Clozapine-Induced Agranulocytosis in Finland, 1982-2007: Long-Term Monitoring of Patients Is Still Warranted

Objective: Recent studies suggest that restrictions on the use of clozapine should be reassessed considering the risk-benefit ratio. We analyzed all cases of clozapine-induced agranulocytosis reported to the Finnish National Agency for Medicines between 1982 and 2007.

Method: In this retrospective longitudinal study, we defined agranulocytosis as a neutrophil count below 0.5 × 10⁹/L and, accordingly, identified a total of 163 patients with clozapine-induced agranulocytosis. We collected all available information on patient demography, as well as on daily clozapine doses, treatment duration, concomitant medication prior to the onset of agranulocytosis, and infections during the adverse event. The amount of clozapine used annually in Finland was estimated on the basis of the defined daily dose, and the frequency of agranulocytosis was calculated from the absolute number of cases in relation to the defined daily dose each year, as reported by the Finnish National Agency for Medicines.

Results: In 10.3% of cases, agranulocytosis occurred after the second treatment year, and, in some patients, agranulocytosis occurred even after 13, 14, and 22 years of clozapine treatment. Strikingly, a total of 40% of all patients and 80% of those with fatal agranulocytosis had received, concomitantly with clozapine, other medication associated with agranulocytosis.

Conclusions: Some restrictions and long-term blood monitoring during the use of clozapine are still needed. In addition, we raise the question of whether guidelines for concomitant use of drugs associated with agranulocytosis during clozapine therapy are warranted.

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