Clozapine and agranulocytosis: Re-assessing the risks

Objective: The aim of the study was to estimate the maximum incidence of agranulocytosis which clozapine would have caused between 2006 and 2010 had there been no blood monitoring system; and to determine the number of clozapine-associated cases of agranulocytosis and related deaths recorded between 1993 and 2011. Method: Records associating clozapine use with white blood cell deficiency (WBCD), in the Therapeutic Goods Administration's Case Line Listing of adverse drug reactions, were examined. The figure of 11,000 was used as the population on clozapine each year from 2006-2010. Results: Between 2006 and 2010 there were 209 cases of clozapine-associated WBCD recorded, probably caused by clozapine in 141 cases. WBCD caused by clozapine could have progressed to agranulocytosis if clozapine had not been withdrawn. The risk of WBCD/agranulocytosis decreased with increasing duration of clozapine use. Between 1993 and 2011 there were 141 recorded cases of agranulocytosis, and four deaths, from clozapine-associated WBDC. Conclusions: During 2006-2010, without any monitoring system, the maximum annual incidence of agranulocytosis caused by clozapine would have been 0.26%. The risks of agranulocytosis, and related deaths, decreased with length of time on clozapine. During 1993-2011 141 cases of agranulocytosis, with four deaths, were recorded in association with clozapine use. The monitoring system could have successfully prevented relatively few deaths.