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Atypical antipsychotic (treatment-resistant schizophrenia) Pregnancy: Use only if absolutely necessary. Neonatal metabolic and EPS effects.

Clozapine

Brand names: Clozaril, Denzapine, Zaponex

Adult dose

Dose: Start 12.5–25 mg once or twice daily; increase gradually to 300–450 mg/day
Route: Oral
Frequency: Twice daily (during titration and maintenance)
Max: 900 mg/day (rarely needed; usual max 600 mg/day)
Start 12.5 mg once or twice on day 1. Increase by 25–50 mg/day over 2–3 weeks to 300–450 mg/day. Titrate slowly to minimise haemodynamic effects. Monitoring mandatory — CPMS or Zaponex/Denzapine treatment system. Clozapine ONLY after failure of 2 antipsychotics.

Paediatric dose

Route: Oral
Frequency: Twice daily
Max: 450 mg/day (adolescents — specialist only)
16–17 years (specialist only, treatment-resistant): start 12.5 mg OD, titrate slowly as for adults. Haematological monitoring identical to adult protocol. Extremely restricted use.

Dose adjustments

Renal

No formal dose adjustment, but use with caution; reduce dose if renal impairment.

Hepatic

Avoid in severe hepatic impairment; use with caution in moderate impairment.

Clinical pearls

  • Only antipsychotic with proven superior efficacy in treatment-resistant schizophrenia
  • Mandatory neutrophil monitoring: weekly for 18 weeks, 2-weekly to 52 weeks, monthly thereafter
  • STOP clozapine if neutrophils <1.5×10⁹/L (amber) or <0.5×10⁹/L (red — do not rechallenge)
  • Smoking cessation can cause clozapine toxicity — monitor levels and reduce dose
  • Clozapine audit (CQUIN) — measure and encourage adherence in community patients

Contraindications

  • History of agranulocytosis or severe granulocytopenia (clozapine-induced)
  • Active bone marrow disorders
  • Severe cardiac disease (myocarditis/cardiomyopathy)
  • Uncontrolled epilepsy
  • Alcoholic or toxic psychosis
  • Paralytic ileus

Side effects

  • Agranulocytosis (1–2% — potentially fatal; requires mandatory haematological monitoring)
  • Myocarditis/cardiomyopathy (rare but serious — especially in first 6–8 weeks)
  • Sialorrhoea (drooling)
  • Sedation
  • Weight gain and metabolic syndrome
  • Constipation and ileus
  • Tachycardia
  • Seizures (dose-dependent — add sodium valproate if high dose)

Interactions

  • Bone marrow suppressants (carbamazepine, antineoplastics) — contraindicated (agranulocytosis risk)
  • Valproate — increases seizure threshold but useful combination for seizure risk
  • Smoking (CYP1A2 inducer) — levels drop significantly if patient stops smoking
  • Fluvoxamine/ciprofloxacin — CYP1A2 inhibitors — significantly increase clozapine levels
  • Benzodiazepines — increased sedation and respiratory depression risk

Monitoring

  • FBC (mandatory CPMS protocol)
  • Fasting glucose and lipids
  • ECG (baseline and at 4 weeks)
  • Troponin (myocarditis screening — weeks 1–4)
  • Clozapine serum levels
  • Weight

Reference: BNFc; BNF; NICE CG178; Clozapine CPMS SPC; Maudsley Prescribing Guidelines 14th ed.. Verify against your local formulary and the latest BNF before prescribing.

Related

Curated clinical cross-links plus same-class fallbacks.

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