DOXEPIN HYDROCHLORIDE
Clinical safety rating: caution
Animal studies have proved adverse effects but may be safe for humans
Doxepin is a tricyclic antidepressant (TCA) that inhibits the reuptake of serotonin and norepinephrine, thereby increasing their concentrations in the synaptic cleft. It also exhibits potent histamine H1 receptor antagonism, leading to antihistaminic effects, and has anticholinergic, alpha-adrenergic blocking, and anti-serotonergic properties.
| Metabolism | Primarily hepatic via CYP2D6, CYP2C19, and CYP3A4; N-demethylation to active metabolite nordoxepin. |
| Excretion | Primarily renal (50-60% as metabolites, <5% unchanged). Biliary/fecal: approximately 20-30%. |
| Half-life | Terminal elimination half-life: 8-24 hours (mean 15 hours). Steady-state achieved in 3-5 days. Active metabolite nordoxepin has half-life of 31-50 hours. |
| Protein binding | 80-85% bound, primarily to albumin. |
| Volume of Distribution | 20-40 L/kg (mean 30 L/kg). Indicates extensive tissue distribution with accumulation in brain and liver. |
| Bioavailability | Oral: 25-30% due to extensive first-pass metabolism. Topical: approximately 4-10% (systemic absorption minimal). |
| Onset of Action | Oral: antidepressant effect 2-3 weeks; anxiolytic effect 2-4 days; antipruritic effect within hours to days. Topical: antipruritic effect within hours. |
| Duration of Action | Oral: antidepressant effect continuous with chronic dosing; anxiolytic effect 24 hours; antipruritic effect 12-24 hours. Topical: 12-24 hours. |
| Molecular Weight | 315.84 |
25-150 mg orally at bedtime; initially 25 mg, may increase gradually to 150 mg. For minor depression: 25-50 mg orally at bedtime.
| Dosage form | CAPSULE |
| Renal impairment | No specific guidelines; use caution in severe renal impairment (CrCl <10 mL/min). Consider dose reduction or alternative agent. |
| Liver impairment | Contraindicated in severe hepatic impairment. In mild-to-moderate Child-Pugh A/B, reduce dose by 50% or use alternative. |
| Pediatric use | Not recommended for children under 12 years. For adolescents (12-17 years): 25-50 mg orally at bedtime; maximum 100 mg/day. |
| Geriatric use | Initial dose 10-25 mg orally at bedtime; increase slowly to 50-75 mg daily. Monitor for sedation, orthostatic hypotension, and anticholinergic effects. |
| 1st trimester | Avoid unless essential; risk of fetal cardiac defects and spontaneous abortion based on animal data and limited human studies. Crosses placenta. |
| 2nd trimester | Use only if potential benefit justifies risk; associated with preterm birth and poor neonatal adaptation syndrome. |
| 3rd trimester | Avoid near term; neonatal withdrawal (irritability, respiratory distress) and persistent pulmonary hypertension reported. |
Clinical note
MAOIs can cause serotonin syndrome and hyperpyrexia Strong anticholinergic effects may occur with other drugs Increased risk of suicide in children and young adults.
| Placental transfer | Crosses placenta readily; detected in cord blood and amniotic fluid. Ratio of fetal to maternal plasma concentration ~0.35-1.0. |
| Breastfeeding | Doxepin and its active metabolite nordoxepin are excreted into breast milk in clinically significant amounts. Prolonged use may lead to sedation, apnea, and poor feeding in infants. Avoid or use with caution, monitoring the infant for adverse effects. |
■ FDA Black Box Warning
Suicidality and Antidepressant Drugs: Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children, adolescents, and young adults with major depressive disorder and other psychiatric disorders. Patients of all ages should be monitored closely for clinical worsening, suicidality, or unusual changes in behavior.
| Common Effects | insomnia |
| Serious Effects |
Concurrent use with monoamine oxidase inhibitors (MAOIs) or within 14 days of MAOI therapyRecent myocardial infarctionSevere liver diseaseNarrow-angle glaucomaUrinary retention
| Precautions | Activation of mania/hypomania, cardiovascular effects (QT prolongation, orthostatic hypotension, tachycardia), anticholinergic effects (constipation, urinary retention, blurred vision, dry mouth), sedation, risk of suicide, withdrawal symptoms upon abrupt discontinuation, serotonin syndrome (especially with other serotonergic drugs). |
Loading safety data…
| Lactation Rating | L4 (Possibly Hazardous) |
| Teratogenic Risk | Teratogenic risk in first trimester is not known; second and third trimester exposure may cause transient neonatal withdrawal syndrome (irritability, hypertonia, tremors) and anticholinergic effects (constipation, urinary retention). |
| Fetal Monitoring | Monitor maternal blood pressure, heart rate, and ECG; assess for anticholinergic side effects; fetal surveillance with ultrasound for growth and amniotic fluid volume; neonatal monitoring for withdrawal signs for 48 hours after delivery. |
| Fertility Effects | May decrease libido or cause erectile dysfunction/ejaculatory disturbance; potential for hormonal alterations affecting ovulation; no specific data on fertility impairment. |
| Food/Dietary |
| Avoid or limit alcohol and grapefruit juice. Grapefruit juice may increase doxepin levels. Foods high in tyramine (aged cheese, cured meats, fermented foods) should be limited, especially when MAOI therapy was recently discontinued. Maintain adequate fluid and fiber intake to prevent constipation. |
| Clinical Pearls | Doxepin is a tricyclic antidepressant (TCA) with potent H1 antihistamine properties, making it effective at low doses for insomnia. Monitor for anticholinergic effects (constipation, dry mouth, urinary retention) and cardiac toxicity (QT prolongation). Avoid with MAOIs. Use with caution in elderly due to fall risk. Can cause orthostatic hypotension. May increase seizure threshold; use cautiously in seizure disorders. Doxepin overdose is highly lethal; prescribe limited quantities if suicidal risk. |
| Patient Advice | Take exactly as prescribed; do not increase dose or stop abruptly. · May cause drowsiness, especially when starting; avoid driving or operating machinery until you know how it affects you. · Avoid alcohol and other CNS depressants. · May cause dry mouth, constipation, blurred vision; report severe symptoms. · Rise slowly from sitting or lying to prevent dizziness. · Notify your doctor if you experience mood changes, suicidal thoughts, or palpitations. · Do not take with MAO inhibitors (e.g., linezolid, methylene blue) or within 14 days of stopping them. · Store at room temperature, away from moisture and heat. |