Doxepin
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Major Depressive Disorder | Adults | Monotherapy | FDA Approved |
| Insomnia (sleep maintenance difficulty) | Adults (including elderly) | Monotherapy (low-dose, Silenor) | FDA Approved |
| Pruritus (atopic dermatitis, lichen simplex chronicus) | Adults (topical 5% cream) | Short-term topical (up to 8 days) | FDA Approved |
Doxepin occupies a distinctive position among the tricyclic antidepressants owing to its unusually potent histamine H1 receptor blockade, which gives it a dual clinical identity. At full antidepressant doses (75–300 mg/day), it acts primarily through norepinephrine and serotonin reuptake inhibition. At ultra-low doses (3–6 mg), its selectivity for the H1 receptor makes it an effective hypnotic without the anticholinergic burden that characterises higher doses. The topical formulation leverages its antihistaminic properties for itch relief in dermatological conditions.
Chronic urticaria (refractory) — Doxepin 10–25 mg at bedtime may be effective when standard second-generation antihistamines and H2 blockers fail. AAAAI/ACAAI guidelines list it as a treatment option for refractory cases. (Evidence quality: Moderate)
Anxiety disorders — Used at doses of 25–150 mg/day for generalized anxiety, though SSRIs are preferred first-line. (Evidence quality: Moderate)
Chronic pruritus (neuropathic or systemic) — Oral doxepin 10–100 mg/day used by dermatologists for intractable itch conditions. (Evidence quality: Low)
Neuropathic pain — Some evidence for use at 25–150 mg/day as an adjunct analgesic. (Evidence quality: Low)
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Major depression — initial monotherapy | 25 mg TID or 75 mg QHS | 75–150 mg/day | 300 mg/day | May give in divided doses or as a single bedtime dose to exploit sedation Titrate over 1–2 weeks based on response |
| Depression with prominent insomnia | 25–50 mg QHS | 75–150 mg QHS | 300 mg/day | Single bedtime dosing preferred; sedation is a therapeutic advantage Full antidepressant response may take 2–4 weeks |
| Insomnia — sleep maintenance (Silenor) | 6 mg QHS | 3–6 mg QHS | 6 mg/day | Take within 30 min of bedtime; avoid within 3 h of a meal Not a controlled substance; no abuse potential demonstrated |
| Anxiety disorders (off-label) | 25 mg QHS | 75–150 mg/day | 300 mg/day | Increase by 25–50 mg every 3 days as tolerated Divided dosing (BID or TID) may reduce daytime sedation at higher doses |
| Chronic urticaria (off-label) | 10 mg QHS | 10–25 mg QHS | 75 mg/day | Exploits potent H1/H2 blockade at low doses May combine with second-generation antihistamine during the day |
| Pruritus — topical (Zonalon 5% cream) | Thin film QID | Thin film QID | QID × 8 days max | Allow 3–4 h between applications; reduce BSA treated if excessive drowsiness occurs Drowsiness in 22% even with topical use |
Special Population Adjustments
| Population | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Elderly (≥65 years) — insomnia | 3 mg QHS | 3–6 mg QHS | 6 mg/day | Clearance reduced by ~33% from age 20 to 75 Higher risk of confusion and oversedation (Beers Criteria) |
| Elderly (≥65 years) — depression | 10–25 mg QHS | 25–75 mg/day | 150 mg/day | Listed as potentially inappropriate by AGS Beers Criteria Monitor for orthostatic hypotension and falls |
| Hepatic impairment | 3 mg QHS (insomnia) or lowest available (depression) | Titrate cautiously | Individualize | Higher plasma concentrations expected; no formal dose-adjustment studies Monitor for excessive sedation and anticholinergic effects |
| CYP2D6 / CYP2C19 poor metabolizers | Reduce dose | Guided by doxepin plasma levels | Individualize | Up to 4-fold higher nordoxepin AUC in CYP2D6 PMs Consider pharmacogenomic testing before initiation if available |
At doses below approximately 10 mg, doxepin acts as a highly selective H1 receptor antagonist with minimal anticholinergic, antiadrenergic, or serotonergic activity. This is the pharmacological basis for the Silenor formulation. As doses climb above 25 mg, affinity for muscarinic, alpha-1 adrenergic, and monoamine transporter sites becomes relevant, producing both the therapeutic antidepressant effect and the classical TCA side-effect burden. Matching the dose to the clinical scenario is therefore essential.
Doxepin Pharmacology
Mechanism of Action
Doxepin is a dibenzoxepin-derivative tricyclic compound that exerts its effects through multiple receptor interactions. At antidepressant doses, it inhibits the reuptake of norepinephrine (primarily) and serotonin at presynaptic terminals, increasing their availability in the synaptic cleft. The active metabolite nordoxepin contributes additional norepinephrine reuptake blockade. Beyond monoamine reuptake, doxepin is among the most potent histamine H1 receptor antagonists known, with an in-vitro Ki of approximately 0.17 nM—far exceeding conventional antihistamines such as diphenhydramine (Ki ~16 nM). It also blocks muscarinic acetylcholine receptors, alpha-1 adrenergic receptors, and 5-HT2A serotonin receptors. Additionally, doxepin inhibits cardiac sodium and potassium channels, which accounts for its cardiotoxic potential in overdose. The clinical selectivity of doxepin is dose-dependent: at ultra-low doses (3–6 mg), H1 blockade predominates; at standard antidepressant doses, the full polypharmacology profile emerges.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Well absorbed orally; Tmax ~3.5 h; bioavailability ~29% (extensive first-pass ~55–87%); AUC increased ~41% with high-fat meal | For insomnia dosing, administer on an empty stomach (not within 3 h of a meal) to avoid delayed absorption and next-day hangover; food effect less relevant at antidepressant doses |
| Distribution | Vd ~11,930 L (~20 L/kg); protein binding ~80% (albumin and alpha-1 acid glycoprotein) | Very large volume of distribution indicates extensive tissue uptake; haemodialysis is ineffective for overdose removal |
| Metabolism | Hepatic via CYP2D6 (primary), CYP2C19, CYP1A2, CYP2C9; active metabolite: nordoxepin (t½ ~31 h); further glucuronidation | CYP2D6 and CYP2C19 poor metabolizers may have significantly elevated doxepin exposure (up to 4-fold increase in nordoxepin AUC); dose reduction and therapeutic drug monitoring advisable |
| Elimination | t½ ~15 h (doxepin), ~31 h (nordoxepin); <3% excreted unchanged in urine; primarily as glucuronide conjugates | Long active-metabolite half-life supports once-daily dosing; negligible renal excretion means no dose adjustment needed in renal impairment |
Side Effects
The side-effect profile of doxepin is strongly dose-dependent. At ultra-low insomnia doses (3–6 mg), adverse events are comparable to placebo. The incidence data below are from clinical trials of antidepressant-dose doxepin (Sinequan PI, n = 1,635 patients with MDD) unless otherwise noted.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Somnolence | 17% | Most frequently reported effect; often diminishes over the first 1–2 weeks of therapy; dose-related |
| Dry mouth | 15% | Due to muscarinic receptor blockade; oral hygiene counselling recommended to prevent caries |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Dizziness | 6% | Related to alpha-1 adrenergic blockade; advise slow position changes |
| Constipation | 5% | Anticholinergic effect; encourage fibre and hydration |
| Fatigue | 5% | Distinct from somnolence; dose reduction may help |
| Blurred vision | 3% | Anticholinergic; usually transient; rule out acute angle closure if eye pain present |
| Tachycardia | 3% | Vagolytic anticholinergic effect on the heart; obtain ECG if clinically indicated |
| Hypotension | 3% | Orthostatic; falls risk in elderly; measure standing blood pressure early in treatment |
| Insomnia | 2% | Paradoxical; consider bedtime-only dosing |
| Tremor | 2% | Fine postural tremor; may indicate serotonergic contribution |
| Nausea | 2% | Usually resolves with continued use; take with food at antidepressant doses |
| Hyperhidrosis | 2% | Noradrenergic effect; may persist long-term |
| Weight gain | 2% | Related to H1 blockade and metabolic effects; monitor weight regularly |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Suicidal ideation / behaviour | Uncommon (age-dependent) | First weeks to months | Close monitoring especially in patients <25 years; consider stopping if emergent suicidality |
| Serotonin syndrome | Rare | Hours to days after adding serotonergic drug | Discontinue doxepin and all serotonergic agents immediately; supportive care; cyproheptadine |
| Cardiac arrhythmia / QRS prolongation | Rare (dose-dependent) | Any time; increased risk in overdose | Baseline and follow-up ECG; discontinue if QRS >120 ms or new arrhythmia; cardiology consult |
| Seizures | Rare | Any time; more common at high doses or in overdose | Discontinue doxepin; manage seizures per protocol; avoid rechallenge |
| Angle-closure glaucoma | Rare | Any time | Urgent ophthalmology referral; discontinue doxepin; contraindicated in glaucoma |
| Agranulocytosis / severe cytopaenia | Very rare (postmarketing) | Weeks to months | Urgent FBC; discontinue doxepin; haematology review |
| SIADH / hyponatraemia | Very rare (postmarketing) | Weeks | Check sodium; fluid restriction; discontinue if severe |
| Mania / hypomania activation | Uncommon | First weeks | Discontinue doxepin; evaluate for bipolar disorder; initiate mood stabiliser |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Somnolence / excessive sedation | <1% | Most common reason at antidepressant doses; not clinically significant at low doses |
| Anticholinergic effects (dry mouth, constipation, urinary retention) | <1% | Usually dose-related; dose reduction often sufficient |
| Weight gain | <1% | Long-term concern that may affect adherence |
Sedation is the most clinically significant side effect and is strongly dose-dependent. At antidepressant doses, consolidating the entire daily dose at bedtime can transform this side effect into a therapeutic advantage for patients with comorbid insomnia. If persistent daytime drowsiness occurs, dose reduction is often more effective than adding a stimulant. At insomnia doses (3–6 mg), next-day residual sedation is not significantly different from placebo.
Drug Interactions
Doxepin is primarily metabolised by CYP2D6, with secondary contributions from CYP2C19, CYP1A2, and CYP2C9. It does not appear to inhibit or induce CYP enzymes at therapeutic concentrations. The most clinically important interactions involve MAOIs, other serotonergic agents, and CYP2D6 inhibitors.
Monitoring
-
ECG
Baseline; repeat if dose >150 mg/day or symptoms
Routine Assess QRS duration and QTc interval before initiating antidepressant doses. TCAs widen QRS via sodium channel blockade; QRS >100 ms warrants caution. Not required for low-dose insomnia use. -
Blood Pressure
Baseline; weekly for first month, then periodically
Routine Orthostatic measurements (lying and standing) recommended, especially in elderly and patients on antihypertensives. Alpha-1 blockade causes postural hypotension. -
Weight & BMI
Baseline, then every 3 months
Routine H1 blockade contributes to weight gain. Address early with dietary counselling if a rising trend is identified. -
Mental State
Every visit for first 3 months, then periodically
Routine Screen for suicidality, especially in patients under 25. Also monitor for manic switching in patients with undiagnosed bipolar disorder. -
Doxepin Plasma Level
If poor response, suspected toxicity, or CYP2D6 PM
Trigger-Based Therapeutic range (doxepin + nordoxepin combined): 50–250 ng/mL for depression. Wide interpatient variability in metabolism makes TDM particularly useful. -
Sodium
If symptoms of SIADH (confusion, nausea, headache)
Trigger-Based SIADH is a rare postmarketing adverse reaction. Check sodium in elderly patients on diuretics or with unexplained confusion. -
Intraocular Pressure
If eye pain or visual disturbance
Trigger-Based Mydriatic effect may precipitate angle-closure glaucoma in patients with anatomically narrow angles. Contraindicated in glaucoma.
Contraindications & Cautions
Absolute Contraindications
- Hypersensitivity to doxepin or other dibenzoxepines (cross-reactivity possible)
- Glaucoma (all forms per current FDA labelling)
- Current or past urinary retention
- Concurrent MAOI use or use within 14 days of stopping an MAOI (including linezolid and IV methylene blue)
Relative Contraindications (Specialist Input Recommended)
- Severe cardiovascular disease — recent myocardial infarction, heart failure, conduction abnormalities; TCA cardiotoxicity risk
- Elderly patients with dementia or delirium risk — anticholinergic burden may precipitate or worsen cognitive impairment; Beers Criteria lists doxepin as potentially inappropriate for those ≥65
- Bipolar disorder (unscreened) — risk of manic switching; screen before initiation
- Severe hepatic impairment — doxepin undergoes extensive hepatic metabolism; anticipate elevated plasma levels
- Pregnancy — risk of neonatal adaptation syndrome (respiratory distress, feeding difficulty, irritability) with third-trimester exposure; risk-benefit discussion essential
Use with Caution
- Seizure history — doxepin may lower seizure threshold
- Prostatic hypertrophy — anticholinergic effects may worsen urinary symptoms
- Obstructive sleep apnoea — Silenor not recommended in severe OSA due to respiratory drive suppression potential
- CYP2D6 / CYP2C19 poor metabolisers — increased exposure; consider dose reduction and TDM
- Patients at risk of suicide — prescribe the smallest feasible quantity to reduce overdose risk; TCA overdose has a narrow toxic-to-therapeutic ratio
Antidepressants, including doxepin, increase the risk of suicidal thoughts and behaviour in paediatric and young adult patients (under 25 years) in short-term studies. In pooled analyses of approximately 77,000 adults and 4,500 paediatric patients across antidepressant classes, the risk was 14 additional patients per 1,000 treated in those under 18, and 5 additional per 1,000 in those aged 18–24. All antidepressant-treated patients should be monitored for clinical worsening and emergence of suicidal thoughts, especially during the initial months of therapy and at dose changes. Doxepin is not approved for use in paediatric patients.
Patient Counselling
Purpose of Therapy
Doxepin is prescribed to treat depression, help maintain sleep, or relieve persistent itching, depending on the dose and formulation. At higher doses it adjusts brain chemistry to improve mood over several weeks, while at very low doses it primarily promotes sleep by blocking wakefulness signals. It is important for patients to understand that the antidepressant effect takes 2–4 weeks to become apparent, and treatment should not be stopped abruptly.
How to Take
For depression: doxepin can be taken once at bedtime or in divided doses through the day; taking the full dose at bedtime takes advantage of its sedating properties. For insomnia (Silenor): take within 30 minutes of bedtime on an empty stomach; do not eat within 3 hours before the dose. For the oral solution: measure with the supplied calibrated dropper and dilute in 120 mL of water, milk, or compatible fruit juice immediately before drinking. Topical cream should be applied in a thin layer and spaced at least 3–4 hours apart.
Sources
- Sinequan (doxepin hydrochloride) capsules and oral solution — Full Prescribing Information. Pfizer Inc. Revised July 2025. FDA Label Primary source for approved indications, dosing, adverse reactions, contraindications, and drug interactions at antidepressant doses.
- Silenor (doxepin) tablets — Full Prescribing Information. Currax Pharmaceuticals LLC. FDA Label Source for low-dose insomnia indication, safety data at 3–6 mg, pharmacokinetic parameters, and elderly dosing.
- Zonalon (doxepin hydrochloride) cream 5% — Full Prescribing Information. Mylan Pharmaceuticals. FDA Label Source for topical formulation indications, dosing, and systemic absorption data in pruritic dermatoses.
- Roth T, Rogowski R, Hull S, et al. Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in adults with primary insomnia. Sleep. 2007;30(11):1555–1561. DOI Pivotal randomised placebo-controlled trial establishing efficacy of ultra-low-dose doxepin for sleep maintenance in adults.
- Krystal AD, Durrence HH, Scharf M, et al. Efficacy and safety of doxepin 1 mg and 3 mg in a 12-week sleep laboratory and outpatient trial of elderly subjects with chronic primary insomnia. Sleep. 2010;33(11):1553–1561. DOI Long-term trial in elderly demonstrating sustained efficacy of low-dose doxepin without anticholinergic side effects.
- Greene SL, Reed CE, Schroeter AL. Double-blind crossover study comparing doxepin with diphenhydramine for the treatment of chronic urticaria. J Am Acad Dermatol. 1985;12(4):669–675. DOI Landmark study showing doxepin 10 mg TID was superior to diphenhydramine for chronic idiopathic urticaria.
- Sateia MJ, Buysse DJ, Krystal AD, et al. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2017;13(2):307–349. DOI AASM guideline recommending low-dose doxepin for sleep maintenance insomnia based on available evidence.
- Bernstein JA, Lang DM, Khan DA, et al. The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol. 2014;133(5):1270–1277. DOI AAAAI/ACAAI joint consensus listing doxepin as a treatment option for refractory chronic urticaria.
- Gillman PK. Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. Br J Pharmacol. 2007;151(6):737–748. DOI Comprehensive review of TCA receptor pharmacology including doxepin’s uniquely potent H1 antagonism.
- Richelson E. Pharmacology of antidepressants. Mayo Clin Proc. 2001;76(5):511–527. DOI Provides receptor binding affinity data for TCAs, documenting doxepin’s exceptionally high H1 affinity.
- Yan JH, Hubbard JW, McKay G, Korchinski ED, Midha KK. Absolute bioavailability and stereoselective pharmacokinetics of doxepin. Xenobiotica. 2002;32(7):615–623. DOI Definitive crossover PK study establishing absolute oral bioavailability and stereoselectivity of doxepin isomers.
- Kirchheiner J, Meineke I, Müller G, Roots I, Brockmöller J. Contributions of CYP2D6, CYP2C9 and CYP2C19 to the biotransformation of E- and Z-doxepin in healthy volunteers. Pharmacogenetics. 2002;12(7):571–580. DOI Genotype-phenotype study characterising the influence of CYP polymorphisms on doxepin metabolism and supporting pharmacogenomic dose adjustment.
- Almasi A, Patel P, Meza CE. Doxepin. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; updated February 14, 2024. NCBI Bookshelf Peer-reviewed clinical summary covering indications, dosing, pharmacokinetics, adverse effects, and interprofessional considerations.