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Diphenhydramine (systemic): Drug information

Diphenhydramine (systemic): Drug information
(For additional information see "Diphenhydramine (systemic): Patient drug information" and see "Diphenhydramine (systemic): Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • Aler-Dryl [OTC];
  • Allergy Childrens [OTC];
  • Allergy Relief Childrens [OTC];
  • Allergy Relief [OTC];
  • Anti-Hist Allergy [OTC];
  • Aurodryl Allergy Childrens [OTC];
  • Banophen [OTC];
  • Benadryl Allergy Childrens [OTC];
  • Benadryl Allergy Ultratabs [OTC];
  • Benadryl Allergy [OTC];
  • Complete Allergy Medication [OTC] [DSC];
  • Complete Allergy Relief [OTC];
  • Di-Phen [DSC];
  • Diphen;
  • Diphen [OTC];
  • Diphenhist [OTC];
  • Genahist [OTC] [DSC];
  • Geri-Dryl [OTC];
  • GoodSense Allergy Relief [OTC];
  • GoodSense Sleep Aid [OTC];
  • M-Dryl [OTC];
  • Naramin [OTC];
  • Nighttime Sleep Aid [OTC];
  • Nytol Maximum Strength [OTC] [DSC];
  • Nytol [OTC] [DSC];
  • Ormir [OTC] [DSC];
  • PediaCare Childrens Allergy [OTC];
  • Pharbedryl [OTC];
  • Siladryl Allergy [OTC];
  • Silphen Cough [OTC] [DSC];
  • Simply Sleep [OTC];
  • Sleep Tabs [OTC];
  • Tetra-Formula Nighttime Sleep [OTC];
  • Total Allergy Medicine [OTC];
  • Total Allergy [OTC];
  • ZzzQuil [OTC]
Brand Names: Canada
  • Diphenist;
  • PMS-DiphenhydrAMINE
Pharmacologic Category
  • Ethanolamine Derivative;
  • Histamine H1 Antagonist;
  • Histamine H1 Antagonist, First Generation
Dosing: Adult

Note: Dosing recommendations based on clinical experience and general dosing range in manufacturer's labeling unless otherwise noted. Although oral dosing up to 50 mg every 4 hours (maximum: 300 mg/day) and parenteral dosing up to 100 mg every 6 hours (maximum: 400 mg/day) are approved in some labels, adverse effects may be increased at these higher doses. In general, clinical experience dictates that the doses provided below are sufficient.

Allergic reactions

Allergic reactions:

Anaphylaxis (adjunct to epinephrine): Note: Administer epinephrine first when treating anaphylaxis. Do not use diphenhydramine for initial or sole treatment of anaphylaxis because H1 antihistamines do not relieve upper or lower airway obstruction, hypotension, or shock.

IV: 25 to 50 mg once, then every 4 to 6 hours as needed; administer after epinephrine (AAAAI [Lieberman 2015]; Campbell 2021; Simons 2011).

Mild to moderate cutaneous reactions (eg, pruritus): Note: May combine with a topical or systemic glucocorticoid and/or H2 antihistamine, depending on the severity and/or cause of the allergic reaction.

Oral: 25 mg every 4 to 6 hours or 50 mg every 6 to 8 hours as needed.

IM, IV: 10 to 50 mg per dose every 6 hours as needed.

Angioedema, allergic

Angioedema, allergic (acute) (alternative agent) (off-label use): Note: Should not be used as monotherapy for angioedema with anaphylaxis; use epinephrine, prior to diphenhydramine, if anaphylaxis symptoms are present (James 2017; Zuraw 2019).

Oral: 25 mg every 4 to 6 hours or 50 mg every 6 to 8 hours as needed.

IM, IV: 10 to 50 mg per dose every 6 hours as needed.

Common cold symptoms or upper airway cough syndrome

Common cold symptoms (eg, rhinitis, rhinorrhea, sneezing) or upper airway cough syndrome: Note: Used in combination with a decongestant; adverse effects of monotherapy likely outweigh benefits (Björnsdóttir 2007; De Sutter 2012; De Sutter 2015; Irwin 2006; Weinberger 2019).

Oral: 25 mg every 4 to 6 hours or 50 mg every 6 to 8 hours as needed (in combination with a decongestant); doses at the higher end of the dosing range may not be tolerated.

Extrapyramidal symptoms, medication-induced

Extrapyramidal symptoms (eg, dystonia and parkinsonism), medication-induced:

Note: Not recommended for the treatment of akathisia (APA [Keepers 2020]).

Acute treatment: Note: Parenteral administration is preferred for initial treatment of moderate to severe acute reactions (eg, dystonia). Once severe symptoms have resolved, transition to oral treatment. Duration of therapy is based on the severity of extrapyramidal symptoms (EPS) reaction, pharmacologic profile of the causative agent (eg, half-life, adverse effects) and patient risk factors (Holloman 1997; Kreyenbuhl 2010). Some experts recommend attempting taper and discontinuation after several weeks to months (Desmarais 2012).

Initial dose: IM, IV: 25 to 50 mg once (Lavonas 2021; Stroup 2021).

Subsequent doses: Oral: 25 to 50 mg every 4 to 12 hours; maximum: 300 mg/day (Stroup 2021; manufacturer's labeling).

Prophylaxis: Note: May be useful for preventing acute dystonic reactions when administering drugs with increased risk of causing such reactions (eg, haloperidol, metoclopramide) (Kreyenbuhl 2010); however, in general, oral prophylactic use is not recommended to prevent antipsychotic-associated EPS (Tonda 1994).

IM, IV: 12.5 to 50 mg prior to administration of high-risk medication; maximum: 400 mg/day (D’Souza 2018; Kelley 2012; Kreyenbuhl 2010).

Infusion- or transfusion-related reactions

Infusion- or transfusion-related reactions (off-label use):

Premedication: Note: Typically administered prior to the infusion of certain chemotherapy agents, biologics, or other drugs (eg, contrast media); may be given with a glucocorticoid, acetaminophen, and/or an H2 antihistamine. An optimal premedication regimen has not been identified; refer to institutional protocols (Castells 2020). The routine use of premedication with diphenhydramine prior to blood transfusions to prevent febrile nonhemolytic or allergic transfusion reactions is not recommended or supported by data (Silvergleid 2021; Tobian 2007).

IV, Oral: 25 to 50 mg given ~30 to 60 minutes prior to infusion; use of the oral route may require earlier administration (eg, ~1 to 2 hours prior to infusion) to allow for adequate concentrations at the time of infusion or potential reaction.

Treatment: Note: Administer epinephrine first when treating anaphylaxis. Do not use diphenhydramine for initial or sole treatment of anaphylaxis because H1 antihistamines do not relieve upper or lower airway obstruction, hypotension, or shock. Diphenhydramine should be used for symptomatic relief as an adjunct to other appropriate measures (eg, stopping the infusion, reducing the infusion rate).

IV, Oral: 25 to 50 mg; after 15 to 30 minutes, if symptoms persist, may repeat dose as needed. Do not exceed 100 mg within a 1-hour period (Silvergleid 2021). Note: With oral administration, onset of action is delayed.

Insomnia, occasional

Insomnia, occasional (alternative agent):

Note: Routine use is not recommended (AASM [Sateia 2017]). When used, limit to short-term use (≤4 to 8 weeks), preferably in conjunction with nonpharmacologic therapies (ACP [Qaseem 2016]; ESRS [Riemann 2017]; Winkelman 2021).

Oral: 25 to 50 mg at bedtime for occasional use only.

Motion sickness

Motion sickness:

Prophylaxis: Oral: 25 mg every 4 to 6 hours or 50 mg every 6 to 8 hours as needed. Note: Antihistamines may be administered 30 to 60 minutes before motion (Dramamine labeling 2019).

Treatment:

Oral: 25 mg every 4 to 6 hours or 50 mg every 6 to 8 hours as needed.

IM, IV: 10 to 50 mg per dose every 6 hours as needed.

Nausea and vomiting, pregnancy associated, severe or refractory

Nausea and vomiting, pregnancy associated, severe or refractory (alternative agent) (off-label use): Note: May be considered as a component of combination therapy when symptoms persist following initial pharmacologic therapy (ACOG 2018).

Oral: 25 mg every 4 to 6 hours or 50 mg every 6 to 8 hours as needed (ACOG 2018; Magee 2002).

IV: 10 to 50 mg every 6 hours as needed; some experts administer as often as every 4 hours as needed (Smith 2019).

Scombroid poisoning

Scombroid (histamine) poisoning (off-label use): Note: For patients with uncomfortable symptoms (eg, flushing, burning, rash) but without respiratory distress or hypotension (Taylor 1989).

Oral: 25 mg every 4 to 6 hours or 50 mg every 6 to 8 hours as needed.

IM, IV: 10 to 50 mg per dose every 6 hours as needed.

Urticaria, new onset and chronic spontaneous

Urticaria, new onset and chronic spontaneous (alternative agent):

Note: Second-generation H1-antihistamines are preferred due to less sedating and anticholinergic effects (AAAAI/ACAAI [Bernstein 2014]; EAACI [Zuberbier 2018]). May consider use in combination with a second-generation H1-antihistamine in patients in whom bedtime sedating effects may be beneficial, or as initial parenteral therapy in patients with new-onset urticaria in whom more rapid onset of action is desired; avoid use in patients with high-risk occupations (eg, pilots, bus drivers) or who may be more prone to anticholinergic effects (eg, older adults) (AAAAI/ACAAI [Bernstein 2014]; Asero 2021; deShazo 2021; Khan 2021).

Oral: 25 to 50 mg at bedtime, or 25 to 50 mg 3 to 4 times per day as needed (AAAAI/ACAAI [Bernstein 2014]).

IM, IV (new onset only): 25 to 50 mg 3 to 4 times per day as needed; some experts administer as often as every 4 hours as needed (AAAAI/ACAAI [Bernstein 2014]; Asero 2021).

Vertigo, acute treatment

Vertigo, acute treatment (off-label use):

Oral: 25 mg every 4 to 6 hours or 50 mg every 6 to 8 hours as needed (Basura 2020; Furman 2021; Zajonc 2006).

IM, IV: 10 to 50 mg per dose every 6 hours as needed (Basura 2020; Furman 2021; Zajonc 2006).

Duration: Discontinue as soon as severe symptoms resolve, usually after 1 to 2 days (Furman 2021).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Note: There are no data describing diphenhydramine pharmacokinetics in kidney impairment; the following recommendations are based upon pharmacokinetic parameters only; use with caution.

Altered kidney function: IM, IV, Oral: No dosage adjustment necessary for any degree of kidney function (little excreted unchanged in urine) (expert opinion).

Hemodialysis: IM, IV, Oral: Unlikely to be significantly dialyzed (large Vd); no dosage adjustment or supplemental dose necessary (expert opinion).

Peritoneal dialysis: IM, IV, Oral: Unlikely to be significantly dialyzed (large Vd); no dosage adjustment necessary (expert opinion).

CRRT: IM, IV, Oral: Unlikely to be significantly dialyzed (large Vd); no dosage adjustment necessary (expert opinion).

PIRRT: IM, IV, Oral: Unlikely to be significantly dialyzed (large Vd); no dosage adjustment necessary (expert opinion).

Dosing: Hepatic Impairment: Adult

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

Dosing: Pediatric

(For additional information see "Diphenhydramine (systemic): Pediatric drug information")

Note: Oral solutions are available in 2 concentrations (2.5 mg/mL [12.5 mg per 5 mL] and 1.67 mg/mL [50 mg per 30 mL] [eg, ZzzQuil]); precautions should be taken to verify and avoid confusion between the different concentrations. Dose should be clearly presented as "mg" instead of "mL". Many OTC cough/cold/allergy products contain diphenhydramine; all sources of diphenhydramine should be considered when evaluating maximum daily doses.

Allergic rhinitis/rhinoconjunctivitis (including upper respiratory allergies or hay fever):

Note: Due to adverse effects (paradoxical agitation/excitation or sedation), H1 antihistamines (eg, diphenhydramine) are not recommended as first-line therapy for management of allergic rhinitis in pediatric patients; second-generation minimally sedating antihistamines are preferred (AAAI [Dykewicz 2020]).

Infants and Children: Oral: 5 mg/kg/day in equally divided doses administered every 6 to 8 hours as needed; usual dose: 12.5 to 25 mg/dose; maximum dose: 50 mg/dose.

Adolescents: Oral: 5 mg/kg/day in equally divided doses administered every 6 to 8 hours as needed; usual dose: 25 to 50 mg/dose; maximum dose: 50 mg/dose.

Anaphylaxis, adjunct to epinephrine:

Note: Administer epinephrine first when treating anaphylaxis. Do not use diphenhydramine as initial therapy; H1 antihistamines will not alleviate stridor, shortness of breath, wheezing, GI symptoms, hypotension, or shock and are considered second- or third-line agents in the management of anaphylaxis (AAAAI/ACAAI [Lieberman 2015]; AAAAI/ACAAI [Shaker 2020]; AAP [Shenoi 2020]; WAO [Simons 2011]; WAO [Simons 2015]).

Infants and Children: IV, IM, Oral: 1 mg/kg/dose; maximum dose: 50 mg/dose; may repeat every 6 to 8 hours (AAAAI/ACAAI [Lieberman 2015]; AAAAI/ACAAI [Shaker 2020]; AAP [Shenoi 2020]; WAO [Simons 2011]).

Adolescents: IV, IM, Oral: 25 to 50 mg/dose; may repeat every 4 to 8 hours (AAAAI/ACAAI [Lieberman 2015]; AAAAI/ACAAI [Shaker 2020]; AAP [Shenoi 2020]; WAO [Simons 2011]).

Cutaneous disorders with pruritus (eg, urticaria, atopic dermatitis, other pruritic skin conditions):

Note: First-generation antihistamines (eg, diphenhydramine) are not recommended as first-line agents for urticaria (acute or chronic) due to risk of adverse reactions; second-generation antihistamines are preferred (Caffarelli 2019; Del Pozzo-Magaña 2017; EAACI/GA2LEN/EDF/WAO [Zuberbier 2018]). For atopic dermatitis, diphenhydramine may provide intermittent relief of pruritus and may help with sleep loss associated with the pruritus; however, it does not treat underlying condition and is not a substitute for topical therapy. Chronic use is not recommended (AAD [Sidbury 2014]). Dosing recommendations are based on general dosing range in the manufacturer's labeling.

Infants and Children: Oral: 5 mg/kg/day in equally divided doses administered every 6 to 8 hours as needed; usual dose: 12.5 to 25 mg/dose; maximum dose: 50 mg/dose.

Adolescents: Oral: 5 mg/kg/day in equally divided doses administered every 6 to 8 hours as needed; usual dose: 25 to 50 mg/dose; maximum dose: 50 mg/dose.

Extrapyramidal symptoms (EPS) (eg, medication-induced dystonic reactions):

Acute treatment:

Infants, Children, and Adolescents:

Initial: IV (preferred), IM, Oral: 1 to 2 mg/kg/dose; maximum dose: 50 mg/dose; may repeat in 30 minutes if no response. Oral therapy may be considered for home use while medical care is sought (AAP [Shenoi 2020]; Cheslik 1996; Fuhrman 2017; Knight 1988; Pringsheim 2011; Schwartz 1986).

Subsequent doses (if needed): IV, Oral: 5 mg/kg/day in equally divided doses administered every 6 to 8 hours for up to 2 to 5 days may be considered to prevent recurrence. Maximum dose: 50 mg/dose (Pringsheim 2011; manufacturer's labeling).

Pretreatment: Limited data available: Note: Recommended for use when high-dose metoclopramide is required and should be considered when use of other medications known to have a high risk of EPS (eg, high-dose chlorpromazine or prochlorperazine) are required (Allen 1985; POGO [Dupuis 2013]; Sheridan 2014; Trottier 2012; Wolfe 2018). Diphenhydramine has not been shown to prevent akathisia symptoms (Trottier 2012).

Children and Adolescents: IV: 0.5 to 1 mg/kg/dose concomitantly with high-risk medication; repeat dose may be necessary with continued therapy depending on administered medication. Maximum dose: 50 mg/dose (Allen 1985; Sheridan 2014; Trottier 2012). Higher doses of 2 mg/kg/dose (maximum dose: 50 mg/dose) have also been reported in children ≥5 years and adolescents (Kaar 2016).

Infusion or transfusion reactions:

Premedication (eg, radiocontrast agents, IVIG, monoclonal antibody therapy, chemotherapy): Limited data available: Note: Use of premedication should be individualized to patient factors and institutional protocols; may be given in combination with acetaminophen, corticosteroids, and/or H2 antihistamines. For blood products, pretreatment is not routinely recommended because use has not been shown to significantly impact the rate of allergic reaction (Duran 2014; Martí-Carvajal 2010; McCormick 2020; Sanders 2005).

Infants, Children, and Adolescents: IV, Oral: 1 mg/kg/dose administered 30 to 60 minutes prior to infusion; maximum dose: 50 mg/dose (AAAI [Perez 2017]; ACR 2021; Marina 2002).

Treatment: Limited data available: Note: If patient is experiencing anaphylaxis, administer epinephrine first. Do not use diphenhydramine for initial or sole treatment of anaphylaxis because H1 antihistamines do not relieve upper or lower airway obstruction, hypotension, or shock. Diphenhydramine should be used for symptomatic relief as an adjunct to other appropriate measures (eg, stopping the infusion, reducing the infusion rate).

Infants and Children: IV: 1 mg/kg/dose; maximum dose: 50 mg/dose; may repeat every 6 to 8 hours (AAAAI/ACAAI [Lieberman 2015]; ACR 2021).

Adolescents: IV, IM, Oral: 25 to 50 mg/dose; may repeat every 4 to 8 hours (AAAAI/ACAAI [Lieberman 2015]; ACR 2021).

Insomnia, occasional:

Note: Efficacy results are variable. Evaluation of sleep hygiene and use of nonpharmacologic (ie, behavioral) treatment are preferred; medications may be used as adjunct treatment (Owens 2005). While diphenhydramine has been shown to improve sleep latency and reduce nighttime awakenings in children 2 to 12 years of age, studies have not supported the use of diphenhydramine to improve sleep in younger children or infants; routine use is not recommended in adults (AASM [Sateia 2017]; Merenstein 2006; Russo 1976).

Children ≥2 years and Adolescents: Limited data are available for children <12 years: Oral: 0.5 to 1 mg/kg administered 30 minutes before bedtime as needed; usual dose: 12.5 to 50 mg/dose; maximum dose: 50 mg/dose (Felt 2014; Russo 1976; manufacturer's labeling).

Nausea and vomiting:

General dosing: Limited data available: Note: Diphenhydramine may be used for both its antihistamine (causing drowsiness) and antimuscarinic (reducing nausea) effects as adjunct therapy with antiemetics to manage nausea and vomiting associated with various presenting conditions (eg, chemotherapy-induced nausea/vomiting, cyclic vomiting syndrome, migraine, palliative care) (ASER/SAA [Gan 2020]; Kovacic 2018; Sheridan 2014; Wolfe 2018).

Infants, Children, and Adolescents: IV, IM, Oral: 0.625 to 1.25 mg/kg/dose every 6 hours; maximum dose: 50 mg/dose (Coté 2019; Kovacic 2018; Li 2018; Wyllie 2016).

Motion sickness:

Prophylaxis: Note: First dose should be administered 30 to 60 minutes before travel (CDC 2020; manufacturer's labeling).

Children: Oral: 0.5 to 1 mg/kg/dose every 6 hours during triggering motion; usual dose: 12.5 to 25 mg/dose; maximum dose: 25 mg/dose (CDC 2020; manufacturer's labeling).

Adolescents: Oral: 12.5 to 25 mg every 6 to 8 hours during triggering motion (manufacturer's labeling).

Treatment:

Infants, Children, and Adolescents:

IV, IM: 1.25 mg/kg/dose every 6 hours as needed; maximum dose: 50 mg/dose. Note: Usual adult dose: 10 to 50 mg/dose (manufacturer's labeling).

Oral: 5 mg/kg/day in equally divided doses administered every 6 to 8 hours as needed; usual dose: 12.5 to 25 mg/dose; maximum dose: 50 mg/dose (manufacturer's labeling).

Scombroid (histamine) poisoning:

Note: May be useful for patients with uncomfortable symptoms (eg, flushing, burning, rash) but without respiratory distress or hypotension (Taylor 1989). For patients with moderate to severe symptoms, utilize the IV route (Guergué-Díaz de Cerio 2016).

Very limited data available: Children and Adolescents: IV, Oral: 1 mg/kg/dose; maximum dose: 50 mg/dose. May repeat every 6 to 8 hours if necessary; however, most symptoms should resolve within 6 to 8 hours after the initial dose (AAAI/ACAAI [Lieberman 2015]; Feng 2016; Guergué-Díaz de Cerio 2016; Wu 2003).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

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

Dosing: Hepatic Impairment: Pediatric

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

Dosage Forms: US

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 (edta) 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 Allergy: 25 mg [dye free]

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

Genahist: 25 mg [DSC]

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)]

Ormir: 50 mg [DSC] [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]

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

Generic: 25 mg, 50 mg

Elixir, Oral, as hydrochloride:

Di-Phen: 12.5 mg/5 mL (118 mL [DSC]) [contains alcohol, usp, fd&c red #40; cinnamon-anise flavor]

Diphen: 12.5 mg/5 mL (118 mL) [contains alcohol, usp, fd&c red #40; cinnamon-anise flavor]

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

Liquid, Oral, as hydrochloride:

Allergy Childrens: 12.5 mg/5 mL (118 mL [DSC], 236 mL [DSC], 473 mL) [alcohol free, dye free; contains saccharin sodium, sodium benzoate, sorbitol]

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

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

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

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

Benadryl Allergy Childrens: 12.5 mg/5 mL (118 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; bubble-gum flavor]

Diphenhist: 12.5 mg/5 mL (118 mL [DSC], 473 mL [DSC]) [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, methylparaben, propylene glycol, propylparaben]

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

M-Dryl: 12.5 mg/5 mL (120 mL, 473 mL) [alcohol free; contains fd&c red #40, propylene glycol, saccharin sodium, sodium benzoate; cherry 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]

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: 12.5 mg/5 mL (5 mL, 10 mL, 118 mL, 473 mL); 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)

Syrup, Oral, as hydrochloride:

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]

Tablet, Oral, as hydrochloride:

Aler-Dryl: 50 mg

Anti-Hist Allergy: 25 mg

Banophen: 25 mg

Benadryl Allergy: 25 mg

Benadryl Allergy Ultratabs: 25 mg

Complete Allergy Medication: 25 mg [DSC]

Complete Allergy Relief: 25 mg

Diphen: 25 mg

Diphenhist: 25 mg [DSC]

Geri-Dryl: 25 mg

Nighttime Sleep Aid: 25 mg

Nytol: 25 mg [DSC]

Nytol Maximum Strength: 50 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]

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 [contains fd&c blue #1 aluminum lake]

Generic: 12.5 mg

Generic Equivalent Available: US

Yes

Dosage Forms Considerations

Dicopanol FusePaq is a compounding kit for the preparation of an oral suspension. Refer to manufacturer's labeling for compounding instructions.

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Injection, as hydrochloride:

Generic: 50 mg/mL (1 mL, 10 mL, 30 mL)

Administration: Adult

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.

Administration: Pediatric

Oral: May administer without regards to meals; when used to prevent motion sickness, first dose should be given 30 to 60 minutes prior to exposure (CDC 2020; manufacturer's labeling).

Parenteral: For IV or IM administration only. Local necrosis may result with SUBQ or intradermal use. For IV administration, may administer IV push undiluted at a rate ≤25 mg/minute or further diluted as an intermittent infusion over 10 to 15 minutes.

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 drug-induced extrapyramidal symptoms (eg, dystonia, parkinsonism) and parkinsonian syndrome 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: American Academy of Sleep Medicine guidelines for the treatment 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]). The US Department of Veterans Affairs/Department of Defense guidelines for the chronic management of insomnia disorder and obstructive sleep apnea suggest against the use of diphenhydramine for chronic insomnia (VA/DoD 2019).

Use: Off-Label: Adult

Angioedema, allergic (acute); Infusion- or transfusion-related reactions; Nausea and vomiting, pregnancy associated, severe or refractory; Scombroid (histamine) poisoning; Urticaria, new onset and chronic spontaneous; Vertigo, acute treatment

Medication Safety Issues
Sound-alike/look-alike issues:

DiphenhydrAMINE may be confused with desipramine, dicyclomine, dimenhyDRINATE

Benadryl may be confused with benazepril, Bentyl, Benylin, Caladryl

Geriatric Patients: High-Risk Medication:

Beers Criteria: Diphenhydramine (oral), a first-generation antihistamine, is identified in the Beers Criteria as a potentially inappropriate medication to be avoided in patients 65 years and older (independent of diagnosis or condition) due to its potent anticholinergic properties resulting in increased risk of confusion, dry mouth, constipation, and other anticholinergic effects or toxicity; use should also be avoided due to reduced clearance with advanced age and tolerance associated with use as a hypnotic. However, use of diphenhydramine may be appropriate in certain situations such as acute treatment of severe allergic reaction (Beers Criteria [AGS 2019]).

Pharmacy Quality Alliance (PQA): Diphenhydramine (oral), as a single agent or as part of a combination (excludes OTC products), is identified as a high-risk medication in patients 65 years and older on the PQA’s Use of High-Risk Medications in the Elderly performance measure, a safety measure used by the Centers for Medicare and Medicaid Services (CMS) for Medicare plans (Ref).

International issues:

Benadryl brand name for diphenhydramine [US, Canada], but also the brand name for cetirizine [Great Britain, Philippines] and acrivastine and pseudoephedrine [Great Britain]

Sominex brand name for diphenhydramine [US, Canada], but also the brand name for promethazine [Great Britain]; valerian [Chile]

Adverse Reactions (Significant): Considerations
Anticholinergic (antimuscarinic) effects

Diphenhydramine may cause reversible, dose-dependent effects including blurred vision; xerostomia; urinary retention; impotence; tachycardia; gastrointestinal effects (eg, nausea, constipation); and CNS effects (eg, agitation, confusion, cognitive dysfunction, delirium) (Ref).

Mechanism: Dose-related; an extension of antimuscarinic pharmacological properties (Ref).

Risk factors:

• Older patients (Ref)

CNS effects

Diphenhydramine may cause CNS depression, including daytime drowsiness, sedated state, fatigue, lack of concentration, and memory impairment (Ref). Use has been linked to accidental injury and fatalities due to car, plane, and boating accidents (Ref). May cause paradoxical stimulatory CNS effects including irritability, paradoxical excitation, and insomnia, especially in young children (Ref). In overdose, infants and children often exhibit initial paradoxical CNS stimulation, including convulsions, before progressing to coma (Ref). In adults, CNS depression reactions, including drowsiness and coma, are most often observed in overdose situations (Ref).

Mechanism: Dose-related; crosses blood-brain barrier and blocks the neurotransmitter effect of histamine at H1-receptors in CNS, leading to significant CNS depression and toxicity (Ref).

Onset: May occur after 1 dose. Bedtime dosing may lead to hang-over effects the following morning (Ref). Conflicting evidence whether tolerance to sedation or psychomotor impairment occurs (Ref).

Risk factors:

• Females (Ref)

• Older patients (Ref)

• Preexisting CNS disorder (Ref)

• Patients with small body mass (Ref)

• Kidney or hepatic impairment (Ref)

• Concurrent alcohol or CNS sedative (eg, benzodiazepine) (Ref)

• CYP2D6 ultrarapid metabolizer (may increase risk of paradoxical excitation) (Ref)

• Neonates and premature infants (use is contraindicated)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

Frequency not defined:

Cardiovascular: Chest tightness, extrasystoles, hypotension, palpitations, tachycardia (Ochs 2012)

Dermatologic: Diaphoresis, skin photosensitivity (Yamada 1998), skin rash, urticaria

Gastrointestinal: Anorexia, constipation, diarrhea, dry mucous membranes (Ochs 2012), epigastric discomfort, nausea, vomiting, xerostomia (Ochs 2012)

Genitourinary: Difficulty in micturition, early menses, urinary frequency, urinary retention (Shimizu 2011)

Hematologic & oncologic: Agranulocytosis, hemolytic anemia, thrombocytopenia

Hypersensitivity: Anaphylactic shock (Mur Gimeno 2011)

Nervous system: Ataxia, chills, confusion (Church 2010), dizziness, drowsiness (Church 2010), euphoria, fatigue (Church 2010), headache, irritability (Simons 2007), nervousness (Simons 2007), neuritis, paradoxical excitation (Church 2010), paresthesia, restlessness, sedated state (Church 2010), seizure (Church 2010), vertigo

Neuromuscular & skeletal: Tremor (Etzel 1994)

Ophthalmic: Blurred vision, diplopia

Otic: Acute labyrinthitis, tinnitus

Respiratory: Nasal congestion, pharyngeal edema, thickening of bronchial secretions, wheezing

Postmarketing:

Nervous system: Agitation (Church 2010; Ochs 2012), cognitive dysfunction (Church 2010), delirium (Ochs 2012), drug abuse (Thomas 2009), hallucination (Church 2010), insomnia (Simons 2007), lack of concentration (Church 2010), memory impairment (Church 2010)

Miscellaneous: Accidental injury (Fein 2019)

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)

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.

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.

Warnings: Additional Pediatric Considerations

Safety and efficacy for the use of cough and cold products in pediatric patients <4 years of age is limited; the AAP warns against the use of these products for respiratory illnesses in young children. Serious adverse effects, including death, have been reported. Many of these products contain multiple active ingredients, increasing the risk of accidental overdose when used with other products. The FDA does not recommend OTC uses for these products in pediatric patients <2 years of age and recommends to use with caution in pediatric patients ≥2 years of age. Health care providers are reminded to ask caregivers about the use of OTC cough and cold products in order to avoid exposure to multiple medications containing the same ingredient (AAP 2018; CDC 2007; FDA 2017; FDA 2018). Toxicity (overdosage) in pediatric patients can result in hallucinations, convulsions, or death. Neonates and infants are highly sensitive to depressive effects of diphenhydramine; use is contraindicated in neonates (premature and term); use with extreme caution in infants and young children.

Some dosage forms may contain propylene glycol; in neonates large amounts of propylene glycol delivered orally, intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities which can include metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults including hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Shehab 2009).

Metabolism/Transport Effects

Substrate of CYP1A2 (minor), CYP2C19 (minor), CYP2C9 (minor), CYP2D6 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP2D6 (weak)

Drug Interactions

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

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

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

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

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

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

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

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

Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: 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. Risk D: Consider therapy modification

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

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification

Botulinum Toxin-Containing Products: May enhance the anticholinergic effect of Anticholinergic Agents. Risk C: Monitor therapy

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy

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

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

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: 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 at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification

Cannabinoid-Containing Products: Anticholinergic Agents may enhance the tachycardic effect of Cannabinoid-Containing Products. Risk C: Monitor therapy

Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy

Chloral Betaine: May enhance the adverse/toxic effect of Anticholinergic Agents. Risk C: 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. Risk D: Consider therapy modification

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

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

CloZAPine: Anticholinergic Agents may enhance the constipating effect of CloZAPine. Management: Consider alternatives to this combination whenever possible. If combined, monitor closely for signs and symptoms of gastrointestinal hypomotility and consider prophylactic laxative treatment. Risk D: Consider therapy modification

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

COVID-19 Vaccine (Adenovirus Vector): Antihistamines may enhance the adverse/toxic effect of COVID-19 Vaccine (Adenovirus Vector). Specifically, the prophylactic use of antihistamines may mask symptoms and delay diagnosis and management of anaphylaxis. Management: Do not administer antihistamines to COVID-19 adenovirus vector vaccine recipients prior to vaccination to prevent allergic reactions. Use may mask cutaneous symptoms, which could lead to a delay in the diagnosis and management of anaphylaxis. Risk D: Consider therapy modification

COVID-19 Vaccine (mRNA): Antihistamines may enhance the adverse/toxic effect of COVID-19 Vaccine (mRNA). Specifically, the prophylactic use of antihistamines may mask symptoms and delay diagnosis and management of anaphylaxis. Management: Do not administer antihistamines to COVID-19 mRNA vaccine recipients prior to vaccination to prevent allergic reactions. Use may mask cutaneous symptoms, which could lead to a delay in the diagnosis and management of anaphylaxis. Risk D: Consider therapy modification

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

Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

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

Disulfiram: May enhance the adverse/toxic effect of Products Containing Ethanol. Management: Do not use disulfiram with dosage forms that contain ethanol. Risk X: Avoid combination

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. Risk C: Monitor therapy

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

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

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification

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

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

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

Glycopyrronium (Topical): May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination

Hyaluronidase: Antihistamines may diminish the therapeutic effect of Hyaluronidase. Risk C: Monitor therapy

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

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

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

Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification

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

Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

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

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

Methotrimeprazine: Products Containing Ethanol may enhance the adverse/toxic effect of Methotrimeprazine. Specifically, CNS depressant effects may be increased. Management: Avoid products containing alcohol in patients treated with methotrimeprazine. Risk X: Avoid combination

Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

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

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

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

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

Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists 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. Risk D: Consider therapy modification

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

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

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

Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification

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. Risk D: Consider therapy modification

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

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

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

Pitolisant: Antihistamines may diminish the therapeutic effect of Pitolisant. Risk X: Avoid combination

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. Risk X: Avoid combination

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

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

Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Risk X: Avoid combination

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

Revefenacin: Anticholinergic Agents may enhance the anticholinergic effect of Revefenacin. Risk X: Avoid combination

Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification

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

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

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

Secnidazole: Products Containing Ethanol may enhance the adverse/toxic effect of Secnidazole. Risk X: Avoid combination

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. Risk D: 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. Risk D: Consider therapy modification

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

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

Thioridazine: CYP2D6 Inhibitors (Weak) may increase the serum concentration of Thioridazine. Management: Consider avoiding concomitant use of thioridazine and weak CYP2D6 inhibitors. If combined, monitor closely for QTc interval prolongation and arrhythmias. Some weak CYP2D6 inhibitors list use with thioridazine as a contraindication. Risk D: Consider therapy modification

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

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

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

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

Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

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. Risk D: Consider therapy modification

Pregnancy Considerations

Diphenhydramine crosses the placenta (Miller 2000; Parkin 1974).

Maternal use of diphenhydramine has generally not resulted in an increased risk of birth defects (Anderka 2012; Aselton 1985; Etwel 2017; Gilboa 2009; Heinonen 1977; Jick 1981; Li 2013; Saxen 1974). Fetal tachycardia, respiratory depression, and possible withdrawal symptoms (diarrhea, tremors) have been observed in case reports (Abernathy 2017; Miller 2000; Parkin 1974). Diphenhydramine may have an oxytocic effect following maternal overdose (Brost 1996; Shenai 2018).

Antihistamines may be used for the treatment of rhinitis, urticaria, and pruritus in pregnant patients. Although second-generation antihistamines may be preferred, diphenhydramine may be used when a first-generation antihistamine is needed during pregnancy. The lowest effective dose should be used (Dykewicz 2020; Murase 2014; Zuberbier 2018).

Diphenhydramine may be used as adjunctive therapy in the management of nausea and vomiting of pregnancy when the preferred agents do not provide initial symptom improvement (ACOG 2018).

Some OTC products contain alcohol; use of alternative formulations in pregnancy is preferred.

Breastfeeding Considerations

Diphenhydramine is present in breast milk (Rindi 1951).

Drowsiness and irritability have been reported in breastfed infants exposed to antihistamines; of these effects, drowsiness was reported in infants exposed to diphenhydramine (Ito 1993). The manufacturer warns that premature infants and newborns have a higher risk of intolerance to antihistamines. In general, if a breastfed infant is exposed to a first-generation antihistamine via breast milk, they should be monitored for irritability or drowsiness (Butler 2014).

Breastfeeding is contraindicated by the manufacturer. When treatment with an antihistamine is needed in breastfeeding women, second-generation antihistamines are preferred (Butler 2014; Zuberbier 2018).

Antihistamines may temporarily decrease maternal serum prolactin concentrations when administered prior to the establishment of lactation. This effect was observed following the injection of an antihistamine to women on their first postpartum day prior to the initiation of breastfeeding (Messinis 1985).

Dietary Considerations

Some products may contain sodium and/or phenylalanine.

Monitoring Parameters

Relief of symptoms, mental alertness

Mechanism of Action

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

Pharmacokinetics

Duration:

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

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

Distribution: Vd: 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)

Protein binding: 98.5% (Vozeh 1988)

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)

Bioavailability: 42% to 62% (Paton 1985)

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)

Time to peak, serum: ~2 hours (Blyden 1986; Simons 1990)

Excretion: Urine (as metabolites; <4% unchanged drug) (Albert 1975; Maurer 1988)

Pricing: US

Capsules (Banophen Oral)

25 mg (per each): $0.02

50 mg (per each): $0.02

Capsules (diphenhydrAMINE HCl Oral)

25 mg (per each): $0.02 - $0.10

50 mg (per each): $0.02 - $0.09

Chewable (Benadryl Allergy Childrens Oral)

12.5 mg (per each): $0.27

Chewable (diphenhydrAMINE HCl Oral)

12.5 mg (per each): $12.35

Elixir (diphenhydrAMINE HCl Oral)

12.5 mg/5 mL (per mL): $0.18 - $0.38

Liquid (Benadryl Allergy Childrens Oral)

12.5 mg/5 mL (per mL): $0.05

Liquid (diphenhydrAMINE HCl Oral)

6.25 mg/mL (per mL): $2.25

12.5 mg/5 mL (per mL): $0.30 - $0.51

Liquid (Naramin Oral)

12.5 mg/5 mL (per mL): $0.25

Liquid (Total Allergy Medicine Oral)

12.5 mg/5 mL (per mL): $0.03

Liquid (ZzzQuil Oral)

50 mg/30 mL (per mL): $0.02

Solution (diphenhydrAMINE HCl Injection)

50 mg/mL (per mL): $0.98 - $6.00

Tablets (Banophen Oral)

25 mg (per each): $0.08

Tablets (Benadryl Allergy Oral)

25 mg (per each): $0.11

Tablets (Benadryl Allergy Ultratabs Oral)

25 mg (per each): $0.28

Tablets (diphenhydrAMINE HCl Oral)

25 mg (per each): $0.02 - $0.06

Tablets (Simply Sleep Oral)

25 mg (per each): $0.12

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Aliserin (IT);
  • Allermin (JP);
  • Amydramine (KW);
  • Amydramine-II (AE, QA);
  • Amydramkine-II (SA);
  • Azaron (BE);
  • Beanamine (SG);
  • Belarmin (TR);
  • Belarmin Expectorant (BH);
  • Bena (HK);
  • Benadrex (PH);
  • Benadryl (AR, CO, ES, GR, IN, MY, PH, PK, TH, VE, VN);
  • Benadryl A (UY);
  • Benadryl Allergy (PE);
  • Benadryl for the Family Original (AU);
  • Benamine (TW);
  • Bendol (HK);
  • Benocten (AE, CH);
  • Benylan (DK);
  • Bexil (PH);
  • Butix (FR);
  • Calmaben (AT, BG);
  • Cerylana (VE);
  • Danzamin (KR);
  • Desentol (SE);
  • DiBendryl (TH);
  • Dibrondrin (AT);
  • Didra (BD);
  • Didryl (BD);
  • Difenidrin (BR);
  • Dormutil (DE);
  • Dramylin (QA);
  • Exylin (BH, KW, QA);
  • Histergan (BF, BJ, CI, CY, ET, GH, GM, GN, IQ, IR, JO, KE, LR, LY, MA, ML, MR, MU, MW, NE, NG, OM, SC, SD, SL, SN, SY, TN, TZ, UG, YE, ZM, ZW);
  • Hydramine (TW);
  • Hydrazol (PH);
  • Hyphen (PH);
  • Menna (TW);
  • Nardyl (DE);
  • Otede (ID);
  • Pediphen (BD);
  • Phenadryl (BD);
  • Phenycof (LK);
  • Psilo Balsam (CZ, RU);
  • R Calm (BE);
  • Rabaphen (PH);
  • Recodryl (ID);
  • Resmin (JP);
  • Rivedramine (JO);
  • Rosmylin Expectorant (LB);
  • Sleepeze-PM (ZA);
  • Snuzaid (AU);
  • Somol (CL);
  • Soniphen (PH);
  • Sonodor (ES);
  • Stopkof P (BH);
  • Sultan (EG);
  • Unisom Sleepgels (AU, NZ);
  • Valdres (ID);
  • Vena (JP);
  • Venapas Oint (TW);
  • Venasmin (JP);
  • Vertirosan (AT);
  • Vivinox (DE)


For country abbreviations used in Lexicomp (show table)

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