Clozaril (clozapine) is the only medication that requires routine blood monitoring to detect a rare but serious side effect known as agranulocytosis, a sharp drop in white blood cells which increases the risk of dangerous infections. As such, regular blood tests are mandatory to ensure this potentially life-threatening complication is identified early.
Agranulocytosis Risk
Clozaril causes agranulocytosis by suppressing the bone marrow’s production of granulocytes, a type of white blood cell (WBC) that fights infection. The incidence is 0.8% with weekly monitoring, but increases to 3% without monitoring. Agranulocytosis usually occurs within 6 months, although it can develop at any time throughout treatment.
Clozaril Risk Evaluation and Mitigation Strategy (REMS)
Due to risks, Clozaril has a strict REMS program including:
- Baseline WBC and absolute neutrophil count (ANC) before starting Clozaril. Normal ranges are 3.5-11 x 10^9 cells/L and 2.0-7.5 x 10^9 cells/L respectively.
- Weekly blood tests for 18 weeks, then biweekly up to 1 year. After 1 year and stable, monitoring reduces to monthly but must continue lifelong.
- Immediately stop Clozaril if WBC <3.0 or ANC <1.5. Do not rechallenge.
- Withhold Clozaril and repeat bloods if WBC 3.0-3.5 or ANC 1.5-2.0. May restart after levels increase if approved by the Novartis Clozaril National Registry.
- Reduce dose or withhold Clozaril if WBC >15.0 or ANC >11.0 to avoid toxicity. Resume at a lower dose once levels decrease to within range.
- Report results to registry within 2 weeks to continue accessing Clozaril. Alert registry immediately if out of range values.
- Educate patients and caregivers on risks and importance of blood monitoring compliance. Intervening at the Earliest Signs
Prompt intervention is critical once reduced blood cell counts are detected to avoid infection and serious complications. Options include: - Immediately stop Clozaril and do not rechallenge if neutrophil count <1,500 cells/μL or lowers over successive tests. The risk of agranulocytosis is too high.
- Granulocyte colony stimulating factor (G-CSF) to stimulate bone marrow if levels 1,000-1,500 cells/μL. Temporarily withhold Clozaril, then may restart at lower dose if levels rise and remain stable. However, recurrence risk with rechallenge is high.
- Prophylactic antibiotics and very close monitoring if levels marginally reduced but still over 1,500 cells/μL. Withhold Clozaril at discretion of prescribing psychiatrist based on clinical status.
- Hospitalization for isolation and management may be required, especially if fever or other signs of infection are present along with reduced WBCs. IV antibiotics will be administered and all drugs with potential bone marrow toxicity ceased.
In summary, routine blood cell count monitoring remains the only way to mitigate risks with Clozaril and avoid delaying identification and treatment of agranulocytosis or related complications. Strict compliance with the REMS program is essential to accessing this vital medication and ensuring patient safety is maximized based on close clinical supervision and early medical intervention where required.