What are the adult dosing guidelines, contraindications, and monitoring recommendations for doxepin when used for depression, anxiety, insomnia, and chronic pruritus?

Doxepin: Adult Dosing, Contraindications, and Monitoring

Depression and Anxiety Dosing

For depression and anxiety disorders, start doxepin at 75 mg daily, with a usual therapeutic range of 75–150 mg daily; doses may be increased to 300 mg daily in severely ill patients, though additional benefit beyond 300 mg is rare. 1

• The 150 mg capsule strength is intended for maintenance therapy only and should not be used to initiate treatment 1
• Once-daily dosing at bedtime is acceptable for doses up to 150 mg daily 1
• Anti-anxiety effects appear before antidepressant effects; optimal antidepressant response may take 2–3 weeks 1
• In patients with mild symptomatology or emotional symptoms accompanying organic disease, doses as low as 25–50 mg daily may suffice 1

Insomnia Dosing

For sleep-maintenance insomnia, the American Academy of Sleep Medicine recommends low-dose doxepin 3–6 mg at bedtime as a first-line pharmacologic option after initiating Cognitive Behavioral Therapy for Insomnia (CBT-I). 2, 3

• Start with 3 mg at bedtime; if insufficient after 1–2 weeks, increase to 6 mg 2, 3
• At these hypnotic doses (3–6 mg), doxepin exhibits minimal anticholinergic activity and no abuse potential 2, 3
• Low-dose doxepin reduces wake after sleep onset by 22–23 minutes and improves sleep efficiency, total sleep time, and sleep quality 2, 3
• Treatment should be limited to 8 days and 10% of body surface area (maximum 12 g daily) when used topically for pruritus 2

Critical Distinction in Dosing

The 3–6 mg hypnotic dose is fundamentally different from the 25–300 mg antidepressant dose. At low doses, doxepin acts as a selective H₁-histamine antagonist with minimal anticholinergic effects, whereas higher doses engage multiple receptor systems (norepinephrine reuptake inhibition, anticholinergic, antiserotonin effects) 1, 4, 5

Chronic Pruritus Dosing

For chronic pruritus, oral doxepin has shown marked improvement in multiple studies, though optimal dosing varies by condition. 6

• Topical doxepin may be used for generalized pruritus, but treatment should be limited to 8 days, 10% of body surface area, and 12 g daily due to risk of allergic contact dermatitis 2
• Oral antidepressants including doxepin should be considered for chronic pruritus unresponsive to topical treatment and oral antihistamines, particularly in uremic, cholestatic, or paraneoplastic pruritus 6

Absolute Contraindications

Doxepin is contraindicated in patients with:

• Hypersensitivity to doxepin or other dibenzoxepines 1
• Glaucoma or angle-closure glaucoma 1
• Urinary retention or tendency toward urinary retention 1

These disorders must be ruled out before initiating therapy, particularly in older patients 1

Critical Safety Warnings

Suicidality Risk

All patients started on doxepin must be monitored for clinical worsening, suicidality, or unusual changes in behavior, with families and caregivers advised of the need for close observation. 1

• Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (ages 18–24) with major depressive disorder 1
• Short-term studies showed no increased risk beyond age 24, and a reduction in risk in adults aged 65 and older 1
• Doxepin is not approved for use in pediatric patients 1

Cardiovascular Considerations

At clinical dosages up to 150 mg daily, doxepin can be given concomitantly with guanethidine without blocking its antihypertensive effect; at doses above 150 mg daily, blocking has been reported. 1

• Doxepin is generally well tolerated in patients with cardiovascular disease, causing fewer cardiovascular side effects than other tricyclics at usual therapeutic doses 7
• However, doxepin has intrinsic cardiotoxicity on overdosage similar to other tricyclics 7
• Cardiovascular effects including hypotension, hypertension, and tachycardia have been reported occasionally 1

Elderly Patients

Elderly patients should be started on low doses and observed closely due to increased risk of confusion, oversedation, and decreased renal function. 1

• Sedating drugs may cause confusion and oversedation in the elderly 1
• The extent of renal excretion has not been determined, so care should be taken in dose selection for patients with decreased renal function 1

Common Adverse Effects

The most common side effects are:

• Drowsiness (most commonly noticed, tends to disappear with continued therapy) 1
• Dry mouth (anticholinergic effect) 1
• Constipation (anticholinergic effect) 1
• Blurred vision (anticholinergic effect) 1

If anticholinergic effects do not subside with continued therapy or become severe, dosage reduction may be necessary 1

Less Common but Serious Adverse Effects

• CNS: confusion, disorientation, hallucinations, numbness, paresthesias, ataxia, extrapyramidal symptoms, seizures, tardive dyskinesia, tremor 1
• Hematologic: eosinophilia, bone marrow depression (agranulocytosis, leukopenia, thrombocytopenia, purpura) 1
• Allergic: skin rash, edema, photosensitization, pruritus 1
• Endocrine: altered libido, testicular swelling, gynecomastia, breast enlargement, galactorrhea, blood sugar changes, SIADH 1

Monitoring Requirements

Initial and Ongoing Assessment

For depression/anxiety treatment:

• Monitor for clinical worsening, suicidality, or unusual behavior changes, especially during the first few weeks of treatment 1
• Assess anticholinergic side effects (dry mouth, constipation, urinary retention, blurred vision) at each visit 1
• Optimal antidepressant effect may not be evident for 2–3 weeks 1

For insomnia treatment:

• Reassess sleep parameters (sleep-onset latency, wake after sleep onset, total sleep time, daytime functioning) after 1–2 weeks 2, 3
• Monitor for adverse effects including morning sedation, cognitive impairment, and complex sleep behaviors 2, 3
• FDA labeling indicates hypnotics are intended for short-term use (≤4 weeks); evidence beyond this period is limited 3

Laboratory Monitoring

• No routine laboratory monitoring is specified in FDA labeling, but consider baseline and periodic monitoring for hematologic effects (CBC) given rare reports of bone marrow depression 1
• Monitor blood sugar in diabetic patients, as tricyclics can raise or lower blood sugar levels 1

Withdrawal and Discontinuation

Gradual withdrawal is essential to prevent withdrawal symptoms after prolonged administration. 1

• Withdrawal symptoms may include nausea, headache, and malaise, but are not indicative of addiction 1
• For antidepressant doses, taper over 10–14 days to limit withdrawal symptoms 8
• Abrupt cessation should be avoided 1

Overdose Management

Deaths may occur from overdosage; multiple drug ingestion (including alcohol) is common in deliberate tricyclic overdose. 1

Critical manifestations include cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression including coma 1

• Obtain ECG immediately and initiate cardiac monitoring 1
• Protect airway, establish IV line, and initiate gastric decontamination 1
• Minimum 6 hours of observation with cardiac monitoring is strongly advised 1
• QRS duration ≥0.10 seconds may be the best indication of overdose severity 1
• Intravenous sodium bicarbonate should maintain serum pH 7.45–7.55 1

Special Populations and Considerations

Pregnancy and Lactation

The FDA labeling does not provide specific pregnancy category information in the excerpts provided, but tricyclic antidepressants generally require careful risk-benefit assessment during pregnancy 1

Drug Interactions

At doses above 150 mg daily, doxepin may block the antihypertensive effect of guanethidine and related compounds. 1

• The possibility of drug interaction should be considered if the patient is receiving other drugs concomitantly, particularly in depression/anxiety associated with organic disease 1

Alcohol

Doxepin should not be taken concomitantly with alcohol when treating depression/anxiety associated with alcoholism. 1

Common Prescribing Pitfalls

• Using high antidepressant doses for insomnia: The 3–6 mg hypnotic dose is vastly different from the 75–300 mg antidepressant dose; using higher doses for insomnia increases anticholinergic burden without improving sleep 2, 3, 1
• Failing to implement CBT-I alongside low-dose doxepin for insomnia: The American Academy of Sleep Medicine mandates CBT-I as first-line treatment, with medication as adjunct 2, 3
• Inadequate monitoring for suicidality: All patients, especially those under age 24, require close monitoring for worsening depression and suicidal ideation 1
• Abrupt discontinuation: Always taper gradually to avoid withdrawal symptoms 1
• Ignoring contraindications: Always rule out glaucoma and urinary retention before initiating therapy, particularly in elderly patients 1