Providing a Long-Lasting Supply of Contraception May Lead to More Consistent Use and Reduction in Unintended Pregnancies
Published as a promotional supplement to Contemporary OB/GYN.
Sponsored by: TherapeuticsMD
Of all unintended pregnancies, 41% are due to the inconsistent use of contraceptives.1 The Centers for Disease Control and Prevention recommend that women be provided with a 1-year supply of birth control.2 Birth control pills, patches, one-month rings, and injections are typically dispensed in only 1- or 3-month supplies, making additional trips to a clinic or pharmacy a potential barrier to consistent use. Women who receive a 1-year supply of birth control have been found to be 30% less likely to have an unintended pregnancy compared with women receiving a 1- to 3-month supply.3,4 Long-acting reversible contraception (LARC) methods such as intrauterine devices (IUDs) and implants must be administered by a healthcare professional and require a procedure for insertion and removal.
Annovera (segesterone acetate and ethinyl estradiol vaginal system)
The segesterone acetate and ethinyl estradiol vaginal system was developed to address the needs of women who desire a long-lasting form of birth control without requiring a procedure for insertion and removal coupled with the patient control and immediate reversibility aspect of short-acting products (Figure).
It is a soft, flexible vaginal ring that is self-administered and does not require a procedure. Although the overall diameter is roughly the same as NuvaRing (etonogestrel/ethinyl estradiol vaginal ring), the increase in its width was purposeful because it is composed of a “squishy” silicone elastomer to make it soft and flexible for easy insertion and removal while remaining comfortably in place throughout daily activities including sex.5,6 It is inserted into the vagina and remains in place for 21 days and then removed for 7 days each cycle. It can be used for up to a full year or 13 menstrual cycles.5 It is also as effective as a pill without the daily commitment. In clinical trials, the 13-cycle (1-year) cumulative probability of not becoming pregnant was 97.3%.5 Unlike other contraceptive vaginal rings, it does not require refrigeration at any time.
Created with a novel hormonal profile
This ring-shaped vaginal system contains two active hormones, releasing one of the lowest daily doses of ethinyl estradiol (13 mcg/day) and including a new nonandrogenic progestin, segesterone acetate. Unlike the other progestins contained in combination hormonal contraceptives that are all derived from testosterone, segesterone acetate is derived from natural progesterone. Segesterone acetate is of the highest anti-ovulatory potency and unlike other progestins, it demonstrates no androgenic or glucocorticoid activity that can be responsible for changes in weight and acne.7,8* Based on the residual amount of drug in the productused in clinical trials over 13 cycles, approximately 40% (41.2 mg) of segesterone acetate and 20% (3.48 mg) of ethinyl estradiol were released over this period.5
Cycle control – Bleeding profile
In clinical trials of 2070 women, 98% of women had scheduled bleeding with amenorrhea occurring in 2.6% to 4.9% of women per cycle.9 The mean number of bleeding-only days averaged 3.3 days.9 Unscheduled bleeding or spotting occurred in 5% to 10% of women and lasted for an average of 1 day or less per cycle.9
Overall satisfaction with this form of contraception was approximately 90%.10† No clinically relevant increase in weight or other androgenic side effects were observed.8,11 Its use did not increase the risk of vaginal infection nor did it affect the vaginal microbiome.12‡ There were no increases in bacterial vaginosis, candidiasis, or trichomoniasis throughout the study.12‡
Safety was demonstrated in 3 open-label, 13-cycle (1-year) clinical trials that enrolled 2308 women.11
Adverse events occurred most frequently within the first days of the first cycle and were both mild and self-limiting (Table). Expulsion occurred primarily in the first few weeks as women were getting used to the product and resulted in 1.4% discontinuation.
How to start
The segesterone acetate and ethinyl estradiol vaginal system is ideal for women who want to be in control of both their fertility and menstruation with a 21/7 cyclical, self-administered, long-lasting product with immediate reversibility. It should be considered for adolescents or anyone who does not want to take a product every day and does not want a procedure. It is appropriate for nulliparous women and those not in a monogamous relationship who in the past may have been denied LARCs; women who are birth spacing and in-between children who do not want to commit to a contraceptive of longer duration; college women with unpredictable schedules who do not want a daily-use product or worry about getting their monthly refills; women in the military who want control of fertility and menstruation for 1 year; and women who are approaching menopause and still want contraception. It represents a single contraceptive product amenable for most patient and prescriber types.
The segesterone acetate and ethinyl estradiol vaginal system is the only long-lasting reversible contraception that is procedure free, used for 21/7 day cyclical dosing for one year (13 cycles), empowering women to be in control of their fertility and menstruation.5 It contains a nonandrogenic progestin, segesterone acetate,with the highest anti-ovulatory that has no androgenic or glucocorticoid effects at contraceptive doses.7,8* It also has one of the lowest average daily releases of ethinyl estradiol (13 mcg/day), and users report high patient satisfaction (~90%).5,10† Women should be counseled about its unique features when discussing their birth control options.
To learn more about the segesterone acetate and ethinyl estradiol vaginal system, visit annoverahcp.com.
Please see brief summary of Full Prescribing Information, including BOXED WARNING, on the following page or visit annovera.com/pi.pdf.
*Based on pharmacologic studies in animals and in vitro studies. The clinical significance of these data is not known.
†In a phase 3 study, a product acceptability questionnaire was administered and completed at the end of Cycle 3 (n=1036). Results were based on data from 905 subjects in the areas of ease of use, expulsion, side effects, and sex/intercourse.
‡Vulvovaginal infections and vaginal discharge were common adverse reactions. For a full list of common adverse reactions, see table above or review the Full Prescribing Information.
1. Sonfield A, Hasstedt K, Gold RB. Moving forward: family planning in the era of health reform. Guttmacher Institute, 2014.
2. Centers for Disease Control and Prevention. Reproductive health. Combined hormonal contraceptives. Available at https://www.cdc.gov/reproductivehealth/contraception/mmwr/spr/combined.html. Accessed August 26, 2020.
3. Foster DG, Hulett D, Bradsberry M, et al. Number of oral contraceptive pill packages dispensed and subsequent unintended pregnancies. Obstet Gynecol. 2011;117(3):566-572.
4. McMenamin SB, Charles SA, Tabatabaeepour N, et al. Implications of dispensing self-administered hormonal contraceptives in a 1-year supply: a California case study. Contraception. 2017;95(5):449-451.
5. Annovera [package insert]. Boca Raton, FL: TherapeuticsMD, Inc; 2020.
6. NuvaRing [package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme: 2001.
7. Kumar N, Koide SS, Tsong Y, Sundaram K. Nestorone: a progestin with a unique pharmacological profile. Steroids. 2000;65(10-11):629-636.
8. Nelson A. 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.
9. 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.
10. Merkatz RB, Plagianos M, Hoskin E, et al. Acceptability of the Nestorone/ethinyl estradiol contraceptive vaginal ring: development of a model; implications for introduction. Contraception. 2014;90(5):514-521.
11. 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.
12. 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
13. 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.
ANNOVERA® (segesterone acetate and ethinyl estradiol vaginal system)
BRIEF SUMMARY OF PRESCRIBING INFORMATION
This Brief Summary does not include all the information needed to use ANNOVERA safely and effectively. Please visit ANNOVERA.com/pi.pdf for Full Prescribing Information (PI).
INDICATIONS AND USAGE
ANNOVERA is indicated for use by females of reproductive potential to prevent pregnancy.
Limitations of Use: ANNOVERA has not been adequately studied in females with a BMI >29 kg/m2.
DOSAGE AND ADMINISTRATION
One ANNOVERA is inserted in the vagina. The vaginal system must remain in place continuously for 3 weeks (21 days) followed by a 1-week (7-day) vaginal system-free interval. One vaginal system provides contraception for thirteen 28-day cycles (1 year). Follow instructions for starting ANNOVERA, including switching from other contraceptive methods, and use after abortion, miscarriage, or childbirth [see How to Start ANNOVERA (2.2) in PI].
Contraceptive efficacy of ANNOVERA may be reduced if a woman deviates from the recommended use. If ANNOVERA is out of the vagina for more than 2 continuous hours or more than 2 cumulative hours during the 21 days of continuous use, then back-up contraception, such as male condoms or spermicide, should be used until the vaginal system has been in the vagina for 7 consecutive days.
ANNOVERA is contraindicated in females who are known to have the following conditions: • A high risk of arterial or venous thrombotic diseases. Examples include females who are known to: smoke, if over age 35; have current or history of deep vein thrombosis or pulmonary embolism; have cerebrovascular disease; have coronary artery disease; have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation); have inherited or acquired hypercoagulopathies; have uncontrolled hypertension or hypertension with vascular disease; have diabetes mellitus and are over age 35, diabetes mellitus with hypertension or vascular disease, or other end-organ damage, or diabetes mellitus of >20 years duration; have headaches with focal neurological symptoms, migraine headaches with aura, or are over age 35 with any migraine headaches. • Current or history of breast cancer or other estrogen- or progestin-sensitive cancer. • Liver tumors, acute hepatitis, or severe (decompensated) cirrhosis.
• Undiagnosed abnormal uterine bleeding. • Hypersensitivity to any of the components of ANNOVERA. Hypersensitivity reactions reported include: throat constriction, facial edema, urticaria, hives, and wheezing. • Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for alanine transaminase (ALT) elevations.
WARNINGS AND PRECAUTIONS
Thromboembolic Disorders and Other Vascular Conditions
Females are at increased risk for a venous thrombotic event (VTE) when using ANNOVERA.
Stop ANNOVERA if a thrombotic or thromboembolic event occurs, or unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions and evaluate for retinal vein thrombosis immediately. Stop ANNOVERA at least 4 weeks before and through 2 weeks after major surgery. Start ANNOVERA no earlier than 4 weeks after delivery in females who are not breastfeeding.
Before starting ANNOVERA, consider history and risk factors of thrombotic or thromboembolic disorders. ANNOVERA is contraindicated in females with a high risk of arterial or venous thrombotic/thromboembolic diseases.
Consider cardiovascular risk factors before initiating in all females, particularly those over 35 years. CHCs increase the risk of cardiovascular events and cerebrovascular events, such as stroke and myocardial infarction. The risk is greater among older females (>35 years of age), smokers, and females with hypertension, dyslipidemia, diabetes, or obesity.
The use of CHCs increases the risk of VTE, such as deep vein thrombosis and pulmonary embolism. Risk factors for VTEs include smoking, obesity, and family history of VTE, in addition to other factors that contraindicate use of CHCs. The rates of VTE are even greater during pregnancy, and especially during the postpartum period. The risk of VTE is highest during the first year of CHC use and when restarting hormonal contraception following a break of 4 weeks or longer. The risk of VTE due to CHCs gradually disappears after use is discontinued.
Impaired Liver Function
ANNOVERA is contraindicated in females with acute hepatitis or severe (decompensated) cirrhosis of the liver. Discontinue ANNOVERA if jaundice develops. Acute liver test abnormalities may necessitate the discontinuation of ANNOVERA use until the liver tests return to normal and ANNOVERA causation has been excluded.
ANNOVERA is contraindicated in females with benign or malignant liver tumors. Hepatic adenomas are associated with CHC use (estimated 3.3 cases/100,000 CHC users). Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage.
Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment
Stop ANNOVERA prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir. ANNOVERA can be restarted 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.
ANNOVERA is contraindicated in females with uncontrolled hypertension or hypertension with vascular disease. For all females, including those with well-controlled hypertension, monitor blood pressure at routine visits and stop ANNOVERA if blood pressure rises significantly.
The risk for cardiovascular disease and prevalence of risk factors for cardiovascular disease increase with age. Certain conditions, such as smoking and migraine headache without aura, that do not contraindicate CHC use in younger females, are contraindications to use in women over 35 years of age.
Consider the presence of underlying risk factors that may increase the risk of cardiovascular disease or VTE, particularly before initiating ANNOVERA for women over 35 years, such as hypertension, diabetes, dyslipidemia, and obesity.
Studies suggest a small increased relative risk of developing gallbladder disease among CHC users. Use of CHCs may also worsen existing gallbladder disease. A past history of CHC- related cholestasis predicts an increased risk with subsequent CHC use. Females with a history of pregnancy-related cholestasis may be at an increased risk for CHC-related cholestasis.
Adverse Carbohydrate and Lipid Metabolic Effects
ANNOVERA is contraindicated in diabetic females over age 35, or females who have diabetes with hypertension, nephropathy, retinopathy, neuropathy, other vascular disease, or females with diabetes of >20 years duration. ANNOVERA may decrease glucose tolerance. Carefully monitor prediabetic and diabetic females who are taking ANNOVERA.
Consider alternative contraception for females with uncontrolled dyslipidemia. ANNOVERA may cause adverse lipid changes.
Females with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using ANNOVERA.
ANNOVERA is contraindicated in females with certain headaches. Evaluate new or significant changes in headaches, including migraines, and discontinue ANNOVERA if indicated.
Bleeding Irregularities and Amenorrhea
Females using ANNOVERA may experience unscheduled (breakthrough) bleeding and spotting, especially during the first month of use. If unscheduled bleeding occurs or persists, check for causes such as pregnancy or malignancy.
Based on subject diaries from the two clinical efficacy trials of ANNOVERA, 5-10% of females experienced unscheduled bleeding per 28-day cycle. A total of 41 subjects (1.7%) discontinued use due to menstrual disorders including metrorrhagia, menorrhagia, and abnormal withdrawal bleeding. Females who are not pregnant and use ANNOVERA may experience amenorrhea. Based on subject diary data from two clinical trials for up to 13 cycles, amenorrhea occurred in 3-5% of females per cycle using ANNOVERA and in 0.9% of females in all 13 cycles. If scheduled bleeding does not occur, consider the possibility of pregnancy.
Carefully observe females with a history of depression and discontinue ANNOVERA if depression recurs to a serious degree.
Some studies suggest that CHCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia.
Effect on Binding Globulins
The estrogen component of ANNOVERA may raise the serum concentrations of thyroxine-binding globulin, sex hormone- binding globulin, and cortisol-binding globulin. The dose of replacement thyroid hormone or cortisol therapy may need to be increased.
In females with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.
Chloasma may occur with ANNOVERA use, especially in females with a history of chloasma gravidarum. Advise females who tend to develop chloasma to avoid exposure to the sun or ultraviolet radiation while using ANNOVERA.
Toxic Shock Syndrome (TSS)
If a patient exhibits signs/symptoms of TSS, consider the possibility of this diagnosis, remove ANNOVERA, and initiate appropriate medical evaluation and treatment.
Some females are aware of the vaginal system on occasion during the 21 days of use or during coitus, and partners may feel the vaginal system during coitus. ANNOVERA may not be suitable for females with conditions that make the vagina more susceptible to vaginal irritation or ulceration. Vaginal and cervical erosion and/or ulceration has been reported in females using other contraceptive vaginal devices. In some cases, the ring adhered to vaginal tissue, which necessitated removal by a healthcare provider.
Clinical Trial Experience
Most Common Adverse Reactions
In clinical trials, adverse reactions reported in by ≥5% of ANNOVERA-treated subjects include: headache, including migraine (38.6%); nausea/vomiting (25.0%); vulvovaginal mycotic infection/vaginal candidiasis (14.5%); abdominal pain/ lower/upper (13.3%); dysmenorrhea (12.5%); vaginal discharge (11.8%); UTI/cystitis/pyelonephritis/genitourinary tract infection (10.0%); breast pain/tenderness/discomfort (9.5%); metrorrhagia/menstrual disorder (7.5%); diarrhea (7.2%); and genital pruritus (5.5%).
Adverse Reactions Leading to Discontinuation
Among subjects using ANNOVERA for contraception, 12% discontinued from the clinical trials due to an adverse reaction. Adverse reactions leading to discontinuation by ≥1% of ANNOVERA-treated subjects, include: metrorrhagia/menorrhagia (1.7%); headache, including migraine (1.3%), vaginal discharge/ vulvovaginal mycotic infections (1.3%); nausea/vomiting (1.2%). In addition, 1.4% of subjects discontinued ANNOVERA use due to vaginal system expulsions.
Serious Adverse Reactions
Serious adverse reactions occurring in ≥2 subjects were: VTEs (deep venous thrombosis, cerebral vein thrombosis, pulmonary embolism); psychiatric events; drug hypersensitivity reactions; and spontaneous abortions.
Drugs or herbal products that induce certain enzymes, including CYP3A4, may decrease the effectiveness of ANNOVERA or increase breakthrough bleeding. Counsel patients to use a backup or alternative method of contraception when enzyme inducers are used with ANNOVERA. Do not co-administer ANNOVERA with HCV drug combinations containing ombitasvir/ paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations.
USE IN SPECIFIC POPULATIONS
Discontinue ANNOVERA if pregnancy occurs.
Not recommended for nursing mothers; can decrease milk production.
Safety and efficacy of ANNOVERA have been established in women of reproductive age. Efficacy is expected to be the same for postpubertal adolescents under the age of 18 as for users 18 years and older. Use of ANNOVERA before menarche is not indicated.
ANNOVERA has not been studied in females who have reached menopause and is not indicated in this population.
No studies have been conducted to evaluate the effect of hepatic impairment on the disposition of ANNOVERA. Acute or chronic disturbances of liver function may necessitate the discontinuation of CHC use until markers of liver function return to normal and CHC causation has been excluded.
No studies were conducted in subjects with renal impairment; ANNOVERA is not recommended in patients with renal impairment.
Body Mass Index (BMI)/Body Weight
The safety and efficacy of ANNOVERA in females with a BMI >29 kg/m2 have not been adequately evaluated because this subpopulation was excluded from the clinical trials after 2 VTEs occurred in females with a BMI > 29 kg/m2. Higher body weight is associated with lower systemic exposure of SA and EE.
Manufactured for: TherapeuticsMD, Inc.
Boca Raton, FL 33431
Based on ANVA-LAB-20001.2 01/2020