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Doxepin (Sinequan)

TCA • Last reviewed 2025-09-27

General information

Doxepin is a tertiary amine TCA indicated for depression and anxiety disorders; low-dose formulations (Silenor) treat insomnia via strong antihistamine action.

It has among the most potent H1 antagonism of TCAs, leading to pronounced sedation and weight gain.

Therapeutic drug monitoring (target combined doxepin + nordoxepin 150–250 ng/mL) optimizes efficacy and safety.

Potent anticholinergic effects can precipitate urinary retention, blurred vision, and worsening narrow-angle glaucoma; monitor high-risk patients closely.

Dosing & administration

Depression/anxiety: start 25–50 mg nightly; increase by 25–50 mg every few days to 75–300 mg/day (divided or bedtime).

Insomnia: 3–6 mg taken 30 minutes before bedtime (do not exceed 6 mg).

Use lower doses in elderly or hepatic impairment.

Mechanism of action

Inhibits serotonin and norepinephrine reuptake while potently antagonizing histamine H1, muscarinic, and alpha-1 receptors.

Metabolism & pharmacokinetics

Peak concentrations 2–3 h post-dose. Metabolized hepatically via CYP2D6/CYP2C19 to nordoxepin. Half-life ~28–31 h (longer in elderly).

Drug interactions

Avoid MAOIs; allow 14-day washouts.

CYP2D6 inhibitors (fluoxetine, paroxetine, quinidine) elevate levels; enzyme inducers reduce efficacy.

Additive sedation with alcohol, benzodiazepines, antihistamines.

Monitoring & safety checks

Discontinuation guidance

Taper gradually over ≥4 weeks to minimize insomnia, nausea, and cholinergic rebound.

References

  1. Doxepin Prescribing Information — DailyMed
  2. CANMAT guidance on tertiary amine TCAs (2024)
  3. Silenor (doxepin) insomnia label — DailyMed (2023)

Educational use only — verify details in current prescribing information and authoritative clinical guidelines before making prescribing decisions.