Doxepin
Doxepin is available in two distinct formulations: higher-dose capsules (Sinequan) for depression and anxiety, and low-dose tablets (Silenor) specifically for insomnia. The dual applications reflect its potent antihistaminergic properties at low doses and antidepressant effects at higher doses.
Clinical Overview
Primary Clinical Applications
High-dose doxepin (Sinequan) is indicated for depression and anxiety, particularly in patients with significant sleep disturbances. Low-dose doxepin (Silenor) is specifically indicated for sleep maintenance insomnia. The medication’s strong sedating properties make it valuable for patients with comorbid mood and sleep disorders.
Mechanism and Clinical Profile
Doxepin is a tricyclic antidepressant that blocks serotonin and norepinephrine reuptake at higher doses. At low doses (3-6 mg), it selectively antagonizes H1 histamine receptors, providing sedating effects for sleep without significant anticholinergic or cardiac effects.
Dosing Considerations
The two formulations have completely different dosing ranges and indications. High-dose doxepin requires gradual titration and monitoring for anticholinergic and cardiac effects, while low-dose doxepin for insomnia has minimal systemic effects and can be started at therapeutic doses.
Key Clinical Points
Two products with a fiftyfold dose difference
Sinequan at 75 to 300 mg treats depression and anxiety, while Silenor at 3 to 6 mg treats sleep maintenance insomnia. Confusing the two is a serious prescribing error in either direction.
Low doses are purely antihistaminergic
At 3 to 6 mg doxepin selectively blocks H1 receptors, giving hypnotic effect without meaningful anticholinergic or cardiac activity. The tricyclic risk profile belongs to the higher-dose formulation.
Silenor requires a seven-hour sleep window
Taken within thirty minutes of bedtime and at least seven hours before planned waking. Shorter windows produce next-day impairment affecting driving.
Alcohol is contraindicated with the sleep formulation
Complex sleep behaviours have been reported with hypnotics, and alcohol raises that risk. This is a firmer restriction than the general caution applying to the antidepressant formulation.
Boxed warning applies to the high-dose form
The antidepressant boxed warning for suicidal thinking in patients under 25 attaches to Sinequan. Contraindicated in untreated narrow-angle glaucoma, severe urinary retention, and within fourteen days of an MAOI.
Prescribing Information
Dosing & Administration
Depression/Anxiety (Sinequan) – Adults:
- Outpatients – Initial: 25 mg three times daily or 75 mg at bedtime
- Range: 75-150 mg daily
- Maximum: 300 mg daily for severe cases
- Elderly: 25-50 mg daily initially
Insomnia (Silenor) – Adults:
- Recommended dose: 6 mg once daily within 30 minutes of bedtime
- Elderly (≥65 years): 3 mg once daily
Administration:
- Depression: May divide doses or give at bedtime
- Insomnia: Take within 30 minutes of bedtime, 7+ hours before planned awakening
- Do not take with alcohol
Indications
- High-dose: Depression, anxiety (particularly with insomnia)
- Low-dose: Sleep maintenance insomnia
Contraindications
- Hypersensitivity to doxepin or tricyclic antidepressants
- Untreated narrow-angle glaucoma
- Severe urinary retention
- Use with MAOIs (within 14 days)
Warnings & Precautions
- Boxed Warning (High-dose): Increased risk of suicidal thoughts and behavior in patients under 25 years
- Anticholinergic effects: Particularly with high doses – dry mouth, constipation, urinary retention
- Cardiovascular effects: Monitor ECG in patients with cardiac disease (high doses)
- Next-day impairment: May affect driving ability (insomnia formulation)
- Complex sleep behaviors: Risk with sleep formulation
Drug Interactions
- MAOIs: Contraindicated – risk of serotonin syndrome
- CNS depressants: Enhanced sedation
- Anticholinergic drugs: Additive anticholinergic effects (high doses)
- CYP2D6 inhibitors: Increase doxepin levels
- Alcohol: Contraindicated with sleep formulation
Adverse Reactions
High-dose (Depression):
- Drowsiness, dry mouth, constipation, blurred vision
- Orthostatic hypotension, urinary retention
Low-dose (Insomnia):
- Somnolence, nausea, upper respiratory tract infection
Serious:
- Cardiac arrhythmias (high doses), severe anticholinergic toxicity
Special Populations
- Elderly: Increased sensitivity to anticholinergic effects, use lower doses
- Cardiac Disease: Monitor ECG with high doses
- Pregnancy: Category C – use only if benefits outweigh risks
- Hepatic Impairment: Use caution, may require dose reduction
Frequently Asked Questions
What is Doxepin used for?
Doxepin is available in two distinct formulations: higher-dose capsules (Sinequan) for depression and anxiety, and low-dose tablets (Silenor) specifically for insomnia. The dual applications reflect its potent antihistaminergic properties at low doses and antidepressant effects at higher doses.
What class of drug is Doxepin?
Doxepin is classified as: Tricyclic Antidepressant/Sedating Antihistamine.
Two products with a fiftyfold dose difference?
Sinequan at 75 to 300 mg treats depression and anxiety, while Silenor at 3 to 6 mg treats sleep maintenance insomnia. Confusing the two is a serious prescribing error in either direction.
Low doses are purely antihistaminergic?
At 3 to 6 mg doxepin selectively blocks H1 receptors, giving hypnotic effect without meaningful anticholinergic or cardiac activity. The tricyclic risk profile belongs to the higher-dose formulation.
Silenor requires a seven-hour sleep window?
Taken within thirty minutes of bedtime and at least seven hours before planned waking. Shorter windows produce next-day impairment affecting driving.
Alcohol is contraindicated with the sleep formulation?
Complex sleep behaviours have been reported with hypnotics, and alcohol raises that risk. This is a firmer restriction than the general caution applying to the antidepressant formulation.
Source: FDA prescribing information (DailyMed)