A FATAL DRUG-INTERACTION BETWEEN CLOZAPINE AND FLUOXETINE

A case is presented of a fatal drug interaction caused by ingestion of clozapine (Clozaril(TM)) and fluoxetine (Prozac(TM)), Clozapine is a tricyclic dibenzodiazepine derivative used as an ''atypical antipsycho lic'' in the treatment of severe paranoid schizophrenia. Fluoxetine is a selective serotonin reuptake inhibitor used for the treatment of ma jor depression. Clinical studies have proven that concomitant administ ration of fluoxetine and clozapine produces increased plasma concentra tions of clozapine and enhances clozapine's pharmacological effects du e to suspected inhibition of clozapine metabolism by fluoxetine. Blood , gastric, and urine specimens were analyzed for fluoxetine by gas chr omatography/mass spectrometry (GC/MS) and for clozapine by gas-liquid chromatography (GLC). Clozapine concentrations were: plasma, 4.9 mu g/ mL; gastric contents, 265 mg; and urine, 51.5 mu g/mL. Fluoxetine conc entrations were: blood, 0.7 mu g/mL; gastric contents, 3.7 mg; and uri ne 1.6 mu g/mL. Norfluoxetine concentrations were: blood, 0.6 mu g/mL, and none detected in the gastric contents or urine. Analysis of the b iological specimens for other drugs revealed the presence of ethanol ( blood, 35 mg/dL; vitreous, 56 mg/dL; and urine 153 mg/dL) and caffeine (present in all specimens). The combination of these drugs produced l ethal concentrations of clozapine and high therapeutic to toxic concen trations of fluoxetine. The deceased had pulmonary edema, visceral vas cular congestion,paralytic ileus, gastroenteritis and eosinophilia. Th ese conditions are associated with clozapine toxicity. The combined ce ntral nervous system. respiratory and cardiovascular depression of the se drugs was sufficient to cause death. The death was determined to be a clozapine overdose due to a fatal drug interaction.