New 13-Cycle Vaginal Contraceptive System

 

From principal investigator Anita Nelson, MD, an inside look at the new combined hormonal vaginal ring, effective over one year of use:

This new vaginal contraceptive system (Annovera) has unique features that combine to provide convenient, long lasting, rapidly reversible contraception with excellent cycle control. Developed by the Population Council, Annovera introduces a new progestational compound—segesterone acetate—which is partnered with ethynyl estradiol in sufficient quantities that one ring can be used cyclically (21/7 regimen) for up to one year (13 cycles). Women can initiate and discontinue the method themselves without any procedures or reliance on their clinician’s availability. The delivery system itself has a design that may enable other applications to be added in the future.

The Annovera ring is a soft, flexible (squishy), toroidal-shaped ring that is opaque white in color composed of nonbiodegradable elastomer. This new ring is thicker in cross section (8.4 mm) than the existing monthly vaginal contraceptive ring (4 mm), but the outer diameters of the two different rings are quite similar (56 mm vs 54 mm). This system uses softer, more compressible material to facilitate its placement and removal and to enable sexual activity without it being noticed by either partner. In contrast to the current ring system, in which the sex steroids are mixed in the elastomer itself and the rate of release is controlled by a thin releasing membrane, this new system provides channels into which are placed two cores with the hormonal agents that released through the cover of the ring. Another important difference between these two vaginal contraceptives is the fact that this new system is temperature stable and does not need any refrigeration. This markedly simplifies the supply chain.

Segesterone acetate is a new progestin developed years ago by the Population Council. It is very potent and very selective. It binds to the progesterone receptor with great affinity; it has progestational activity that is 100 times greater than progesterone itself.[1] At the concentrations produced by this ring, segesterone has no androgenic, estrogenic, or glucocorticoid activity. This can be seen in its side effect profile. Readers may remember hearing about this compound before when it was called Aciform or Nesterone. Although it has been tested before in products by itself or in combination with estrogen, segesterone acetate has not been used in birth control pills because it is very poorly absorbed when administered orally.[2] However, segesterone acetate is ideally suited to transdermal (vaginal) applications.

In two identically conducted clinical trials of Annovera, 2,308 women completed 21,590 cycles for safety studies and provided 17,427 evaluable cycles for pregnancy calculations. These evaluable cycles are all the the cycles from women age 18-35 years once the cycles were excluded when women used an additional birth control method. Each subject was instructed to place the ring high in her vagina during the first 5 days of menses, keep it in place for 21 days and remove it for 7 days. The woman was told to gently wash the ring off with mild soap and water after removal and put it in its case. After 7 days, she was to re-rinse it and place it again back high in her vagina.

A diverse group of women participated in these trials. African American women constituted 14.1% of the study population; Caucasians made up 71.2%. BMIs of the subjects ranged from 16.0 to 41.5 kg/m², but 69% had BMIs between 20 and 27 kg.m².[3] The overall Pearl Index (the pregnancy rate of the intent-to-treat efficacy population) was 2.98 pregnancies/100 women-years, which is quite in line with the findings of other hormonal methods tested under the “creeping pearl” conditions.[4],[5] Importantly, the risk of pregnancy did not increase the longer the woman used her ring; the hormone levels from the ring at the 13^th cycle were as effective as those in earlier cycles.[3] The manufacturer points out that at the end of the 13-cycle clinical trial only 25.6% of the EE and 40.3% of the segesterone acetate had been used from the ring.[6] However, the fact that so much of the hormone is still available in the ring does not support either longer use of the ring or decreasing the ring-free days until new clinical trials of the safety and efficacy of those regimens have been tested.

Pregnancy rates were lower when women did not have prolonged episodes of ring removal (2.11/100 women-years) and were higher when the ring was removed for longer than the recommended maximum time (5.89/100 women-years).[3],[7] Due to concern for VTE, part way into the study, women with BMIs > 29 kg/m² were exited from the study. Pregnancy rates were not affected by BMI within the range in the population tested. The Kaplan-Meier life table analysis of the cumulative probability of not becoming pregnant while using the vaginal contraceptive system or within 7 days of last ring removal was 97.2%.

The data on bleeding patterns were very robust for this study; 91% of women provided daily data for cycle control analysis.[8] Overall, bleeding patterns were predictable and well tolerated. Only 1.7% of participants discontinued ring use prematurely because they considered their bleeding to be unacceptable. Bleeding and/or spotting was considered to be scheduled if it started when the ring was removed—days 22-28 of the cycle and continued no further than 4 days into the next cycle. All other bleeding/spotting episodes were classified as unscheduled.

Table A shows the most important measures of bleeding patterns

Table A: Bleeding Patterns with Annovera
Over Entire Study
Mean days of scheduled spotting/bleeding per cycle	4.9 +/- 1.1%
% of women with ≥ 1-episode unscheduled spotting/bleeding	56.3%
% women with unscheduled spotting/bleeding in any cycle	13.2 – 21.7%
Mean duration of unscheduled spotting/bleeding per cycle	< 1 day
% women with amenorrhea in any given cycle	2.5-4.9%

African American women much more likely than Caucasian women to have unscheduled spotting/bleeding OR = 1.49, even though age and BMI did not impact on bleeding patterns.[8]

Only 12% of study participants discontinued early because of any adverse effects.[9] The most common adverse events that lead to early discontinuation were heavy, prolonged or unscheduled bleeding (1.7%), headache (1.3%), vaginal discharge/infection (1.3%), nausea/vomiting (1.2%). However, many more women reported symptoms they attributed to the ring (treatment-related adverse events). The most common of these include headache (26%), nausea (18%), vaginal discharge (10%), cramping (10%), vulvovaginitis (7%), metrorrhagia (sic) (7%), breast tenderness (6%), and vomiting (5%). Mood swings were reported by 3% of subjects and weight changes by only 0.015%. The majority of these events were rated mild and many occurred in the first month or two of use.[9]

Two percent (51) of women experienced serious adverse events, but only 15 of these had issues that could be related to ring use. This included 4 venous thromboembolisms, psychological events, drug hypersensitivity reaction and a spontaneous abortion.[3],[4] Because the VTE rate was higher for women with BMI ≥ 29 kg/m², the FDA has required that the manufacturer conduct post-marketing studies to better quantify those risks. However, in contrast to the BMI limitations placed on each of the currently approved transdermal contraceptive patches (“only for use by women with BMI < 30 kg/m²”), the FDA-approved labeling for this ring includes wording only about “limitations of use”. It reads “Not adequately evaluated in females with a body mass index of > 29 kg/m²”.[4]

Ring expulsion were also evaluated. Over half of users recorded at least one complete expulsion (24.6%) or partial expulsion (44.4%). In general, the ring can be retrieved, rinsed, and replaced. Only 5.5% of women required a replacement ring due to expulsion. It should be noted that there was a sharp learning curve; most expulsions occurred in the first cycle.[9] Importantly, only 1.4% of women discontinued early due to ring expulsion.[4]

Finally, 89% of respondents reported that they were “satisfied” or “highly satisfied” with Annovera. The features women liked best about the ring were its ease of use and that it lasts for a year. Of those who were dissatisfied, side effects and putting the ring in or having it come out were the most common complaints.[7]

Overall, this contraceptive system offers a user-controlled method that provides up to one year of effective (failure rate < 3%) pregnancy protection. Bleeding patterns were well tolerated. Discontinuation rates for adverse events are low and satisfaction levels are high.[10],[11]

Cost is always a problem with new methods. The Affordable Care Act specifically states that no woman should have to pay any co-pay for her contraceptive method if it is one of the 17 approved product categories. In addition, insurance companies are supposed to respect (and pay for) any method the clinician requests coverage for if the clinician justifies medical necessity. A sample letter that clinicians can submit to defend medical necessity is available at ANNOVERAHCP.com website. The manufacturer has also established a program for women to use to reduce their copay to as little as $60/year if they have met their deductible. The website to apply for that is https://savings.annovera.com/ most Medicaid programs across the country are covering this ring as do most private insurers. The company generously worked hard early on to make sure that women in our military have access to this method that gives them both cycle control and control over their fertility.

In addition to answering questions about women with BMI > 29 kg/m², I think we all want to know if this ring contains enough hormones to enable women to use it continuously and avoid scheduled bleeding. And we would like to know, do we really need to use ethinyl estradiol or could we use a weaker (maybe less pro-thrombotic) estrogen like the natural ovarian estradiol? We are all excited to do the studies to see if we can extend the use of this new selective, strong progestin in this new vaginal delivery system. But this product already has several attractive special features that warrant adding it to the options we highlight with our patients.

STAY TUNED…

Submitted by: Anita Nelson, MD. [Dr. Nelson is a principal investigator for the phase-3 trials of Annovera and she participates on the Advisory Board and the Speaker’s Bureau for the Population Council.]

References

[1].     Kumar N, Koide SS, Tsong Y, Sundaram K. Nestorone: a progestin with a unique pharmacological profile. Steroids. 2000;65(10-11):629-36.

[2].     Noé G, Salvatierra A, Heikinheimo O, Maturana X, Croxatto HB. Pharmacokinetics and bioavailability of ST 1435 administered by different routes. Contraception. 1993;48(6):548-56.

[3].     Archer DF, Merkatz RB, Bahamondes L, Westhoff CL, Darney P, Apter D, Jensen JT, Brache V, Nelson AL, Banks E, Bártfai G, Portman DJ, Plagianos M, Dart C, Kumar N, Creasy GW, Sitruk-Ware R, Blithe DL. Efficacy of the 1-year (13-cycle) segesterone acetate and ethinylestradiol contraceptive vaginal system: results of two multicentre, open-label, single-arm, phase 3 trials. Lancet Glob Health. 2019;7(8):e1054-e1064.

[4].     Drug Approval Package: Annovera (segesterone acetate and ethinyl estradiol) https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209627Orig1s000TOC.cfm Last accessed 10/06/20

[5].     Trussell J, Portman D. The creeping Pearl: Why has the rate of contraceptive failure increased in clinical trials of combined hormonal contraceptive pills? Contraception. 2013;88(5):604-10.

[6].     Center for drug evaluation and research. Multi-discipline review application number 209627 Orig1s000.Jun 29, 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209627Orig1s000MultidisciplineR.pdf. Last accessed 10/06/20

[7]      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):514-21.

[8].     Nelson AL, Vieira CS, Fraser I, Burke AE, Gilliam ML, Brache V. Bleeding patterns with a 1-year, segesterone acetate/ethinyl estradiol contraceptive vaginal system. Abstract ACOG Nashville, TN 05/03-06/19. Accepted 2/02/19

[9].     Gemzell-Danielsson K, Sitruk-Ware R, Creinin MD, Thomas M, Barnhart KT, Creasy G, Sussman H, Alami M, Burke AE, Weisberg E, Fraser I, Miranda MJ, Gilliam M, Liu J, Carr BR, Plagianos M, Roberts K, Blithe D. Segesterone acetate/ethinyl estradiol 12-month contraceptive vaginal system safety evaluation. Contraception. 2019;99(6):323-328.

[10].   Paton DM. Contraceptive vaginal ring containing segesterone acetate and ethinyl estradiol: long-acting, patient-controlled, procedure-free, reversible prescription birth control. Drugs Today (Barc). 2019;55(7):449-457.

[11].   Nelson AL. Comprehensive overview of the recently FDA-approved contraceptive vaginal ring releasing segesterone acetate and ethinylestradiol: A new year-long, patient controlled, reversible birth control method. Expert Rev Clin Pharmacol. 2019;12(10):953-963.