Regulatory Decision Summary for Corzyna

This Supplement to a New Drug Submission was filed to obtain market authorization pursuant to Section C.08.004 of the Food and Drugs Regulations for Corzyna (ranolazine extended-release tablets) to expand the current authorized indication and to add two new strengths, 375 milligrams (mg) and 750 mg.

This submission was filed as a Submission Relying on Third-Party Data according to the Guidance Document: Drug Submissions Relying on Third-Party Data (Literature and Market Experience).

Upon review of the submitted data package, there was insufficient evidence to support the use of ranolazine as a monotherapy (new indication) however Health Canada authorized the new strengths, 375 and 750 mg ranolazine twice daily.

To support the expansion of the indication to include the use as a monotherapy, one published randomized controlled clinical trial (MARISA study) was considered pivotal and assessed. The MARISA study was a double-blind four-period crossover study, with 191 angina patients receiving one of three doses of ranolazine (500, 1,000, or 1,500 milligrams [mg]) or placebo, each administered twice daily for one week. The primary efficacy endpoint was exercise duration at trough. The safety endpoint reported was adverse events observed during the study. The study was too brief to permit an adequate benefit-harm-uncertainty assessment of a drug used to treat a chronic condition and the sponsor was requested to respond to major concerns about this study. When responding to the major objection comment from Health Canada, the sponsor withdrew the monotherapy claim and retained the initially authorized indication, restricting ranolazine use as an add-on therapy which was acceptable.

To support the addition of two new strengths (375 mg and 750 mg) to the current dosing regimen of ranolazine up to 1,000 mg twice daily, the sponsor provided clinical evidence from published pivotal and supportive studies. Additionally, the fact that these two new strengths of ranolazine have been marketed in Europe for more than 10 years also contributed to support the new dosing regimen. The evidence submitted was sufficient to support the initial dosing at 375 mg twice daily for special populations who cannot tolerate the 500 mg initial dose (e.g., concomitant use of drugs transported or inhibited by P-glycoprotein or moderate CYP 3A4 Inhibitors) as well as the intermediate efficacious dose of 750 mg ranolazine twice daily.

The Product Monograph was reformatted to the Master Template.

The sponsor provided comparative bioavailability studies to bridge the proposed strengths to the comparator product administered in the published pivotal safety and efficacy studies. All pivotal studies met the applicable bioequivalence standards for ranolazine on log transformed parameters calculated from measured data. Based on the totality of the pharmacokinetic and biopharmaceutics data, as well as composition and in vitro comparative dissolution data, the proposed strengths of 375 mg and 750 mg extended-release tablets were bioequivalent to the respective strengths used in the studies.

The chemistry and manufacturing review for the proposed new 375 mg and 750 mg strengths identified the need for an updated nitrosamine risk assessment and confirmatory testing for the nitrosamine impurities identified or suspected. The sponsor provided the updated assessment and a confirmatory testing of Nitroso-Ranolazine in the drug product. Low levels of this impurity (less than 10% of the acceptable intake, i.e., 400 nanograms per day based on maximum daily dose, were observed. The sponsor also updated the strategy for future product control as recommended by Health Canada.

Overall, the benefit-harm-uncertainty profile was favorable for Corzyna including new dosage strengths 375 mg and 750 mg for the approved indication when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance was recommended.

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