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Doxepin (Topical) (Monograph)

Brand names: Prudoxin, Zonalon
Drug class: Antipruritics and Local Anesthetics
ATC class: N06AA12
VA class: CN601
Chemical name: 3-Dibenz[b, e]oxepin-11(6H)ylidene-N, N-dimethyl-1-propanamine hydrochloride
Molecular formula: C19H21NO
CAS number: 1668-19-5

Medically reviewed by on Feb 13, 2023. Written by ASHP.


Antipruritic agent; dibenzoxepin-derivative tricyclic antidepressant compound with antihistaminic activity.

Uses for Doxepin (Topical)

Dermatologic Conditions

Used for short-term (up to 8 days) relief of moderate pruritus associated with various forms of eczematous dermatitis, including atopic dermatitis and lichen simplex chronicus (circumscribed or localized neurodermatitis).

Doxepin (Topical) Dosage and Administration


Topical Administration

Apply topically to the skin as a 5% cream.

For external use only; should not be used near or in eyes, orally, or intravaginally.

Do not use with occlusive dressings (e.g., bandaged or otherwise covered or wrapped). (See Occlusive Dressings under Cautions.)


Available as doxepin hydrochloride; dosage expressed in terms of the salt.


Dermatologic Conditions

Apply a thin film to affected area(s) of the skin 4 times daily, with an interval of at least 3–4 hours between applications, for up to 8 days.

Prescribing Limits


Dermatologic Conditions

Safety and efficacy of >8 days of therapy not established.

Special Populations

Geriatric Patients

Select dosage with caution, generally start at low end of dosing range, due to possible age-related decrease in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Cautions for Doxepin (Topical)


  • Untreated narrow angle glaucoma.

  • Urinary retention.

  • Known sensitivity to doxepin or any ingredient in the formulation.



CNS Effects

Drowsiness reported in >20% of patients following topical application, especially when applied to >10% of body surface area.

Performance of activities requiring mental alertness and physical coordination may be impaired.

Concurrent use of other CNS depressants may cause additive or potentiated CNS depression. (See Specific Drugs under Interactions.)

If excessive drowsiness occurs, reduce number of daily applications, the amount of cream applied, and/or the percentage of body surface area treated, or discontinue the drug. Efficacy of cream with reduced frequency applications not established.

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions, including allergic contact dermatitis reported.

General Precautions

Occlusive Dressings

Possible increased absorption; avoid occlusive dressings.

Specific Populations


Category B.


Not known whether topical doxepin is distributed into milk, but systemic exposure may occur after topical administration. Distributed into milk following oral administration. Discontinue nursing or the drug.

Pediatric Use

Safety and efficacy of topical doxepin not established. Manufacturer does not recommend topical doxepin in pediatric patients.

Somnolence, grand mal seizure, respiratory depression, ECG abnormalities, and coma reported in a 2.5 year old pediatric patient following topical doxepin administration (27 grams) over 3 days.

Geriatric Use

Clinical studies did not include sufficient numbers of subjects ≥65 years of age to determine whether they respond differently from younger subjects.

May cause confusion and oversedation in geriatric patients; observe geriatric patients closely following doxepin cream administration.

Common Adverse Effects

Drowsiness, burning, dry mouth, dry lips, thirst.

Interactions for Doxepin (Topical)

No interactions identified to date when topical doxepin used concomitantly with other topical or systemic drugs. Because clinically relevant systemic absorption may occur following topical application, drug interactions between topical doxepin and systemically administered drugs may occur. (See Absorption under Pharmacokinetics.)

Metabolized in the liver by various CYP isoenzymes (e.g., CYP2D6, CYP1A2, CYP3A4).

Drugs Metabolized by Hepatic Microsomal Enzymes

Inhibitors and substrates of CYP2D6; potential pharmacokinetic interaction (increased plasma doxepin concentrations). Consider possible interactions related to TCA class of drugs.

Specific Drugs





May potentiate sedative effects

Use concomitantly with caution

Antiarrhythmics: class 1C (propafenone, flecainide); quinidine

Possible increased plasma doxepin concentrations

Monitor for TCA toxicity

Use concomitantly with caution; decreased doxepin dosage may be required

Antidepressants, tricyclics (TCAs)

May potentiate sedative effects

Use concomitantly with caution; may require lower doses and monitoring of TCA concentrations


May potentiate sedative effects


Possible increased plasma doxepin concentrations

Use concomitantly with caution


Possible increased plasma doxepin concentrations

Potential for tricyclic toxicity, particularly anticholinergic adverse effects

MAO inhibitors

Potentially life-threatening serotonin syndrome

Discontinue MAO inhibitor ≥2 weeks prior to cautious initiation of doxepin cream


Possible increased plasma doxepin concentrations

Use concomitantly with caution

SSRIs (e.g., fluoxetine, paroxetine, sertraline)

Possible increased plasma doxepin concentrations

Use with caution; monitor for TCA toxicity

Discontinue fluoxetine ≥5 weeks prior to initiating doxepin


Severe hypoglycemia reported in a diabetic patient receiving oral doxepin

Doxepin (Topical) Pharmacokinetics



Absorbed percutaneously into systemic circulation following topical application. Plasma concentrations following topical application may be similar to those occurring following oral administration.

Percutaneous penetration can be increased by use of occlusive dressings.


Following topical application, antipruritic effects may occur within 15 minutes.



Widely distributed in body tissues including lungs, heart, brain, and liver.

Not known whether topical doxepin is distributed into milk; distributed into milk following oral administration.



Extensively metabolized in the liver by various CYP isoenzymes (principally CYP2D6); undergoes demethylation to pharmacologically active metabolite, desmethyldoxepin.

Elimination Route

Excreted in urine following glucuronidation as unchanged drug and metabolites.


Half-life of desmethyldoxepin ranges from 28 to 52 hours and is not affected by multiple dosing.

Special Populations

Renal disease, genetic factors, age, and other medications may affect the metabolism and subsequent elimination of doxepin.







  • Exact mechanism of antipruritic activity is unknown; appears to exhibit potent histamine H1- and H2-receptor antagonist activity.

  • Sedative effect may contribute to antipruritic activity; however, antipruritic efficacy does not appear to depend on sedative effect.

Advice to Patients

  • Importance of using only as directed, only for the disorder for which it was prescribed, and for no longer than prescribed; avoid contact with the eyes and only apply externally as directed.

  • Importance of avoiding use of occlusive dressings.

  • Risk of drowsiness, especially if doxepin cream is applied to >10% of body surface area.

  • Importance of considering possible impaired ability to perform hazardous activities (e.g., operating hazardous machinery, driving a motor vehicle).

  • Inform patients that their response to alcohol may be increased.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

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


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

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

Doxepin Hydrochloride


Dosage Forms


Brand Names




5% (4.43% of doxepin)





AHFS DI Essentials™. © Copyright 2023, Selected Revisions February 23, 2015. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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