Summary Basis of Decision for Mifegymiso

Clinical Pharmacology

Mifegymiso (one mifepristone 200 mg tablet and four misoprostol 200 µg tablets) is indicated for medical termination of a developing intra-uterine pregnancy with a gestational age up to 49 days as measured from the first day of the Last Menstrual Period (LMP) in a presumed 28-day cycle.

When mifepristone blocks progesterone receptors, the endometrium can no longer sustain the growing embryo. Without the effect of progesterone, the lining of the uterus breaks down, and bleeding begins. Mifepristone also triggers an increase in prostaglandin levels and dilates the cervix, facilitating abortion. Misoprostol then induces contractions of the smooth muscle fibres in the myometrium, relaxation of the uterine cervix, and evacuation of intrauterine contents.

Mifepristone is a new chemical entity in Canada, although not a first in class, since ulipristal acetate, another progesterone antagonist, was recently approved to treat symptoms of uterine fibroids and as an emergency contraceptive. Misoprostol is not a new chemical entity in Canada, since it was previously approved for the treatment and prevention of gastroduodenal ulcers induced by a nonsteroidal anti-inflammatory drug (NSAID) and for the treatment of duodenal ulcers caused by peptic ulcer disease, at the same dose.

No clinical pharmacology studies were performed by the sponsor, apart from three bioequivalence studies establishing a relationship between Mifegymiso and Mifeprex mifepristone (approved in the United States), Mifegyne mifepristone (approved in Europe), and Cytotec misoprostol (approved in the United States). Instead, published studies provided sufficient information to establish an acceptable pharmacodynamic and pharmacokinetic profile of mifepristone and misoprostol. Mifepristone binds principally to alpha 1-acid glycoprotein in plasma. The primary pathway of mifepristone metabolism is hepatic through the cytochrome P450 (CYP) enzyme CYP3A4 which results in three principal metabolites, which are weakly active toward the progesterone receptor (10-20% affinity compared to the parent drug). The primary pathway of mifepristone excretion is biliary, as 90% of a dose mifepristone was excreted through the faeces. The elimination half-life was reported between 18 to 54 hours in the literature and was reported as 38.4 and 36.5 hours in two bioequivalence studies performed by the sponsor. Misoprostol pharmacokinetic proprieties were based on the approved Canadian product monograph of misoprostol. After absorption, misoprostol is rapidly de-esterified in human plasma to misoprostol acid (the active metabolite). Misoprostol acid is subject to β-oxydation to more polar inactive compounds that are excreted mostly by the kidney (64-73%). Overall, the pharmacology profiles were consistent with the non-clinical findings.

Mifepristone was shown to be a potent antagonist at the progesterone receptor which allows for mifepristone to be used in the medical termination of pregnancy. It also has some affinity for the glucocorticoid receptor and a weak affinity for the androgen receptor, although those are not clinically relevant in women with normal adrenal function at the proposed dosage. Misoprostol is a prostaglandin analogue that binds to the prostaglandin E receptors and stimulates contractility of smooth muscles, including the uterine myometrium. The pharmacodynamic studies also indicated that misoprostol was active when administered by the oral, vaginal, buccal, and sublingual routes. The uterine response appeared to be greater after buccal, vaginal, or sublingual misoprostol than oral misoprostol administration. These differences in misoprostol bioactivity between its varying routes of administration are consistent with the differences in misoprostol clinical efficacy for termination of pregnancy noted in the systematic review of published studies, where buccal, vaginal, or sublingual misoprostol administration had generally a higher efficacy than oral misoprostol. The buccal route of administration proposed by the sponsor for misoprostol administration in Mifegymiso is supported by its efficacy and safety in the pivotal studies.

The sponsor identified three clinical pivotal studies (Study 1, Study 2 and Study 3, discussed in the Clinical Efficacy section and the Clinical Safety section) that were the most representative of the expected performance of Mifegymiso. Because the three studies were conducted by a third-party, it was necessary to demonstrate that the drugs used in these studies were equivalent to the one proposed for marketing approval (Mifegymiso).

Study CAL052015-001 demonstrated that the Linepharma’s mifepristone 200 mg tablets met the recommended standards for bioequivalence in comparison to the Mifeprex 200 mg tablets (marketed in the United States) used in two of the three identified pivotal clinical studies (Study 1 and Study 2), when administered orally in healthy female volunteers under fasting conditions. Linepharma’s mifepristone was used in the Study 3 pivotal study. Therefore, the three pivotal studies were considered to reliably represent the in vivo performance of Linepharma’s mifepristone.

Study JEI308 demonstrated that the Linepharma’s misoprostol 200 µg tablets met the recommended standards for bioequivalence in comparison to Cytotec 200 µg tablets used in two of the three identified pivotal clinical studies (Study 1 and Study 3), when administered orally in healthy female volunteers under fasting conditions. A generic of Cytotec approved in the United States was used in the Study 2 pivotal study. Linepharma’s misoprostol bridging was considered sufficiently robust for regulatory approval. Many factors were taken into consideration, such as it is an active substance with a well-established safety profile in Canada, its therapeutic index is wide, it is highly soluble and bioavailable, it is formulated as a simple immediate-release tablet, it is administered as a single-dose, and it has a short half-life with simple pharmacokinetics. The likelihood of a different buccal bioavailability considering the oral bioequivalence was low. The risk of this hypothetical difference making a clinically meaningful efficacy impact on the Canadian market was considered acceptable, considering the efficacy shown in 5,356 patients enrolled in the Mifegymiso Australian post-market study. Overall, the clinical pharmacological data supported the use of Mifegymiso for the specified indication.

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

Clinical Efficacy

The clinical efficacy of Mifegymiso (a combination product of a 200 mg mifepristone tablet and four 200 µg misoprostol tablets) for the purpose of terminating pregnancies with a gestational age up to 49 days was based on two randomized open-label studies and one single-arm study. The inconsistencies in the design of the studies, such as time interval between mifepristone and misoprostol, were addressed in the sponsor’s submission.

The three pivotal studies enrolled a total of 934 patients with a gestational age of 49 days or less. Study 1 reported a rate of completed termination of pregnancy without surgery for the targeted population of 95.2% [number of patients (N) = 146] for buccal misoprostol. Study 2 reported a rate of completed termination of pregnancy without surgery for the gestational age 49 days or less population of 97.3% (N = 214) with buccal misoprostol. Study 3 reported a rate of completed termination of pregnancy without surgery for the targeted population of 98.0% (N = 551) for buccal misoprostol. Together, the efficacy of a 200 mg mifepristone followed by 800 µg buccal misoprostol regimen in the gestational age group of 49 days or less is well supported by the pivotal clinical study package. The efficacy rates were robust considering the minimal effect of different sensitivity analyses and the consistent efficacy in different age, race, and gravidity status. It is noted that two studies were allowing a second dose of misoprostol in case of an incomplete abortion (persistent non-viable pregnancy) at follow-up (Study 2 and Study 3), although data on such a practice indicated that only 8 patients in the buccal misoprostol group with a gestational age of 49 days or less opted for this option (buccally) and 7 (87.5%) of them had successful termination of pregnancy without surgery and one required a subsequent surgical intervention.

Linepharma provided the full description of its secondary endpoints for the three studies, including stratification for gestational age. The median time to expulsion of patients with a gestational age of 49 days or less was between 4 to 5 hours following buccal misoprostol. The average bleeding time was 11.4 days in the buccal group, including about 2 days of heavy bleeding, 4.5 days of normal bleeding, and 5 days of spotting. Patients reported pain perception to be “less pain than expected” in 46.0% of cases and “more than expected” in 25.1% of cases. Bleeding was reported as “more than expected” in 22.3% of patients.  

Other regimen parameters not tested in the pivotal studies, such as doses of mifepristone and misoprostol and time interval between mifepristone and misoprostol were resolved by a critical review of the literature, which provided support for the proposed conditions of use negotiated with the sponsor.

In Study 3, 35 patients of less than 18 years of age were included in the study. The rate of patients with successful termination of pregnancy without surgery was 100%. A total of 27 patients of less than 18 years of age and a gestational age of 49 days or less were enrolled in the Australian Authorised Prescriber Program and were administered mifepristone and misoprostol in the currently approved conditions of use. In those patients, 100% had successful termination of pregnancy without surgery. Linepharma presented the outcome of 64 patients with less than 18 years of age enrolled in an Australian post-market study. Among them, 62 (96.9%) had successful termination of pregnancy without surgery. Two women reported persistent vaginal bleeding due to incomplete abortion requiring surgical termination of pregnancy. Based on the data in patients less than 18 years of age, the efficacy in this population is comparable to the adult population.

During the original filing of this New Drug Submission (NDS), the proposed indication by the sponsor was: “Mifepristone Linepharma 200 mg/GyMiso 200 µg tablets (mifepristone/misoprostol) are indicated in sequential combination in females of childbearing age for medical termination of a developing intra-uterine pregnancy up to 49 days of gestation.”

Following the review of the submission, Health Canada revised the indication to:
“Mifegymiso (mifepristone tablet/misoprostol tablets) is indicated for medical termination of a developing intra-uterine pregnancy with a gestational age up to 49 days as measured from the first day of the Last Menstrual Period (LMP) in a presumed 28-day cycle.”

In the Response to the Notice of Non-Compliance (NON), the sponsor satisfactorily addressed all of the issues stated in the NON and the submission was found to be in compliance with the Food and Drugs Act and Regulations. The clinical pivotal studies along with the bioequivalence studies, and the literature package support the use of Mifegymiso for the specified indication.

For more information, refer to the Mifegymiso Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Mifegymiso (a combination product of a 200 mg mifepristone tablet and four 200 µg misoprostol tablets) for the purpose of terminating pregnancies of gestational age up to 49 days was based on three pivotal studies and a literature package.

Study 1 was a randomized open-label study conducted in two sites in the United States. It compared the efficacy and safety of 800 µg buccal misoprostol 24 to 72 hours after 200 mg oral mifepristone in 143 women with a gestational age of 49 days or less. The investigators collected adverse events (AEs) based on a list of 8 predefined events. The most frequent AEs were pain (92%), nausea (68%), weakness (56%), dizziness (45%), headache (42%), fever (39%), diarrhea (36%) and vomiting (29%). The concomitant medications list provided by the sponsor indicated that 1.4% of patients took antibiotics prophylactically or as-needed based on symptoms in the buccal misoprostol group.

Study 2 was a randomized open-label study conducted in seven sites in the United States and compared the efficacy and safety of 800 µg buccal misoprostol 24 to 36 hours after 200 mg oral mifepristone in 204 women with a gestational age of 49 days or less. The most frequent AEs were nausea (64%), weakness (46%), chills (37%), dizziness (36%), vomiting (34%), headache (33%) and diarrhea (32%). The concomitant medications list provided by the sponsor indicated that approximately 30% of patients took antibiotics prophylactically or as-needed based on symptoms.

Study 3 was a single-arm prospective study conducted in three sites in Mexico and investigated the efficacy and safety of 800 µg buccal misoprostol 24 to 48 hours after 200 mg oral mifepristone in 551 women with a gestational age of 49 days or less. The most common AEs reported in the study were diarrhea (59%), fever/chills (44%), nausea (31%), vomiting (22%), weakness (20%), headache (12%) and dizziness (13%). The most frequent severe AEs were vomiting (20%), fever/chills (20%) and headache (17%). “Other” AEs were reported and included single cases of anxiety/irritability/depression, dry throat, rash, hypotension, flu, difficulty breathing, hands fell asleep, and hunger.

Vaginal bleeding and abdominal pain were experienced by participants. No deaths occurred during the pivotal studies. Unscheduled visits to the clinic were due mostly to persistent bleeding. Suspected infections were reported at 0-0.21% in the pivotal studies and patients were treated with oral or intravenous antibiotics. Serious AEs included mostly persistent heavy bleeding, but also included single cases of pulmonary embolism, ruptured ectopic pregnancy, and right hip pain that were found unrelated to the study drug. Cases of heavy bleeding requiring an unscheduled clinic visit in the patient population with a gestational age of 49 days or less were reported at rates between 3.3% and 5.5% of patients.

Overall, all missing safety endpoints notified to Linepharma as part of the Notice of Non‑Compliance dated December 18, 2014 were provided and reviewed, providing a complete safety profile of the proposed regimen used in the proposed conditions of use.  

The efficacy and safety of Mifegymiso were investigated in patients less than 18 years of age with a pregnancy with a gestational age of 49 days or less (35 in pivotal studies and 91 in post-market studies). The rate of patients less than 18 years of age with successful termination of pregnancy without surgery was 100% in the pivotal studies and 96.9% in the two post-market studies. In post-market studies, two women reported persistent vaginal bleeding due to non-viable pregnancy or gestational sac seen on ultrasound at follow-up and treated by surgical abortion. Based on the data in patients less than 18 years of age, the efficacy and safety in this population are comparable to the adult population. Women less than 18 years of age reported vomiting nearly twice as frequently as women 18 years and older. In addition, patient-reported pain score and the rate of patients reporting “more pain than expected” were higher in patients less than 18 years of age than in adult patients. Bleeding perception compared to expectation was also slightly higher in the pediatric population. The outcome of women less than 18 years of age taking Mifegymiso has been included in the Product Monograph.

Periodic safety update reports were reviewed for Linepharma mifepristone and misoprostol and provided an estimation of Linepharma’s mifepristone use world-wide (216,506 patients) along with adverse drug reactions associated with its use. Linepharma’s misoprostol patient exposure is estimated to be 362,424 patients in France and Australia.

The Australian Authorised Prescriber Program (N = 4,488) and Australian post-market study (N = 8,165) reported a Mifegymiso safety profile consistent with the one observed in the pivotal studies.

Serious risks are described in a Serious Warnings and Precautions Box within the Mifegymiso Product Monograph. Included are the risks of infection and sepsis, bleeding and embryotoxicity for an ongoing pregnancy (treatment failure) or any immediate subsequent pregnancy. Patients are warned to expect an immediate return to fertility after Mifegymiso administration. A warning that all patients should be followed by a physician 7 to 14 days after taking mifepristone to confirm safety and complete pregnancy termination is also included.

The updated labelling, education and distribution programs, along with the Risk Management Plan will help ensure safe use of the product.

Linepharma International Limited has agreed to implement the following post-authorization commitments:

• a Restrictive Distribution and Administration Program;
• an Education and Registration Program for Mifegymiso prescribers;
• a Canadian Phase IV observational study of Mifegymiso safety;
• a 24-hour support‑line in both English and French for patients taking Mifegymiso;
• a Patient Consent Form to be provided to each patient by the authorized prescriber;
• a Patient Medication Information and a Patient Information Card be provided to each patient by the authorized prescriber.

The Restricted Distribution Program would necessitate that only registered physicians, having successfully completed the education program, would prescribe and provide Mifegymiso to patients, and would supervise the patient’s administration of mifepristone. This measure would minimize the likelihood of incorrect drug intake, and associated health risks, and support the efficacy of the product. This distribution pattern is consistent with the recommended setting in other international jurisdictions in which mifepristone and misoprostol are approved for termination of pregnancy of a gestational age of 49 days or less. In addition, it is the conditions in which Mifegymiso was provided to patients in the three pivotal studies that were used to support the approval decision.

Overall, the sponsor addressed the deficiencies and safety concerns noted in the Notice of Deficiency (NOD) and Notice of Non-Compliance (NON). The safety profile of Mifegymiso is considered acceptable and manageable for the medical termination of a developing intra-uterine pregnancy up to 49 days since the first day of the last menstrual period in women of childbearing age.

For more information, refer to the Mifegymiso Product Monograph, approved by Health Canada and available through the Drug Product Database.