# Anafranil ### (clomipramine hydrochloride) **Anafranil** (clomipramine hydrochloride); not controlled
[**Full Prescribing Information**](https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=4074b555-7635-41a9-809d-fae3b3610059&type=display)[**DailyMed Drug Information**](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4074b555-7635-41a9-809d-fae3b3610059)
--- ### **Summary** Anafranil is a tricyclic antidepressant, clomipramine, supplied only as an oral capsule and approved for obsessive-compulsive disorder from age 10. Benefit builds over weeks, and the label approves no other pediatric use. Cardiac conduction effects, dose-related seizures and lethality in overdose place it behind the SSRIs, which match it for efficacy. Not controlled; brand and generic. --- ### **Forms & Strengths** - **Capsules:** 25 mg, 50 mg, 75 mg --- ### **Dosing** - **Age:** - OCD: 10-17 y/o; not established below age 10. - OCD: ≥ 18 y/o, at a higher ceiling. - **Onset:** 2 to 3 weeks for early effect; judge response after several weeks at a therapeutic dose - **Duration:** continuous with once-daily dosing - **Initial Dose:** 25 mg daily, divided, with meals - **Titration:** - First 2 weeks: to 3 mg/kg or 100 mg daily, whichever is smaller. - Thereafter: toward the ceiling, allowing 2 to 3 weeks between adjustments. - **Max Dose:** - 10-17 y/o: 3 mg/kg or 200 mg daily, whichever is smaller. - ≥ 18 y/o: 250 mg daily. - These ceilings limit seizure risk; do not exceed them to chase response. - **Considerations:** Divide doses with meals during titration, then give the total at bedtime to limit sedation. The mg/kg cap is a seizure limit and moves with weight. --- ### **Pharmacology** - **Mechanism:** Tricyclic; inhibits serotonin and, via its active metabolite, norepinephrine reuptake, with muscarinic, histamine H1 and alpha-1 blockade causing most adverse effects - **Metabolism:** Hepatic, to desmethylclomipramine; half-life 32 hours parent, 69 hours metabolite, so steady state takes 2 to 3 weeks - **Nonlinear kinetics, a safety property:** exposure is not dose-proportional; above 150 mg/day accumulation can be dramatic, raising dose-dependent seizure risk. - **Pharmacogenomics:** CYP2D6 poor metabolizers, 7% to 10% of Caucasians, reach 8-fold higher AUC; adding an inhibitor makes a stable patient toxic. - **Class Positioning:** the only tricyclic with an FDA pediatric indication. Against [Zoloft](https://wiki.joshnp.com/link/148), [Prozac](https://wiki.joshnp.com/link/147) and [Luvox](https://wiki.joshnp.com/link/152) it adds no efficacy and costs receptor blockade. --- ### **Indications** - **Obsessive-Compulsive Disorder** (ICD-10: F42.2, F42.3, F42.8, F42.9): patients 10-17 y/o and adults, where symptoms cause marked distress or impair function --- ### **Off-Label Uses** - **Before anything off-label:** in pediatric OCD an SSRI is as effective and better tolerated. Use [Zoloft](https://wiki.joshnp.com/link/148), [Prozac](https://wiki.joshnp.com/link/147) or [Luvox](https://wiki.joshnp.com/link/152) with exposure and response prevention first. (AHRQ 2024) - **Depression in youth** (ICD-10: F32.x, F33.x): not supported; no pre-pubertal benefit, marginal in adolescents. (Cochrane 2013) - **Looked for, evidence not found:** - **Trichotillomania and body-focused repetitive behaviors** (ICD-10: F63.3): adult data only; insufficient in youth. - **Repetitive behaviors in autism** (ICD-10: F84.0): insufficient; no graded conclusion. - **Cataplexy in narcolepsy** (ICD-10: G47.411): adult tricyclic use; insufficient pediatric evidence. --- ### **Contraindications & Warnings** - **Boxed Warning, suicidal thoughts and behaviors:** antidepressants increase suicidal thinking and behavior in children, adolescents and young adults. Monitor closely for clinical worsening; families observe daily. - **Overdose lethality makes quantity dispensed a prescribing decision.** A tricyclic overdose kills where an SSRI overdose generally does not: the lowest reported fatal dose is 750 mg. - **Quantity, in practice:** the label twice instructs prescribing the smallest quantity consistent with good patient management. Confirm locked storage at every refill. - **Dose-related seizure risk, the label's principal risk:** cumulative incidence up to 300 mg/day was 0.64% at 90 days, 1.12% at 180 days, 1.45% at 365 days. - **Seizure ceilings:** dose predicts risk, hence 250 mg daily maximum in adults, 3 mg/kg or 200 mg daily in youth. - **Contraindicated:** - Hypersensitivity to clomipramine or other tricyclics. - An MAOI, linezolid or intravenous methylene blue, or within 14 days of either. - The acute recovery period after a myocardial infarction. - **Use with caution:** - Cardiovascular disease, seizure history, brain injury, or a seizure-threshold-lowering drug. - Unrecognized bipolar disorder or schizophrenia; mania or psychosis may follow. - Hyperthyroidism, liver or renal disease, or adrenal medulla tumors. - Planned electroconvulsive therapy or surgery; stop well before, tell the anesthetist. - **Screen before starting:** - Cardiac and family history of sudden death, and a baseline ECG. - Seizure history, head injury, and family history of bipolar disorder or suicide. - Baseline weight, height, heart rate, and blood pressure sitting and standing. - CYP2D6 inhibitors, and who stores the medication at home. --- ### **Drug Interactions** - **MAOIs** (phenelzine, tranylcypromine, linezolid, methylene blue): contraindicated. Allow 14 days in either direction. - **SSRIs** (fluoxetine, sertraline, paroxetine, fluvoxamine): inhibit CYP2D6 and raise clomipramine levels. Use lower doses; allow 5 weeks after stopping fluoxetine. - **Other CYP2D6 inhibitors** (quinidine, cimetidine, phenothiazines, propafenone, flecainide): a stable patient can turn abruptly toxic. Lower the dose. - **Other serotonergic drugs** (triptans, fentanyl, lithium, tramadol, buspirone, St John's Wort): serotonin syndrome. Stop both if it occurs. - **Methylphenidate and other stimulants:** raise tricyclic levels, a live combination in ADHD practice. Titrate slowly, watch cardiac effects. - **Level shifters** (phenytoin, carbamazepine, haloperidol, warfarin, digoxin, clonidine, alcohol): recheck response, INR or blood pressure after any change. --- ### **Administration** - Give in divided doses with meals during titration, for gastrointestinal tolerance. - After titration, give the total dose at bedtime; 46% of pediatric trial patients reported somnolence. - Swallow capsules whole; no liquid form exists and they are not opened or divided. - Allow 2 to 3 weeks between dose adjustments; steady state is not reached sooner. - Do not stop abruptly; see Discontinuation & Taper. - Store locked; dispense the smallest quantity consistent with good management, per the label. --- ### **Side Effects** - **Common, pediatric trial rates:** dry mouth 63% (placebo 16%), somnolence 46% (11%), dizziness 41% (14%), fatigue 35% (9%), tremor 33% (2%), constipation 22%, anorexia 22%, urinary retention 7% - **Serious:** - Suicidal thinking and behavior, per the boxed warning. Ask directly at every dose change. - Seizure, dose related and the label's most significant identified risk. Stop the drug. - Cardiac conduction abnormality: 1.5% on treatment against 0.7% on placebo, chiefly ventricular ectopy and conduction delay. - Serotonin syndrome, particularly with an MAOI. Stop both drugs. - Angle-closure glaucoma, hepatic injury, agranulocytosis. - Hyponatremia from SIADH, with reported seizure, coma and death. - DRESS, drug rash with eosinophilia and systemic symptoms. Stop immediately. - Psychosis, hallucinations, paranoia, precipitated hypomania or mania. - Sexual dysfunction, above placebo in males, a common reason adolescents quietly stop. --- ### **Monitoring & Labs** - **ECG:** at baseline for unsuspected long QT, at steady state on the target dose, and after every subsequent increase. (AACAP 2012; AHA 1999) - **ECG thresholds that stop escalation:** heart rate above 130 bpm, PR above 200 ms, QRS above 120 ms, QTc above 460 ms. Hold and refer. (AHA 1999) - **Suicidality:** every visit for 12 weeks, every dose change, then at least every 3 months. Ask about agitation, hostility and akathisia. - **Weight, height, blood pressure and heart rate:** baseline, each dose change, every 3 months. Weight sets the 3 mg/kg ceiling. - **Seizure surveillance:** ask about seizure, aura, staring spell or fall at every visit; reconfirm each new dose stays under the cap. - **Quantity dispensed and storage:** at every refill, confirm how much is in the home, that it is locked, and who holds it. - **On trigger:** CY-BOCS every 4 to 6 weeks in titration; sodium for confusion; liver enzymes for jaundice; CBC for fever with sore throat. --- ### **Discontinuation & Taper** - **Do not stop abruptly.** The label calls for gradual tapering with careful monitoring. - Withdrawal brings dizziness, nausea, vomiting, headache, malaise, sleep disturbance, hyperthermia, irritability, psychiatric worsening. - Long half-lives mean withdrawal may appear days after a reduction; judge each step over a week. - Discontinue immediately for a seizure, DRESS, symptomatic hyponatremia, or serotonin syndrome. - Drug holidays are not appropriate; interruption risks withdrawal and relapse. - OCD is chronic; continue a responder on the lowest effective dose. Benefit held a year under double-blind conditions. --- ### **Pregnancy & Lactation** - **Pregnancy:** No adequate controlled studies. Use only if benefit justifies risk, weighing untreated severe OCD. No exposure registry is named. - **Pregnancy, neonatal:** jitteriness, tremor and seizures reported in neonates exposed until delivery. - **Lactation:** acceptable on limited evidence; a fully breastfed infant receives about 1.3% to 2.2% of the maternal weight-adjusted dose. (LactMed 2022) - **Lactation, caveats:** after pregnancy exposure the milk amount may not prevent neonatal withdrawal; better-studied agents exist for depression. --- ### **Counseling Points** - **Counsel the family on:** - Storing capsules locked, and why the prescription is deliberately small: a tricyclic overdose is dangerous as other medicines are not. - Dry mouth, in nearly two thirds of children. Offer sugar-free gum, water and a dental check. - Daytime sleepiness early; moving the dose to bedtime is the planned fix. - A realistic timeline: little change in the first fortnight; 2 to 3 weeks between changes. - Reporting any staring spell, fall or convulsion, since seizure is the dose-limiting risk. - Never stopping suddenly, and telling you before planned surgery. - **Advise them to call for:** - New or worsening thoughts of self-harm, or new agitation or hostility. - Any seizure, staring spell, or unexplained fall. - Fainting, near-fainting, or a racing heartbeat. - Fever with sore throat, or rash with fever or facial swelling. - Inability to pass urine, or eye pain with blurred vision or halos. --- ### **References** 1. DailyMed. Anafranil (clomipramine hydrochloride) capsules prescribing information. 2024. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4074b555-7635-41a9-809d-fae3b3610059 2. AHRQ. Obsessive Compulsive Disorders in Children. Effectiveness Review 276. 2024. https://www.ncbi.nlm.nih.gov/books/NBK611136/ 3. AACAP. Practice Parameter, Obsessive-Compulsive Disorder. 2012. https://www.jaacap.org/article/S0890-8567(11)00882-3/fulltext 4. Cochrane. Tricyclic drugs for depression in children. CD002317. 2013. https://www.cochrane.org/evidence/CD002317\_tricyclic-drugs-depressed-children-and-adolescents 5. LactMed. Clomipramine. Drugs and Lactation Database. 2022. https://www.ncbi.nlm.nih.gov/books/NBK501175/ 6. American Heart Association. Cardiovascular monitoring of children on psychotropics. 1999. https://www.ahajournals.org/doi/10.1161/01.cir.99.7.979