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. |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
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.
| Breastfeeding | Limited data; M/P ratio unknown. Small amounts excreted in breast milk; avoid breastfeeding due to potential for sedation and lowering of seizure threshold in infant. |
| 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). |
■ 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 |
Hypersensitivity to doxepin or any TCA, recent myocardial infarction, concomitant use with MAOIs (within 14 days), narrow-angle glaucoma, urinary retention (due to anticholinergic effects), concurrent use with drugs that prolong QT interval.
| 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). |
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| 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. |