CLOMIPRAMINE HYDROCHLORIDE
Clinical safety rating: caution
Animal studies have proved adverse effects but may be safe for humans
Tricyclic antidepressant that inhibits serotonin and norepinephrine reuptake, with additional anticholinergic, antihistaminergic, and alpha-adrenergic blocking effects.
| Metabolism | Hepatic via CYP1A2, CYP2C19, CYP3A4, and CYP2D6; active metabolite desmethylclomipramine inhibits serotonin reuptake. |
| Excretion | Renal: ~60% (as conjugated metabolites and unchanged drug); Fecal: ~30% (biliary excretion); 2-3% excreted unchanged in urine. |
| Half-life | Terminal elimination half-life of clomipramine is 19-37 hours (mean ~30 hours); active metabolite desmethylclomipramine has half-life of 54-77 hours. Steady-state achieved within 1-2 weeks. |
| Protein binding | 97-98% bound; primarily to albumin and α1-acid glycoprotein. |
| Volume of Distribution | Vd: 9-16 L/kg (mean ~12 L/kg); extensive tissue distribution (higher in brain, lungs, liver). |
| Bioavailability | Oral: ~50% (first-pass hepatic metabolism reduces bioavailability; range 36-62%). |
| Onset of Action | Oral: 2-3 weeks for antidepressant effect (initial therapeutic response); IV: not clinically available. |
| Duration of Action | Duration of therapeutic effect persists for several days after discontinuation due to long half-life; tapers gradually over 1-2 weeks. |
Oral, initial 25 mg three times daily; increase gradually to 100-250 mg/day in divided doses; maximum 300 mg/day for severe conditions.
| Dosage form | CAPSULE |
| Renal impairment | GFR 30-59 mL/min: reduce dose by 25-50%; GFR <30 mL/min: avoid use or reduce by 50-75% with monitoring. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 50%; Child-Pugh C: contraindicated or use with extreme caution at 25% of normal dose. |
| Pediatric use | Children 10-17 years: oral 25 mg/day initially, increase over 2 weeks to 3 mg/kg/day or 100 mg/day (whichever is less) in divided doses; maximum 200 mg/day. |
| Geriatric use | Initial 20-30 mg/day in divided doses; increase slowly to max 100 mg/day; monitor for orthostasis, sedation, anticholinergic effects, and QT prolongation. |
| 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 | Clomipramine is excreted into breast milk in small amounts. M/P ratio approximately 0.4–0.9. Infant serum levels generally low (typically <5% of maternal weight-adjusted dose). Monitor infant for sedation, poor feeding, and weight gain. Caution if infant is preterm or with hepatic impairment. American Academy of Pediatrics considers use compatible with breastfeeding. |
| Teratogenic Risk | First trimester: Limited data suggest a small increased risk of cardiovascular malformations (e.g., VSD). Second and third trimesters: Risk of neonatal withdrawal symptoms (irritability, tachypnea, poor feeding) and possible serotonin syndrome if used near term. Overall, not considered a major teratogen but use only if benefit outweighs risk. |
■ FDA Black Box Warning
Suicidality and Antidepressant Drugs: Antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults in short-term studies. Clomipramine is not approved for use in pediatric patients except for OCD in children aged 10 and older.
| Common Effects | Dry mouth |
| Serious Effects |
["Hypersensitivity to clomipramine or other tricyclics","Concomitant use of MAOIs or within 14 days of discontinuation","Recent myocardial infarction","Concurrent use of cisapride or other QTc-prolonging agents"]
| Precautions | ["Seizure potential: dose-dependent, increased at daily doses >250 mg","Activation of mania/hypomania","Cardiovascular effects: QTc prolongation, orthostatic hypotension, arrhythmias","Anticholinergic effects: urinary retention, constipation, blurred vision","Serotonin syndrome when combined with serotonergic drugs","Withdrawal symptoms with abrupt discontinuation"] |
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| Fetal Monitoring | Maternal: Blood pressure, heart rate, and ECG for QTc prolongation; hepatic and renal function tests; serum drug levels if toxicity suspected. Fetal/neonatal: Ultrasound for cardiac anomalies if first-trimester exposure; monitor neonate for withdrawal symptoms (tremors, respiratory distress, irritability) and serotonin syndrome (hypertonia, hyperreflexia) for at least 48 hours after delivery. |
| Fertility Effects | Clomipramine can elevate prolactin levels, potentially causing galactorrhea, menstrual irregularities, and reduced fertility in women. In men, may cause ejaculatory dysfunction or decreased libido. These effects are reversible upon drug discontinuation. No direct evidence of permanent impairment. |