Monitoring clozapine use in adults and young people

Clozapine is associated with significant adverse effects, including:

  • the adverse effects listed in Approximate relative frequency of common adverse effects of antipsychotics
  • neutropenia in 2 to 3% of patients and agranulocytosis in 1% of patients, which are associated with an increased risk of febrile neutropenia and mortality
  • myocarditis in 3 to 8% of patients, usually occurring in the first 3 months of treatment
  • cardiomyopathy in up to 1% of patients after 1 year of treatment
  • gastrointestinal hypomotility ranging from constipation to bowel perforation and death
  • hypersalivation and swallowing difficulties, which (combined with neutropenia and agranulocytosis) may increase the risk of respiratory infection
  • seizures, particularly at blood concentrations higher than 600 micrograms/L.
It is crucial to monitor for, prevent and address these adverse effects. For advice on monitoring, preventing and managing the adverse effects listed in Approximate relative frequency of common adverse effects of antipsychotics, see Antipsychotic adverse effects. In addition, monitor for, prevent and manage clozapine-specific adverse effects, as follows:
  • neutropenia and agranulocytosis—measure white cell and neutrophil counts and check for signs of infection (ie temperature, heart rate, blood pressure) weekly for the first 18 weeks of treatment, then monthly. White cell count must be more than 3.5 × 109/L, and neutrophil count must be more than 2.0 × 109/L
    • if white cell count is 3.0 to 3.5 × 109/L or neutrophil count is 1.5 to 2.0 × 109/L, check for signs of infection and white cell and neutrophil count twice weekly until these blood tests normalise
    • if white cell count is less than 3.0 × 109/L or neutrophil count is less than 1.5 × 109/L, stop clozapine, inform the manufacturer and start another antipsychotic to prevent rebound psychosis—seek psychiatrist advice. Check for signs of infection and white cell and neutrophil count twice weekly until these blood tests normalise. Do not restart clozapine unless an alternative cause of the blood dyscrasia is identified (eg viral infection, reaction to another drug) and the clozapine manufacturer approves restarting
  • myocarditis and other cardiac events—measure temperature daily for the first 28 days of treatment, and perform weekly electrocardiogram (ECG), and C-reactive protein (CRP) and troponin levels. Thereafter, urgently perform an ECG, and measure CRP and troponin levels if the patient has a fever (38°C or higher)
    • if significant cardiac pathology is identified, arrange urgent transport to hospital by ambulance
    • if significant cardiovascular symptoms occur (eg chest pain, heart rate more than 120 beats per minute), depending on severity, urgently perform an ECG, and measure CRP and troponin levels, or arrange immediate transport to hospital by ambulance; see also Assessment of acute chest pain of possible cardiac origin. If myocarditis occurs, stop clozapine and start another antipsychotic to prevent rebound psychosis—seek psychiatrist advice. Do not restart clozapine unless an alternative cause of myocarditis is likely (eg viral myocarditis) and the clozapine manufacturer approves restarting
  • cardiomyopathy—check for signs of heart failure monthly and perform an annual echocardiogram. If cardiomyopathy is identified, discuss the harms and benefits of continuing clozapine with a cardiologist and the patient
  • constipation—at each review (ie at least monthly) ask about the patient’s bowel habits and recommend diet and lifestyle interventions that may relieve constipation. If a laxative is required, see here.

Measure the trough clozapine blood concentration (using a sample taken early in the morning) when steady state has been reached (ie the patient has been on the same dose for at least 1 week) then every 6 months. Additional monitoring is required if the patient:

  • does not respond to therapy
  • is suspected to be poorly adherent
  • experiences a severe adverse effect
  • is of advanced age
  • has a medical condition (especially liver disease, infection or inflammation)
  • starts or stops taking an interacting drug
  • starts or stops smoking
  • changes their caffeine intake.

Clozapine blood concentrations should be taken weekly after a change in smoking status, caffeine intake or interacting drugs. If dosage adjustment is required, it should be guided by the psychiatrist to achieve the target concentration (usually between 200 to 550 micrograms/L, but up to 1000 micrograms/L for patients who do not respond). Rapid dose increases, doses more than 600 mg daily and a clozapine blood concentration more than 600 micrograms/L are associated with a higher incidence of seizures.

Infection can significantly increase clozapine blood concentrations, which can suppress white cell counts and make infection difficult to recognise. If a patient displays signs of clozapine toxicity (eg sedation, confusion, myoclonus), measure CRP, and white cell and neutrophil counts to assess for infection.