Regulatory Decision Summary for Gen-Clozapine

This Supplement New Drug Submission was filed for Gen-Clozapine (clozapine) for an additional dosage form, the orally disintegrating tablet, at the same dose strengths as the currently approved Gen-Clozapine tablets, namely 25 milligram (mg), 50 mg, 100 mg and 200 mg, as well as at a new dose strength of 12.5 mg. Upon review of the submitted data package, Health Canada authorized the orally disintegrating tablet at the five proposed dose strengths, 12.5 mg, 25 mg, 50 mg, 100 mg and 200 mg.

The chemistry and manufacturing information submitted for Gen-Clozapine (Clozapine Orally Disintegrating Tablets 12.5 milligram [mg], 25 mg, 50 mg, 100 mg and 200 mg) has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.

Comparative bioavailability data was reviewed and demonstrated that the Clozapine Orally Disintegrating Tablets 12.5 mg by Mylan Pharmaceuticals ULC met the recommended standards for comparative bioavailability with Clozaril (clozapine) tablets 25 mg, administered as a half tablet (12.5 mg dose). A request for waiver to perform comparative in vivo bioequivalence studies was provided for the 25 mg, 50 mg, 100 mg and 200 mg strengths based on proportionality to the 12.5 mg strength used in the comparative bioavailability study. The waiver request was found acceptable based on review of formulation proportionality across the series of proposed strengths, and the review of the comparative dissolution data. A narrative and table describing the comparative bioavailability study with the Clozapine Orally Disintegrating Tablets 12.5 mg and Clozaril was added in the Product Monograph for Gen-Clozapine.

Other revisions to the Product Monograph included the addition of administration instructions for the orally disintegrating tablets as well as the addition of information on phenylalanine content and a warning about phenylketonuria because all strengths of orally disintegrating tablets contain aspartame, a source of phenylalanine.

The final labelling and Product Monograph were considered acceptable.

Overall, with the revisions made to the Product Monograph for Gen-Clozapine as a result of the addition of the orally disintegrating tablet as a new dosage form, the benefit-harm-uncertainty profile of Gen-Clozapine remained unchanged when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance was recommended.

For further details about Gen-Clozapine, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.