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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

  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
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