Reducing clozapine-related morbidity and mortality: 5 years of experience with the Clozaril National Registry

The Clozaril National Registry (CNR) was created to help protect patients from developing potentially fatal agranulocytosis secondary to treatment with the antipsychotic medicine clozapine. The CNR, designed and maintained by the manufacturer of the branded Clozaril (clozapine), has the principal goals of (1) prophylaxis-preventing inappropriate retreatment, and (2) quality assurance-overseeing adherence to a "no blood, no drug" policy. This article reviews the estimated impact of the CNR on clozapine-related morbidity and mortality over the first 5 years of commercial experience in the United States.

Complete data on leukopenia and agranulocytosis, gathered from the CNR database for the period of 1990-1994, were reviewed and compared with data from the pre-CNR period.

Use of clozapine in 99,502 patients according to package labeling requirements (distribution of the medicine linked to mandated white blood cell count testing) was associated with a total of 382 cases of agranulocytosis (0.38%) versus an expected cumulative total of 995 cases (based on the pre-CNR rate of 1% to 2%). Based on the expected agranulocytosis rate, up to 149 deaths might have been anticipated. Instead, there were only 12 deaths attributed to complications of agranulocytosis.

The CNR provides for universal rechallenge protection as well as controlled dispensing of clozapine. It also serves as an early warning system to promote the safe and effective use of clozapine. The CNR includes quality assurance mechanisms designed to enhance compliance. Despite the added logistic requirements this system places upon physician, pharmacist, and manufacturer, the CNR has helped to reduce substantially potential fatal outcomes. The CNR reinforces both patient and treatment system compliance. Based on this favorable experience concerning agranulocytosis and associated fatalities, the Neuropsychopharmacology Advisory Committee to the U.S. Food and Drug Administration has unanimously recommended a reduction in frequency of the white blood cell count testing requirement after 6 months to every 14 days, instead of weekly. Finally, the CNR database containing white blood cell count and demographic data on every patient in the United States who has received the medicine has served as a unique epidemiologic database.