Section 10 · Monograph

Doxepin (low-dose)

Reviewed Nov 2026FDA label

SilenorTCA (low-dose H1 antagonist)

Indications

Insomnia characterized by difficulty with sleep maintenance (frequent or prolonged nighttime awakenings) in adults — FDA-approved indication for Silenor (doxepin) 3 mg and 6 mg tablets.FDA-labeled

Off-label use of low-dose doxepin at strengths other than the FDA-approved 3 mg/6 mg tablets (e.g., compounded/repackaged 10 mg or 25 mg capsules) for insomnia predates the Silenor approval and persists in practice, particularly in older adults.Off-label
Note for clarity: doxepin at substantially higher oral doses (75-300 mg/day) is a separate FDA-approved indication as a tricyclic antidepressant (TCA) for major depressive disorder and anxiety disorders — the FDA label notes doxepin acts as an antidepressant at '10- to 100-fold higher' doses than the insomnia dose, reflecting a distinct pharmacologic and risk profile not seen at the 3-6 mg insomnia dose. This monograph addresses the low-dose insomnia (Silenor) use only.Off-label
A separate topical doxepin 5% cream (Zonalon) is FDA-approved for pruritus and is a distinct product/indication, not covered here.Off-label

At the low 3-6 mg insomnia doses, doxepin acts primarily as a highly potent and selective histamine H1-receptor antagonist (Ki <1 nM); the sleep-maintenance effect could be mediated through antagonism of the H1 receptor.
At these low doses, clinically significant activity at muscarinic (anticholinergic), alpha-adrenergic, and serotonin/norepinephrine reuptake sites — responsible for doxepin's antidepressant effect and much of its TCA side-effect burden at 75-300 mg — is largely absent.
Unlike benzodiazepine and 'Z-drug' hypnotics, doxepin at insomnia doses is not a federally controlled substance.

Adults <65 years: initiate at 6 mg once daily; 3 mg may be appropriate for some patients.
Elderly (≥65 years): initiate at 3 mg once daily; may increase to 6 mg if clinically indicated and tolerated.
Maximum dose: 6 mg once daily — this ceiling applies regardless of age.
Administration: take within 30 minutes of bedtime; do not take within 3 hours of a meal.
Do not take more than once per night; only use when a full night's sleep (≥7-8 hours) is possible.
If coadministered with cimetidine (doubles doxepin exposure), limit the maximum dose to 3 mg/day.
If insomnia fails to improve, reassess the patient after 7-10 days.
This 3 mg/6 mg dosing paradigm is entirely distinct from — and far lower than — the 75-300 mg/day range used when doxepin is prescribed as a TCA antidepressant.

Hypersensitivity to doxepin or other dibenzoxepines.
Concomitant use of monoamine oxidase inhibitors (MAOIs), or use within 14 days of MAOI discontinuation.
Untreated narrow-angle glaucoma.
Severe urinary retention.

MAOIs: contraindicated; avoid within 14 days of MAOI use in either direction.
Cimetidine: doubles doxepin plasma exposure — limit maximum dose to 3 mg/day when coadministered.
Alcohol: potentiates sedative/psychomotor effects and increases risk of complex sleep behaviors; avoid entirely.
Other CNS depressants and sedating antihistamines: additive sedation and impairment risk.
Tolazamide: a case report describes severe hypoglycemia with concomitant use.

Somnolence/sedation — most common adverse reaction.
Nausea.
Upper respiratory tract infection.
Complex sleep behaviors, including sleep-driving, sleep-walking, and preparing/eating food while not fully awake, with or without amnesia; risk increases with alcohol or other CNS depressants.
Worsening depression or emergence/worsening of suicidal ideation.
Anticholinergic effects (dry mouth, constipation, blurred vision) are far less prominent than at antidepressant doses but not entirely absent, particularly if the 6 mg dose is exceeded or cimetidine is coadministered without dose reduction.
Fewer than 1% of patients discontinued treatment due to adverse events in clinical trials.

Reassess the need for continued therapy if insomnia does not improve within 7-10 days.
Screen for and avoid use in patients with severe, untreated obstructive sleep apnea.
Ask about alcohol use before initiating and periodically during treatment.
Monitor for emergence of complex sleep behaviors, next-day sedation/psychomotor impairment, and mood/suicidality changes.
Confirm the dose being prescribed/dispensed corresponds to the 3 mg/6 mg insomnia formulation rather than a higher-strength antidepressant-dose doxepin product.

Pregnancy: limited human data. Third-trimester exposure has been associated with poor neonatal adaptation syndrome. Animal reproduction studies showed developmental toxicity at doses far exceeding the maximum recommended human insomnia dose.
Lactation: breastfeeding is not recommended during Silenor treatment. Doxepin and its active metabolite are present in breast milk, with case reports of excessive infant sedation and respiratory depression.