A Novel, Long-Lasting, Reversible Contraceptive Option
This article was sponsored by TherapeuticsMD. Copyright 2021 and published by MJH Life Sciences™. No portion of this program may be reproduced or transmitted in any form, by any means, without the prior written permission of MJH Life Sciences™. The views and opinions expressed in this material do not necessarily reflect the views and opinions of MJH Life Sciences™ or Contemporary OB/GYN®.
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Introduction
During 2015-2017, 46.9 million women aged 15-49 years the United States (64.9% of that population) were using various forms of contraception, including prescription and non-prescription, hormonal and non-hormonal, and permanent sterilization.1,2 Based on a 2011 report, unintended pregnancies account for 45% of all pregnancies in the United States despite the availability and use of contraceptives.3 Forty one percent of unintended pregnancies are caused by inconsistent use of contraceptives.4 Long-acting reversible contraceptive options (which include implants and intrauterine devices (IUDs)1,2) do not require daily engagement from women and are more effective than short-acting contraceptives. However, less than 15% of women on birth control use long-acting reversible contraceptives.1
In fall 2020, Contemporary OB/GYN® hosted a multichannel learning series regarding the current landscape of contraception. The series featured a conversation between Brian A. Bernick, MD, Cofounder and Chief Scientific Officer of TherapeuticsMD and Anita Nelson, MD, Professor and Chair of Obstetrics and Gynecology at Western University Health Sciences, in which they discussed challenges associated with current contraceptive methods—including long-acting reversible contraceptives—and reviewed a contraceptive that could offer a solution to some of these challenges.
Part 1: Considerations for Long-lasting Reversible Contraception
Contraception is not a one-size-fits all approach, according to Dr. Nelson, who thinks it is important for prescribers to take the time to listen to what method women think will best fit their individual circumstances and lifestyle. Dr. Nelson states, “Women need to understand their bodies, their anatomy, their menstrual cycle, and the risks of an unintended pregnancy.” Clinicians should confirm this understanding with women of any reproductive age and counseling should be adjusted accordingly.
Dr Nelson noted that as women grow through their reproductive years, their attitudes, lifestyle, and medical conditions may change, warranting adjusted counseling. In addition, contraceptive accessibility and cost should be considered. Access to contraceptives has been difficult for some women during the COVID-19 pandemic, said Dr Nelson.
Despite barriers to in-person office visits and economic challenges, assuring access to contraception is essential, and may be heightened during times of crisis. Because there is so much to review in a short visit, often combined with an annual exam, Dr Nelson recommends that clinicians consider scheduling a separate visit for contraceptive counseling.
During the counseling, clinicians should take the opportunity to educate across 4 broad categories of contraception, said Dr Nelson. One category is barrier methods, such as condoms and diaphragms. Women are in control of this method; however, they must remember to use them each time they have sex, and many women are looking for a more reliable option. Another category is short-acting contraceptives that are taken every day, week, or month, such as pills, patches, or monthly ring. Prescriptions are refilled every month and can be stopped at any time.
A third category is long-lasting reversible contraceptive methods. Most require a procedure, such as a 3-month shot, intrauterine device or implant. In contrast, the contraceptive vaginal system, is a procedure-free long-lasting method. In this method, women insert a vaginal ring for 21 days and remove it for 7 days each cycle, and repeat up to 1-year (13 cycles), with the ability to discontinue whenever desired. The fourth category is tubal ligation, which prevents pregnancy permanently via surgery.
Dr Bernick questioned whether the high rate of unintended pregnancies may be associated with use of short-acting contraceptives, which are typically dispensed in 1- to 3-month supplies. Studies have shown that women who receive a 1-year supply are 30% less likely to have an unintended pregnancy than women who receive a 1- to 3-month supply.5 “These findings were so impressive that the CDC now recommends that women routinely be provided a 1-year supply of birth control,” noted Dr Nelson.6 Dr Bernick said that one might expect that IUDs and implants (approximately 12% and 4% use, respectively) would be used more widely if they did not require a procedure.1 According to Dr Nelson, “Because long-acting methods [usually] require a procedure, they are often declined by women and not routinely offered by a large segment of women’s health care providers.” In fact, a 2011 report by the Centers for Disease Control and Prevention, based on results from office-based obstetricians/gynecologists, family practitioners, and adolescent medicine specialists, noted only 56% offered on-site IUDs and 32% offered implants, according to Dr Nelson.7
“Some women may prefer a contraceptive option that is long-lasting, but also patient-controlled and procedure-free,” said Dr Bernick. An FDA-approved, long-lasting reversible contraceptive that does not require a procedure is Annovera® (segesterone acetate and ethinyl estradiol vaginal system), a progestin/estrogen combination hormonal contraceptive indicated for use by females of reproductive potential to prevent pregnancy.8
Part 2: Considerations for Annovera as a Long-Acting Contraception Option
Annovera is a soft, flexible ring that is no wider than a tampon when squeezed together for insertion, providing simple insertion and removal.8,9 Dr Nelson noted that Annovera is roughly the same overall diameter as NuvaRing. The increased width of Annovera was purposeful, as it is composed of a squishy silicone material for easy insertion and removal and comfort throughout daily activities, including sex.8 Once inserted, Annovera should be left in place continuously for 21 days and then removed for a 7-day vaginal system-free interval. This 28-day cycle can be repeated 13 times for one year with just one prescription.8
When inserted, the ring releases on average 13 mcg per day of ethinyl estradiol daily. “This makes Annovera one of the lowest-dose estrogen contraceptive products on the market,” according to Dr Nelson.8 The ring also releases an average of 150 mcg per day of segesterone acetate, which is a novel progestin derived from progesterone. Based on preclinical studies, segesterone acetate has high anti-ovulatory potential and lacks androgenic and glucocorticoid activity at contraceptive doses.10 In contrast, most progestins used in combination hormonal contraception are derived from testosterone, and their androgenic activity may be responsible for adverse effects such as acne, oily skin, hair growth, weight gain, breast tenderness, and mood changes. Dr Nelson noted that results from studies have demonstrated no thromboembolic events associated with “segesterone acetate in various nonoral progestin-only contraceptive systems … for 20,000 combined cycles. However, it is important to keep in mind that combination estrogen/progestin contraceptives do carry a risk of venous thromboembolism.”11,12
The approval of Annovera was based on results from 3 open-label, single-arm, multicenter, 1-year, phase 3 trials (NCT00455156, NCT00263341, and NCT04272008).13 Women aged 18 to 40 years who were not pregnant (n = 2265) started Annovera on the second to fifth day of their menstruation cycle and were instructed to insert the ring and leave the ring in for 21 days and remove the ring for 7 days, continuing this regimen for 13 cycles. The 1-year cumulative probability of not becoming pregnant, during or within 7 days of last contraceptive vaginal system use, was approximately 97.3% (95% CI, 0.96%-0.98%).13 Pregnancy rate was not influenced by body mass index (BMI),13 although the vaginal system was not adequately evaluated in women with a BMI greater than 29 kg/m2. After completion of the clinical trials, results from a sub-study (n = 290) showed that 100% of subjects reported return of menses or pregnancy within 6 months of discontinuing Annovera. Moreover, 63% of the women who desired pregnancy became pregnant within 6 months of exiting the study.13 Dr Bernick noted this is an impressive fecundity rate.
Like all other combination hormonal contraceptives, the labeling for Annovera includes a boxed warning about smoking in women over 35 years and serious cardiovascular events. “Cigarette smoking increases the risk of serious cardiovascular events from combination hormonal contraceptive use.”9 Women who smoke and are over 35 should not use Annovera. For contraindications and additional warnings and precautions, please review the accompanying Brief Summary below or refer to the Annovera Full Prescribing Information. In the year-long clinical trials, the most common adverse reactions reported in at least 5% of women who received ANNOVERA were: headache/migraine, nausea/vomiting, vulvovaginal mycotic infection/candidiasis, lower/upper abdominal pain, dysmenorrhea, vaginal discharge, urinary tract infection/cystitis/pyelonephritis/genitourinary tract infection, breast pain/tenderness/discomfort, bleeding irregularities including metrorrhagia, diarrhea, and genital pruritus. 12% discontinued from the clinical trials due to an adverse reaction. The most common adverse events leading to discontinuation included metrorrhagia/menorrhagia (1.7%), headache, including migraine (1.3%), vaginal discharge/vulvovaginal mycotic infection (1.3%), and nausea/vomiting (1.2%).14 Notably, no clinically relevant weight changes were reported by participants in the clinical trials.14,15 In one of the phase 3 trials (NCT00263341), a microbiology sub-study of healthy, sexually active women aged 18 to less than 40 years showed that use of Annovera did not increase the rate of vaginal infection and was not disruptive to the vaginal ecosystem. There was no increase in bacterial vaginosis, candidiasis, or trichomoniasis throughout the sub-study.16 This is important to be aware of, noted Dr. Bernick, as the risk of vaginal infections associated with vaginal contraceptives is a common concern among both healthcare providers and patients.
Results from a pooled analysis of the aforementioned two pivotal phase 3 efficacy trials (NCT00263341 and NCT00455156) showed that bleeding patterns associated with Annovera were well tolerated among women aged 18 to 40 years.17 When the ring was removed cyclically as directed, approximately 98% of women had predictable, scheduled bleeding, with an average of 3.3 bleeding days per cycle. Approximately 2.6% to 4.9% of women had amenorrhea each cycle.17 Unscheduled bleeding or spotting occurred in 5% to 10% of women and lasted for an average of 1 day or less per cycle. Unacceptable vaginal bleeding led to only 1.7% of women discontinuing Annovera, which Dr Nelson found impressive.17
Results from an acceptability sub-study (part of NCT00263341) showed nearly 90% of women were satisfied with Annovera as a form of contraception, most women rated Annovera highly related to ease of use, side effects, expulsions, feeling the ring, and physical effect during sexual activity.18
Annovera is covered by most insurance plans, including Medicaid. Its coverage is improving every day, according to Dr Bernick. In addition, under the Affordable Care Act, insurance plans must pay without a copay or deductible if a healthcare provider decides a specific product is the most appropriate for a patient and submits a letter of medical necessity, said Dr Nelson. An example of a medical necessity letter for Annovera can be found on AnnoveraHCP.com. For patients who do not have full coverage, TherapeuticsMD offers an affordability program to help with patient copays. The Annovera Savings Program offers copayment support for eligible patients who have met their deductible. Patients in this program can pay as little as $60 – amounting to about $5 a month – for 1 full year of contraceptive protection. Details, including terms, conditions, and eligibility criteria are available at savings.annovera.com.
Annovera can benefit a diverse population of women across all reproductive ages and demographics—it is ideal for anyone who does not want to take a product every day and does not want a procedure, from adolescents to women who are approaching menopause and still want contraception. This includes women in college with unpredictable schedules, women who travel frequently, women in the military who may face difficulties with obtaining or consistently using certain contraceptives, women birth-spacing in between children, and women approaching menopause who still want contraception.
Administering Annovera requires no special training, equipment, or inventory, and is available to all prescribers. Dr Bernick said he is hopeful that women will be counseled about the unique features of Annovera when discussing their birth control options with their provider.
Please see the Brief Summary of Full Prescribing Information, including BOXED WARNING, below or visit annovera.com/pi.pdf.
References
1. Daniels K, Abma, JC. Current contraceptive status among women aged 15–49: United States, 2015-2017. Centers for Disease Control and Prevention: NCHS Data Brief. Published December 2018. Accessed November 2, 2020. https://www.cdc.gov/nchs/data/databriefs/db327-h.pdf
2. Carlin EP, Spielmann HM, inventors; The Proctor & Gamble Company, assignee. Tampon. US Patent 7,338,483 B2. March 4, 2008.
3. Colquitt CW, Martin TS. Contraceptive methods: A review of nonbarrier and barrier products. J Pharm Pract. 2017;30(1):130-135. doi:10.1177/0897190015585751
4. Finer LB, Zolna MR. Declines in unintended pregnancy in the United States, 2008-2011. N Engl J Med. 2016;374(9):843-852. doi:10.1056/NEJMsa1506575
5. Tibaijuka L, Odongo R, Welikhe E, et al. Factors influencing use of long-acting versus short-acting contraceptive methods among reproductive-age women in a resource-limited setting. BMC Women’s Health. 2017;17(1):25. doi:10.1186/s12905-017-0382-2
6. Foster DG, Hulett D, Bradsberry M, Darney P, Policar M. Number of oral contraceptive pill packages dispensed and subsequent unintended pregnancies. Obstet Gynecol. 2011;117(3):566-572. doi:10.1097/AOG.0b013e3182056309
7. Combined hormonal contraceptives. The Centers for Disease Control and Prevention. Accessed November 2, 2020. https://www.cdc.gov/reproductivehealth/contraception/mmwr/spr/combined.html
8. Contraceptive methods available to patients of office-based physicians and title X clinics – United States, 2009-2010. MMWR Morb Mortal Wkly Rep. 2011;60(1):1-4.
9. Annovera. Prescribing Information. TherapeuticsMD; 2020. Accessed November 2, 2020. https://Annovera.com/pi.pdf?_ga=2.68327832.88356623.1585240849-1540396272.1585240849
10. Kumar N, Koide SS, Tsong Y, Sundaram K. Nestorone: A progestin with a unique pharmacological profile. Steroids. 2000;65(10-11):629-636. doi:10.1016/s0039-128x(00)00119-7
11. van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, Doggen CJ, Rosendaal FR. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study. BMJ. 2009;339:b2921. doi:10.1136/bmj.b2921
12. Gialeraki A, Valsami S, Pittaras T, Panayiotakopoulos G, Politou M. Oral contraceptives and HRT risk of thrombosis. Clin Appl Thromb Hemost. 2018;24(2):217-225. doi:10.1177/1076029616683802
13. Archer DF, Merkatz RB, Bahamondes L, et al. Efficacy of the 1-year (13-cycle) segesterone acetate and ethinlyestradiol contraceptive vaginal system: results of two multicenter, open-label, single arm, phase 3 trials. Lancet. 2019;7(8):e1054-e1064. doi:10.1016/S2214-109X(19)30265-7
14. Gemzell-Danielsson K, Sitruk-Ware R, Creinin MD, et al. Segesterone acetate/ethinyl estradiol 12-month contraceptive vaginal system safety evaluation. Contraception. 2019;99(6):323-328. doi:10.1016/j.contraception.2019.02.001
15. Nelson A. Comprehensive overview of the recently FDA-approved contraceptive vaginal ring releasing segesterone acetate and ethinyl estradiol: a new year-long, patient controlled, reversible birth control method. Expert Rev Clin Pharmacol. 2019;12(10):953-963. doi:10.1080/17512433.2019.1669448
16. Huang Y, Merkatz RB, Hillier SL, 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(8):e0134460. doi:10.1371/journal.pone.0134460
17. Vieira, CS, Fraser IS, Plagianos MG, et al. Bleeding profile associated with 1-year use of the segesterone acetate/ethinyl estradiol contraceptive vaginal system: pooled analysis from phase 3 trials. Contraception. 2019;100(6):438-444. doi:10.1016/j.contraception.2019.07.145
18. Merkatz, RB, Plagianos M, Hoskin E, Cooney M, Hewett PC, Mensch BS. Acceptability of the Nestorone/ethinyl estradiol contraceptive vaginal ring: development of a model; implications for introduction. Contraception. 2014;90(5):514-521. doi:10.1016/j.contraception.2014.05.015
