Brand names: AllerMax, Benadryl, Benadryl Allergy, Compoz, Diphenhist, ... show all 12 brands Hydramine, Nighttime Sleep Aid, Nytol, Sleepinal, Sominex, Twilite, Unisom
Drug class: First Generation Antihistamines
- Antiparkinsonian Agents

Medically reviewed by Drugs.com on Oct 3, 2024. Written by ASHP.

Introduction

First generation antihistamine; an ethanolamine-derivative.^a

Uses for diphenhydrAMINE

Acute Allergic Reactions

Amelioration of allergic reactions to blood or plasma.¹⁰¹

Adjunct to epinephrine and other standard measures for management of anaphylaxis after acute symptoms have been controlled.^{101 102 103}

Used IV or IM for management of other uncomplicated allergic conditions of the immediate type when oral therapy is impossible or contraindicated.¹⁰¹

Allergic Rhinitis

Self-medication for temporary relief of rhinorrhea, sneezing, lacrimation, itching eyes, oronasopharyngeal irritation or itching, or cough associated with allergic rhinitis (e.g., hay fever) or other upper respiratory allergies.^{b o p q r s xx zz bbb}

Used in fixed combination with other agents (e.g., acetaminophen, phenylephrine) for relief of rhinorrhea, sneezing, lacrimation, itching eyes, oronasopharyngeal itching, and/or other symptoms (e.g., headache, nasal/sinus congestion) associated with seasonal or perennial allergic rhinitis or other upper respiratory allergies.^{110 112 114}

Use fixed-combination preparations only when symptoms amenable to each ingredient are present concurrently.^b

Common Cold

Self-medication for temporary relief of symptoms associated with the common cold (e.g., rhinorrhea, sneezing, cough).^{d q s qq r ss ccc fff}

Used in fixed combination with other agents (e.g., acetaminophen, phenylephrine) for symptomatic relief of rhinorrhea, sneezing, and/or other symptoms associated with the common cold (e.g., headache, minor aches and pains, sore throat, cough, nasal congestion).^{108 112 114}

Insomnia

Self-medication for short-term (i.e., ≤2 weeks) management of occasional sleeplessness,^{v tt uu} particularly in individuals who have difficulty falling asleep.¹⁰⁴

Used in fixed combination with other agents (e.g., acetaminophen) for short-term management of occasional sleeplessness.^{107 109 111 113}

Development of tolerance reported with repeated use.¹⁰⁴

Dermatologic Disorders

Systemic antihistamines may be more effective than topical, especially if pruritus is generalized, and less likely to cause sensitivity reactions than when applied topically for pruritus associated with various dermatologic conditions.^mm

Motion Sickness

Prevention and treatment of nausea, vomiting, and/or vertigo associated with motion sickness.^{101 hh ii jj kk ll}

Parkinsonian Syndrome

May be useful as alternative therapy in the management of tremor early in the course of parkinsonian syndrome.^{kkk lll mmm} Also may be useful in the management of drug-induced extrapyramidal reactions.^mmm

Used IV for management of parkinsonian syndrome when oral therapy is impossible or contraindicated.¹⁰¹ Used specifically in geriatric patients who are unable to tolerate more potent agents; for mild cases of parkinsonism in younger patients; and in combination with centrally acting anticholinergic agents in other cases of parkinsonism.¹⁰¹

diphenhydrAMINE Dosage and Administration

Administration

Administer diphenhydramine hydrochloride orally^s or by IV or deep IM injection.^a

Administer diphenhydramine citrate-containing preparations orally.^a

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

IV injection preferred over deep IM injection.^a

IV use in a home-care setting should be employed under careful supervision.^a

Rate of Administration

≤25 mg/minute.^vv

Dosage

Available as diphenhydramine hydrochloride and diphenhydramine citrate; dosage is expressed in terms of diphenhydramine hydrochloride^s or diphenhydramine citrate.^a

Diphenhydramine citrate available only in fixed-combination preparations.^a

12.5 mg diphenhydramine hydrochloride equivalent to 19 mg diphenhydramine citrate.^a

Fixed-combination preparations do not permit individual titration of dosages.^b When used in fixed combination with other agents (e.g., acetaminophen, phenylephrine), select a dosage that is within the usual therapeutic range for each ingredient.^b Because combinations and dosage strengths vary for fixed-combination preparations, consult manufacturer’s product labeling for appropriate dosage of the specific preparation.

Pediatric Patients

Allergic Conditions and the Common Cold

Acute Allergic Reactions

IV or IM

Children >1 month of age: 5 mg/kg daily or 150 mg/m² daily (up to a maximum of 300 mg daily) divided in 4 doses.^vv

Alternatively, 1–2 mg/kg recommended by some experts.^{102 103}

Allergic Rhinitis and the Common Cold

Oral

Self-medication in children 2–5 years of age: 6.25 mg every 4–6 hours (as diphenhydramine hydrochloride) or 9.5 mg every 4 hours (as diphenhydramine citrate) when directed by a clinician; do not exceed 37.5 mg (as diphenhydramine hydrochloride) or 57 mg (as diphenhydramine citrate) in 24 hours.^{q ww yy} (See Pediatric Use under Cautions.)

Self-medication in children 6–11 years of age: 12.5–25 mg every 4–6 hours (as diphenhydramine hydrochloride) or 19 mg every 4 hours (as diphenhydramine citrate); do not exceed 150 mg (as diphenhydramine hydrochloride) or 76 mg (as diphenhydramine citrate) in 24 hours.^{q s ww}

Self-medication in children ≥12 years of age: 25–50 mg every 4–6 hours (as diphenhydramine hydrochloride)^{q s ww} or 38 mg every 4 hours (as diphenhydramine citrate);^{yy aaa} do not exceed 300 mg (as diphenhydramine hydrochloride) or 152 mg (as diphenhydramine citrate) in 24 hours.^{q s ww yy aaa}

Insomnia

Oral

Children 2–11 years of age^{† [off-label]}: 1 mg/kg (as diphenhydramine hydrochloride) 30 minutes before retiring; do not exceed 50 mg.ⁿ

Self-medication in children ≥12 years of age: 50 mg (as diphenhydramine hydrochloride) or 76 mg (as diphenhydramine citrate) at bedtime as needed, or as directed by a clinician.^tt Higher dosages do not produce substantially greater benefit but may be associated with a higher incidence of adverse (e.g., anticholinergic) effects.^tt

Use not recommended for ≥7–10 nights.¹⁰⁴

Motion Sickness

Oral

Children 2–5 years of age^{† [off-label]}: 6.25 mg (as diphenhydramine hydrochloride) 30–60 minutes before travel and every 4–6 hours during travel; do not exceed 37.5 mg in 24 hours.¹⁰⁵

Self-medication in children 6–11 years of age: 12.5–25 mg (as diphenhydramine hydrochloride) 30–60 minutes before travel and every 4–6 hours during travel; do not exceed 150 mg in 24 hours.^{105 hh}

Self-medication in children ≥12 years of age: 25–50 mg (as diphenhydramine hydrochloride) 30 minutes before exposure to motion and then every 4–6 hours (before meals and at bedtime) for duration of exposure; do not exceed 300 mg in 24 hours.^hh

IV or IM

Children >1 month of age: 5 mg/kg daily or 150 mg/m² daily (up to a maximum of 300 mg daily) divided in 4 doses.^vv

Parkinsonian Syndrome

IV or IM

Children >1 month of age: 5 mg/kg daily or 150 mg/m² daily (up to a maximum of 300 mg daily) divided in 4 doses.^vv

Adults

Allergic Conditions and the Common Cold

Acute Allergic Reactions

IV or IM

10–50 mg; in a few patients, up to 100 mg may be required.^vv

Alternatively, 25–50 mg recommended by some experts.^{102 103}

Allergic Rhinitis and the Common Cold

Oral

Self-medication: 25–50 mg every 4–6 hours (as diphenhydramine hydrochloride)^{q s ww} or 38 mg every 4 hours (as diphenhydramine citrate);^{yy aaa} do not exceed 300 mg (as diphenhydramine hydrochloride) or 152 mg (as diphenhydramine citrate) in 24 hours.^{q s ww yy aaa}

Insomnia

Oral

Self-medication: 50 mg (as diphenhydramine hydrochloride) or 76 mg (as diphenhydramine citrate) at bedtime as needed, or as directed by a clinician.^tt Higher dosages do not produce substantially greater benefit but may be associated with a higher incidence of adverse (e.g., anticholinergic) effects.^tt

Use not recommended for ≥7–10 nights.¹⁰⁴

Motion Sickness

Oral

Self-medication: 25–50 mg (as diphenhydramine hydrochloride) 30 minutes before exposure to motion and then every 4–6 hours (before meals and at bedtime) for duration of exposure; do not exceed 300 mg in 24 hours.^hh

IV or IM

10–50 mg; in a few patients, up to 100 mg may be required.^vv

Parkinsonian Syndrome

Oral

Initially, 25 mg 3 times daily (as diphenhydramine hydrochloride).^a If necessary, gradually increase dosage to 50 mg 4 times daily.^a

IV or IM

10–50 mg; in a few patients, up to 100 mg may be required.^vv

Prescribing Limits

Pediatric Patients

Oral

Children 2–5 years of age: Maximum 37.5 mg (as diphenhydramine hydrochloride) or 57 mg (as diphenhydramine citrate) in 24 hours.^{q ww yy} (See Pediatric Use under Cautions.)

Children 6–11 years of age: Maximum 150 mg (as diphenhydramine hydrochloride) or 76 mg (as diphenhydramine citrate) in 24 hours.^{q s ww}

Children ≥12 years of age: Maximum 300 mg (as diphenhydramine hydrochloride) or 152 mg (as diphenhydramine citrate) in 24 hours.^{q s ww yy aaa}

IV or IM

Children >1 month: Maximum 300 mg daily.¹⁰¹

Adults

Oral

Maximum 300 mg in 24 hours.^{q s ww}

IV or IM

Maximum 400 mg daily.¹⁰¹

Cautions for diphenhydrAMINE

Contraindications

• Use contraindicated in neonates and premature infants.¹⁰¹ (See Pediatric Use under Cautions.)

• Women who are breast-feeding.¹⁰¹ (See Lactation under Cautions.)

• Injection should not be used as a local anesthetic.¹⁰¹ (See Local Necrosis under Cautions.)

• Concomitant use with other preparations containing diphenhydramine, including oral and topical preparations.^{s eee}

• Known hypersensitivity to diphenhydramine, other antihistamines with similar chemical structure, or any ingredient in the formulation.^vv

Warnings/Precautions

Warnings

Concomitant Diseases

Patients with glaucoma, respiratory conditions (e.g., emphysema, chronic bronchitis), or difficulty urinating due to prostatic hypertrophy should consult a clinician before initiating therapy with diphenhydramine.^s

Use with caution in patients with increased IOP, angle-closure glaucoma, stenosing peptic ulcer, pyloroduodenal obstruction, bladder-neck obstruction, symptomatic prostatic hypertrophy, active or a history of lower respiratory disease (e.g., bronchial asthma), hyperthyroidism, or cardiovascular disease (e.g., hypertension).^vv

CNS Effects

Risk of marked drowsiness.^s Among first generation antihistamines, ethanolamines (e.g., diphenhydramine) considered the most sedating^{106 c} and alkylamines (e.g., brompheniramine, chlorpheniramine) considered the least sedating.¹⁰⁶

Possible excitability (especially in children).^s

Caution when driving a motor vehicle, operating machinery, or engaging in other potentially hazardous tasks.^{s c} (See CNS Depressants under Interactions.)

Diphenhydramine Toxicity

Risk of toxicity.^ddd (See Pediatric Use under Cautions.) Do not use more often than directed for any condition; do not concomitantly use more than one preparation containing diphenhydramine (e.g., avoid simultaneous use of oral and topical preparations).^{ddd jjj}

Local Necrosis

Risk of local necrosis with subcutaneous or intradermal administration.^vv Do not use diphenhydramine injection as a local anesthetic.^vv

Sensitivity Reactions

Sulfite Sensitivity

Some formulations may contain sulfites, which may cause allergic-type reactions (including anaphylaxis and life-threatening or less severe asthmatic episodes) in certain susceptible individuals.^a

General Precautions

Duration of Therapy

When used for insomnia, avoid using for self-medication for longer than 7–10 nights,¹⁰⁴ and consult a clinician if insomnia persists continuously for >2 weeks.^{v tt}

Use of Fixed Combinations

When used in fixed combination with other agents (e.g., acetaminophen, phenylephrine), consider the cautions, precautions, and contraindications associated with the concomitant agent(s).^{107 108 109 110 111 112 113 114}

Specific Populations

Pregnancy

Category B.^vv

Lactation

Has been detected in milk.^{k l} Discontinue nursing or the drug because of potential risk to nursing infants.^{s u vv}

Pediatric Use

Risk of diminished mental alertness.^vv Risk of excitation in young pediatric patients.^vv

Risk of diphenhydramine toxicity (e.g., dilated pupils, flushed face, hallucinations, ataxic gait, urinary retention) when oral preparations used concomitantly with topical preparations of diphenhydramine.^ddd (See Diphenhydramine Toxicity under Cautions.)

Potential for misuse and abuse following parenteral administration over a prolonged period of time.ⁱⁱⁱ

Use with caution in infants and young children; should not be used in premature or full-term neonates.^{s u vv} Children <6 years of age should receive oral diphenhydramine only under the direction of a physician.^{b q t hh}

Safety and efficacy of diphenhydramine as a nighttime sleep aid in children <12 years of age have not been established.^{v tt} Consider risk of possible CNS stimulation when used as nighttime sleep aids.^{v w}

Risk of overdosage and toxicity (including death) in children <2 years of age receiving OTC preparations containing antihistamines, cough suppressants, expectorants, and nasal decongestants alone or in combination for relief of symptoms of upper respiratory tract infection.^{nnn ooo} Limited evidence of efficacy for these preparations in this age group; appropriate dosages not established.ⁿⁿⁿ Therefore, FDA recommended not to use such preparations in children <2 years of age;^ppp safety and efficacy in older children under evaluation.^{rr ttt} 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 <4 years of age.^{qqq rr sss ttt} FDA recommends that parents and caregivers adhere to dosage instructions and warnings on the product labeling that accompanies the preparation and consult a clinician about any concerns.^{qqq rr sss} Clinicians should ask caregivers about use of OTC cough/cold preparations to avoid overdosage.ⁿⁿⁿ

Geriatric Use

Possible increased risk of dizziness, sedation, and hypotension in patients ≥60 years of age.^vv

Common Adverse Effects

Sedation, sleepiness, dizziness, disturbed coordination, epigastric distress, thickening of bronchial secretions.^vv

Drug Interactions

CNS Depressants

Potential pharmacologic interaction (additive CNS depression) with alcohol and other CNS depressants (e.g., hypnotics, sedatives, tranquilizers).^vv

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.^{x y z aa bb cc dd ee ff}

Specific Drugs

diphenhydrAMINE Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration, but only about 40–60% of an oral dose reaches systemic circulation as unchanged drug.^{e f gg oo pp}

Onset

Appears in plasma within 15 minutes^e following oral administration of a single dose; peak plasma concentrations are attained within 1–4 hours.^{e f g h}

Antihistamine effect peaks within 1–3 hours and persists for up to 7 hours after administration of a single dose.^{f s}

Sedative effects peak within 1–3 hours after administration of a single dose.^{e f oo pp}

Distribution

Extent

Highest concentrations detected in the lungs, spleen, and brain in rats; small amounts detected in the heart, muscle, and liver.ⁱ

Crosses the placenta^j and has been detected in milk, although the extent of distribution into milk has not been quantitated.^{k l}

Plasma Protein Binding

Approximately 80–85%.^{e oo uuu}

Special Populations

Larger volume of distribution in Asian adults (about 480 L) than in white adults (188–336 L).^{f oo pp oo}

Less extensive protein binding reported in healthy Asian adults^oo and in adults with liver cirrhosis.^uuu

Elimination

Metabolism

Rapidly and apparently almost completely metabolized.^{e f g m}

Undergoes substantial first-pass metabolism in the liver following oral administration.^{e f gg}

Elimination Route

Excreted in urine (50–75%) mainly as metabolites.^{m s}

Half-Life

2.4–9.3 hours in healthy adults.^{e f g gg oo uuu pp}

Special Populations

Terminal elimination half-life is prolonged in adults with liver cirrhosis.^uuu

Stability

Storage

Oral

Capsules and Tablets

15–25°C.^s Protect from heat, light, and moisture.^vv

Parenteral

Injection

15–30°C.^vv Protect from freezing and light.^vv

Compatibility

Parenteral

Solution CompatibilityHID

Drug Compatibility

Actions

• Blocks H₁-receptor sites, thereby preventing the action of histamine on the cell.^c

• Suppresses flare and pruritus that accompany the endogenous release of histamine.^c

• Exhibits some activities common to anticholinergics, ganglionic and adrenergic blocking agents, local anesthetics, and antispasmodics.^c

• Antihistamines do not block the stimulating effect of histamine on gastric acid secretion, which is mediated by H₂-receptors of the parietal cells.^c

• Effects on parkinsonian syndrome and drug-induced extrapyramidal reactions are apparently related to central anticholinergic effects.^c

Advice to Patients

• Risk of drowsiness; avoid alcohol and use caution when driving, operating machinery, or engaging in other hazardous tasks.^{s vv}

• When used for insomnia, consult a clinician if sleeplessness persists continuously for >2 weeks.^{v tt}

• Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.^s Importance of patients already receiving another CNS depressant (e.g., sedatives, tranquilizers) not undertaking self-medication without first consulting a clinician.^{nn tt ggg hhh}

• Importance of not using multiple diphenhydramine-containing preparations (either oral or topical) simultaneously because of risk of toxicity.^{ddd jjj} (See Diphenhydramine Toxicity under Cautions.)

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.^s

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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