SINEQUAN
Clinical safety rating: caution
Comprehensive clinical and safety monograph for SINEQUAN (SINEQUAN).
Inhibits reuptake of serotonin and norepinephrine in the CNS; also has anticholinergic, antihistaminergic, and sedative effects.
| Metabolism | Hepatic via CYP2D6 and other CYP450 enzymes; active metabolite desmethyldoxepin. |
| Excretion | Renal (approximately 30-40% as unchanged drug, with extensive hepatic metabolism to metabolites; minor biliary/fecal excretion). |
| Half-life | Terminal elimination half-life: 8–24 hours (parent drug); steady state achieved in 2–4 weeks; clinical context: may require dose adjustment in hepatic impairment. |
| Protein binding | 80–85% bound to plasma proteins (albumin). |
| Volume of Distribution | Vd: 13–17 L/kg; high, indicating extensive tissue distribution including CNS. |
| Bioavailability | Oral: variable, 30–70% due to first-pass metabolism; intramuscular: 100%. |
| Onset of Action | Oral: 1–3 weeks for antidepressant effect; 1–2 hours for sedation. Intramuscular: 1–3 hours for antidepressant effect; 30–60 minutes for sedation. |
| Duration of Action | Oral: 24–36 hours after single dose; chronic dosing maintains steady state. Intramuscular: 12–24 hours. Clinical notes: sustained antidepressant effect requires daily dosing; sedation may persist with continued use. |
Initial: 50-150 mg/day PO divided 1-3 times daily; max 300 mg/day. Maintenance: lowest effective dose.
| Dosage form | CONCENTRATE |
| Renal impairment | No specific guidelines; caution in severe impairment (CrCl <30 mL/min) with dose reduction of 25-50%. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 50%; Child-Pugh C: avoid use. |
| Pediatric use | Not recommended for children <12 years. Adolescents: initial 25-50 mg/day PO in divided doses; max 100 mg/day based on weight (1-3 mg/kg/day). |
| Geriatric use | Start with lowest dose (10-25 mg/day PO); increase slowly; max 150 mg/day due to anticholinergic effects and QT prolongation risk. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for SINEQUAN (SINEQUAN).
| Breastfeeding | Doxepin is excreted into breast milk with M/P ratio approximately 1.3. Active metabolite nordoxepin accumulates in infants. Cases of infant sedation and respiratory depression reported. Contraindicated in breastfeeding; use alternative antidepressant if necessary. |
| Teratogenic Risk | First trimester: Limited data; no consistent evidence of major malformations in humans, but animal studies show fetal abnormalities at high doses. Second and third trimesters: Risk of neonatal withdrawal (irritability, respiratory distress, feeding difficulties) and anticholinergic effects (ileus, urinary retention). Avoid near term due to potential neonatal sedation. |
■ FDA Black Box Warning
Increased risk of suicidal thinking and behavior in children, adolescents, and young adults with major depressive disorder and other psychiatric disorders.
| Serious Effects |
["Hypersensitivity to doxepin or other tricyclic antidepressants","Concomitant use of MAOIs","Recent myocardial infarction","Narrow-angle glaucoma","Urinary retention"]
| Precautions | ["Suicidality risk","Serotonin syndrome","Cardiotoxicity (QT prolongation)","Anticholinergic effects (e.g., urinary retention, angle-closure glaucoma)","Sedation impairs ability to drive"] |
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| Fetal Monitoring | Monitor for maternal anticholinergic effects (constipation, blurred vision). Fetal ultrasound for growth and amniotic fluid if used long-term. Neonatal monitoring for withdrawal symptoms and respiratory status for 48 hours postpartum. |
| Fertility Effects | Animal studies suggest doxepin may impair fertility via hormonal disruption. Human data limited; case reports of altered libido and menstrual irregularities. May affect sperm parameters in males. |