The Clozaril REMS: Balancing Risks and Benefits of Clozapine

Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia, but also carries significant safety risks including agranulocytosis, myocarditis, and other side effects. To ensure the risks of clozapine do not outweigh benefits, it is subject to the Clozaril Risk Evaluation and Mitigation Strategy (REMS) in the US and comparable monitoring programs in other countries.

Agranulocytosis Risk

The most serious risk of clozapine is agranulocytosis, a rare but potentially life-threatening drop in white blood cell count (neutropenia). Clozapine is the only antipsychotic to cause agranulocytosis, in 0.38% of patients. To monitor for this, the Clozaril REMS requires:

  • Weekly blood tests for white cell count and ANC for the first 6 months of treatment
  • Biweekly monitoring from 6-12 months
  • 4 weekly monitoring after 12 months if stable
  • More frequent monitoring with dosage changes

If agranulocytosis develops, clozapine must be immediately discontinued and not rechallenged. Granulocyte colony stimulating factor (G-CSF) may be used to boost white cell count.

Myocarditis Risk

Clozapine also confers a risk of myocarditis, inflammation of the heart muscle. The incidence is 1-2% within the first month of treatment. Due to this risk:

  • Patients have a baseline ECG and troponin before starting clozapine
  • Signs and symptoms of myocarditis are closely monitored in the first month
  • Weekly ECG and troponin recommended for some patients in the first month
  • Patients are educated on symptoms to immediately report

Other Monitoring

In addition to blood and heart testing, the Clozaril REMS requires:

  • Metabolic monitoring: Weight, blood pressure, blood sugar, lipids
  • Liver function tests
  • Daily seizure risk assessment
  • Consideration of drug interactions and dosage adjustments
  • Patient and caregiver education on risks, side effects, and monitoring requirements

The goal of the REMS is to allow access to clozapine for patients who need it most while strictly controlling for risks through close clinical management and monitoring. When properly implemented, the likelihood of adverse outcomes can be reduced significantly despite the inherent safety concerns of the drug.

However, the burden of such intensive monitoring also limits more widespread use of clozapine. Safer yet similarly effective alternatives remain urgently needed for most patients with schizophrenia. Ongoing research aims to develop new antipsychotics that retain the superior efficacy of clozapine for treatment resistance but with a side effect and risk profile comparable to safer existing agents. Until then, judicious use of clozapine under careful REMS monitoring will continue for many of the most severely ill patients unresponsive to other treatments.

There are various forms of drugs available, such as tablets or liquids, and each may have a separate patient information leaflet (PIL) for different doses. It is important to refer to the PIL for the specific form and dose of the drug that you have been prescribed.

You can search for further information and PILs on websites such as: