Anafranil

(clomipramine hydrochloride)
Anafranil (clomipramine hydrochloride); not controlled
Full Prescribing Information
DailyMed Drug Information
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, Prozac and Luvox 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, Prozac or Luvox 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
DailyMed. Anafranil (clomipramine hydrochloride) capsules prescribing information. 2024. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4074b555-7635-41a9-809d-fae3b3610059
AHRQ. Obsessive Compulsive Disorders in Children. Effectiveness Review 276. 2024. https://www.ncbi.nlm.nih.gov/books/NBK611136/
AACAP. Practice Parameter, Obsessive-Compulsive Disorder. 2012. https://www.jaacap.org/article/S0890-8567(11)00882-3/fulltext
Cochrane. Tricyclic drugs for depression in children. CD002317. 2013. https://www.cochrane.org/evidence/CD002317_tricyclic-drugs-depressed-children-and-adolescents
LactMed. Clomipramine. Drugs and Lactation Database. 2022. https://www.ncbi.nlm.nih.gov/books/NBK501175/
American Heart Association. Cardiovascular monitoring of children on psychotropics. 1999. https://www.ahajournals.org/doi/10.1161/01.cir.99.7.979