3. A 1-year contraceptive vaginal ring
The need to obtain new supplies every month or every 3 months contributes to high rates of contraceptive failure and unintended pregnancy among women using short-acting hormonal contraceptives (pills, patches, and vaginal rings).5 A woman-controlled contraceptive that would provide 1 year of protection against unintended pregnancy represents a step forward. A contraceptive vaginal ring (CVR) that releases the novel progestin segesterone acetate and EE provides woman-controlled contraception for up to 1 year. This CVR (Annovera) received FDA approval in 2018 and has been marketed in the United States since 2020.
The segesterone acetate/EE CVR is a soft, flexible ring that is opaque white in color and fabricated from nonbiodegradable silicone (FIGURE 2). The outside diameter is 5.6 cm, compared with the 5.4-cm outer diameter of the etonogestrel/EE vaginal ring (NuvaRing). The segesterone acetate/EE CVR has 2 channels: one releases segesterone acetate only and the other releases segesterone acetate and EE. In contrast with the etonogestrel/EE CVR, the segesterone acetate/EE CVR does not need to be refrigerated when stored.6
Segesterone is a 19-nor-progesterone derivative that binds in a highly selective fashion to progesterone receptors, and it is potent in suppressing ovulation. During use of the segesterone acetate/EE CVR, mean levels of EE are incrementally higher than those observed with use of the etonogestrel/EE CVR.
Two 13-cycle (1 year) phase 3 clinical trials conducted from 2006 to 2009 enrolled 2,308 women aged 18 to 40 years, including 2,265 women aged 18 to 35 (the age group the FDA considers for efficacy analysis). Trial participants placed the ring vaginally on cycle days 2 to 5 and were asked to keep the ring in place for 21 days, then to remove the CVR for 7 days, during which scheduled bleeding was anticipated. For sexual intercourse, rings could be removed, depending on patient/couple preference, for up to 2 hours.
In the combined trials, the PI was 2.98 per 100 woman-years, a pregnancy rate comparable to those seen in other recent trials of combination estrogen-progestin contraceptives. The incidence of contraceptive failure did not increase over time during the 1-year trials, indicating that contraceptive efficacy of the segesterone acetate/EE was maintained during 1 year of use. While the pregnancy rate was lower in participants who did not report any instances of CVR removal during the 21-day periods of use, the rate was substantially higher among those who reported prolonged episodes of CVR removal.
In the 2 trials, bleeding patterns were similar to those observed with other combination estrogen-progestin contraceptives. Fewer than 2% of trial participants discontinued the trial early due to what they considered unacceptable bleeding.
More than one-half of trial participants reported at least 1 episode of complete or partial CVR expulsion. Most expulsions occurred in the first cycle, suggesting a learning curve with CVR use. Fewer than 2% of participants discontinued trial participation due to expulsions.
Almost 90% of participants reported that they were “highly satisfied” or “satisfied” with the CVR. Although more than two-thirds of participants reported that they never felt the ring during intercourse, if a couple did report feeling the ring during sex, the likelihood of dissatisfaction with the CVR doubled. In addition, feeling the CVR at other times was strongly associated with dissatisfaction. Because a deeply positioned CVR is less likely to be felt by users, these observations underscore the importance of counseling users to place the ring into the upper vagina. Of note, neither prior ring use nor tampon use was associated with CVR satisfaction.
One other important counseling point regarding CVR use relates to the discoloration of the ring that occurs over time. The initially white ring tends to become dark brown during the 1-year usage period. Although this discoloration does not indicate hygiene problems, women who are not advised about this in advance may be put off by the color change.
Four nonfatal VTE events occurred, all in the US trial sites. The overall VTE incidence was higher than expected, particularly among participants with a BMI of 29 kg/m2 or higher. After this association was noted, participants with a BMI >29 kg/m2 were discontinued from the trials. The package labeling for the segesterone acetate/EE CVR states that “Limited data are available in females with a BMI >29.0 kg/m2 because this subpopulation was excluded from the clinical trials after VTEs were reported.”6
A 1-year CVR raises the possibility that users could use their rings in an experimental extended fashion to reduce the frequency of withdrawal bleeding or continuously so as to eliminate withdrawal bleeding. In a randomly chosen sample of CVRs that had been used in the 13-cycle clinical trials, residual steroids in the CVRs were assessed. Sixty percent of segesterone acetate and 80% of EE remained. Using these observations as well as pharmacokinetic data collected from phase 3 trial participants, predicted segesterone acetate levels after 1 year of hypothetical continuous use appear to be sufficient to provide effective contraception.7 These observations suggest that performing clinical trials of extended as well as continuous segesterone acetate/EE CVR use is warranted.
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