Regulatory Decision Summary for Mifegymiso

To support the increase of gestational age limit to 63 days, data from three pivotal trials were reviewed. All three trials used a regimen of 200 mg oral mifepristone administered at the clinic followed by 800 mcg buccal misoprostol administered at home. Termination of pregnancy was induced in 94.2 to 96.4% of the 714 women with a gestational age of 50 to 63 days. This regimens efficacy was also supported by the systematic literature review and by post-marketing studies that reported the outcome of 1,773 and 7,577 patients, respectively. Supportive studies also confirmed that the current conditions of use (doses and routes of administration) of mifepristone and misoprostol for pregnancies in this new gestational age group were appropriate. Clinical efficacy was slightly lower in this gestational age group compared to the previously approved patient population with 49 days or less of gestation, although it remained within an acceptable range. Efficacy remained robust in most subpopulations studied in the 50 to 63 days of gestation group, including patients of less than 18 years of age. Patients who have had 4 or more previous pregnancies appeared to have a 2-fold higher risk of treatment failures, which required additional labelling in the Product Monograph.

Mifegymiso efficacy in patients of gestational age of 63 days or less and less than 18 years of age (N = 67 patients) was similar to the adult population, although not as well tolerated, due to more frequent vomiting and more frequent reporting of "pain and bleeding is more than expected". An acceptable treatment failure rate was also noted for an additional 259 patients of less than 18 years of age in post-market safety trials. There are insufficient data in patients less than 15 years old to establish efficacy and safety. Modifications to the product monograph were performed to provide the available data on this patient population.

The risks associated with Mifegymiso in patients with a gestational age of 50 to 63 days were similar to those previously identified. Patients taking Mifegymiso reported frequently experiencing abdominal pain, diarrhea, nausea, vomiting, fever/chills, headache, dizziness and weakness, some of which can be severe and may require oral medication. Rates of occurrence of frequent adverse events and serious adverse events were similar in women with a gestational age of 50 to 63 days compared to lower gestational age groups. Mifegymiso administration induces a significant amount of vaginal bleeding in all women, which may be serious in some and may require intravenous hydration or blood transfusion. A 1-day increase in bleeding duration was noted in the 50-63 days of gestation group compared to 49 days or less. Patients taking Mifegymiso have experienced pelvic infections (endometritis, salpingitis) and may require oral or intravenous antibiotic administration. Some infections may be serious and become life-threatening if not promptly treated.

To support changes to the distribution plan, the sponsor provided post marketing data from Australia where the proposed distribution through retail pharmacies has been in place since 2015. While limited data on direct to patient dispensing was provided, the sponsor reported that no safety concern has been raised with the distribution through retail pharmacies after over a year of marketing. In addition, the efficacy and safety of Mifegymiso was also investigated in 9 studies involving 1,486 patients that were given mifepristone to take at home. In those studies, patients received Mifegymiso from a physician and self-administered mifepristone and misoprostol at home with clear instructions and emergency contact information in case of complications. Although the studies had limitations, the efficacy results were within an acceptable range and no unexpected safety concerns were noted. The risk of harm due to the delay between Mifegymiso prescription and administration is mitigated by safeguards that were implemented in the supporting trials and that are proposed on the Canadian market by Linepharma. Those safeguards include adequate prescriber knowledge of the procedure, adequate information for patients at the time of prescription, adequate documentation given to the patient on the procedure and its side effects and contact information for patients in case they need information after drug product dispensing.

The Risk Management Plan was further modified to better support the practice of medicine and pharmacy determined by each provincial and territorial jurisdiction. Changes included recommending rather than requiring physician training and modifying the requirement to obtain the patients written consent to obtaining an informed consent. In addition, the product monographs Dosage and Administration section was clarified to indicate that copies of the Mifegymiso Patient Medication Information and Patient Medication Card should be completed and provided to the patient.

In summary, labelling was changed to indicate that health professionals should have sufficient knowledge of medical abortion to prescribe Mifegymiso and/or should complete a Mifegymiso education program. An overall product monograph update was also performed to present efficacy and safety data for the patient population with a gestational age of 63 days or less. The term "Doctors" was replaced by "health professionals" throughout the Mifegymiso product monograph as practice of medicine, including who can prescribe Mifegymiso, varies by province. The requirement for patients written consent was modified to informed consent. Previous requirements for the prescribing health professional were maintained, such as screening for gestational age and exclusion of ectopic pregnancy by ultrasound, counselling patients on the Mifegymiso abortion process and its possible complications, scheduling a follow-up appointment, providing all Mifegymiso completed documentation, including contact information for inquiries and for emergency situations.