Summary Basis of Decision for Ringza

Clinical Pharmacology

The clinical pharmacology data included reports on human pharmacodynamic and pharmacokinetic studies. The clinical pharmacology data support the use of Ringza for the recommended indication.

Pharmacodynamics

In two different pharmacodynamic studies conducted with segesterone acetate-only contraceptive vaginal rings (CVRs; 50, 75, or 100 mcg/day), segesterone acetate caused adequate luteal activity suppression, dose-dependent estradiol levels suppression, good bleeding patterns, and segesterone acetate serum levels that reflected calculated in vitro release rates. In another Phase II pharmacodynamic study comparing the bleeding profiles in patients using segesterone acetate-only subdermal implants, Norplant subdermal implants, or segesterone acetate-only CVRs, both segesterone acetate-only implants and CVRs achieved adequate ovulation inhibition and an adequate bleeding profile in the absence of endometrial pathology, along with a good safety profile. In a Phase I/II pharmacodynamic study conducted in breastfeeding mothers (from postpartum day 60 to postpartum day 420) using segesterone acetate-only subdermal implants for 1 year, there were no pregnancies reported, infant mean weight did not differ from that of infants whose mothers used a copper intrauterine device. Additionally, in a published report, lactating women using subdermal implants had levels of segesterone acetate in breast milk that were comparable to levels of segesterone acetate in serum, with levels of segesterone acetate in the blood of breast-fed infants significantly low due to its poor bioavailability. Therefore, the use of segesterone acetate subdermal implants does not seem to pose any negative effects on the development of breast-fed infants.

In a Phase II pharmacodynamic study, ethinyl estradiol delivered via a segesterone acetate/ethinyl estradiol CVR caused similar effects on angiotensinogen and most other hepatic and coagulation factors to those caused by ethinyl estradiol delivered via a levonorgestrel/ethinyl estradiol oral contraceptive pill. Although differences were noted in Protein S activity and Factor VII-t (%), global tests of coagulation activity showed no differences in most coagulation factors. In another pharmacodynamic study, results reconfirmed that the effects of vaginally delivered ethinyl estradiol on angiotensinogen and most coagulation factors were similar to the effects of orally delivered ethinyl estradiol.

Pharmacokinetics

In the supportive pharmacokinetic study (Study 300PK), the proposed segesterone acetate and ethinyl estradiol doses in the Ringza CVR were associated with adequate ovulation suppression. Pharmacokinetic analysis revealed that the area under the concentration-time curve (AUC) and maximum serum concentration (C_max) were the highest early in Cycle 1, declined between Days 4 to 7, and became relatively stable until CVR removal. After CVR removal in Cycle 1, segesterone acetate serum concentrations declined very rapidly (half-life = 4.48 ± 3.4 hours), while ethinyl estradiol serum concentration declined more slowly (half-life = 15.12 ± 7.5 hours). Throughout the 13-cycle period, both segesterone acetate and ethinyl estradiol serum concentrations declined; however, their concentrations remained above the established therapeutic effect threshold levels.

In a Phase I pharmacokinetic study to compare the pharmacokinetic profiles of ethinyl estradiol when it is delivered by a CVR (segesterone acetate [150 mcg/d]/ethinyl estradiol [15 mcg/d]) and as a combination birth control (COC) tablet (levonorgestrel [150 mcg/d]/ethinyl estradiol [30 mcg/d]), the initial Day 1 ethinyl estradiol C_max for CVR users was comparable to the highest ethinyl estradiol C_max for COC tablet users (ratio of 0.93). The AUC and C_max of both segesterone acetate and ethinyl estradiol were the highest on Day 1 of CVR use, while the AUC and C_max of both levonorgestrel and ethinyl estradiol were the highest on Day 21 of COC tablet use. In a post-market Phase I pharmacokinetic study, bioequivalence was observed for both segesterone acetate and ethinyl estradiol when comparing the segesterone acetate/ethinyl estradiol CVR with tampon use and the segesterone acetate/ethinyl estradiol CVR without tampon use from Days 2 to 3 and from Days 2 to 5 after insertion.

The pharmacokinetics of Ringza in adolescents under the age of 18 has not been studied. There were no studies performed in prepubescent or menopausal subjects. As for race and ethnicity, there were no meaningful differences in the efficacy or safety of Ringza in any of the subpopulations studied. In several Phase I/II studies, it was observed that body weight and body mass index (BMI) were inversely correlated with segesterone acetate and ethinyl estradiol serum concentrations. There were no studies conducted to evaluate the effects of renal impairment or hepatic impairment on the efficacy, pharmacokinetics, pharmacodynamics, and safety of Ringza. In patients with hepatic impairment, steroid hormones may be poorly metabolized, and any acute/chronic liver function anomalies may necessitate the discontinuation of Ringza use until the normalization of liver function markers, as long as combined hormonal contraceptive ring causation has been excluded.

Drug-Drug Interactions

The use of drugs that inhibit cytochrome p450 (CYP)3A (itraconazole) in women using Ringza would likely not significantly increase levels of segesterone acetate or ethinyl estradiol, posing no additional safety issues. The use of drugs that induce CYP3A (rifampin) should not affect contraceptive efficacy given the lack of influence of rifampin on segesterone acetate levels.

Cardiac Electrophysiology

A single intravenous 200 mcg dose of segesterone acetate was not found to have any pharmacodynamic effect on the QTcF interval (QT corrected for heart rate by Fridericia's cube root formula), the QRS duration, the PR interval, or heart rate.

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

Clinical Efficacy

The clinical efficacy of Ringza was evaluated in two independent, multicentre, open-label, 13-cycle (1 year) Phase III clinical studies (Studies 300A and 300B). The primary objective was 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, followed by 7 non-dosing days in which the ring was not worn, consistent with a traditional 21 days in/7 days out combined hormonal contraceptive dosing regimen. Study 300A was conducted at 15 study sites in the United States. Study 300B was conducted at 12 study sites: 5 in the United States, 3 in Europe, 3 in Latin America, and 1 in Australia.

Studies 300A and 300B included sexually active, healthy women with regular menstrual cycles who were 18 to 40 years of age at the enrolment visit. Key exclusion criteria were similar, including women: 1) with a BMI greater than 29.0 kg/m² (at approximately 50% enrollment, women with a BMI greater than 29.0 kg/m² were no longer enrolled and all women with a BMI greater than 29.0 kg/m² were discontinued from the studies); 2) who smoke and were 35 years of age or older; 3) who had a diastolic blood pressure of 85 mmHg or higher and/or systolic blood pressure of 135 mmHg or higher; 4) with current or past thrombophlebitis or thromboembolic disorders, family history of venous thrombosis or thromboembolism, or cerebrovascular or cardiovascular disease; 5) with known or suspected pregnancy, or who were breastfeeding; 6) with undiagnosed abnormal genital bleeding, vaginal discharge, or vaginal lesions or abnormalities; 7) with known or suspected carcinoma of the breast, endometrium, or other estrogen-dependent neoplasms; 8) with benign or malignant liver tumours, active liver disease, or history of cholestatic jaundice; 9) with current severe depression or a history of severe depression; and 10) with headaches with focal neurological symptoms, etc.

The primary efficacy endpoint was the Pearl Index in women 18 to 35 years of age with cycles of adjunctive contraception excluded, 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 also calculated using the Kaplan-Meier life table analysis.

Based on pooled data from Studies 300A and 300B, 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, was 2.98 (95% Confidence Interval [CI]: 2.13, 4.06) per 100 woman-years of Ringza use. The Kaplan-Meier cumulative pregnancy rate provided supportive evidence of efficacy (number of subjects [n] = 2,264). In the intent-to-treat life table analysis of pooled data from Studies 300A and 300B, Ringza was 97.5% effective in preventing pregnancies. After 1 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).

The bleeding pattern observed with Ringza in Studies 300A and 300B 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 and 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 less than 1 day of unscheduled bleeding per cycle and less than 1 day of unscheduled bleeding and/or spotting per cycle.

The use of Ringza does not alter the course of future fertility. Return to fertility was assessed in 290 women from Studies 300A and 300B (147 women from Study 300A and 143 women from Study 300B) who either desired pregnancy or switched to a nonhormonal method after the studies. All 290 women (100%) reported a return to fertility by 6 months after discontinuing Ringza (defined as a return of menses or pregnancy).

Indication

The New Drug Submission for Ringza was filed by the sponsor with the following proposed indication:

Ringza (segesterone acetate/ethinyl estradiol slow-release vaginal system) is indicated for conception control.

To support safe and effective use of the product, Health Canada approved the following indication:

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) greater than 29.0 kg/m².

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

Clinical Safety

The safety of Ringza was demonstrated in the two pivotal Phase III studies (300A and 300B) described in the Clinical Efficacy section, as well as in a supportive pharmacokinetic Phase III study (300PK). All three 13-cycle studies were open label and enrolled 2,308 healthy women aged 18 to 40 years. These women contributed to 21,590 cycles of exposure for safety evaluation and 999 women completed 13 cycles. The safety population (n = 2,308) had a mean age of 26.71 years and a mean BMI of 24.13 kg/m² (range: 16.0 to 41.5 kg/m²). Sixty-seven percent of the participants were from the United States. The racial distribution was 71% Caucasian, 14% Black or African American, 4% Asian, and 11% from other racial backgrounds. Additionally, 30% of the population identified as Hispanic or Latina.

The most common adverse reactions (occurring in 2% or more of subjects) observed included headache (26.0%), nausea (18.2%), vaginal discharge (10.5%), uterine spasm (9.7%), vulvovaginal mycotic infection (7.5%), intermenstrual bleeding/metrorrhagia (6.9%), breast tenderness (5.8%), vomiting (4.7%), pruritus genital (4.2%), urinary tract infection (4.0%), migraine (3.3%), vulvovaginal candidiasis (3.0%), decreased libido (3.0%), acne (2.9%), mood swings (2.6%), dizziness (2.5%), dyspareunia (2.4%), vulvovaginal discomfort (2.4%), withdrawal bleed (2.4%), and breast pain (2.1%).

Overall 51 (2%) of the 2,843 subjects in all the Ringza Studies pooled analysis set experienced 55 treatment-emergent serious adverse events. These included 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 thromboembolic events (VTEs) were reported. Three of these cases were reported in women who had risk factors for VTEs: 2 women had a high pre-treatment BMI and 1 woman was particularly susceptible to VTEs due to her positive Factor V Leiden mutation status and her age (39 years). The fourth case was reported in a 28-year-old woman with a BMI of 25.2 kg/m² who withdrew from the study before a clotting evaluation could be conducted. All four subjects recovered from their VTEs.

The most common adverse reactions leading to discontinuation included metrorrhagia/menorrhagia (1.7%), ring expulsion (1.4%), headache/migraine (1.3%), and vaginal discharge/vulvovaginal mycotic infections (1.3%).

Three sub-studies, carried out in selected sites of Study 300A, evaluated hepatic safety, endometrial safety, and infectious risks associated with Ringza. A hepatic factors sub-study was carried out in 2 sites in the United States where 51 subjects completed at least 13 cycles. Two of the three DVT/pulmonary embolism events in Study 300A occurred at 1 of the sites in this hepatic factors sub-study; 1 of those events occurred in a 39-year-old subject who was found to be positive for Factor V Leiden and the other event occurred in a subject who had a baseline BMI greater than 29 kg/m². An endometrial safety sub-study was carried out in 6 sites in the United States where 46 subjects completed at least 13 cycles. No cases of endometrial hyperplasia or carcinoma were observed. A microbiology sub-study was carried out in 1 site in the United States where 53 subjects completed at least 13 cycles. Based on the results of a single-center microbiology sub-study that included 120 women, the use of Ringza on a 21 days in/7 days out schedule for up to 13 consecutive cycles was not associated with any increase in vaginitis or clinically significant change in vaginal flora when used according to instructions. Specifically, there was no increase in the diagnosis of bacterial vaginosis by either the Amsel Criteria or the Nugent Score, the diagnosis of yeast vaginitis, or the occurrence of white blood cells in vaginal fluid.

The safety of the device component of Ringza (silicone elastomer ring without the steroid cores) 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.

Supportive Studies

Based on findings from several Phase I and Phase II supportive studies, the lowest effective dose of each of the two hormones, segesterone acetate (150 mcg/d) and ethinyl estradiol (13 mcg/d), on a 21 days in/7 days out regimen was selected for the pivotal Phase III studies. Moreover, based on the findings from these supportive studies, the safety and tolerability of the segesterone acetate (150 mcg/d)/ethinyl estradiol (13 mcg/d) ring on a 21 days in/7 days out regimen was superior when compared to the safety and tolerability of all other tested doses, schedules, and regimens. Thus, its use in the pivotal Phase III studies is justified.

Appropriate warnings and precautions are in place in the approved Product Monograph for Ringza to address the identified safety concerns.

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

Segesterone acetate was shown to be 100 times more potent when injected subcutaneously than when ingested orally, likely due to rapid metabolism after oral dosing. It was shown to block spontaneous ovulation, estrus cycling, and implantation in female rats and to block fertilization in female rabbits. Segesterone acetate was found to inhibit the human ether-a-go-go-related gene cardiac potassium channel current with an estimated half-maximal inhibitory concentration of 33.8 μM. Subcutaneous injections of segesterone acetate produced no changes in blood pressure, heart rate, action potential duration, or QT intervals in cynomolgus monkeys. A single subcutaneous injection of segesterone acetate (10 mg/kg; approximately 130 times the clinical exposure) in rats did not produce any mortality, clinical signs, respiratory, or neurobehavioral effects.

In several in vivo and in vitro non-clinical pharmacokinetic studies, segesterone acetate was shown to be rapidly absorbed and distributed following oral, intravaginal, or subcutaneous administration. Levels of segesterone acetate rapidly rise in the portal circulation and then quickly decrease in the systemic circulation with metabolites appearing in bile. In all non-clinical species, segesterone acetate was subjected to extensive first-pass metabolism by cytochrome p450 A4 and carbonyl reductase enzymes, with several metabolites detected in plasma, urine, and feces. Systemically administered segesterone acetate was mainly excreted via feces, with almost 50% of the segesterone acetate dose recovered in feces within the first 24 hours.

The toxicological properties of segesterone acetate were only evaluated via parenteral routes of administration. In mice, single doses of segesterone acetate induced mortality at 1,000 mg/kg and greater (intraperitoneal) and at 6,400 mg/kg and greater (oral). In rats, single doses of segesterone acetate induced mortality at 1,250 mg/kg and greater (intraperitoneal) and at 10,000 mg/kg (oral). A single subcutaneous dose of 10 mg/kg segesterone acetate caused an increased body weight gain in female rats and no acute effects in female rabbits. All observations in multiple repeated-dose toxicity studies were a consequence of the primary and secondary pharmacodynamic properties of segesterone acetate, and no systemic or local toxicities were noted. Serum concentrations at the highest administered dose levels in the repeat-dose studies were at least 16 times the steady-state serum concentrations observed in the pivotal clinical pharmacokinetic study (see Clinical Pharmacology section).

Segesterone acetate was neither mutagenic nor clastogenic in the Ames test, the chromosomal aberration assay, or in the in vivo mouse micronucleus test. In a two-year carcinogenicity study in rats with subdermal implants that were releasing segesterone acetate at around 17 to 86 times the clinical daily dose based on body surface area, there were no drug-related increases in tumour incidence. In a two-year intravaginal carcinogenicity study in mice, segesterone acetate gel produced an increased incidence of adenocarcinoma and lobular hyperplasia in the breast at a dose of 30 mg/kg/day, approximately 10 times the clinical systemic exposure of segesterone acetate based on the area under the concentration-time curve (AUC). A dose of 10 mg/kg/day in mice, approximately 3 times the clinical systemic exposure of segesterone acetate based on AUC, did not result in carcinogenic findings.

In a rat fertility study, treatment with segesterone acetate subdermal implants for 90 days did not impair the return to fertility seven weeks after cessation of treatment, and there were no adverse effects on ovulation or resulting litter parameters. The subcutaneous administration of segesterone acetate to pregnant rats at dose levels of 10, 50 or 250 mcg/kg/day during gestation days 6 to 15 did not cause embryotoxicity or teratogenicity. In rabbits treated subcutaneously at dose levels up to 250 mcg/kg/day during gestation days 6 to 18, no maternal toxicity was observed (the maternal no-observed-adverse-effect level was 250 mcg/kg/day), but the total incidence of embryo death, litter resorption, as well as fetal skeletal malformations increased in the high-dose group. Serum concentrations at the developmental no-observed-effect level (NOEL; 50 mcg/kg/day) were 2.84 times the clinical exposure based on steady-state concentrations. Systemic exposure was not determined in the embryo-fetal development studies, but based on dose expressed as mcg/m², the high dose used in the embryo-fetal development studies (1,500 mcg/m² in rats and 3,000 mcg/m² in rabbits) was 16 to 32 times the human dose (92.5 mcg/m²). In a perinatal/postnatal study in rats, subcutaneous injections of segesterone acetate (10, 50, and 250 mcg/kg/day) from gestation days 15 to 25 or on lactation (postpartum) day 21 resulted in prolonged gestation, delivery complications leading to the death of mothers at the highest dose, and death of pups at all doses. An NOEL for either maternal or fetal toxicity could not be identified. In a local tolerance study in monkeys, treatment with segesterone acetate vaginal rings for four weeks did not result in any local toxicity, with a systemic margin of safety of more than 4.8 times the clinical average plasma concentration.

The segesterone acetate/ethinyl estradiol ring drug product impurity/degradation specifications are below the qualification limit for all impurities. Moreover, 6-β-hydroxy-segesterone acetate, a known impurity in the segesterone acetate drug substance and segesterone acetate/ethinyl estradiol ring, was not mutagenic in the Ames test, did not induce chromosomal aberrations in human peripheral blood lymphocytes, and was not associated with any significant adverse effects in an in vivo four-week repeat-dose toxicity study in rats.

The safety of ethinyl estradiol is well-established and its non-clinical toxicology is widely documented in the published literature following decades of clinical use. Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver. In Canada, there are several marketed products that contain ethinyl estradiol at the same or similar dose and for the same or similar indication. There were no studies conducted to evaluate the toxicology of the segesterone acetate/ethinyl estradiol combination. Clinical studies established the pharmacokinetics of the segesterone acetate/ethinyl estradiol vaginal ring system, thus eliminating the necessity for non-clinical pharmacokinetic and pharmacodynamic studies with this combination.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Product Monograph for Ringza. In view of the intended use of Ringza, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

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

The quality (chemistry and manufacturing) information submitted for Ringza has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper pharmaceutical development and supporting studies were conducted and an adequate control strategy is in place for the commercial processes. Changes to the manufacturing process and formulation (if any) made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 18 months is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC) and protected from direct sunlight.

The proposed drug-related impurity limits are considered adequately qualified (e.g., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use limits and/or qualified from toxicological studies, as needed).

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy.)

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations.

None of the excipients used in the formulation of Ringza is of human or animal origin.