What are the uses and dosages of DOXEPIN (doxepin hydrochloride)?

Doxepin (Doxepin Hydrochloride): Clinical Uses and Dosing

Primary Indication: Sleep Maintenance Insomnia

Doxepin at low doses (3-6 mg) is specifically recommended for treating sleep maintenance insomnia in adults, with demonstrated efficacy in reducing wake after sleep onset (WASO), increasing total sleep time (TST), and improving sleep efficiency (SE). 1

Mechanism of Action

• At low doses (1-6 mg), doxepin functions as a highly selective histamine H1 receptor antagonist, which is distinct from its antidepressant mechanism at higher doses 2, 3, 4
• This selective H1 antagonism specifically targets sleep maintenance rather than sleep initiation, given histamine's role in the sleep-wake cycle 2

Dosing for Insomnia

Recommended Doses

• Starting dose: 3 mg nightly at bedtime 1
• Alternative dose: 6 mg nightly for patients requiring additional benefit 1
• Lower dose: 1 mg may be considered in elderly or frail patients 5

Efficacy Data by Dose

• 3 mg dose: Produces clinically significant improvements in WASO (exceeds clinical threshold), TST (exceeds threshold on both objective and subjective measures), and SE (exceeds threshold), with moderate improvement in sleep quality 1
• 6 mg dose: Shows similar improvements in WASO and TST on objective measures, with mild improvement in sleep quality and mild increase in somnolence as the primary side effect 1
• Both doses show minimal improvement in sleep latency (below clinical significance threshold), confirming this is primarily a sleep maintenance agent 1

Duration of Efficacy

• Sustained efficacy demonstrated for up to 12 weeks in elderly patients with no evidence of tolerance, rebound insomnia, or discontinuation symptoms 5
• The longest placebo-controlled polysomnographic trial in elderly insomnia patients supports sustained benefit without next-day residual sedation 5

Alternative Indication: Depression and Anxiety Disorders

Higher-Dose Antidepressant Use

• Depression/anxiety dosing: 75-150 mg daily for mild to moderate illness 6
• Severe depression: May require up to 300 mg daily (doses above 300 mg rarely provide additional benefit) 6
• Mild symptoms: 25-50 mg daily may suffice 6
• Maximum single daily dose: 150 mg at bedtime (the 150 mg capsule is for maintenance only, not treatment initiation) 6

Specific Indications at Antidepressant Doses

• Psychoneurotic patients with depression and/or anxiety 6
• Depression/anxiety associated with alcoholism (not to be taken concomitantly with alcohol) 6
• Depression/anxiety associated with organic disease 6
• Psychotic depressive disorders with associated anxiety, including involutional depression and manic-depressive disorders 6

Time to Effect

• Anti-anxiety effect appears before antidepressant effect 6
• Optimal antidepressant effect may not be evident for 2-3 weeks 6

Off-Label Use: Agitation in Alzheimer's Disease

• Dosing for agitation: Initial 25 mg daily, maximum 200 mg twice daily 1
• Classified as a mood-stabilizing (antiagitation) drug in this context 1
• More sedating than other options; clinicians should be aware of transient orthostatic hypotension 1

Safety Profile and Adverse Effects

Low-Dose (3-6 mg) Safety

• Most common adverse effects: headache, diarrhea, somnolence (mild increase at 6 mg), and upper respiratory infection 1
• No evidence of: next-day residual sedation, memory impairment, complex sleep behaviors, anticholinergic effects, weight gain, or increased appetite at low doses 5
• No tolerance, rebound insomnia, or withdrawal symptoms in trials up to 3 months 3, 5

Higher-Dose (Antidepressant) Safety Concerns

• Anticholinergic effects: Dry mouth, blurred vision, constipation, urinary retention 6
• CNS effects: Drowsiness (most common), confusion, disorientation, hallucinations, seizures, extrapyramidal symptoms 6
• Cardiovascular: Hypotension, hypertension, tachycardia, QTc prolongation 1, 6
• Hematologic: Rare bone marrow depression (agranulocytosis, leukopenia, thrombocytopenia) 6

Black Box Warning

• Increased suicidality risk in children, adolescents, and young adults (ages 18-24) with major depressive disorder 6
• All patients on antidepressant doses require close monitoring for clinical worsening, suicidality, or unusual behavioral changes, especially during initial treatment months or dose changes 6
• Not approved for pediatric use 6

Special Populations

Elderly Patients

• Preferred for elderly insomnia patients due to specific efficacy for sleep maintenance and early morning awakenings, which are primary complaints in this population 5
• Start with lower doses (1-3 mg for insomnia; reduce antidepressant doses) and observe closely for confusion and oversedation 6
• Elderly patients are more sensitive to sedative effects of all doses 7

Hepatic Impairment

• Use with caution; reduce doses in patients with hepatic impairment 1
• All benzodiazepines and tricyclics have reduced clearance in hepatic dysfunction, though doxepin's specific metabolism is not fully characterized 7

Renal Impairment

• Extent of renal excretion not fully determined; use caution in dose selection for elderly patients with likely decreased renal function 6

Pregnancy and Nursing

• Avoid in pregnancy and nursing 8
• Report of apnea and drowsiness in nursing infant whose mother was taking doxepin 6

Critical Contraindications

Absolute Contraindications

• Hypersensitivity to doxepin or cross-sensitivity with other dibenzoxepines 6
• Glaucoma (particularly angle-closure risk) 6
• Urinary retention tendency 6

Angle-Closure Glaucoma Risk

• Pupillary dilation from doxepin may trigger angle-closure attack in patients with anatomically narrow angles without patent iridectomy 6
• Patients should be screened for susceptibility and consider prophylactic iridectomy if at risk 6

Drug Interactions

Antihypertensive Interactions

• At doses ≤150 mg daily, doxepin does not block antihypertensive effects of guanethidine and related compounds 6
• At doses >150 mg daily, blocking of antihypertensive effect has been reported 6

CYP450 Interactions

• Doxepin is metabolized by cytochrome P450 2D6 6
• Poor metabolizers (7-10% of Caucasians) may have significantly higher plasma concentrations (up to 8-fold increase) 6

Sedative Combinations

• Caution with concurrent sedating medications due to additive effects 8
• Fatalities reported with concurrent high-dose olanzapine and benzodiazepines 1

Clinical Decision Algorithm for Insomnia

First-Line Treatment

• Cognitive Behavioral Therapy for Insomnia (CBT-I) should be offered initially 1, 8

Second-Line Pharmacologic Options

• For sleep onset and maintenance: Eszopiclone 2-3 mg, zolpidem 10 mg, temazepam 15 mg 8
• For sleep onset only: Zaleplon 10 mg, ramelteon 8 mg, triazolam 0.25 mg 8
• For sleep maintenance only: Suvorexant or doxepin 3-6 mg 1, 8

When to Choose Doxepin

• Primary indication: Sleep maintenance insomnia (difficulty staying asleep, early morning awakenings) rather than sleep onset problems 1, 2
• Elderly patients: Particularly appropriate given efficacy profile and safety in this population 5
• Comorbid anxiety: May provide dual benefit when combined with appropriate antidepressant therapy for depression 9

Common Pitfalls to Avoid

• Do not use antidepressant doses (25-300 mg) for insomnia treatment - only 3-6 mg doses are appropriate for sleep disorders 1
• Do not use as first-line for sleep onset insomnia - minimal effect on sleep latency; better options exist for this complaint 1
• Do not combine with other sedating medications without extreme caution due to additive respiratory depression and oversedation risk 1, 8
• Do not prescribe without screening for angle-closure glaucoma risk in susceptible patients 6
• Do not use in children under 12 years - safety not established 6
• Do not abruptly discontinue after prolonged use at antidepressant doses - taper gradually to avoid withdrawal symptoms 6