavior or anticholinergic effects after repeated parenteral (e.g., bolus IV injection) administration of diphenhydramine over a prolonged period of time. It has been suggested that such route of administration may be associated with the development of adverse effects and the abuse potential of the drug and therefore, some clinicians recommend oral administration of diphenhydramine whenever possible. Alternatively, if the IV route is indicated, the drug should be infused over 20 minutes or longer and the lowest effective dosage of diphenhydramine should be employed. In addition, some clinicians suggest that IV diphenhydramine should not be used empirically for premedication, but should be reserved for patients with a history of reactions requiring treatment with an antihistamine. It is recommended that IV diphenhydramine be administered under careful supervision in a home-care setting.
Diphenhydramine toxicity (e.g., dilated pupils, facial flushing, hallucinations, ataxic gait, urinary retention) has been reported in pediatric patients (19 months to 9 years of age) 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 the drug for self-medication in the symptomatic management of pain and pruritus associated with varicella (chickenpox), poison ivy, or sunburn. Manifestations typically resolved within 48 hours following discontinuance of the drug, and no deaths have been reported following topical use of diphenhydramine alone. For a complete discussion of acute diphenhydramine toxicity,
Like other antihistamines, diphenhydramine should be used with caution in infants and young children and should not be used in premature or full-term neonates. and Children younger than 6 years of age should receive diphenhydramine only under the direction of a physician. Safety and efficacy of diphenhydramine as a nighttime sleep aid in children younger than 12 years of age have not been established. In addition, children may be more prone than adults to paradoxically experience CNS stimulation rather than sedation when antihistamines are used as nighttime sleep aids. Because diphenhydramine may cause marked drowsiness that may be potentiated by other CNS depressants (e.g., sedatives, tranquilizers), the antihistamine should be used in children receiving one of these drugs only under the direction of a physician.
Depending on the manufacturer and the particular formulation of the drug, topical preparations containing diphenhydramine should be used in children younger than 2, 6, or 12 years of age only under the direction of a clinician.
The possibility of drug-seeking behavior and anticholinergic effects in pediatric patients receiving repeated parenteral diphenhydramine over prolonged periods should be considered.
Overdosage and toxicity (including death) have been reported in children younger than 2 years of age receiving nonprescription (over-the-counter, OTC) preparations containing antihistamines, cough suppressants, expectorants, and nasal decongestants alone or in combination for relief of symptoms of upper respiratory tract infection. There is limited evidence of efficacy for these preparations in this age group, and appropriate dosages (i.e., approved by the US Food and Drug Administration [FDA]) for the symptomatic treatment of cold and cough have not been established. Therefore, FDA stated that nonprescription cough and cold preparations should not be used in children younger than 2 years of age; the agency continues to assess safety and efficacy of these preparations in older children. 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. 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. Clinicians should ask caregivers about use of nonprescription cough and cold preparations to avoid overdosage. For additional information on precautions associated with the use of cough and cold preparations in pediatric patients,
Mutagenicity and Carcinogenicity
Long-term animal studies to determine the carcinogenic and mutagenic potential of diphenhydramine have not been performed to date.
Pregnancy, Fertility, and Lactation
Reproduction studies in rats and rabbits receiving diphenhydramine hydrochloride dosages up to 5 times the recommended human dosage have not revealed evidence of harm to the fetus. However, diphenhydramine has been shown to cross the placenta. In one epidemiologic study, use of bromodiphenhydramine (no longer commercially available) but not diphenhydramine was associated with an increased risk of teratogenic effects. In another epidemiologic study, there also was no evidence of increased risk of teratogenicity associated with diphenhydramine use during the first trimester, although a modest association could not be ruled out. Use of diphenhydramine during the first trimester of pregnancy has been associated with an increased risk of cleft palate alone or combined with other fetal abnormalities, and the drug has been reported to potentiate the teratogenic effect of morphine in mice. The manufacturers state that there are no adequate and controlled studies to date using diphenhydramine in pregnant women, and the drugs should be used during pregnancy only when clearly needed.
Reproduction studies in rats and rabbits receiving diphenhydramine hydrochloride dosages up to 5 times the recommended human dosage have not revealed evidence of impaired fertility.
Diphenhydramine has been detected in milk. Because of the potential for serious adverse reactions to antihistamines in nursing infants, a decision should be made whether to discontinue nursing or diphenhydramine, taking into account the importance of the drug to the woman.