Extensive elevation of creatine kinase with generic clozapine, but not with Leponex

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Mr. M., a 27-year-old man, was hospitalized due to an exacerbation of his paranoid schizophrenia persisting for 8 years. Laboratory tests, a magnetic resonance imaging scan and an electroencephalogram revealed no indication of an organic cause of his recurrent psychotic symptoms. When the patient was earlier treated with several atypical as well as typical antipsychotics, either inadequate symptom control, or multiple adverse effects such as severe sleepiness, extrapyramidal motor side effects and sexual dysfunction were observed. Therefore we decided to treat him with clozapine. At that point, all laboratory results including creatine kinase (CK) (47 U/l) werewithin the normal range. After 5 days of upwardly titrating the dose of a generic manufactured clozapine to 50 mg, an increase of CK up to 1219 U/l was noted in a routine blood test. The patient did not receive concomitant medication. The increasing CK was not related to trauma or excessive muscle activity. Another blood sample taken 24 h later showed that the CK had risen further to 2763 U/l. Therefore, we stopped the generic clozapine at 50 mg. Despite discontinuation of the treatment with generic clozapine, CK levels continued to increase up to 3644 U/l within the next 2 days. To prevent acute kidney failure, treatment with sodium-chloride infusions 4 l/daywas instituted. The CK tapered off to normal levels over the next 6 days. This was the first time the patient had developed CK elevation while receiving antipsychotic treatment. Suspecting that the increase of CK was due to the generic clozapine and considering the patient's chronicity and earlier resistance to treatment, we decided to start antipsychotic treatment again with clozapine, but this time using Leponex. After upward titration of Leponex to a maximum of 300 mg/day, daily blood samples showed the CK levels to be within normal range. Studies have been examining the differences between Leponex and generic clozapine since the Leponex patent was extended in 1998. Concerning side effects, generic clozapine was not associated with an increase in reported adverse effects compared with Leponex in general. However, several studies showed differences in bioequivalence and interchangeability between Leponex and generic clozapine. Furthermore, it has been reported that these differences in bioequivalence might have consequences for the pharmacokinetic profile that result in a higher maximum plasma concentration leading to increased or emergent adverse effects. CK elevations related to clozapine treatment have been reported several times before. To our knowledge this is the first case in which an adverse effect associated with generic clozapine disappeared after changing the treatment to Leponex. We therefore suggest that due to certain risk factors, such as genetic variety or enzyme dysfunctions, differences in bioequivalence and interchangeability occur. These differences might lead to an individual tolerability and adverse effect profile. If CK elevation is observed during clinical monitoring in treatment with generic clozapine, switching to Leponex treatment might be a satisfactory choice.