Increasing Psychosis in a Patient Switched From Clozaril to Generic Clozapine

To the Editor:

Since Clozaril’s patent expired in 1998, three generic products have entered the market (Zenith Goldline Pharmaceuticals, Geneva Pharmaceuticals, and Mylan Pharmaceuticals). These products have been deemed by the U.S. Food and Drug Administration (FDA) as therapeutically equivalent to the branded product. However, bioequivalency was based on pharmacokinetic studies utilizing a significantly subtherapeutic clozapine dose of 12.5 mg/day in healthy male volunteers (1) . In the few studies performed in the target population, clinical differences between products have been detected.

A pharmacokinetic study comparing the Zenith Goldline Pharmaceuticals product and Clozaril in schizophrenic patients found a significant difference between the mean log-transformed C _max,ss and that the 90% confidence interval ratio for the C _max,ss of the two products fell outside the FDA’s established range for bioequivalence (2) . In a randomized crossover study of 45 schizophrenic patients, mean Brief Psychiatric Rating Scale and Clinical Global Impression scores were significantly improved with Clozaril compared to the Zenith Goldline Pharmaceuticals generic (3) . Five patients in this study experienced a relapse after switching from Clozaril to a generic, but there were no instances when the switching was in the opposite direction. Several cases of exacerbation of psychosis have been reported with the Zenith Goldline Pharmaceuticals product (3, 4), but this is the first report of worsening psychosis with the Mylan Pharmaceuticals brand, to our knowledge. This case demonstrates the need for careful consideration before switching to a generic product in fragile patients stabilized with Clozaril.