Regulatory Decision Summary for Nexplanon

Nexplanon (etonogestrel) is a Long Acting Reversible method of Contraception (LARC). LARCs can be defined as acting continuously for several years.

Upon review of the bioequivalence data, this New Drug Submission (Control #226314) for Nexplanon (68 mg etonogestrel) subdermal implant by Merck Canada Inc. was considered to meet the requirements of the Food and Drug Act and Regulations insofar as the comparative bioavailability information presented is concerned.

Safety concerns identified in the NON (issued for the original NDS submission, Control #136842) included breast cancer, uterine bleeding, vascular complications, metabolism and progressive weight gain, and insertion/removal-related events. Regarding the safety concerns of breast cancer and insertion/removal-related events, it was found that the evidence submitted supports the overall favourable safety profile of etonogestrel subdermal implant with respect to these concerns, in appropriately-chosen patients.

For efficacy and safety, clinical data obtained from studies conducted with Implanon (non-radiopaque implant) were extended to Nexplanon (radiopaque implant). In addition, results of a Phase IV-Nexplanon Observational Risk Assessment Study as well as post-marketing experience data were considered.

In clinical trials using the non-radiopaque implant for up to 3 years in duration, 923 subjects (18-40 years of age at entry) were studied. This accounted for 1,756 women-years of use with the non-radiopaque etonogestrel implant (Implanon). The total exposures expressed as 28-day cycle equivalents by study year were: Year 1: 10,866 cycles, Year 2: 8,581 cycles, and Year 3: 3,442 cycles. The clinical trials excluded women who weighed more than 130% of their ideal body weight, and who were chronically taking medications that induce liver enzymes.

In the subgroup of women 18-35 years of age at entry, 6 pregnancies during 20,648 cycles of use were reported. Two pregnancies occurred in each of Years 1, 2, and 3. Each conception was likely to have occurred shortly before or within 2 weeks after removal of the non-radiopaque etonogestrel implant. With these 6 pregnancies, the cumulative Pearl Index was 0.38 pregnancies per 100 women-years of use.

In a clinical trial using the radiopaque implant (Nexplanon), the mean insertion time for 301 insertions (from the removal of the protection cap of the applicator until retraction of the needle from the arm) was 27.9 ± 29.3 seconds. After insertion, 300 out of 301 (99.7%) Nexplanon implants were palpable. The single, non-palpable implant was not inserted according to the instructions. For 112 out of 114 (98.2%) subjects in 2 clinical trials for whom insertion and removal data were available, Nexplanon implants were visible with use of two-dimensional x-ray after insertion. The two implants that were not clearly visible after insertion were visible with two-dimensional x-ray before removal.

Important identified risks of Implanon/Nexplanon include complications of insertion and removal procedures: incorrect insertion, implant migration (including intravascular migration), implant expulsion, difficult localization and difficult removals. Complications related to insertion and removal procedures also include bruising, local irritation, pain or itching, paresthesias or paresthesia-like events, bleeding, hematoma, infection or abscess, scarring and fibrosis at the implant site.

Other adverse events reported include changes in menstrual bleeding patterns, unintended pregnancies, venous thromboembolic events, cerebrovascular accidents, breast cancer, ectopic pregnancies (on rare occasions), liver disease and broken or bent implants (there have been reports of broken or bent implants while in the patient’s arm).

A Risk Management Plan (RMP) for Nexplanon will monitor described known and potential safety issues and minimise risks associated with the product. To manage important identified risks regarding implant migration, HCP training regarding insertion and removal was included as a serious warning and precaution, as was the guidance regarding the localization and removal of non-palpable implants as soon as medically appropriate.

A Patient Alert Card has been designed by the Sponsor to record the date of insertion, the arm used for insertion, and the lot number. The Patient Alert Card is considered an additional risk minimization measure as the card serves as a reminder to patients to seek medical assistance should they not be able to palpate their implant at any time.

Overall, based on the information in the submissions, and supported by clinical experience and pharmacovigilance activities in other jurisdictions over two decades, the available evidence supports a positive benefit-risk balance for Nexplanon, in appropriately-chosen patients, when it is prescribed under the conditions of use recommended in the Product Monograph (PM).