Guidelines for Establishing Bioequivalence

At the time The Mylan Brand of Clozapine was approved, the FDA guidelines allowed products to be studied at a dose of 12.5 mg (1/2 of a 25 mg tablet) in healthy volunteers.  This recommendation was established for safety reasons, because healthy volunteers are extremely sensitive to clozapine and can experience severe bradycardia, cardiac pauses, and cardiac arrest.1

According to established FDA guidelines, new forms of clozapine would be considered bioequivalent if the pharmacokinetic parameters describing rate (Cmax, or peak drug level using log-transformed data) and extent (AUC, or area under the plasma concentration time curve, using log-transformed data) were within ±20% of the results achieved following administration with the Clozaril formulation.1

Results of Bioequivalence Study

Results of an open-label, single-dose, two-period crossover study in fasting, healthy, male volunteers aged 18-50 showed that the mean Cmax and AUC of The Mylan Brand of Clozapine did fall within the 80-125% of those produced by Clozaril.  The variability in values for these pharmacokinetic parameters (determined from the 90, 95, and 99% confidence intervals about mean values) were also within 80-125% of that seen following Clozaril administration.

These results demonstrated that The Mylan Brand of Clozapine delivered clozapine to the systemic circulation in males at the same rate and extent as Clozaril and therefore the FDA determined that the two drugs were bioequivalent and therapeutically equivalent. 

  • Open-label, single-dose, two-period bioequivalence study
  • Single, oral 12.5 mg (one half of a 25 mg tablet) dose administered to fasting, healthy, male volunteers aged 18-50

Do not use clozapine in patients with hypersensitivity to clozapine, myeloproliferative disorders, uncontrolled epilepsy, agranulocytosis, or severe granulocytopenia. Do not use simultaneously with other agents that can cause agranulocytosis or suppress bone marrow function.

* Registered trademark of Novartis Pharmaceuticals Corporation.

Reference: 1. Data on file, Mylan Pharmaceuticals Inc.

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