AHFS Class:

• First Generation Antihistamines 4:04

Generic Name(s):

• diphenhydrAMINE Citrate

• diphenhydrAMINE Hydrochloride

• Acetaminophen and diphenhydrAMINE Citrate

• BromodiphenhydrAMINE Hydrochloride

Associated Monographs

• Antihistamines General Statement

Diphenhydramine is an ethanolamine-derivative, first generation antihistamine.

Diphenhydramine shares the actions and uses of other antihistamines.

Diphenhydramine also is used as an antitussive for temporary relief of cough caused by minor throat and bronchial irritation such as may occur with common colds or inhaled irritants.

Diphenhydramine is effective for the prevention and treatment of nausea, vomiting, and/or vertigo associated with motion sickness.101

Diphenhydramine may be useful as an adjunctive antiemetic agent to prevent chemotherapy-induced nausea and vomiting†; however, the American Society of Clinical Oncology (ASCO) currently does not recommend that antihistamines be used alone as antiemetic agents in patients receiving chemotherapy.

Diphenhydramine also is used as a nighttime sleep aid for the short-term management of insomnia. In individuals who experience occasional sleeplessness or those who have difficulty falling asleep, the drug is more effective than placebo in reducing sleep onset (i.e., time to fall asleep) and increasing the depth and quality of sleep.

Diphenhydramine, alone or in conjunction with other antiparkinsonian agents, may be useful as alternative therapy in the management of tremor early in the course of parkinsonian syndrome. The drug also may be useful in the management of drug-induced extrapyramidal reactions.

Diphenhydramine may be used topically for temporary relief of pruritus and pain associated with various skin conditions including minor burns, sunburn, minor cuts or scrapes, insect bites, minor skin irritations, or rashes associated with poison oak, poison ivy, or poison sumac. However, because systemic diphenhydramine toxicity (e.g., psychosis) has been reported in pediatric patients following topical application of the drug to large areas of the body (often areas with broken skin), many clinicians suggest that topical diphenhydramine be used only on limited areas of skin and not used more often than directed to avoid excessive percutaneous absorption of the drug. (See Acute Toxicity: Manifestations, in the Antihistamines General Statement 4:00.) Topical diphenhydramine also should not be used for self-medication in the management of varicella (chickenpox) or measles without first consulting a clinician.

Administration

Diphenhydramine hydrochloride usually is administered orally.

Diphenhydramine citrate usually is administered orally.

When oral therapy is not feasible, diphenhydramine hydrochloride may be given by deep IM or, preferably, IV injection. The drug should not be given subcutaneously, intradermally, or perivascularly because of its irritating effects; local necrosis has been reported following subcutaneous or intradermal administration of parenteral diphenhydramine. IV use of the drug in a home-care setting should be employed under careful supervision. Use of diphenhydramine for local anesthesia via local infiltration is discouraged because of the risk of local tissue necrosis.101 Diphenhydramine hydrochloride should not be given to premature or full-term neonates. (See Cautions: Pediatric Precautions.)

For the temporary relief of pruritus associated with various skin conditions and disorders, diphenhydramine hydrochloride-containing preparations are applied topically in the form of a cream, lotion, or topical solution. The possibility of clinically important percutaneous absorption of the drug following topical application should be considered. (See Cautions.)

Dosage

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

Adult Dosage

Usual Dosage

The usual adult oral dosage of diphenhydramine hydrochloride is 25-50 mg 3 or 4 times daily at 4- to 6-hour intervals, not to exceed 300 mg in 24 hours.

The usual adult IM or IV dose of diphenhydramine hydrochloride is 10-50 mg; in a few patients, up to 100 mg may be required. Some experts recommend a dose of 25-50 mg.102,103 The rate of IV administration should not exceed 25 mg/minute.

The maximum adult IM or IV dosage of diphenhydramine hydrochloride is 400 mg daily.101

Allergic Rhinitis, the Common Cold, and Cough

For temporary symptomatic relief of allergic rhinitis or for temporary relief of rhinorrhea and sneezing associated with the common cold, the usual oral dosage of diphenhydramine hydrochloride for self-medication in adults is 25-50 mg every 4-6 hours, not to exceed 300 mg in 24 hours.

For the temporary relief of cough caused by minor throat and bronchial irritation, the usual oral dosage of diphenhydramine hydrochloride for self-medication in adults is 25 mg (equivalent to 38 mg of diphenhydramine citrate) every 4 hours, not to exceed 150 mg (equivalent to 228 mg of diphenhydramine citrate) in 24 hours.

When used both for temporary symptomatic relief of allergic rhinitis or rhinorrhea and sneezing associated with the common cold and also for relief of cough caused by minor throat and bronchial irritation, the usual oral dosage of diphenhydramine hydrochloride for self-medication in adults is 25 mg (equivalent to 38 mg of diphenhydramine citrate) every 4-6 hours, not to exceed 150 mg (equivalent to 228 mg of diphenhydramine citrate) in 24 hours.

Motion Sickness

For the prevention and treatment of nausea, vomiting, and/or vertigo associated with motion sickness, the usual oral dosage of diphenhydramine hydrochloride for self-medication in adults is 25-50 mg every 4-6 hours, not to exceed 300 mg in 24 hours. For the prevention of motion sickness, a dose should be given 30 minutes before exposure to motion; subsequent doses may be given before meals and at bedtime for the duration of the exposure.

Insomnia

As a nighttime sleep aid, the usual oral dosage of diphenhydramine hydrochloride for self-medication in adults is 50 mg (equivalent to 76 mg of diphenhydramine citrate) at bedtime as needed, or as directed by a clinician. Higher dosages also occasionally have been used for sedative effects as directed by a clinician, but some evidence suggests that the efficacy of a 100-mg dose is not substantially greater than that of a 50-mg dose, although adverse (e.g., anticholinergic) effects may be increased.

Because insomnia may be indicative of a serious underlying physical, emotional, or psychological condition requiring professional medical attention, patients should be advised to avoid using diphenhydramine for self-medication for longer than 7-10 nights104 and to consult a clinician if insomnia persists continuously for longer than 2 weeks.

Parkinsonian Syndrome

For the symptomatic treatment of parkinsonian syndrome, some clinicians have suggested an initial oral dosage of 25 mg of diphenhydramine hydrochloride 3 times daily; if necessary, dosage is then gradually increased to 50 mg 4 times daily.

Pediatric Dosage

Usual Dosage

When diphenhydramine was available only by prescription, the prescribing information for the drug indicated a usual oral diphenhydramine hydrochloride dosage for children weighing more than 9.1 kg of 12.5-25 mg 3 or 4 times daily at 4- to 6-hour intervals and for children weighing 9.1 kg or less an oral diphenhydramine hydrochloride dosage of 6.25-12.5 mg 3 or 4 times daily at 4- to 6-hour intervals. However, these dosage recommendations are not included in the current labeling of nonprescription oral diphenhydramine preparations, and clinicians should use caution when considering use of nonprescription oral diphenhydramine in children younger than 4 years of age. (See Cautions: Pediatric Precautions.)

Alternatively, for oral, deep IM, or IV therapy, children (other than premature or full-term neonates) may be given 5 mg/kg daily or 150 mg/m² daily divided in 4 doses; some experts recommend a dosage of 1-2 mg/kg daily.102,103 The rate of IV administration should not exceed 25 mg/minute.

The maximum oral, IM, or IV dosage of diphenhydramine hydrochloride in children older than 1 month of age is 300 mg daily.101

Allergic Rhinitis, the Common Cold, and Cough

For self-medication to provide temporary symptomatic relief of allergic rhinitis or temporary relief of rhinorrhea or sneezing associated with the common cold, children 12 years of age and older may receive the dosage used in adults; children 6 to younger than 12 years of age may receive 12.5-25 mg orally every 4-6 hours, not to exceed 150 mg in 24 hours. Diphenhydramine hydrochloride should not be used for self-medication of these conditions in children younger than 6 years of a when directed by a clinician, the usual oral dosage in children 2 to younger than 6 years of age is 6.25 mg every 4-6 hours, not to exceed 37.5 mg in 24 hours.

For self-medication of cough caused by minor throat and bronchial irritation, children 12 years of age and older may receive the dosage used in adults; children 6 to younger than 12 years of age may receive 12.5 mg (equivalent to 19 mg of diphenhydramine citrate) orally every 4 hours, not to exceed 75 mg (equivalent to 114 mg of diphenhydramine citrate) in 24 hours. Diphenhydramine hydrochloride should not be used for self-medication of cough in children younger than 6 years of a when directed by a clinician, the usual oral dosage in children 2 to younger than 6 years of age is 6.25 mg (equivalent to 9.5 mg of diphenhydramine citrate) every 4 hours, not to exceed 37.5 mg (equivalent to 57 mg of diphenhydramine citrate) in 24 hours.

Motion Sickness

For self-medication to prevent and treat nausea, vomiting, and/or vertigo associated with motion sickness, children 12 years of age and older may receive the dosage used in adults; children 6 to younger than 12 years of age may receive 12.5-25 mg of diphenhydramine hydrochloride 30-60 minutes before travel and every 4-6 hours, not to exceed 150 mg in 24 hours.105 Children 2-5 years of age† may receive a dosage of 6.25 mg of diphenhydramine hydrochloride 30-60 minutes before travel and every 4-6 hours during travel, not to exceed 37.5 mg in 24 hours.105 (See Cautions: Pediatric Precautions.)

Insomnia

For self-medication as a nighttime sleep aid, children 12 years of age and older may receive the dosage used in adults. In children 2 to younger than 12 years of age with sleep disorders†, oral diphenhydramine hydrochloride doses of 1 mg/kg (up to a maximum dose of 50 mg) have been given 30 minutes before retiring. (See Cautions: Pediatric Precautions.) Diphenhydramine should not be used for self-medication for longer than 7-10 nights.104

Topical Dosage

For temporary relief of pruritus and pain associated with various skin conditions in adults and children 2 years of age or older, creams, lotions, or solutions containing 1-2% diphenhydramine hydrochloride are applied to the affected areas 3 or 4 times daily or as directed by a clinician; topical diphenhydramine should not be used more often than directed.

If the condition worsens, or if symptoms persist for longer than 7 days or resolve and then recur within a few days, topical therapy with diphenhydramine hydrochloride should be discontinued and a clinician consulted; the possibility of sensitization by, or hypersensitivity to, the drug should be considered.

Topical preparations containing diphenhydramine hydrochloride should not be used on large areas of the body or concomitantly with other preparations containing the antihistamine, including those used orally, since increased serum concentrations of diphenhydramine may occur that can result in systemic toxicity. (See Acute Toxicity: Manifestations, in the Antihistamines General Statement 4:00.) The drug also should not be used for topical self-medication in the management of varicella (chickenpox) or measles without first consulting a clinician.

Diphenhydramine shares the toxic potentials of other antihistamines, and the usual precautions of antihistamine therapy should be observed. (See Cautions in the Antihistamines General Statement 4:00.)

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.107,108,109,110,111,112,113,114

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. (See Acute Toxicity: Manifestations, in the Antihistamines General Statement 4:00.) 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. (See Acute Toxicity: Manifestations, in the Antihistamines General Statement 4:00.) 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.

Pediatric Precautions

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, see Acute Toxicity: Manifestations, in the Antihistamines General Statement 4:00.

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.101 (See Cautions: CNS Effects and see Pediatric Precautions, in the Antihistamines General Statement 4:00.) 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 a 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, see Cautions: Pediatric Precautions in the Antihistamines General Statement 4:00.

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

Pregnancy

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.

Fertility

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.

Lactation

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.

Pharmacokinetics

Absorption

Diphenhydramine hydrochloride is well absorbed following oral administration, but apparently undergoes first-pass metabolism in the liver and only about 40-60% of an oral dose reaches systemic circulation as unchanged diphenhydramine. Diphenhydramine can be absorbed percutaneously following topical administration and rarely may result in systemic effects and toxicity, especially following concomitant oral and topical administration of the drug or when extensive disruption of the epidermal barrier (e.g., blistered or oozing skin) is present. (See Acute Toxicity: Manifestations, in the Antihistamines General Statement 4:00.)

Following oral administration of a single dose of diphenhydramine, the drug appears in plasma within 15 minutes and peak plasma concentrations are attained within 1-4 hours. Following single oral doses of 50 and 100 mg in healthy adults, peak plasma drug concentrations of 37-83 and 81-159 ng/mL, respectively, have been reported. Following oral administration of diphenhydramine hydrochloride dosages of 25 mg every 4 hours or 50 mg every 6 hours, peak steady-state plasma concentrations of the drug were 55 or 85 ng/mL, respectively, and minimum steady-state plasma concentrations were 27.5 or 30 ng/mL, respectively. Following IV injection of a single 50-mg dose over a 1-minute period in healthy adults in one study, plasma diphenhydramine concentration 1 hour after the injection ranged from 99-196 ng/mL. The antihistamine effect, as determined by suppression of the wheal response induced by intradermal injection of histamine, appears to be maximal within 1-3 hours and may persist for up to 7 hours after administration of a single dose of the drug, and appears to be positively correlated with plasma concentration of the drug. The sedative effect also appears to be maximal within 1-3 hours after administration of a single dose of diphenhydramine and appears to be positively correlated with plasma drug concentration, with marked drowsiness and/or sleep occurring at plasma concentrations of 70 ng/mL or greater.

Distribution

Distribution of diphenhydramine into human body tissues and fluids has not been fully characterized. Following IV administration in rats, highest concentrations of the drug are attained in the lungs, spleen, and brain, with lower concentrations in the heart, muscle, and liver. Following IV administration in healthy adults, diphenhydramine reportedly has an apparent volume of distribution of 188-336 L. Volume of distribution of the drug reportedly is larger in Asian (about 480 L) than white adults. The drug crosses the placenta and has been detected in milk, although the extent of distribution into milk has not been quantitated.

Diphenhydramine is approximately 80-85% bound to plasma proteins in vitro. Less extensive protein binding of the drug has been reported in healthy Asian adults and in adults with liver cirrhosis.

Elimination

Plasma concentrations of diphenhydramine appear to decline in a monophasic manner, although some pharmacokinetic data suggest a polyphasic elimination. The terminal elimination half-life of diphenhydramine has not been fully elucidated, but appears to range from 2.4-9.3 hours in healthy adults. The terminal elimination half-life reportedly is prolonged in adults with liver cirrhosis.

Diphenhydramine is rapidly and apparently almost completely metabolized. Following oral administration, the drug apparently undergoes substantial first-pass metabolism in the liver. Diphenhydramine appears to be metabolized principally to diphenylmethoxyacetic acid, which may further undergo conjugation. The drug also undergoes dealkylation to form the N -demethyl and N , N -didemethyl derivatives. Diphenhydramine and its metabolites are excreted principally in urine. Following oral administration of a single 100-mg dose in healthy adults, about 50-75% of the dose is excreted in urine within 4 days, almost completely as metabolites and with most urinary excretion occurring within the first 24-48 hours; only about 1% of a single oral dose is excreted unchanged in urine.

Chemistry and Stability

Chemistry

Diphenhydramine and bromodiphenhydramine (no longer commercially available) are ethanolamine-derivative antihistamines. Bromodiphenhydramine differs structurally from diphenhydramine in the para -substitution of a bromine atom for a hydrogen atom on one phenyl group. Diphenhydramine is commercially available as the hydrochloride or citrate salt; the citrate salt is only available in fixed-combination preparations. Diphenhydramine hydrochloride occurs as a white, odorless, crystalline powder which slowly darkens on exposure to light. Diphenhydramine hydrochloride has solubilities of approximately 1 g/mL in water and 0.5 g/mL in alcohol at 25°C. The pK_a of diphenhydramine is approximately 9. Commercially available diphenhydramine hydrochloride injection has a pH of 5-6, which may have been adjusted with either sodium hydroxide or hydrochloric acid.

Stability

Diphenhydramine hydrochloride preparations generally should be stored at 15-30°C and protected from moisture; freezing of the elixir, injection, oral solution, or topical lotion should be avoided. The injection and elixir should be stored in light-resistant containers. Diphenhydramine hydrochloride capsules and elixir should be stored in tight containers and the elixir, oral solution, and tablets in well-closed containers.

Diphenhydramine hydrochloride injection is reportedly compatible with most IV infusion solutions. The injection has been reported to be physically incompatible with some drugs, but the compatibility depends on several factors (e.g., concentration of the drugs, specific diluents used, resulting pH, temperature). Specialized references should be consulted for specific compatibility information.

Additional Information

For further information on chemistry, pharmacology, pharmacokinetics, uses, cautions, acute toxicity, drug interactions, laboratory test interferences, and dosage and administration of diphenhydramine, see the Antihistamines General Statement 4:00.

Please see the general statement for a list of references.