Medically reviewed on March 25, 2018.

Pronunciation

(dye fen HYE dra meen)

Index Terms

• Benadryl
• Diphenhydramine Citrate
• Diphenhydramine HCl
• Diphenhydramine Hydrochloride
• Diphenhydramine Tannate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule, Oral, as hydrochloride:

Allergy Relief: 25 mg [contains brilliant blue fcf (fd&c blue #1), butylparaben, edetate calcium disodium, fd&c blue #2 (indigotine), fd&c red #40, fd&c yellow #10 (quinoline yellow), methylparaben, polysorbate 80, propylparaben]

Banophen: 25 mg, 50 mg [contains brilliant blue fcf (fd&c blue #1), fd&c red #40]

Benadryl: 25 mg [DSC]

Benadryl Allergy: 25 mg [dye free]

Benadryl Dye-Free Allergy: 25 mg [DSC] [dye free]

Diphenhist: 25 mg [DSC] [contains brilliant blue fcf (fd&c blue #1), butylparaben, fd&c red #40, methylparaben, propylparaben]

Diphenhist: 25 mg [contains brilliant blue fcf (fd&c blue #1), fd&c red #40]

Genahist: 25 mg

Geri-Dryl: 25 mg

GoodSense Allergy Relief: 25 mg [dye free]

GoodSense Sleep Aid: 50 mg [gluten free; contains brilliant blue fcf (fd&c blue #1)]

GoodSense SleepTime: 25 mg [contains brilliant blue fcf (fd&c blue #1), fd&c red #40]

Ormir: 50 mg [contains fd&c yellow #10 (quinoline yellow), fd&c yellow #6 (sunset yellow)]

Pharbedryl: 25 mg, 50 mg [contains brilliant blue fcf (fd&c blue #1), fd&c red #40]

Q-Dryl: 25 mg [DSC] [contains brilliant blue fcf (fd&c blue #1), butylparaben, fd&c red #40, methylparaben, propylparaben]

ZzzQuil: 25 mg [contains brilliant blue fcf (fd&c blue #1), fd&c red #40]

Generic: 25 mg, 50 mg

Elixir, Oral, as hydrochloride:

Altaryl: 12.5 mg/5 mL (120 mL [DSC], 480 mL [DSC], 3840 mL [DSC]) [contains alcohol, usp]

Generic: 12.5 mg/5 mL (5 mL, 10 mL)

Liquid, Oral, as hydrochloride:

Allergy Relief Childrens: 12.5 mg/5 mL (118 mL, 480 mL) [alcohol free; contains fd&c red #40, sodium benzoate]

Banophen: 12.5 mg/5 mL (118 mL) [alcohol free; cherry flavor]

Banophen: 12.5 mg/5 mL (473 mL) [alcohol free, sugar free; cherry flavor]

Benadryl Allergy Childrens: 12.5 mg/5 mL (5 mL [DSC], 118 mL, 236 mL) [alcohol free; contains fd&c red #40, sodium benzoate]

Benadryl Allergy Childrens: 12.5 mg/5 mL (236 mL) [alcohol free; contains fd&c red #40, sodium benzoate; cherry flavor]

Benadryl Allergy Childrens: 12.5 mg/5 mL (118 mL) [alcohol free, dye free, sugar free; contains saccharin sodium, sodium benzoate]

Diphenhist: 12.5 mg/5 mL (118 mL, 473 mL) [alcohol free; contains fd&c red #40, saccharin sodium, sodium benzoate; fruit flavor]

Geri-Dryl: 12.5 mg/5 mL (473 mL) [alcohol free; contains fd&c red #40, saccharin sodium, sodium benzoate]

GoodSense SleepTime: 50 mg/30 mL (177 mL, 355 mL) [gluten free; contains alcohol, usp, brilliant blue fcf (fd&c blue #1), fd&c red #40, propylene glycol, saccharin sodium, sodium benzoate; berry flavor]

Naramin: 12.5 mg/5 mL (5 mL) [alcohol free; contains fd&c red #40, sodium benzoate; cherry flavor]

PediaCare Childrens Allergy: 12.5 mg/5 mL (118 mL) [alcohol free; contains fd&c red #40, sodium benzoate]

Q-Dryl: 12.5 mg/5 mL (118 mL [DSC], 237 mL [DSC], 473 mL [DSC]) [alcohol free; contains fd&c red #40, saccharin sodium, sodium benzoate; cherry flavor]

Scot-Tussin Allergy Relief: 12.5 mg/5 mL (118.3 mL [DSC], 240 mL [DSC], 480 mL [DSC], 3780 mL [DSC]) [alcohol free, dye free, saccharin free, sodium free, sorbitol free, sugar free]

Siladryl Allergy: 12.5 mg/5 mL (118 mL, 237 mL, 473 mL) [alcohol free, sugar free; contains fd&c red #40, methylparaben, propylene glycol, propylparaben, saccharin sodium; cherry flavor]

Total Allergy Medicine: 12.5 mg/5 mL (118 mL) [alcohol free]

ZzzQuil: 50 mg/30 mL (177 mL, 354 mL) [contains alcohol, usp, brilliant blue fcf (fd&c blue #1), fd&c red #40, propylene glycol, saccharin sodium, sodium benzoate; berry flavor]

ZzzQuil: 50 mg/30 mL (354 mL) [contains alcohol, usp, brilliant blue fcf (fd&c blue #1), fd&c red #40, propylene glycol, saccharin sodium, sodium benzoate; vanilla cherry flavor]

ZzzQuil: 50 mg/30 mL (177 mL, 354 mL) [alcohol free; contains brilliant blue fcf (fd&c blue #1), propylene glycol, saccharin sodium, sodium benzoate; mango berry flavor]

Generic: 6.25 mg/mL (30 mL)

Solution, Injection, as hydrochloride:

Generic: 50 mg/mL (1 mL, 10 mL)

Solution, Injection, as hydrochloride [preservative free]:

Generic: 50 mg/mL (1 mL)

Strip, Oral, as hydrochloride:

Triaminic Cough/Runny Nose: 12.5 mg (16 ea [DSC]) [contains alcohol, usp, brilliant blue fcf (fd&c blue #1), fd&c red #40; grape flavor]

Suspension Reconstituted, Oral, as hydrochloride:

Dicopanol FusePaq: 5 mg/mL (150 mL) [contains sodium benzoate]

Dicopanol RapidPaq: 5 mg/mL (150 mL) [dye free, paraben free, sugar free; contains sodium benzoate]

Syrup, Oral, as hydrochloride:

Altaryl: 12.5 mg/5 mL (120 mL [DSC], 480 mL [DSC], 3785 mL [DSC]) [alcohol free; cherry flavor]

Quenalin: 12.5 mg/5 mL (120 mL [DSC]) [fruit flavor]

Silphen Cough: 12.5 mg/5 mL (118 mL [DSC], 237 mL [DSC], 473 mL [DSC]) [contains alcohol, usp, fd&c red #40, menthol, methylparaben, propylene glycol, propylparaben; strawberry flavor]

Tablet, Oral, as hydrochloride:

Aler-Dryl: 50 mg

Allergy Relief: 25 mg [contains polysorbate 80]

Anti-Hist Allergy: 25 mg

Banophen: 25 mg

Benadryl: 25 mg [DSC]

Benadryl Allergy: 25 mg

Benadryl Allergy: 25 mg [DSC] [contains edetate calcium disodium, fd&c red #40, methylparaben, polysorbate 80, propylparaben]

Complete Allergy Medication: 25 mg [DSC]

Complete Allergy Relief: 25 mg [DSC]

Diphen: 25 mg

Diphenhist: 25 mg

Geri-Dryl: 25 mg

Nighttime Sleep Aid: 25 mg

Nighttime Sleep Aid: 25 mg [contains fd&c blue #1 aluminum lake, fd&c blue #2 aluminum lake, polysorbate 80]

Nighttime Sleep Aid: 50 mg [DSC] [contains fd&c blue #1 aluminum lake]

Nytol: 25 mg

Nytol Maximum Strength: 50 mg

QlearQuil Nighttime Allergy: 25 mg [DSC] [contains fd&c blue #1 aluminum lake, fd&c blue #2 aluminum lake]

Simply Allergy: 25 mg [DSC]

Simply Sleep: 25 mg [contains brilliant blue fcf (fd&c blue #1)]

Sleep Tabs: 25 mg [scored; contains fd&c blue #1 aluminum lake]

Sominex: 25 mg [DSC] [contains fd&c blue #1 aluminum lake]

Sominex Maximum Strength: 50 mg [DSC] [contains fd&c blue #1 aluminum lake, polysorbate 80]

Tetra-Formula Nighttime Sleep: 50 mg [contains fd&c blue #1 aluminum lake]

Total Allergy: 25 mg

Generic: 25 mg

Tablet Chewable, Oral, as hydrochloride:

Benadryl Allergy Childrens: 12.5 mg [DSC] [contains aspartame, fd&c blue #1 aluminum lake]

Benadryl Allergy Childrens: 12.5 mg [contains fd&c blue #1 aluminum lake]

Brand Names: U.S.

• Aler-Dryl [OTC]
• Allergy Relief Childrens [OTC]
• Allergy Relief [OTC]
• Altaryl [OTC] [DSC]
• Anti-Hist Allergy [OTC]
• Banophen [OTC]
• Benadryl Allergy Childrens [OTC]
• Benadryl Allergy [OTC]
• Benadryl Dye-Free Allergy [OTC] [DSC]
• Benadryl [OTC] [DSC]
• Complete Allergy Medication [OTC] [DSC]
• Complete Allergy Relief [OTC] [DSC]
• Dicopanol FusePaq
• Dicopanol RapidPaq
• Diphen [OTC]
• Diphenhist [OTC]
• Genahist [OTC]
• Geri-Dryl [OTC]
• GoodSense Allergy Relief [OTC]
• GoodSense Sleep Aid [OTC]
• GoodSense SleepTime [OTC]
• Naramin [OTC]
• Nighttime Sleep Aid [OTC]
• Nytol Maximum Strength [OTC]
• Nytol [OTC]
• Ormir [OTC]
• PediaCare Childrens Allergy [OTC]
• Pharbedryl
• Pharbedryl [OTC]
• Q-Dryl [OTC] [DSC]
• QlearQuil Nighttime Allergy [OTC] [DSC]
• Quenalin [OTC] [DSC]
• Scot-Tussin Allergy Relief [OTC] [DSC]
• Siladryl Allergy [OTC]
• Silphen Cough [OTC] [DSC]
• Simply Allergy [OTC] [DSC]
• Simply Sleep [OTC]
• Sleep Tabs [OTC]
• Sominex Maximum Strength [OTC] [DSC]
• Sominex [OTC] [DSC]
• Tetra-Formula Nighttime Sleep [OTC]
• Total Allergy Medicine [OTC]
• Total Allergy [OTC]
• Triaminic Cough/Runny Nose [OTC] [DSC]
• ZzzQuil [OTC]

Pharmacologic Category

• Ethanolamine Derivative
• Histamine H₁ Antagonist
• Histamine H₁ Antagonist, First Generation

Pharmacology

Competes with histamine for H₁-receptor sites on effector cells in the gastrointestinal tract, blood vessels, and respiratory tract; anticholinergic and sedative effects are also seen

Distribution

V_d: Children: 22 L/kg (range: 15 to 28 L/kg); Adults: 17 L/kg (range: 13 to 20 L/kg); Elderly: 14 L/kg (range: 7 to 20 L/kg) (Blyden, 1986; Simons, 1990)

Metabolism

Extensively hepatic n-demethylation via CYP2D6; minor demethylation via CYP1A2, 2C9 and 2C19; smaller degrees in pulmonary and renal systems; significant first-pass effect (Akutsu, 2007)

Excretion

Urine (as metabolites and unchanged drug) (Albert, 1975; Maurer, 1988)

Time to Peak

Serum: ~2 hours (Blyden, 1986; Simons, 1990)

Duration of Action

Histamine-induced wheal suppression: ≤10 hours (Simons, 1990)

Histamine-induced flare suppression: ≤12 hours (Simons, 1990)

Half-Life Elimination

Children: 5 hours (range: 4 to 7 hours); Adults: 9 hours (range: 7 to 12 hours); Elderly: 13.5 hours (range: 9 to 18 hours) (Blyden, 1986; Simons, 1990)

Protein Binding

98.5% (Vozeh, 1988)

Use: Labeled Indications

Symptomatic relief of allergic symptoms caused by histamine release including nasal allergies and allergic dermatosis; adjunct to epinephrine in the treatment of anaphylaxis; insomnia, occasional; prevention or treatment of motion sickness; antitussive; management of Parkinsonian syndrome including drug-induced extrapyramidal symptoms (dystonic reactions) alone or in combination with centrally acting anticholinergic agents

Guideline recommendations:

Anaphylaxis: Antihistamines are considered second-line treatment only after epinephrine administration in the adjunct management of anaphylaxis (AAAAI [Lieberman 2015]).

Insomnia: The American Academy of Sleep Medicine guidelines for the management of chronic insomnia suggest diphenhydramine not be used for sleep-onset or sleep-maintenance insomnia in adults due to the absence of evidence for clinically significant improvement (AASM [Sateia 2017]).

Off Label Uses

Oral mucositis

Diphenhydramine is commonly used in mouthwashes for relief of oral mucositis symptoms in patients undergoing treatment for cancer, though empiric evidence to support the use of these mouthwashes is sparse and inconsistent. Other therapies (eg, allopurinol, granulocyte-macrophage colony-stimulating factor) have been found to be effective in improving and resolving oral mucositis. More randomized clinical trials are needed to determine the role of diphenhydramine in the prevention and management of oral mucositis.

Contraindications

Hypersensitivity to diphenhydramine, other structurally related antihistamines, or any component of the formulation; neonates or premature infants; breast-feeding

Additional contraindications: Parenteral: Use as a local anesthetic

OTC labeling: When used for self-medication, do not use in children <6 years, to make a child sleep, or with any other diphenhydramine-containing products (including topical products)

Dosing: Adult

Allergic reactions:

Oral: 25 to 50 mg every 4 to 8 hours; maximum: 300 mg daily

IM, IV: 10 to 50 mg per dose; single doses up to 100 mg may be used if needed; not to exceed 400 mg daily

Anaphylaxis, severe (adjunct to epinephrine; second-line agent) (off-label dose): IV: 25 to 50 mg over 10 to 15 minutes (AAAAI [Lieberman 2015])

Antitussive: Oral: 25 mg every 4 hours; maximum: 150 mg daily

Insomnia, occasional: Oral: 50 mg at bedtime; Note: Use of diphenhydramine to treat insomnia is not recommended in adults (AASM [Sateia 2017]).

Motion sickness: Note: When used for prophylaxis, administer 30 minutes before motion.

Oral (treatment or prophylaxis): 25 to 50 mg every 6 to 8 hours

IM, IV (treatment): 10 to 50 mg per dose; single doses up to 100 mg may be used if needed; maximum: 400 mg daily

Parkinsonism:

Oral: 25 to 50 mg 3 or 4 times daily

IM, IV: 10 to 50 mg per dose; single doses up to 100 mg may be used if needed; maximum: 400 mg daily

Rhinitis, sneezing due to common cold: Oral: 25 to 50 mg every 4 to 6 hours; maximum: 300 mg daily

Dosing: Pediatric

Allergic reactions: Infants, Children, and Adolescents: IM, IV, Oral: 5 mg/kg/day in divided doses every 6 to 8 hours: maximum: 300 mg daily

Alternate dosing by age: Oral:

2 to <6 years (off-label use): 6.25 mg every 4 to 6 hours; maximum: 37.5 mg daily (Kleigman, 2011)

6 to <12 years: 12.5 to 25 mg every 4 to 6 hours; maximum: 150 mg daily

≥12 years: Refer to adult dosing.

Anaphylaxis (adjunct to epinephrine)/allergic reaction (off-label use): Infants, Children, and Adolescents: IM, IV, Oral: 1 to 2 mg/kg/dose; maximum: 50 mg/dose (Hegenbarth, 2008; Kliegman, 2011; Liberman, 2008; Lieberman, 2010; Simons, 2011)

Antitussive: Children ≥12 years: Refer to adult dosing.

Dystonic reactions (off-label use): Infants, Children, and Adolescents: IM, IV: 1 to 2 mg/kg/dose; maximum single dose: 50 mg (Hegenbarth, 2008; Kliegman, 2011)

Insomnia, occasional: Oral:

Children 2 to 12 years, weighing 10 to 50 kg (off-label use): Limited data available: 1 mg/kg administered 30 minutes before bedtime; maximum single dose: 50 mg (Russo, 1976)

Children ≥12 years and Adolescents: Refer to adult dosing.

Motion sickness:

Prophylaxis: Oral:

Manufacturer's labeling: Infants, Children, and Adolescents: Note: Administer 30 minutes before motion

Weight-directed dosing: 5 mg/kg/day divided into 3 to 4 doses; maximum: 300 mg daily

Fixed dosing: 12.5 to 25 mg 3 to 4 times daily

Alternate dosing: Children 2 to 12 years: Limited data available: 0.5 to 1 mg/kg/dose every 6 hours; maximum single dose: 25 mg. First dose should be administered 1 hour before travel (CDC, 2014).

Treatment: Infants, Children, and Adolescents:

IV, IM: 5 mg/kg/day divided into 4 doses; maximum: 300 mg daily

Oral:

Weight-directed dosing: 5 mg/kg/day divided into 3 to 4 doses; maximum: 300 mg daily

Fixed dosing: 12.5 to 25 mg 3 to 4 times daily

Rhinitis, sneezing due to common cold: Oral:

Children 6 to <12 years: 12.5 to 25 mg every 4 to 6 hours; maximum: 150 mg daily

Children ≥12 years and Adolescents: Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Administration

Oral: When used to prevent motion sickness, first dose should be given 30 minutes prior to exposure. When used for occasional insomnia, dose should be given 30 minutes before bedtime.

IM, IV: Injection solution is for IV or deep IM administration only. For IV administration, inject at a rate ≤25 mg/minute. Local necrosis may result with SubQ or intradermal use.

Dietary Considerations

Some products may contain sodium and/or phenylalanine.

Storage

Injection: Store at room temperature of 20°C to 25°C (68°F to 77°F); protect from light and freezing.

Oral: Store at room temperature. Protect capsules and tablets from moisture. Protect oral solution from freezing and light.

Drug Interactions

AbobotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic effect of AbobotulinumtoxinA. Monitor therapy

Acetylcholinesterase Inhibitors: May diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Monitor therapy

Aclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Amantadine: May enhance the anticholinergic effect of Anticholinergic Agents. Monitor therapy

Amezinium: Antihistamines may enhance the stimulatory effect of Amezinium. Monitor therapy

Amifampridine: May diminish the anticholinergic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Amifampridine. Monitor therapy

Amphetamines: May diminish the sedative effect of Antihistamines. Monitor therapy

Anticholinergic Agents: May enhance the adverse/toxic effect of other Anticholinergic Agents. Monitor therapy

ARIPiprazole: CYP2D6 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Benzylpenicilloyl Polylysine: Antihistamines may diminish the diagnostic effect of Benzylpenicilloyl Polylysine. Management: Suspend systemic H1 antagonists for benzylpenicilloyl-polylysine skin testing and delay testing until systemic antihistaminic effects have dissipated. A histamine skin test may be used to assess persistent antihistaminic effects. Consider therapy modification

Betahistine: Antihistamines may diminish the therapeutic effect of Betahistine. Monitor therapy

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Chloral Betaine: May enhance the adverse/toxic effect of Anticholinergic Agents. Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Cimetropium: Anticholinergic Agents may enhance the anticholinergic effect of Cimetropium. Avoid combination

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

Eluxadoline: Anticholinergic Agents may enhance the constipating effect of Eluxadoline. Avoid combination

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

Gastrointestinal Agents (Prokinetic): Anticholinergic Agents may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Monitor therapy

Glucagon: Anticholinergic Agents may enhance the adverse/toxic effect of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Monitor therapy

Glycopyrrolate (Oral Inhalation): Anticholinergic Agents may enhance the anticholinergic effect of Glycopyrrolate (Oral Inhalation). Avoid combination

Hyaluronidase: Antihistamines may diminish the therapeutic effect of Hyaluronidase. Management: Patients receiving antihistamines (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Consider therapy modification

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Ipratropium (Oral Inhalation): May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Itopride: Anticholinergic Agents may diminish the therapeutic effect of Itopride. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Levosulpiride: Anticholinergic Agents may diminish the therapeutic effect of Levosulpiride. Avoid combination

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

Mianserin: May enhance the anticholinergic effect of Anticholinergic Agents. Monitor therapy

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mirabegron: Anticholinergic Agents may enhance the adverse/toxic effect of Mirabegron. Monitor therapy

Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Nitroglycerin: Anticholinergic Agents may decrease the absorption of Nitroglycerin. Specifically, anticholinergic agents may decrease the dissolution of sublingual nitroglycerin tablets, possibly impairing or slowing nitroglycerin absorption. Monitor therapy

OnabotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic effect of OnabotulinumtoxinA. Monitor therapy

Opioid Analgesics: CNS Depressants may enhance the CNS depressant effect of Opioid Analgesics. Management: Avoid concomitant use of opioid analgesics and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Oxatomide: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Perhexiline: CYP2D6 Inhibitors (Weak) may increase the serum concentration of Perhexiline. Monitor therapy

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Monitor therapy

Pitolisant: Antihistamines may diminish the therapeutic effect of Pitolisant. Monitor therapy

Potassium Chloride: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Chloride. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium chloride. Avoid combination

Potassium Citrate: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Citrate. Avoid combination

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Consider therapy modification

QTc-Prolonging Agents (Highest Risk): QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

QTc-Prolonging Agents (Moderate Risk): QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Monitor therapy

Ramosetron: Anticholinergic Agents may enhance the constipating effect of Ramosetron. Monitor therapy

RimabotulinumtoxinB: Anticholinergic Agents may enhance the anticholinergic effect of RimabotulinumtoxinB. Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Secretin: Anticholinergic Agents may diminish the therapeutic effect of Secretin. Management: Avoid concomitant use of anticholinergic agents and secretin. Discontinue anticholinergic agents at least 5 half-lives prior to administration of secretin. Consider therapy modification

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Thiazide and Thiazide-Like Diuretics: Anticholinergic Agents may increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Tiotropium: Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium. Avoid combination

Topiramate: Anticholinergic Agents may enhance the adverse/toxic effect of Topiramate. Monitor therapy

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Umeclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Test Interactions

May interfere with urine detection of methadone and phencyclidine (false-positives); may cause false-positive serum TCA screen; may suppress the wheal and flare reactions to skin test antigens

Adverse Reactions

Frequency not defined.

Cardiovascular: Chest tightness, extrasystoles, hypotension, palpitations, tachycardia

Central nervous system: Ataxia, chills, confusion, dizziness, drowsiness, euphoria, excitement, fatigue, headache, insomnia, irritability, nervousness, neuritis, paradoxical excitation, paresthesia, restlessness, sedation, seizure, vertigo

Dermatologic: Diaphoresis

Endocrine & metabolic: Menstrual disease (early menses)

Gastrointestinal: Anorexia, constipation, diarrhea, dry mucous membranes, epigastric distress, nausea, vomiting, xerostomia

Genitourinary: Difficulty in micturition, urinary frequency, urinary retention

Hematologic & oncologic: Agranulocytosis, hemolytic anemia, thrombocytopenia

Hypersensitivity: Anaphylactic shock

Neuromuscular & skeletal: Tremor

Ophthalmic: Blurred vision, diplopia

Otic: Labyrinthitis (acute), tinnitus

Respiratory: Constriction of the pharynx, nasal congestion, thickening of bronchial secretions, wheezing

Warnings/Precautions

Concerns related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

Disease-related concerns:

• Asthma: Use with caution in patients with a history of asthma.

• Cardiovascular disease: Use with caution in patients with cardiovascular disease (including hypertension and ischemic heart disease).

• Increased intraocular pressure/glaucoma: Use with caution in patients with increased intraocular pressure or angle-closure glaucoma.

• Prostatic hyperplasia/urinary obstruction: Use with caution in patients with prostatic hyperplasia, bladder neck obstruction, and/or GU obstruction.

• Pyloroduodenal obstruction: Use with caution in patients with pyloroduodenal obstruction (including stenotic peptic ulcer).

• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Pediatric: Antihistamines may cause excitation in young children. Toxicity (overdose) in pediatric patients may result in hallucinations, convulsions, or death; neonates and young children are highly sensitive to depressive effects of diphenhydramine; use is contraindicated in neonates and premature infants.

Dosage form specific issues:

• Alcohol: Some oral liquid products may contain alcohol.

• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC, 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors, 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer’s labeling.

• Oral liquid: Oral solutions are available in two concentrations (ie, 12.5 mg/5 mL and 50 mg/30 mL [eg, ZzzQuil]); precautions should be taken to verify and avoid confusion between the different concentrations; dose should be clearly presented as "mg"; the 50 mg/30 mL oral solution is indicated for the occasional treatment of insomnia.

• Parenteral: Subcutaneous or intradermal use has been associated with tissue necrosis; administer IV or IM only.

• Phenylalanine: Some products may contain phenylalanine.

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson, 2002; Lucente 2000; Shelley, 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade, 1986; CDC, 1984). See manufacturer’s labeling.

• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP ["Inactive" 1997]; Zar, 2007).

• Soy protein: Some preparations contain soy protein; avoid use in patients with soy protein or peanut allergies.

Other warnings/precautions:

• Self-medication (OTC use): Do not use with other products containing diphenhydramine, even ones used on the skin. Oral products are not for OTC use in children <6 years of age.

Monitoring Parameters

Relief of symptoms, mental alertness

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies. Diphenhydramine crosses the placenta (Miller 2000; Parkin 1974). In general, the use of first generation antihistamines immediately before parturition may cause respiratory depression in the newborn (Zuberbier 2014). Diphenhydramine may be used for the treatment of allergic conditions in pregnant women when a first generation antihistamine is indicated (Babalola 2013; Murase 2014; Zuberbier 2014). Antihistamines are not recommended for treatment of pruritus associated with intrahepatic cholestasis in pregnancy (Ambros-Rudolph 2011; Kremer 2014).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience fatigue, thickening of mucus, anxiety, vomiting, or nausea. Have patient report immediately to prescriber severe dizziness, passing out, or change in balance (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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