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. |
| 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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ANAFRANIL (ANAFRANIL).
| Breastfeeding | Anafranil (clomipramine) is excreted into breast milk. M/P ratio approximately 0.5-1.0. Relative infant dose estimated 1-2% of maternal weight-adjusted dose. Monitor infant for drowsiness, feeding difficulties, and weight loss. Generally compatible with caution. |
| 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. |
■ 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 |
Hypersensitivity to clomipramine or other tricyclics; concurrent use or within 14 days of MAO inhibitors; recent myocardial infarction; history of seizure disorder; narrow-angle glaucoma; urinary retention; concurrent use with linezolid or methylene blue.
| 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 |
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| 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. |
| 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. |
| 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. |