Regulatory Decision Summary for Lynparza

The recommendation to issue a NOC/c for olaparib tablets in the population of patients with BRCA wild-type status was based upon promising evidence from Study 19 demonstrating superior benefit of olaparib capsules versus placebo in patients with BRCA wild type ovarian cancer. The link between capsule and tablet is based on comparative bioavailability data showing that exposure to olaparib tablets 300 mg twice daily in ovarian cancer patients from SOLO2 was within the range observed in a similar patient population receiving olaparib capsules 400 mg twice daily. Confirmatory evidence of the benefit of olaparib tablets in patients with BRCA wild type status will be derived from the final analysis of the phase IIIb open-label single-arm study (OPINION) in patients with BRCA wild type ovarian cancer receiving olaparib tablets.

The toxicities of olaparib tablets including myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML), pneumonitis, anemia and other important toxicities are substantial and appropriately managed via labelling which highlights these risks. This includes recommendations for enhanced monitoring and dose adjustments, reduced starting doses for patients with moderate renal insufficiency and patients requiring coadministration with strong or moderate CYP3A inhibitors, and warning verbiage throughout the labelling.

Another important safety concern was identified with the dual market availability in Canada of the new Lynparza tablet formulation with the currently approved Lynparza capsules, in relation to possible brand name confusion and risk of medication errors and potential for overdose. It is possible that the same brand name for the tablet and capsule formulations may lead to medication errors if the formulations are used interchangeably given the differences in bioavailability and dosing regimens (two 150 mg tablets twice daily versus eight 50 mg capsules twice daily for the recommended starting dose).

AstraZeneca informed Health Canada about a robust strategy to minimize the risk of medication confusion/ error during the period of dual commercial availability. This risk mitigation strategy involves the Controlled Distribution Program (CDP) and AstraZeneca Oncology Patient Support Program (PSP) associated with the capsule; its implementation is expected to ensure strict surveillance of patients receiving capsules and allow for targeted communication and educational initiatives for prescribers, pharmacies and patients/caregivers.

The following risk mitigation strategies have been agreed to in order to minimize medication confusion errors during dual market availability of Lynparza tablets and capsules: Separate Product Monographs (PMs) and Patient Medication Information sections for the Lynparza tablet and capsule formulations, with these documents maintained separately for the period of dual market availability; Clear and repetitive warnings in each PM about the risk of medication confusion error and the non-interchangeability due to differences in bioavailability and dosing; The capsule PM includes a table which clearly highlights the differences in dosing between the formulations via text and pictorially. Additionally, the capsule PM and Patient Medication Information sections include information about the CDP and AstraZeneca Oncology PSP and the recommendation to prescribers and dispensers to encourage patients receiving capsules to register in the PSP. After careful consideration, these measures along with active surveillance activities are deemed by Health Canada to be adequate at this time to mitigate the risk of medication errors.

Additional strategies specific to the CDP and PSP are captured in the revised Letter of Undertaking dated April 26, 2018 under the sections: Post-Market Safety Monitoring, Active Surveillance and Healthcare Professional Communication. Health Canada has reviewed the CDP and PSP and, at this time, deems these to be acceptable components of the overall risk mitigation strategy for the tablets. With regard to the associated documentation (risk communication, educational material) the Marketed Health Products Directorate (MHPD) will further assess the completeness of the materials and they may be revised post NOC.

Health Canada considers the documentation provided in this Response to Qualifying Notice to be sufficient to recommend approval for Lynparza tablets 100 mg and 150 mg for the BRCA wild type population under the NOC/c policy.

The Benefit Risk profile of Lynparza (olaparib) tablets 300 mg twice daily for use in the maintenance treatment of patients with BRCA wild type (NOC/c) and mutated (NOC) ovarian, fallopian tube or primary peritoneal cancer is considered favourable in this disease setting.