ANAFRANIL
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ANAFRANIL (ANAFRANIL).
Clomipramine is a tricyclic antidepressant (TCA) that inhibits the reuptake of serotonin and norepinephrine, with a higher potency for serotonin reuptake inhibition. It also has anticholinergic, antihistaminergic, and alpha-adrenergic blocking properties.
| Metabolism | Primarily hepatic via CYP1A2, CYP3A4, CYP2C19, and CYP2D6; active metabolite desmethylclomipramine formed via N-demethylation. |
| Excretion | Renal (primarily as conjugated metabolites, ~60-70% over 72 hours); fecal (biliary excretion of ~10-20%); <2% excreted unchanged in urine. |
| Half-life | Terminal elimination half-life of clomipramine is approximately 21-26 hours; its active metabolite, desmethylclomipramine, has a half-life of approximately 36-42 hours. Steady-state is achieved within 7-14 days. |
| Protein binding | 97.6% bound primarily to alpha1-acid glycoprotein and albumin. |
| Volume of Distribution | Approximately 12-17 L/kg, indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability is approximately 45-55% due to first-pass metabolism. IV administration yields 100%. |
| Onset of Action | Oral: 2-3 weeks for antidepressant effect; OCD improvement may take 4-6 weeks. IV (investigational): possibly faster onset but not standard. |
| Duration of Action | Due to long half-life, effects persist for several days after discontinuation. Clinical response is maintained with once-daily dosing. |
| Molecular Weight | 314.8 |
| Action Class | Tricyclic antidepressants |
| Brand Substitutes | Clomine 25mg Tablet, Syconil 25mg Tablet, Klomin 25mg Tablet, Clora 25mg Tablet, Obnil 25mg Tablet, Clomifril 10mg Tablet, Imi-CI 10mg Tablet, Obnil 10mg Tablet, Clomilent 10mg Tablet, Sycomip 10mg Tablet |
Initial: 25 mg PO tid; increase gradually to 100-150 mg/day. Maximum: 250 mg/day. Maintenance: lowest effective dose.
| Dosage form | CAPSULE |
| Renal impairment | No specific guidelines. Use with caution in severe renal impairment (CrCl <30 mL/min); consider dose reduction based on tolerability. |
| Liver impairment | Child-Pugh A: no adjustment needed. Child-Pugh B: reduce dose by 50%. Child-Pugh C: contraindicated. |
| Pediatric use | Not recommended for children <10 years. For adolescents: initial 25 mg PO daily, increase slowly to 3 mg/kg/day or 100 mg/day maximum (whichever is lower). |
| Geriatric use | Initial: 10 mg PO daily; increase slowly to 30-50 mg/day. Monitor for orthostatic hypotension, sedation, and anticholinergic effects. |
| 1st trimester | Limited human data; animal studies show fetal harm. Use only if benefit outweighs risk. |
| 2nd trimester | Avoid unless essential; may cause fetal tachycardia, jitteriness, and withdrawal symptoms. |
| 3rd trimester | Near term, risk of neonatal withdrawal (respiratory distress, feeding difficulty, irritability). |
Clinical note
Comprehensive clinical and safety monograph for ANAFRANIL (ANAFRANIL).
| Placental transfer | Crosses placenta freely; fetal levels can approach maternal levels. |
| Breastfeeding | Clomipramine is excreted into breast milk in small amounts. Infant serum levels may be detectable but usually low. Monitor infant for drowsiness, poor feeding, and weight gain. Benefits likely outweigh risks; however, caution is advised. |
■ 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. Closely monitor for clinical worsening, suicidality, or unusual changes in behavior.
| Serious Effects |
History of myocardial infarctionConcurrent MAOI therapy or within 14 daysKnown hypersensitivity to clomipramineAcute angle-closure glaucomaSevere hepatic impairment
| Precautions | May increase risk of suicidal thoughts/behaviors; serotonin syndrome when used with other serotonergic drugs; lowering of seizure threshold; orthostatic hypotension; anticholinergic effects (e.g., urinary retention, blurred vision); cardiac conduction abnormalities; QT prolongation; neuroleptic malignant syndrome; angle-closure glaucoma; hyperpyrexia; withdrawal symptoms upon abrupt discontinuation; use with caution in patients with cardiovascular disease, hepatic impairment, renal impairment, history of seizures, and elderly patients. |
| Food/Dietary | Avoid grapefruit and grapefruit juice as they may increase clomipramine levels. Take with food to reduce gastric upset. Avoid excessive caffeine; it may increase side effects like anxiety or tremors. Limit alcohol due to additive CNS depression. |
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| Lactation Rating |
| L2 |
| Teratogenic Risk | First trimester: Limited data; possible increased risk of congenital heart defects (RR ~1.3). Second/third trimester: Risk of neonatal withdrawal syndrome (jitteriness, feeding difficulties, respiratory distress) and persistent pulmonary hypertension of the newborn (PPHN) with late exposure. |
| Fetal Monitoring | Maternal: Monitor for serotonin syndrome, seizures, ECG changes (QTc prolongation), and blood pressure. Fetal: Ultrasound for fetal growth and anatomy; neonatal monitoring for withdrawal and PPHN if used near term. Consider fetal echocardiography if first-trimester exposure. |
| Fertility Effects | May cause reversible sexual dysfunction (ejaculatory delay, libido changes) in both sexes. No evidence of permanent impairment to fertility. In men, slight reduction in sperm motility reported. |
| Clinical Pearls | Anafranil (clomipramine) is a tricyclic antidepressant (TCA) primarily used for obsessive-compulsive disorder (OCD). Monitor for QT prolongation, especially in patients with cardiac risk factors or on other QT-prolonging drugs. Due to anticholinergic effects, use cautiously in elderly, those with BPH, or narrow-angle glaucoma. Start low and titrate slowly to minimize side effects. Therapeutic response may take 2-4 weeks. Do not discontinue abruptly due to withdrawal symptoms. |
| Patient Advice | Take exactly as prescribed; do not adjust dose without consulting your doctor. · It may take several weeks to feel the full benefit; do not stop suddenly. · Avoid alcohol and other CNS depressants. · Report any suicidal thoughts, worsening depression, or mood changes immediately. · May cause drowsiness, dizziness, or blurred vision; avoid driving until you know how it affects you. · Dry mouth, constipation, and urinary retention are common; increase fluid intake and dietary fiber. · Use sun protection; this medication can increase sensitivity to sunlight. · Do not take with MAO inhibitors (e.g., linezolid, methylene blue) or within 14 days of stopping them. |