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.
Mr. A was a 79-year-old man with a history of paranoid schizophrenia who was treated as an outpatient with Clozaril (Novartis Pharmaceuticals), 200 mg in the morning and 300 mg at bedtime. Mr. A’s psychosis had been stable with this dose for more than 4 years. During one visit, Clozaril was switched inadvertently to generic clozapine (Mylan Pharmaceuticals). One month later, Mr. A was admitted to the hospital with increasing paranoid delusions of being poisoned as well as failure to thrive after refusing to take anything by mouth for several days. Other causes for his altered mental status were ruled out, and it was concluded that Mr. A’s symptoms were due to an exacerbation of his schizophrenia. Mr. A was discharged 3 days later with the same dose of generic clozapine. He was readmitted the following month for similar symptoms and hospitalized for 10 days. During this admission, Mr. A was switched back to name-brand Clozaril. Two months after his, his psychosis was stable without a need for further intervention.
A pharmacokinetic study comparing the Zenith Goldline Pharmaceuticals product and Clozaril in schizophrenic patients found a significant difference between the mean log-transformed Cmax,ss and that the 90% confidence interval ratio for the Cmax,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.
Pokorny R, Finkel MJ, Robinson WT: Normal volunteers should not be used for bioavailability or bioequivalence studies of clozapine. Pharm Res 1994; 11:1221
Lam YW, Ereshefsky L, Toney GB, Gonzales C: Branded versus generic clozapine: bioavailability comparison and interchangeability issues. J Clin Psychiatry 2001; 62(suppl 5):18–22; discussion, 23–24
Mofsen R, Balter J: Case reports of the reemergence of psychotic symptoms after conversion from brand-name clozapine to a generic formulation. Clin Ther 2001; 23:1720–1731
Sajbel TA, Carter GW, Wiley RB: Converting patients from brand-name clozapine to generic clozapine. Ann Pharmacother 2001; 35:281–284