ANNOVERA Vaginal system (Ring) Ref.[10392] Active ingredients: 17 alpha-Ethinylestradiol

5.1 Thromboembolic Disorders and Other Vascular Conditions

Females are at increased risk for a venous thrombotic event (VTE) when using ANNOVERA. Limited data are available in females with a BMI >29.0 kg/m² because this subpopulation was excluded from the clinical trials after VTEs were reported.

• Stop ANNOVERA if an arterial or deep venous thrombotic event occurs.
• Stop ANNOVERA if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions and evaluate for retinal vein thrombosis immediately.
• Discontinue ANNOVERA during prolonged immobilization. If feasible, stop ANNOVERA at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of VTE.
• Start ANNOVERA no earlier than 4 weeks after delivery in females who are not breastfeeding. The risk of postpartum VTE decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week.
• Before starting ANNOVERA, evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy. ANNOVERA is contraindicated in females with a high risk of arterial or venous thrombotic/thromboembolic diseases [see Contraindications (4)].

Arterial Events

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.

ANNOVERA is contraindicated in females over 35 years of age who smoke [see Contraindications (4)]. Cigarette smoking increases the risk of serious cardiovascular events from CHC use. This risk increases with age, particularly in females over 35 years of age, and with the number of cigarettes smoked.

Venous Events

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 [see Contraindications (4)]. While the increased risk of VTE associated with use of CHCs is well established, the rates of VTE are even greater during pregnancy, and especially during the postpartum period (see Figure 1). The rate of VTE in females using CHCs has been estimated to be 3–12 cases per 10,000 woman-years.

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.

Figure 1 shows the risk of developing a VTE for females who are not pregnant and do not use CHCs, for females who use CHCs, for pregnant females, and for females in the postpartum period. To put the risk of developing a VTE into perspective: If 10,000 females who are not pregnant and do not use CHCs are followed for 1 year, between 1 and 5 of these women will develop a VTE.

Figure 1. Likelihood of Developing a VTE:

* CHC = combination hormonal contraception
** Pregnancy data based on actual duration of pregnancy in the reference studies. Based on a model assumption that pregnancy duration is 9 months, the rate is 7 to 27 per 10,000 WY.

5.2 Liver Disease

Impaired Liver Function

ANNOVERA is contraindicated in females with acute hepatitis or severe (decompensated) cirrhosis of the liver [see Contraindications (4)]. 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.

Liver Tumors

ANNOVERA is contraindicated in females with benign or malignant liver tumors [see Contraindications (4)]. Hepatic adenomas are associated with CHC use. An estimate of the attributable risk is 3.3 cases/100,000 CHC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage.

Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) CHC users. The attributable risk of liver cancers in CHC users is less than one case per million users.

5.3 Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment

During clinical trials with the Hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with and without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in females using ethinyl estradiol-containing medications, such as ANNOVERA. Discontinue ANNOVERA prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications (4)]. ANNOVERA can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.

5.4 Hypertension

ANNOVERA is contraindicated in females with uncontrolled hypertension or hypertension with vascular disease [see Contraindications (4)]. For all females, including those with well-controlled hypertension, monitor blood pressure at routine visits and stop ANNOVERA if blood pressure rises significantly.

An increase in blood pressure has been reported in females using CHCs, and this increase is more likely in older females and with extended duration of use. The effect of CHCs on blood pressure may vary according to the progestin in the CHC.

5.5 Age-Related Considerations

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 [see Contraindications (4) and Warnings and Precautions (5.1)]. 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
• Obesity

5.6 Gallbladder Disease

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.

5.7 Adverse Carbohydrate and Lipid Metabolic Effects

Hyperglycemia

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 [see Contraindications (4)]. ANNOVERA may decrease glucose tolerance. Carefully monitor prediabetic and diabetic females who are taking ANNOVERA.

Dyslipidemia

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.

5.8 Headache

ANNOVERA is contraindicated in females who have headaches with focal neurological symptoms or have migraine headaches with aura, and in females over age 35 years who have migraine headaches with or without aura [see Contraindications (4)].

If a woman taking ANNOVERA develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue ANNOVERA if indicated.

Consider discontinuation of ANNOVERA in the case of increased frequency or severity of migraine during CHC use (which may be prodromal of a cerebrovascular event) [see Contraindications (4)].

5.9 Bleeding Irregularities and Amenorrhea

Bleeding and/or spotting that occurs at any time while the vaginal system is inserted is considered “unscheduled” bleeding/spotting. Bleeding/spotting that occurs during the dose-free week when the vaginal system is out is considered “scheduled” bleeding.

Unscheduled and Scheduled Bleeding and Spotting

Females using ANNOVERA may experience unscheduled (breakthrough) bleeding and spotting, especially during the first month of use. If unscheduled bleeding persists or occurs after previously regular cycles on ANNOVERA, check for causes such as pregnancy or malignancy. If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different CHC.

Based on subject diaries from the two clinical efficacy trials of ANNOVERA [see Clinical Trial Experience (6.1)], 5-10% of females experienced unscheduled bleeding per 28-day cycle. The average number of days with unscheduled bleeding and/or spotting, in Treatment Cycles 1 to 13 for those females who experienced unscheduled bleeding and/or spotting, was 1 day or less per cycle. A total of 41 subjects (1.7%) discontinued use due to menstrual disorders including metrorrhagia, menorrhagia, and abnormal withdrawal bleeding.

Amenorrhea and Oligomenorrhea

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. If the patient has not adhered to the prescribed dosing schedule (removed vaginal system for >2 hours during the first 21 days or does not replace after 7 days of vaginal system-free period), consider the possibility of pregnancy at the time of the first missed period and perform a pregnancy test. If the patient has adhered to the prescribed dosing schedule and misses 2 consecutive periods, perform a pregnancy test to rule out pregnancy.

Some females may experience amenorrhea or oligomenorrhea after stopping ANNOVERA, especially when such a condition was pre-existent.

5.10 Depression

Carefully observe females with a history of depression and discontinue ANNOVERA if depression recurs to a serious degree. Data on the association of CHCs with onset of depression or exacerbation of existing depression are limited.

5.11 Cervical Cancer

Some studies suggest that CHCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which these findings are due to differences in sexual behavior and other factors.

5.12 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.

5.13 Hereditary Angioedema

In females with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

5.14 Chloasma

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.

5.15 Toxic Shock Syndrome (TSS)

Cases of TSS have been reported by vaginal ring users. TSS has been associated with tampons and certain barrier contraceptives, and in some TSS cases ring users were also using tampons. Causal relationship between the use of a vaginal ring and TSS has not been established. No cases of TSS occurred in clinical trials with ANNOVERA. If a patient exhibits signs or symptoms of TSS, consider the possibility of this diagnosis, remove ANNOVERA, and initiate appropriate medical evaluation and treatment.

5.16 Vaginal Use

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.

There is no information on the concomitant use of ANNOVERA with diaphragms, cervical caps, and female condoms.

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.

The following adverse reactions are described elsewhere in other sections of the labeling:

• Serious cardiovascular events and stroke [see Boxed Warning and Warnings and Precautions (5.1)]
• Vascular events [see Warnings and Precautions (5.1)]
• Liver disease [see Warnings and Precautions (5.2)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The clinical trials that evaluated the safety of ANNOVERA were obtained from three 13-cycle trials. One trial was conducted entirely in the U.S. (15 sites), and the other two were global studies that included 5 U.S. sites and 7 international sites (Australia, Brazil, Chile, Dominican Republic, Finland, Hungary, Sweden). All three trials were open label and enrolled healthy females, desiring contraception, 18 to 40 years of age. At about 50% enrollment, females with BMI >29 kg/m² were excluded due to the occurrence of two VTEs in this subgroup. In total, 2,308 females contributed 21,590 cycles of exposure for safety evaluation and 999 completed 13 cycles; there were 209 subjects with BMI >29 kg/m² who contributed 1,254 cycles of exposure with 36 subjects completing 13 cycles. The demographic profile for subjects was: mean age 26.7 years, mean BMI 24.1 (16.0-41.5) kg/m²; 67% were from the U.S. The racial distribution was 71% Caucasian, 14% African American, 4% Asian, and 11% Other; 30% of the population was Hispanic.

Most Common Adverse Reactions

Table 1 summarizes the most common adverse reactions reported by females using ANNOVERA. This table shows adverse reactions reported in at least 5% of subjects. In addition, 25% of subjects reported at least 1 complete expulsion during their use of ANNOVERA.

Table 1. Adverse Drug Reactions Reported by ≥5% of ANNOVERA-treated Subjects:

Adverse Reactions Leading to Discontinuation

Among subjects using ANNOVERA for contraception, 12% discontinued from the clinical trials due to an adverse reaction. Table 2 summarizes the most common adverse reactions leading to discontinuation. In addition, 1.4% of subjects discontinued ANNOVERA use due to vaginal system expulsions.

Table 2. Adverse Reactions Leading to Discontinuation by ≥1% of ANNOVERA-treated Subjects:

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.

The sections below provide information on substances for which data on drug interactions with CHCs are available. There is little information available about the clinical effect of most drug interactions that may affect ANNOVERA. However, based on the known pharmacokinetic effects of these drugs, clinical strategies to minimize any potential adverse effect on contraceptive effectiveness or safety are suggested.

Consult the approved product labeling of all concurrently used drugs to obtain further information about interactions with ANNOVERA or the potential for metabolic enzyme or transporter system alterations.

7.1 Effects of Other Drugs on Combined Hormonal Contraceptives

Substances Decreasing the Systemic Exposure of CHCs and Potentially Diminishing the Efficacy of ANNOVERA: Table 3 includes substances that demonstrated an important drug interaction with CHCs.

Table 3. Significant Drug Interactions Involving Substances That Decrease Systemic Exposure of CHCs:

^a Induction potency of St. John’s wort may vary widely based on preparation.

Substances Increasing the Systemic Exposure of CHCs and Potentially Increasing Exposure to Estrogen and/or Progestin in ANNOVERA: Co-administration of atorvastatin or rosuvastatin and certain CHCs containing EE increase systemic exposure of EE by approximately 20–25%. Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase systemic exposure of the estrogen and/or progestin component of ANNOVERA.

Human Immunodeficiency Virus (HIV)/ Hepatitis C Virus (HCV) Protease Inhibitors and Non-nucleoside Reverse Transcriptase Inhibitors: Significant decreases in systemic exposure of estrogen and/or progestin have been noted when CHCs are co-administered with some HIV protease inhibitors (eg, nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir), some HCV protease inhibitors (eg, boceprevir and telaprevir), and some non-nucleoside reverse transcriptase inhibitors (eg, nevirapine).

In contrast, significant increases in systemic exposure of estrogen and/or progestin have been noted when CHCs are co-administered with certain other HIV protease inhibitors (eg, indinavir and atazanavir/ritonavir) and with other non-nucleoside reverse transcriptase inhibitors (eg, etravirine).

7.2 Effects of Combined Hormonal Contraceptives on Other Drugs

Table 4 provides significant drug interaction information for drugs co-administered with CHCs.

Table 4. Significant Drug Interaction Information for Drugs Co-Administered with CHCs:

7.3 Use of Vaginal Products with ANNOVERA

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 EE or SA from the vaginal system. 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 EE and 32% for SA. Considering the potential long-term effect on vaginal system performance, concurrent use of oil-based vaginal suppositories should not occur with ANNOVERA use. If there is a need to treat a vaginal condition, water-based vaginal cream or oral therapy may be used concurrently with the vaginal system [see Clinical Pharmacology (12.3)].

Lubricants: Water-based vaginal lubricants have no effect on ANNOVERA; however, oil-based (including silicone-based) vaginal lubricants will alter the vaginal system and/or exposure to EE and SA and should not be used.

ANNOVERA use is compatible with male condoms made with natural rubber latex, polyisoprene, and polyurethane.

The effect of tampon use on the systemic exposure of SA and EE from ANNOVERA has not been studied.

7.4 Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation

Do not co-administer ANNOVERA with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Contraindications (4) and Warnings and Precautions (5.3)].

7.5 Interference with Laboratory Tests

The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

Risk Summary

Epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to CHCs before conception or during early pregnancy.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Discontinue ANNOVERA if pregnancy occurs, because there is no reason to use CHCs during pregnancy.

Data

Human Data

No studies have been conducted of the use of ANNOVERA in pregnant females.

Risk Summary

Contraceptive hormones and/or metabolites are present in human milk. CHCs can reduce milk production in breastfeeding females. This reduction can occur at any time but is less likely to occur once breastfeeding is well established. Advise the nursing female to use another method of contraception until she discontinues breastfeeding [see Dosage and Administration (2.2)].

Data

Human Data

No studies have been conducted of the use of ANNOVERA in breastfeeding females. Two studies have been conducted in breastfeeding females of segesterone acetate implants delivering lower levels of segesterone acetate than ANNOVERA. Maternal serum levels of up to 141 pg/mL were associated with infant exposure of up to 7 pg/mL. No safety signals in feeding, growth, and development were observed in the infants between the segesterone acetate implant group and the control group.

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 were conducted in subjects with renal impairment; ANNOVERA is not recommended in patients with renal impairment.

No studies have been conducted to evaluate the effect of hepatic impairment on the disposition of ANNOVERA. However, steroid hormones may be poorly metabolized in patients with hepatic impairment. 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 [See Contraindications (4) and Warnings and Precautions (5.2)].

8.8 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 [see Adverse Reactions (6.1) and Clinical Studies (14)]. Higher body weight is associated with lower systemic exposure of SA and EE [see Clinical Pharmacology (12.3)].