Doxepin for Major Depression, Insomnia, and Itching

Doxepin is a medication available in oral capsules, tablets, topical cream, and oral solution forms. It is primarily used to treat major depressive disorder in adults, insomnia related to sleep maintenance, and moderate itching associated with certain skin conditions. The drug acts as a tricyclic antidepressant and has additional antihistamine effects when applied topically.

Approved Uses of Doxepin:

• Major Depressive Disorder (MDD) in Adults: Oral capsules and oral solution are indicated for treating MDD.
• Insomnia with Difficulty Maintaining Sleep: Oral tablets (3 mg and 6 mg) are indicated for short-term treatment of insomnia to help maintain sleep, with clinical trials up to 3 months.
• Moderate Pruritus from Atopic Dermatitis or Lichen Simplex Chronicus: Topical 5% cream is approved for short-term use up to 8 days in adults.

Doxepin hydrochloride

Doxepin works as a tricyclic antidepressant by affecting neurotransmitters in the brain to improve mood in depression. Topically, it blocks the H1 and H2 histamine receptors, which helps reduce itching, though the exact mechanism for its antipruritic effect is not fully understood.

Oral Capsules and Oral Solution (Major Depressive Disorder):

• Start with 25 mg three times daily or 75 mg once daily, orally.
• Target total dose is 75 mg to 150 mg daily, given once daily or divided doses.
• Maximum dose is 100 mg three times daily.
• Screen for bipolar disorder before initiating treatment.
• Wait at least 14 days after stopping monoamine oxidase inhibitors (MAOIs) before starting doxepin, and vice versa.
• Reduce dose if anticholinergic side effects develop or when used with strong CYP2D6 inhibitors or in poor CYP2D6/CYP2C19 metabolizers.
• Gradually taper dosage when discontinuing.

Oral Tablets (Insomnia):

• Adults: 6 mg once daily within 30 minutes of bedtime.
• Elderly (≥65 years): Start at 3 mg once daily, increase to 6 mg if needed.
• Do not exceed a total daily dose of 6 mg.
• Avoid taking within 3 hours of a meal to reduce next-day sedation.

Topical Cream (Moderate Pruritus):

• Apply a thin layer four times daily with at least 3 to 4 hours between applications.
• Do not use for more than 8 days.
• Avoid occlusive dressings.
• Patients with body surface area involvement over 10% should be cautioned about sedation risks and monitored carefully.

• Hypersensitivity to doxepin or related dibenzoxepine compounds (possible cross sensitivity)
• Concurrent or recent (within 14 days) use of monoamine oxidase inhibitors (MAOIs), including linezolid or intravenous methylene blue
• Untreated narrow-angle glaucoma
• Current or past urinary retention

Key Warnings and Precautions:

• Suicidal Thoughts and Behaviors: Antidepressants, including doxepin, increase risk of suicidal thoughts in children, adolescents, and young adults during short-term use. Close monitoring is essential, especially at therapy start and dosage changes. Doxepin capsules and oral solution are not approved for pediatric use.
• Serotonin Syndrome: Risk increases with concomitant serotonergic drugs. Monitor for symptoms such as confusion, agitation, tremor, hyperreflexia, and autonomic instability. Discontinue doxepin and other serotonergic agents immediately if syndrome occurs.
• Contraindicated with MAOIs: Doxepin must not be used concurrently with monoamine oxidase inhibitors or within 14 days of stopping them.
• Glaucoma and Urinary Retention: Contraindicated in patients with narrow-angle glaucoma or a history of urinary retention due to anticholinergic effects.
• Sedation and Impaired Driving: Doxepin may cause drowsiness; patients should avoid driving or operating machinery while under treatment, and alcohol may increase sedation.
• Mania or Hypomania Activation: Screen for bipolar disorder before prescribing; doxepin is not approved for bipolar depression.
• Seizure Risk: Use caution in patients with a seizure history, as doxepin may lower the seizure threshold.
• Complex Behaviors (Sleep-driving, etc.): Report and evaluate any unusual behaviors while taking doxepin, especially for insomnia treatment.

Common Side Effects (≥5% incidence):

• Somnolence (sleepiness)
• Dry mouth
• Dizziness
• Constipation
• Fatigue

Additional Adverse Reactions:

• Blurred vision, tachycardia, hypotension, insomnia, tremor, nausea, hyperhidrosis, weight gain
• Local irritation and burning/stinging with topical cream application
• Drowsiness with topical cream, more common if >10% body surface area is treated
• Rarely, allergic reactions, blood disorders, cardiac arrhythmias, psychosis, seizures, serotonin syndrome

• MAO Inhibitors: Contraindicated due to risk of serotonin syndrome.
• Other Serotonergic Agents: Increased risk of serotonin syndrome.
• Strong CYP2D6 Inhibitors: Increase doxepin levels; dosage adjustment may be necessary.
• Cimetidine: Increases doxepin exposure; reduce dose to 3 mg if co-administered with insomnia tablets.
• Alcohol, CNS Depressants, Sedating Antihistamines: Potentiate sedation; avoid alcohol.
• Tolazamide: Seen association with severe hypoglycemia when combined with doxepin.

Pregnancy:

No adequate, well-controlled studies in pregnant women; use only if clearly needed. Animal studies showed no fetal harm at relevant dose levels.

Lactation:

Doxepin is excreted in human milk after oral administration. Use with caution during breastfeeding. One reported case of apnea and drowsiness in a nursing infant.