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Tricyclic antidepressant / topical antipruritic Pregnancy: Avoid 3rd trimester (neonatal anticholinergic and discontinuation effects). Limited data earlier; prefer sertraline if SSRI possible.

Doxepin

Brand names: Sinequan (oral), Xepin (topical)

Adult dose

Dose: Depression / anxiety: 75 mg/day in 1–3 divided doses; titrate up to 300 mg/day if needed (typical 100–150 mg/day). Insomnia (low-dose, off-label): 3–6 mg ON. Topical for pruritus (Xepin 5% cream): apply BD–QDS for max 8 days.
Route: Oral / Topical
Frequency: Once daily (ON) or divided doses
Max: 300 mg/day oral
Low therapeutic index. Avoid in elderly where possible (anticholinergic burden, falls). Topical Xepin: do not exceed 8 days (systemic absorption with anticholinergic and CNS effects reported with chronic use).

Dose adjustments

Renal

Caution; reduce dose.

Hepatic

Reduce dose 50%; severe impairment — avoid.

Clinical pearls

  • Among the most sedating TCAs — useful for depression with severe insomnia or anxiety; prescribe at night.
  • Strong H1-antagonism gives significant sedative and weight-gain effects — many patients cannot tolerate the daytime hangover.
  • Lethal in overdose with even modest amounts (~2 g) — cardiotoxic; consider weekly supply for higher-risk patients.
  • Low-dose 3–6 mg (Silenor in US) is licensed for primary insomnia but rarely used in UK.
  • Topical Xepin 5% has powerful local antipruritic effect (atopic eczema, lichen simplex) but systemic absorption causes sedation and confusion in older patients — STRICT 8-day max.
  • Switching from another antidepressant: full SSRI/SNRI washout (especially fluoxetine — 5 weeks) before initiation.

Contraindications

  • Recent MI (within 3 months)
  • Heart block, pre-existing QT prolongation, arrhythmia
  • Mania
  • Severe hepatic impairment
  • Untreated narrow-angle glaucoma
  • Urinary retention, BPH (relative)
  • MAOI within 14 days
  • Breastfeeding (concentrated in breast milk)

Side effects

  • Anticholinergic: dry mouth, blurred vision, constipation, urinary retention, confusion (esp. elderly)
  • Sedation (very common — limits use to evening dosing)
  • Postural hypotension
  • Weight gain (dose-related)
  • Cardiac: QT prolongation, conduction delay, arrhythmia in overdose
  • Lower seizure threshold
  • Sexual dysfunction
  • Hepatotoxicity (rare)
  • Topical (Xepin): drowsiness from systemic absorption if used over large area or >8 days; local burning, stinging

Interactions

  • MAOIs: hypertensive crisis, serotonin syndrome — contraindicated within 14 days (and 5 weeks for fluoxetine)
  • Other CNS depressants (alcohol, opioids, benzodiazepines): additive sedation
  • QT-prolonging drugs (citalopram, quinolones, methadone): additive QT — avoid
  • CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion): markedly ↑ doxepin levels — caution
  • Other anticholinergics: additive toxicity
  • Sympathomimetics: ↑ pressor effect
  • Antiplatelets/anticoagulants: ↑ bleeding (TCAs may inhibit serotonin uptake by platelets)

Monitoring

  • BP and HR (postural)
  • ECG before initiation in patients ≥50 yr or cardiac risk
  • Weight
  • Mood, suicide risk especially first 4 weeks

Reference: BNF 90; SmPC Sinequan / Xepin; NICE NG222 (Depression in adults 2022); Maudsley Prescribing Guidelines 14th ed.. Verify against your local formulary and the latest BNF before prescribing.

Related

Curated clinical cross-links plus same-class fallbacks.

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