Regulatory Decision Summary for Ringza

The purpose of this New Drug Submission (NDS) for Ringza (segesterone acetate/ethinyl estradiol, 103 mg/17.4 mg contraceptive vaginal system) (i.e. Ringza slow-release ring) was to seek regulatory approval for prevention of pregnancy in women of reproductive potential.

The approved indication, following review, was:

“Ringza (segesterone acetate and ethinyl estradiol vaginal system) is indicated for use by women of reproductive potential to prevent pregnancy.

Ringza has not been adequately studied in women with a Body Mass Index (BMI) > 29.0 kg/m²”.

Two independent, multicentre, open-label, 13 cycle (52 weeks) phase 3 clinical trials (Studies 300A and 300B) were conducted with a primary objective to determine the contraceptive efficacy and safety of Ringza as a new drug delivery system for contraception when used for up to 13 consecutive cycles. The secondary objectives were to assess the cycle control, bleeding patterns, and acceptability of Ringza. A single Ringza slow-release ring was used by each subject for up to 13 cycles (1 year); replacements for lost rings were allowed. Each cycle included 21 dosing days in which the ring was in the vagina (ring-in days) followed by 7 non-dosing days when the ring was not worn (ring-out days). The Phase 3 clinical trials included sexually active healthy women, 18 to ≤ 40 years of age at the enrolment visit, with regular menstrual cycles. Women with the following conditions were excluded from phase 3 pivotal trials: BMI > 29.0 kg/M², smokers and over 35 years of age, pregnant, hypertension, current or family history of venous thrombosis or thromboembolism, known/suspected carcinoma of the breast, endometrium or other estrogen-dependent neoplasm, current or history of medically diagnosed severe depression, alcoholism or drug abuse, liver tumors, active liver disease, history of cholestatic jaundice.

The primary efficacy endpoint was the Pearl Index (PI) in women 18-35 years of age. PI was calculated using only confirmed pregnancies that were on-treatment failures of contraception (i.e. occurred between the date of first ring insertion and 7 days after the last ring removal). The cumulative probability of pregnancy by cycle was calculated using the Kaplan-Meier Life Table analysis. Cycle control, bleeding patterns, and return to fertility were also assessed.

Based on pooled data of the two pivotal clinical studies, a total of 2,111 women between 18 and 35 years of age completed 17,427 evaluable 28-day cycles (cycles in which no back-up contraception was used). The pooled pregnancy rate, evaluated by the Pearl Index (PI), was 2.98 (95% Confidence Interval [CI] [2.13, 4.06]) per 100 woman-years of Ringza use. After one year of Ringza use (13 cycles), the life table estimate of the cumulative probability of not becoming pregnant during or within 7 days of last Ringza use was 0.9749 (95% CI [0.9654, 0.9818]). The life table estimate of the cumulative probability of becoming pregnant during or within 7 days of last Ringza use was 0.0251 (95% CI [0.0346, 0.0182]). Ringza was 97.5% effective in preventing pregnancies based on Kaplan-Meier cumulative pregnancy rate of the pooled data.

The bleeding pattern observed with Ringza in the two pivotal trials was consistent with a planned hormonal withdrawal bleed every 28 days. Scheduled bleeding and/or spotting was experienced by 97.9% of women during Days 22 to 28, the days when Ringza was to be out. A range of 5.4% to 9.7% of women experienced unscheduled bleeding per cycle. A range of 12.9% to 21.4% of women experienced unscheduled bleeding and/or spotting per cycle. During Cycles 1 to 13, women reported < 1 day of unscheduled bleeding and < 1 day of unscheduled bleeding and/or spotting.

The use of Ringza does not alter the course of future fertility. Return to fertility was assessed in 290 women from the two pivotal studies (147 women from Study 300A and 143 women from Study 300B) who either desired pregnancy or switched to a nonhormonal contraception method after the trials. All 290 women (100%) reported a return to fertility by 6 months after discontinuing Ringza (defined as a return of menses or pregnancy). The efficacy profile of Ringza has been accurately reflected in the PM under “14 Clinical Trials”.

Pooled safety data from pivotal trials showed that the most common adverse reactions (ARs) that were ≥ 2% included headache(26.0%), nausea (18.2%), vaginal discharge (10.5%), uterine spasm (9.7%), intermenstrual bleeding/metrorrhagia (6.9%), breast tenderness (5.8%), vomiting (4.7%), urinary tract infection (4.0%), vulvovaginal candidiasis (3.0%), migraine (3.3%), dizziness (2.5%), libido decreased (3.0%), mood swings (2.6%), and acne (2.9%). Overall, 51 subjects experienced 55 treatment-emergent serious adverse events (SAEs). These include deep vein thrombosis (DVT, 2 subjects), pulmonary embolism (1 subject), cerebral venous thrombosis (1 subject), appendicitis (3 subjects); abdominal pain, lymphadenitis, pneumonia, abortion, bipolar disorder, cholelithiasis/cholecystectomy, and hypersensitivity (2 subjects each). Four non-fatal venous thromboembolisms (VTEs) have been reported. Three of these cases were reported in women who had risk factors for VTEs: 2 women had a high pre-treatment BMI (> 29 kg/m²) and 1 woman was particularly susceptible to VTEs due to her positive Factor V Leiden mutation status and her age (39 years). All 4 subjects recovered from their VTE. The most common adverse reactions leading to discontinuation include metrorrhagia/menorrhagia (1.7%), Ringza expulsion (1.4%), headache/migraine (1.3%), and vaginal discharge/vulvovaginal mycotic infections (1.3%). The safety profile of Ringza is adequately reflected in the PM under “8 Adverse Reactions”.

The clinical efficacy of Ringza (segesterone acetate/ethinyl estradiol vaginal system) has not been assessed in women less than 18 nor women over 40 years of age. The protocols for the pivotal Phase 3 studies were initiated without restriction for Body Mass Index (BMI), but with a weight exclusion of > 95kg (209 lbs). However, as a result of the occurrence of 2 venous thromboembolic event (VTEs) in women with a baseline BMI > 29.0 kg/m², the Data and Safety Monitoring Board (DSMB) recommended that the protocols be amended to exclude women with BMI > 29.0 kg/m². Therefore, the efficacy of Ringza has not been adequately studied in women with a BMI > 29.0 kg/m². These uncertainties have been reflected in the PM under “1 Indications”.

The clinical safety of Ringza has not been evaluated in the following populations: 1) women who were over 35 years of age and smoke; 2) women with hypertension; 3) women with current or past thrombophlebitis or thromboembolic disorders, or family history of venous thrombosis or thromboembolism; cerebrovascular or cardiovascular disease; 4) women with undiagnosed abnormal genital bleeding, vaginal discharge, or vaginal lesions or abnormalities; 5) women with known or suspected carcinoma of the breast, endometrium, or other estrogen-dependent neoplasms; 6) women with benign or malignant liver tumors, active liver disease, or history of cholestatic jaundice; 7) women with current or history of severe depression; and 8) women with headaches with focal neurological symptoms. These uncertainties have been adequately reflected in the PM under “2 Contraindications”, “3 Serious Warnings and Precautions Box”, and “7 Warnings and Precautions”. Four VTEs were reported during the clinical development program. United States Food and Drug Administration (FDA) estimated that the VTE rate for Ringza is 24.1 per 10,000 woman-years (95% CI 6.6, 61.7), which is higher than the reported rate in clinical trials of other approved combined hormonal contraceptives (CHC) products. The VTE rate estimate for Ringza has considerable uncertainty evidenced by the wide 95% CI. Since pivotal phase 3 clinical trials were not powered to evaluate uncommon events such as VTE, a post-marketing safety study has been committed to evaluate the risk of VTE in the general population of Ringza users. Health Canada also requests this post-marketing safety study be submitted as soon as it becomes available.

The Medical Devices Directorate (MDD) reviewed the device component of Ringza (silicone elastomer ring without the steroid cores) and concluded that the safety of the device component was supported by an adequate description of the device and materials, bench testing, durometer testing, microbiological testing, shelf life studies, biocompatibility, package testing, shipping study and usability evaluation. A Notice of Compliance (NOC) is recommended for this submission from a quality perspective.

The sponsor submitted a Multiple Level C in vitro/in vivo correlation (IVIVC) model to establish the biorelevance of the in vitro dissolution methodology, and to demonstrate that the proposed commercial product is comparable to the products previously produced and used in Phase 3 clinical trials. The Multiple Level C IVIVC model correlated the segesterone acetate and ethinyl estradiol drug release with the respective area under the curve (AUC) at multiple timepoints for the first cycle of use, out of a possible 13 cycles. The small process differences implemented for scale up and process improvement is not expected to result in significant differences in safety and efficacy of the product.

A Risk Management Plan (RMP) for Ringza (segesterone acetate and ethinyl estradiol vaginal system) was submitted to Health Canada and reviewed by MHPD. The RMP is considered acceptable.

The totality of evidence submitted in this NDS (New Active Substance) supports the safety and efficacy of Ringza (segesterone acetate and ethinyl estradiol vaginal system) for the indication of prevention of pregnancy in women of reproductive potential (18 years of age and older). The benefit-risk profile of Ringza (segesterone acetate and ethinyl estradiol vaginal system) for the recommended indication and dosage/administration is favorable.

The Product Monograph of Ringza (segesterone acetate and ethinyl estradiol vaginal system) dated December 11, 2024 (sequence number 0027) has been reviewed and revised to accurately reflect the efficacy, safety, quality and uncertainties identified in this NDS.

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