Doxepin

Doxepin is a tertiary-amine tricyclic antidepressant with the strongest histamine H1 blockade of any antidepressant. At antidepressant doses of 75 mg and over it is used for depression with anxiety; at 3 to 6 mg it is used for sleep maintenance insomnia; as a topical cream it is used for itch.

Classification. Tricyclic antidepressant, dibenzoxepine structure.

Mechanism. At low doses it is a highly selective H1 antagonist, which explains its hypnotic effect. At higher doses it also inhibits serotonin and noradrenaline reuptake and blocks muscarinic and alpha-1 receptors.

Pharmacokinetics. Well absorbed; extensive first-pass metabolism by CYP2D6 and CYP2C19 to nordoxepin (active). Half-life about 15 hours (nordoxepin about 31 hours). Food delays absorption of low-dose tablets.

All regimens are oral unless stated, with no loading dose.

Major depression with anxiety, adults.

• Start 25 to 75 mg daily, usually at night.
• Titration: increase by 25 mg every 3 to 7 days to a usual 75 to 150 mg daily.
• Maximum 150 mg daily as an outpatient; up to 300 mg daily in hospital under specialist care.
• Duration: at least 6 months after remission.

Sleep maintenance insomnia.

• Adults: 6 mg once daily within 30 minutes of bedtime; older adults 3 mg.
• Maximum 6 mg daily. Do not take within 3 hours of a meal.
• Review need at 2 to 4 weeks.

Pruritus (topical 5% cream, licensed in some regions). Apply a thin film up to 4 times daily, at least 3 to 4 hours apart, for no more than 8 days, and not over more than 10% of the body surface.

Contraindications. Narrow-angle glaucoma not treated, severe urinary retention, recent myocardial infarction, arrhythmias, heart block, mania, MAOI use now or within 14 days of stopping it, hypersensitivity.

Serious adverse effects. Boxed-warning-level risk of suicidal thinking and behaviour in under 25 years (antidepressant doses). Complex sleep behaviours (sleep-walking, sleep-driving) are reported; stop if they occur. Arrhythmia, QT and QRS prolongation, postural hypotension, seizures, urinary retention, delirium, hyponatraemia, mania. In overdose: coma, seizures, QRS over 100 ms and ventricular arrhythmia.

Common adverse effects. Sedation, dry mouth, constipation, blurred vision, weight gain, dizziness, headache, nausea.

Interactions. CYP2D6 and CYP2C19 inhibitors (fluoxetine, paroxetine, cimetidine, omeprazole) and ritonavir raise levels. Rifampicin and carbamazepine lower levels. Alcohol, opioids, benzodiazepines and other sedatives add to sedation. Cimetidine can double exposure.

Common prescribing errors. Using antidepressant doses for insomnia; applying large areas of topical cream; dispensing large quantities in patients at risk of self-harm.

Special groups.

• Pregnancy: use only if benefit outweighs risk.
• Breastfeeding: nordoxepin accumulates in the infant and sedation and respiratory depression are reported; avoid.
• Children: not advised in under 18 years.
• Older adults: use 3 mg for insomnia; avoid antidepressant doses where possible.
• Kidney impairment: no adjustment; start low.
• Liver impairment: use the 3 mg dose for insomnia; reduce antidepressant doses.

Formulations. Capsules 10 mg, 25 mg, 50 mg and 75 mg; tablets 3 mg and 6 mg for insomnia in some regions; 5% cream. Give antidepressant doses at night. No infusion form.

Baseline. ECG in patients over 40 years or with cardiac disease, lying and standing blood pressure, mood history including past mania, suicide risk, sodium in older adults, intraocular pressure risk, bladder symptoms, alcohol and sedative use.

Monitoring. Review within 1 to 2 weeks and after each dose change for suicidality and sedation. Repeat the ECG if the dose exceeds 100 mg daily or an interacting drug is added. Check sodium 2 to 4 weeks after starting in high-risk patients; review the need for the drug if sodium falls under 130 mmol/L and stop it if under 125 mmol/L or if symptomatic.

Stopping. Taper antidepressant doses over at least 4 weeks. Low-dose insomnia treatment can usually be stopped without tapering.

Referral and escalation. Refer to psychiatry for suicidal intent, psychosis, mania or failure of two adequate courses. Overdose, seizures, QRS over 100 ms or syncope needs emergency care.