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®.
To view the full video associated with this Contemporary OB/GYN® K-Cast, click here.
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.
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
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