September 2018

On August 10, 2018, the FDA approved two new contraceptive methods. Annovera is a one-year contraceptive vaginal ring and the NaturalCycles app is a mobile application (app) based fertility awareness tracker. This addition of two contraceptive options—and a new progestin(!)—is welcome news to both providers and patients. Here is what there is to know to better understand the mechanism of action, efficacy, and patient counseling messages for both new methods.

The Annovera vaginal contraceptive system is similar to the NuvaRing, with several significant differences. A single Annovera ring can prevent ovulation for 1 year (13 cycles), whereas each NuvaRing provides pregnancy protection for 1 month. It releases ethinyl estradiol, which is in most other combined hormonal contraceptives, and Segesterone acetate (Nestorone®) a new non-oral progestin. Like NuvaRing, it is intended to be left in place for 21 days and removed for 7 days, during which time the user will have a scheduled bleed similar to a menstrual period. In addition, it can be removed for intercourse or cleaning, but in those circumstances, it should not be out of place for longer than 2 hours. Unlike NuvaRing, an unopened package does not require refrigeration. The daily release rates of estrogen and progestin with the are roughly similar (see Table below). While the diameters of the rings are similar (about 2 ¼ inches), Annovera is twice as thick (8.4 mm), as NuvaRing, which has a thickness of 4 mm.

Annovera was evaluated in 2,308 women 18 and 40 years of age in multi-national studies conducted by the Population Council.¹ In women 35 years old or younger, the perfect-use failure rate was determined to be 2.98 pregnancies per 100 couples per year, but typical-use (“real world”) failure rates have not yet been published. Importantly, women with BMI >29 kg/m2 were excluded from the study. There was an 89% satisfaction rate related to ease of use, side effects, expulsions, feeling the product, and effects during sexual activity. Although the two contraceptive vaginal rings have not been compared in head-to-head trials, bleeding patterns and side effects also appeared to be similar. Based on participant diaries from the two clinical efficacy trials of Annovera, 5–10% of women experienced unscheduled bleeding per 28-day cycle, although the average number of days with unscheduled bleeding and/or spotting was 1 day or less per cycle.^1,2 A total of 41 subjects (1.7%) discontinued use due to menstrual disorders including metrorrhagia, menorrhagia, and abnormal withdrawal bleeding. Common side effects included headaches (including migraines), nausea and vomiting, vaginal yeast infections, abdominal pain, and menstrual cramps.

In a drug-drug interaction study with Annovera and the concurrent use of three different formulations of vaginal miconazole, the use of water-based vaginal miconazole cream resulted in no change in exposure to estrogen or progestin from the vaginal system.³ However, the use of either the 1- day or the 3-day oil-based miconazole suppository was associated with an overall increase in exposure up to 67% for ethinyl estradiol and 32% for segesterone acetate. Considering the potential effect on ring performance, use of oil-based vaginal suppositories should not be used concurrently while using Annovera. According to the patient package insert,¹ water-based vaginal creams or oral therapy may be used concurrently with the vaginal ring system, as well as water-based vaginal lubricants. However, oil based (including silicone-based) vaginal lubricants will alter the vaginal system and/or exposure to ethinyl estradiol and segesterone acetate and should not be used.

A multi-country Phase 3 trial of Annovera with 905 participants used reports of ring removals for longer than 2 hours as a proxy for nonadherence.⁴ Ring removal longer than 2 hours was reported by 120 (13.3%) of participants. Removals for washing or sexual intercourse, ring insertion difficulties, and lower educational attainment were factors associated with nonadherence. Women residing in Europe or Australia were less likely to remove the ring for more than 2 hours compared with women in the United States. Participants who reported removals longer than 2 hours also were more likely to discontinue ring use, report dissatisfaction, and become pregnant during the study. Consequently, the authors suggest that clinicians should provide anticipatory guidance to women considering a vaginal ring, with a focus on how the ring feels in the vagina and during sex. Users need reassurance that the ring does not increase the incidence of vaginal infections⁵ and does not need frequent washing. Asking about a user’s overall experience with a vaginal ring, including ring removals, will help to identify women who need additional counseling and support.⁴

As with previous contraceptive methods it has developed (such as ParaGard and Mirena), the Population Council has entered into a partnership with an outside entity to bring the product to market in the United States. TherapeuticsMD is responsible for releasing Annovera in the US and has stated that it will be commercially available as early as the third quarter of 2019. The company has agreed to provide significantly reduced pricing to Title X family planning clinics, although specifics of this price reduction are not yet known. Based on current information, it will not be classified in the same FDA contraceptive category as NuvaRing, in which case it must be covered by commercial health plans under no cost-sharing rules of the Affordable Care Act (ACA).

TherapeuticsMD intends to market Annovera as “the first woman-controlled, procedure-free, long-acting reversible contraceptive (LARC).” While Annovera certainly is a long-acting and reversible contraceptive, it may be inaccurate to place it in the same category as implants and IUD. Given the need to remove it monthly to induce a withdrawal bleed, and to replace it promptly after cleaning and intercourse, it is not as “forgettable” a contraceptive, as the IUD or implant.

The NaturalCycles® App is the first (and only) fertility monitoring app with FDA approval to be marketed as a contraceptive.⁶ As noted in the new 21st edition of Contraceptive Technology, the app has already been certified by and available for sale in the European Union.⁷ Like other fertility awareness-based methods (FABMs), it can be used either for contraception or for timing intercourse to become pregnant. It uses a proprietary algorithm⁶ that tracks menstrual cycle pattern and basal body temperature (BBT) to predict non-fertile “green days” and fertile “red days,” but it does not include the observation and charting of cervical mucus changes as do some other FABMs. A distinct benefit of the product’s algorithm is that it factors in past menstrual and monitoring history in predicting the date of an upcoming ovulation. A red day is the default; while green days must meet certain criteria. For typical user, 55–61% of days during a 1 month cycle are “green days.”

Based on 18,500-woman years of use, the Pearl Index typical-use failure rate is about 6.9 pregnancies per 100 women per year, while the perfect use failure rate is 1.0 per 100 women per year.⁸ However, a recently published systematic review of FABM efficacy studies⁹ calls into question the validity of reported results of FABM trials, since most are of low-to-moderate quality and are limited by the heterogeneity of the populations studied, making it difficult to know whether differences in efficacy are attributable to differences in the methods or in the populations studied.

So…how does the NaturalCycles app compare to other FABM apps? Its advantages include the fact that it integrates objective data about prior ovulation patterns, there is minimal user intervention other than checking BBT (i.e., no checking of cervical mucus), and it has a visually simple user interface. According to the FABM comparison study,⁹ failure rates are middle of the pack when compared to other FABMs. However, as with all FABMs, successful use of the product requires that a woman have relatively regular menstrual cycles, the motivation to enter data daily, and disciplined observance of green and red days by both partners.

—Submitted by: Michael Policar, MD, MPH, Professor Emeritus, University of California San Francisco School of Medicine

References

1. Annovera Patient Package Insert, August 2018.Accessed on August 17, 2018, at http://www.popcouncil.org/news/fda-approves-the-first-one-year-contraceptive-fully-under-a-womans-control

2. Weisberg E, Brache V, Alvarez F, Massai R, Mishell DR Jr, Apter D, Gale J, Sivin I, Tsong YY, Fraser IS. Clinical performance and menstrual bleeding patterns with three dosage combinations of a Nestorone progestogen/ethinyl estradiol contraceptive vaginal ring used on a bleeding-signaled regimen. Contraception. 2005 Jul;72(1):46-52

3. Simmons KB, Kumar N, Plagianos M, Roberts K, Hoskin E, Han L, Alami M, Creasy G, Variano B, Merkatz R. Effects of concurrent vaginal miconazole treatment on the absorption and exposure of Nestorone® (segesterone acetate) and ethinyl estradiol delivered from a contraceptive vaginal ring: a randomized, crossover drug-drug interaction study. Contraception. 2018 Mar;97(3):270-276

4. Stifani BM, Plagianos M, Vieira CS, Merkatz RB. Factors associated with nonadherence to instructions for using the Nestorone®/ethinyl estradiol contraceptive vaginal ring. Contraception. 2018 May;97(5):415-421

5. Huang Y, Merkatz RB, Hillier SL, Roberts K, Blithe DL, Sitruk-Ware R, et al. Effects of a one year reusable contraceptive vaginal ring on vaginal microflora and the risk of vaginal infection: an open-label
prospective evaluation. PLoS One 2015;10: e0134460.

6. Jennings VH, Polis CB. Fertility awareness-based methods. In: Hatcher RA, Nelson A, Trussell J, et al. Contraceptive Technology, 21st edition. New York, NY: Ayer Company Publishers, Inc., 2018.

7. Berglund Scherwitzl E, Lindén Hirschberg A, Scherwitzl R. Identification and prediction of the fertile window using NaturalCycles. Eur J Contracept Reprod Health Care. 2015;20(5):403-8

8. Berglund Scherwitzl E, Lundberg O, Kopp Kallner H, Gemzell Danielsson K, Trussell J, Scherwitzl R. Perfect-use and typical-use Pearl Index of a contraceptive mobile app. Contraception. 2017 Dec;96(6):420-425

9. Peragallo Urrutia R, Polis CB, Jensen ET, Greene ME, Kennedy E, Stanford JB. Effectiveness of Fertility Awareness-Based Methods for Pregnancy Prevention: A Systematic Review. Obstet Gynecol. 2018 Aug 6. Epub ahead of print