Annovera

Description

ANNOVERA™ (segesterone acetate and ethinyl estradiol vaginal system) is a toroidal-shaped (ring), nonbiodegradable, flexible, opaque white vaginal system containing two active components, a progestin, segesterone acetate, and an estrogen, ethinyl estradiol. When placed in the vagina, each ANNOVERA™ releases an approximate average 0.15 mg/day of segesterone acetate and 0.013 mg/day of ethinyl estradiol over the 21 days in-use period of each cycle for up to 13 cycles (total of 273 days). Each cycle is 28 days, with 21 days in and 7 days out.

The inactive ingredients are silicone elastomers, titanium dioxide, dibutyltin dilaurate, and silicone medical adhesive. The elastomers are all methyl siloxane-based polymers.

The vaginal system body has an overall diameter of 56 mm and a cross-sectional diameter of 8.4 mm. It contains two channels of approximately 3.0 mm diameter and 27 mm length into which steroid-containing cores are inserted. Each ANNOVERA™ contains 103 mg of SA distributed throughout both cores and 17.4 mg of EE distributed throughout only one core. The core containing 40% SA and 12% EE of its mass is 3 mm in diameter and 18 mm in length. The core containing 50% SA of its mass is 3 mm in diameter and 11 mm in length. Contact between the cores and the vaginal system body is fixed by coating the channels with silicone medical adhesive before introducing the cores. After insertion of the cores, the channels are sealed with the silicone medical adhesive.

The structural formulas, and properties for the active components are shown below:

Structural Formulas:

Segesterone Acetate (SA)

Ethinyl Estradiol (EE)

Properties

Established Name: Segesterone Acetate
Chemical Name: 16-methylene-17α-acetoxy-19-nor-pregn-4-ene-3,20-dione
Molecular Formula: C₂₃H₃₀O₄ Molecular Weight: 370.5
Physical Form: White, or yellowish white powder
Solubility: Slightly soluble in n-hexane, soluble in ethyl acetate and methanol, freely soluble in acetone (USP classification)
Melting Point: 173 °C – 177 °C

Established Name: Ethinyl Estradiol
Chemical Name: 19-Nor-17α -pregna-1,3,5(10)-trien-20-yne-3,17-diol
Molecular Formula: C₂₀H₂₄O₂
Molecular Weight: 296.4
Physical Form: White to slightly yellowish-white crystalline powder
Solubility: Practically insoluble in water, freely soluble in alcohol, it dissolves in alkaline solution
Melting Point: 181 °C – 185 °C

The steroids diffuse out of the vaginal system with release rates that vary over time. Based on in vitro data, the daily in vitro release rates of SA and EE are higher during each initial 24–48 hours of use achieving a somewhat lower steady-state with continued use over the subsequent days in each cycle. The vaginal system is designed to be used for 13 cycles (1 year) on a 21/7 days in/out schedule. The total in-use time with the 21/7 days in/out schedule over 13 cycles is 273 days. Based on the residual amount of drug in vaginal systems used in clinical trials over 13 cycles, a total of 41.3 mg of SA and 3.4 mg of EE are released over this period. This translates to an approximate average daily dose of 0.15 mg of segesterone acetate and 0.013 mg of ethinyl estradiol with higher release rate expected at the beginning of dosing and a lower release rate toward the end.

Indications

ANNOVERA™ is indicated for use by females of reproductive potential to prevent pregnancy.

Limitation Of Use

ANNOVERA™ has not been adequately studied in females with a BMI >29 kg/m².

Dosage And Administration

How To Use ANNOVERA™

Instruct patients that ANNOVERA™ should be used as directed [see How to Start ANNOVERA™]. One ANNOVERA™ should be placed in the vagina. For maximum contraceptive effectiveness, ANNOVERA™ is to remain in the vagina continuously for 21 days (3 complete weeks). It is removed for a 1-week dose-free interval, and during this time a withdrawal bleed usually occurs. The removed vaginal system should be cleaned with mild soap and warm water, patted dry with a clean cloth towel or paper towel, and placed in its case during the one-week dose-free interval. At the end of the dose-free interval, the vaginal system should be cleaned prior to being placed back in the vagina for another 21 continuous days (3 complete weeks). This pattern of ANNOVERA™ use made up of 3-weeks in and 1-week out is a cycle of use; one ANNOVERA™ vaginal system will provide contraception for 13 cycles.

With clean hands, the user can choose an insertion position that is comfortable, such as lying down, squatting, or standing. The sides of the vaginal system are pressed together for insertion into the vagina. When properly inserted, the vaginal system should be entirely in the vagina and behind the pelvic bone. The day and time of insertion should be noted so that the vaginal system can be removed 3 weeks later on the same day and at about the same time.

ANNOVERA™ can be removed by hooking an index finger into the vaginal system inside the vagina and gently pulling the vaginal system.

For patient instructions regarding cleaning the vaginal system, see FDA-approved PATIENT INFORMATION.

How To Start ANNOVERA™

IMPORTANT: Consider the possibility of ovulation and conception prior to the first use of ANNOVERA™.

No Hormonal Contraceptive Use In The Preceding Cycle And After Copper IUD Removal

The woman should insert ANNOVERA™ between days 2 and 5 of her regular menstrual bleeding; no back-up contraception is needed. If menstrual cycles are irregular or if the start is more than 5 days from the last menstrual bleeding, the woman should use an additional barrier method during coitus, such as a male condom or spermicide, for the first 7 days of ANNOVERA™ use.

Switching From A CHC

A woman who has been using her CHC method consistently and correctly and who you are reasonably certain is not already pregnant may switch from her previous CHC to ANNOVERA™ on any day of the CHC cycle (Day 1-28), without the need for back-up contraception, but no more than 7 hormone-free days should occur before starting ANNOVERA™.

Switching From A Progestin-Only Method [Progestin-Only Pills (POP), Progestin Injection, Progestin Implant, Progestin Intrauterine System (IUS)]

If a woman has no contraindications to the use of ethinyl estradiol (EE), she may elect to switch from a progestin-only method to ANNOVERA™. If switching from progestin-only pills, she should begin ANNOVERA™ at the time she would have taken her next POP pill. If switching from an injection, she should begin ANNOVERA™ at the time of her next scheduled injection. If switching from an implant or an IUS, she should begin ANNOVERA™ at the time of implant or IUS removal. In all of these cases, the woman should use an additional barrier method during coitus, such as a male condom or spermicide, for the first 7 days of ANNOVERA™ use.

Use After Abortion Or Miscarriage

If a woman has no contraindications to the use of EE, ANNOVERA™ may be initiated for contraception within the first 5 days following a complete first trimester abortion or miscarriage without additional back-up contraception. If more than 5 days have elapsed from the first trimester abortion or miscarriage, then follow the instructions for “No Hormonal Contraceptive Use in the Preceding Cycle” and a barrier method should be used from the time of the first trimester abortion or miscarriage to the initiation of ANNOVERA™.

ANNOVERA™ should not be started earlier than 4 weeks after a second trimester abortion or miscarriage due to the increased risk of thromboembolism. [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]

Following Childbirth

ANNOVERA™ should not be started sooner than 4 weeks postpartum and only in females who choose not to breastfeed. Prior to 4 weeks postpartum there is an increased risk of thromboembolism [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].

The initiation of ANNOVERA™ 4 weeks or more postpartum should be accompanied by an additional method of contraception during coitus, such as male condoms or spermicide, for the first 7 days if the woman has not yet had a period. Consider the possibility of ovulation and conception occurring prior to initiating ANNOVERA™.

Females who are breastfeeding should not use ANNOVERA™ until after weaning.

Deviations From The Recommended Regimen

Contraceptive efficacy of ANNOVERA™ may be reduced if a woman deviates from the recommended use. ANNOVERA™ should remain in the vagina for a continuous period of 21 days (3 weeks); then ANNOVERA™ should be taken out of the vagina for 7 days. In a 28day cycle, a deviation that involves ANNOVERA™ being out of the vagina for less than 7 days will not increase pregnancy risk. In a 28-day cycle, a deviation that involves ANNOVERA™ being out of the vagina for more than 7 days will increase pregnancy risk and back-up contraception is recommended in these instances. Deviations from the recommended regimen may result in a new vaginal system change day. [See FDA-approved PATIENT INFORMATION.]

Inadvertent Removal Or Expulsion

ANNOVERA™ can be accidently expelled. Accidental expulsion could occur while removing a tampon, during coitus, or with straining during a bowel movement. If the vaginal system is accidentally expelled once during the 21 days of intravaginal use and is replaced within 2 hours, contraceptive efficacy should not be reduced and no back-up contraception is needed. If the vaginal system is accidently expelled, wash it with mild soap and warm water, rinse and pat dry with a clean cloth towel or paper towel, and replace it as soon as possible.

During the 21 days of continuous use, if ANNOVERA™ is out of the vagina for more than 2 continuous hours or more than 2 cumulative hours (multiple inadvertent removals or expulsions adding up to 2 hours), 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. The use of combined hormonal contraceptives (those containing an estrogen) for emergency contraception during use of ANNOVERA™ is not recommended.

Prolonged Vaginal System Free Interval

If the Vaginal System Free Interval is prolonged, consider the possibility of pregnancy and have the woman use back-up contraception, such as male condoms or spermicide, during coitus until the vaginal system has been in the vagina for 7 consecutive days. The use of combined hormonal contraceptives (those containing an estrogen) for emergency contraception during use of ANNOVERA™ is not recommended.

Prolonged Use Of ANNOVERA™

If ANNOVERA™ is left in the vagina for more than 21 days, it should be removed for 7 days and then reinserted for 21 days to resume a 21/7 schedule.

How Supplied

Dosage Forms And Strengths

Vaginal system: Each ANNOVERA™ releases an approximate average 0.15 mg/day of segesterone acetate (SA) and 0.013 mg/day of ethinyl estradiol (EE) when placed in the vagina over a period of 21 days of each cycle for up to 13 cycles (total of 273 days). Each cycle of use is 28 days with 21 days in and 7 days out.

ANNOVERA™ (segesterone acetate and ethinyl estradiol vaginal system) is a toroidal-shaped (ring), nonbiodegradable, flexible, opaque white, contraceptive vaginal system containing 103 mg of SA and 17.4 mg EE.

ANNOVERA™ is 56 mm in overall diameter and 8.4 mm in cross-sectional diameter. It contains 2 channels of approximately 3.0 mm diameter and 27 mm length into which steroid-containing cores are inserted. The cores are 3 mm in diameter with one releasing SA alone and the other releasing both SA and EE.

Each ANNOVERA™ is designed to be used for up to 13 cycles (1 year).

ANNOVERA™ is not made with natural rubber latex.

Storage And Handling

ANNOVERA™ (segesterone acetate and ethinyl estradiol vaginal system) is a toroidal-shaped (ring), nonbiodegradable, flexible, opaque white vaginal system. The vaginal system body has an overall diameter of 56 mm and a cross-sectional diameter of 8.4 mm. When placed inside the vagina, each ANNOVERA™ releases an approximate average 0.15mg/day of segesterone acetate and 0.013 mg/day of ethinyl estradiol over 21-day in-use period of each cycle for up to 13 cycles (total 273 days). Each cycle is 28 days, with 21 days in and 7 days out.

Each ANNOVERA™ is individually packaged in an aluminum pouch. The pouch consists of a laminate from outside to inside of polyester, aluminum foil, and polyethylene.

A black compact case is provided with the drug product for storage of ANNOVERA™ by patients during each 7-day vaginal system-out interval.

The vaginal system should be placed in the compact case after 13 cycles of use and discarded via a drug take-back option if one is available. If a take-back option is unavailable, then discard in the waste receptacle out of reach of children and pets. The vaginal system should NOT be flushed down the toilet. See www.fda.gov/drugdisposal for more information about disposal of medicines.

Each box contains 1 pouch. NDC 72468-313-01

Storage Conditions

Prior to dispensing ANNOVERA™ to the user, store ANNOVERA™ at 25 °C (77 °F); excursions permitted to 15 °C to 30 °C (59 °F to 86 °F) [see USP Controlled Room Temperature].

Protect ANNOVERA™ from direct sunlight.

Do not refrigerate or freeze, and avoid excessive heat.

Manufactured for: Population Council One Dag Hammarskjold Plaza New York, NY 10017 United States. Revised: Aug 2018

Side Effects

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

• Serious cardiovascular events and stroke [see BOX WARNING and WARNINGS AND PRECAUTIONS]
• Vascular events [see WARNINGS AND PRECAUTIONS]
• Liver disease [see WARNINGS AND PRECAUTIONS]

Clinical Trial Experience

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	% (N=2,308)
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
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. 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

Adverse Reactions	% (N=2,308)
Metrorrhagia/menorrhagia	1.7
Headache, including migraine	1.3
Vaginal discharge/vulvovaginal mycotic infections	1.3
Nausea/vomiting	1.2

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.

Drug Interactions

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.

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

Metabolic Enzyme Inducers
Clinical effect	Concomitant use of CHCs with metabolic enzyme inducers may decrease the systemic concentrations of the estrogen and/or progestin component of CHCs [see CLINICAL PHARMACOLOGY]. Decreased exposure of the estrogen and/or progestin component of CHCs may potentially diminish the effectiveness of CHCs and may lead to contraceptive failure or an increase in breakthrough bleeding.
Prevention or management	Counsel females to use an alternative method of contraception or a backup method when enzyme inducers are used with CHCs. Continue back-up contraception for 28 days after discontinuing the enzyme inducer to maintain contraceptive reliability.
Examples	Aprepitant, barbiturates, bosentan, carbamazepine, efavirenz, felbamate, griseofulvin, oxcarbazepine, phenytoin, rifampin, rifabutin, rufinamide, topiramate, products containing St. John’s worta, and certain protease inhibitors (see separate section on protease inhibitors below).
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 (e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir), some HCV protease inhibitors (e.g., boceprevir and telaprevir), and some non-nucleoside reverse transcriptase inhibitors (e.g., 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 (e.g., indinavir and atazanavir/ritonavir) and with other non-nucleoside reverse transcriptase inhibitors (e.g., etravirine).

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

Lamotrigine
Clinical effect	Concomitant use of CHCs with lamotrigine may significantly decrease systemic exposure of lamotrigine due to induction of lamotrigine glucuronidation. Decreased systemic exposure of lamotrigine may reduce seizure control.
Prevention or management	Dose adjustment for lamotrigine may be necessary. Consult the approved product labeling for lamotrigine.
Thyroid Hormone Replacement Therapy or Corticosteroid Replacement Therapy
Clinical effect	Concomitant use of CHCs with thyroid hormone replacement therapy or corticosteroid replacement therapy may increase systemic exposure of thyroid-binding and cortisol-binding globulin [see WARNINGS AND PRECAUTIONS].
Prevention or management	The dose of replacement thyroid hormone or cortisol therapy may need to be increased. Consult the approved product labeling for the therapy in use [see WARNINGS AND PRECAUTIONS].
Other Drugs
Clinical effect	Concomitant use of CHCs may decrease systemic exposure of acetaminophen, morphine, salicylic acid, and temazepam. Concomitant use with ethinyl estradiolcontaining CHCs may increase systemic exposure of other drugs (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole).
Prevention or management	The dosage of drugs that can be affected by this interaction may need to be increased or decreased. Consult the approved product labeling for the concomitantly used drug.

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 1day 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].

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.

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 and WARNINGS AND PRECAUTIONS].

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.

Warnings

Included as part of the “PRECAUTIONS” Section

Precautions

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].

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]. 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]. 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

* 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.

Liver Disease

Impaired Liver Function

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

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]. ANNOVERA™ can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.

Hypertension

ANNOVERA™ is contraindicated in females with uncontrolled hypertension or hypertension with vascular disease [see CONTRAINDICATIONS]. 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.

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 and Thromboembolic Disorders And Other Vascular Conditions]. 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

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.

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]. 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™.

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].

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].

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], 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.

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.

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.

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.

Hereditary AngioedemaM

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

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™.

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.

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 health-care provider.

Patient Counseling Information

Advise the patient to read the FDA-approved Patient Information (see PATIENT INFORMATION and Instructions for Use).

Cigarette Smoking

Cigarette smoking increases the risk of serious cardiovascular events from CHC use, and females who are over 35 years old and smoke should not use ANNOVERA™ [see BOX WARNING and WARNINGS AND PRECAUTIONS].

Venous Thromboembolism

Increased risk of VTE compared to nonusers of CHCs is greatest after initially starting a CHC or restarting (following a 4-week or greater dose-free interval) the same or a different CHC [see WARNINGS AND PRECAUTIONS].

Sexually Transmitted Infections

ANNOVERA™ does not protect against HIV-infection (AIDS) and other sexually transmitted infections. ANNOVERA™ is compatible with male condoms made with natural rubber latex, polyisoprene, and polyurethane.

Use During Pregnancy

ANNOVERA™ is not to be used during pregnancy; instruct the patient to remove

ANNOVERA™ if pregnancy is confirmed during treatment [see Use In Specific Populations].

ANNOVERA™ Dosing And Instructions

Advise the woman on proper use of ANNOVERA™ and what to do if she does not comply with the labeled timing of insertion and removal. The efficacy of ANNOVERA™ is greatest when ANNOVERA™ is kept in the vagina continuously for the scheduled 21 consecutive days. Removal of ANNOVERA™ even briefly during the scheduled 21 days of use can reduce efficacy.

ANNOVERA™ should be washed with mild soap and water and rinsed and patted dry with a clean cloth towel or paper towel prior to each insertion and at each removal. Prior to initial use, the storage case should be labeled with the discard date to avoid using the product beyond 13 cycles [see DOSAGE AND ADMINISTRATION and FDA-approved PATIENT INFORMATION].

Place the completely used ANNOVERA™ in the case provided and discard via a drug take-back option if one is available. If a take-back option is unavailable, then discard in the waste receptacle out of reach of children and pets. The vaginal system should NOT be flushed down the toilet. See www.fda.gov/drugdisposal for more information about disposal of medicines. [see HOW SUPPLIED].

Use With Vaginal Products

Water-based vaginal lubricants have no effect on the vaginal system; however, oil-based (including silicone-based) vaginal lubricants will alter the vaginal system and/or exposure to EE and segesterone acetate and should not be used [see DRUG INTERACTIONS].

Need For Additional Contraception

Use a back-up or alternative method of contraception when:

Enzyme inducers are used with CHCs [see DRUG INTERACTIONS].

ANNOVERA™ has been out for more than 2 hours cumulative during the 21 days of continuous use or the vaginal system-free interval exceeds 7 days [see DOSAGE AND ADMINISTRATION].

Postpartum females who have not yet had a period should use an additional method of contraception until ANNOVERA™ has been in place for 7 consecutive days [see DOSAGE AND ADMINISTRATION].

Lactation

ANNOVERA™ may reduce breast milk production. This is less likely to occur if breastfeeding is well established. Females who are breastfeeding should not use ANNOVERA™ until after weaning [see Use In Specific Populations].

Amenorrhea And Possible Symptoms Of Pregnancy

Amenorrhea may occur. Consider pregnancy in the event of amenorrhea, and rule out pregnancy if amenorrhea is associated with symptoms of pregnancy, such as morning sickness or unusual breast tenderness [see WARNINGS AND PRECAUTIONS].

Fertility Following Discontinuation Of ANNOVERA™

Resumption of fertility after discontinuation of ANNOVERA™ is expected. All women followed for return of fertility experienced a return of fertility by 6 months after discontinuing ANNOVERA™ [see Clinical Studies].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

In a 2-year carcinogenicity study in rats with subdermal implants releasing 40, 100, and 200 μg segesterone acetate per day (approximately 17–86 times the daily dose of segesterone acetate in females using ANNOVERA™, based on body surface area), no drug-related increase in tumor incidence was observed. In a 2-year intravaginal carcinogenicity study in mice, segesterone acetate gel produced an increased incidence of adenocarcinoma and lobular hyperplasia in the breast at a dose of 30 mg/kg/day, approximately 10 times the systemic exposure of segesterone acetate per day in females using ANNOVERA™, based on AUC. A dose of 10 mg/kg/day in the mouse, approximately 3 times the systemic exposure of segesterone acetate per day based on AUC, did not result in carcinogenic findings.

Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.

Mutagenesis

Segesterone acetate was neither mutagenic nor clastogenic in the Ames/Salmonella reverse mutation assay, the chromosomal aberration assay in Chinese hamster ovary cells, or in the in vivo mouse micronucleus test.

Impairment Of Fertility

A return to fertility study was conducted with segesterone acetate in rats, using subdermal implants releasing a dose approximately 25 times the anticipated daily vaginal human dose (based on body surface area). Three months of treatment with segesterone acetate suppressed fertility, but 7 weeks after cessation of treatment, there were no adverse effects on ovulation or resulting litter parameters.

Use In Specific Populations

Pregnancy

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.

Lactation

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.]

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.

Pediatric Use

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.

Geriatric Use

ANNOVERA™ has not been studied in females who have reached menopause and is not indicated in this population.

Hepatic 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 and WARNINGS AND PRECAUTIONS.]

Renal Impairment

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 two VTEs occurred in females with a BMI > 29 kg/m² [see ADVERSE REACTIONS and Clinical Studies]. Higher body weight is associated with lower systemic exposure of SA and EE [see CLINICAL PHARMACOLOGY].

Overdose

There have been no reports of serious ill effects from overdose of CHCs. Overdosage may cause withdrawal bleeding in females and nausea. In case of suspected overdose, all ANNOVERA™ vaginal systems should be removed and symptomatic treatment given.

Contraindications

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 [see BOX WARNING and WARNINGS AND PRECAUTIONS].
  • Have current or history of deep vein thrombosis or pulmonary embolism [see WARNINGS AND PRECAUTIONS].
  • Have cerebrovascular disease [see WARNINGS AND PRECAUTIONS].
  • Have coronary artery disease [see WARNINGS AND PRECAUTIONS].
  • Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see WARNINGS AND PRECAUTIONS].
  • Have inherited or acquired hypercoagulopathies [see WARNINGS AND PRECAUTIONS].
  • Have uncontrolled hypertension or hypertension with vascular disease [see WARNINGS AND PRECAUTIONS].
  • 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 [see WARNINGS AND PRECAUTIONS].
  • Have headaches with focal neurological symptoms, migraine headaches with aura, or are over age 35 with any migraine headaches [see WARNINGS AND PRECAUTIONS].
• Current or history of breast cancer or other estrogen-or progestin-sensitive cancer.
• Liver tumors, acute hepatitis, or severe (decompensated) cirrhosis [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
• Undiagnosed abnormal uterine bleeding [see WARNINGS AND PRECAUTIONS].
• Hypersensitivity to any of the components of ANNOVERA™. Hypersensitivity reactions reported include: throat constriction, facial edema, urticaria, hives, and wheezing [see ADVERSE REACTIONS].
• Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for alanine transaminase (ALT) elevations [see WARNINGS AND PRECAUTIONS

Clinical Pharmacology

Mechanism Of Action

CHCs lower the risk of becoming pregnant primarily by suppressing ovulation.

Pharmacodynamics

Cardiac Electrophysiology

The effect of SA on the QTc interval was evaluated in a Phase 1 randomized, placebo and positive controlled, double-blind, single-dose, three-period, crossover thorough QTc study in 44 healthy adult female subjects. At the single intravenous bolus dose which produces 4.5-fold the therapeutic serum concentrations of SA achieved with ANNOVERA™, SA did not prolong the QTc interval to any clinically relevant extent.

Pharmacokinetics

Absorption

The pharmacokinetics (PK) of ANNOVERA™ were determined in 39 women who used ANNOVERA™ for up to 13 cycles. Following vaginal administration, SA and EE were absorbed into systemic circulation with median Tmax of about 2 hours in Cycle 1, Cycle 3, and Cycle 13. Concentrations of both components declined after Tmax and became more constant after 96 hours post-dose. Over subsequent cycles of use, the peak serum concentrations of SA and EE declined. Serum concentration-time profiles of SA and EE for Cycles 1, 3, and 13 of ANNOVERA™ use are provided in Figure 2 and Figure 3 with PK parameters summarized in Table 5 and Table 6.

Figure 2: Mean SA and EE Serum Concentrations Delivered by ANNOVERA™ Over 21 Days of Dosing for Cycles 1, 3, and 13

Figure 3: Mean SA and EE Serum Concentrations Delivered by ANNOVERA™ Over the First 48 Hours of Dosing for Cycles 1, 3, and 13

Table 5: Mean (SD) PK Parameters for SA following ANNOVERA™ Administration

Cycle	AUC0-21day (ng*hr/mL)	AUC0-1 day (ng*hr/mL)	Cmax (pg/mL)	Cavg (pg/mL)
1	96.2 (16.9)	15 (3.2)	1,147 (315)	191 (34)
3	65.9 (14.8)	5 (1.6)	363 (133)	131 (29)
13	47.2 (10.1)	3.9 (1.4)	294 (116)	94 (20)

Table 6: Mean (SD) PK Parameters for EE following ANNOVERA™ Administration

Cycle	AUC0-21day (ng*hr/mL)	AUC0-1 day (ng*hr/mL)	Cmax (pg/mL)	Cavg (pg/mL)
1	22.2 (9.8)	2.1 (0.7)	129 (39)	44 (19)
3	14.7 (4.7)	0.9 (0.4)	60 (32)	29 (9)
13	9.6 (4.1)	0.7 (0.3)	39 (16)	19 (8)

Distribution

The volume of distribution of SA is 19.6 L/kg. SA is approximately 95% bound to human serum proteins and has negligible binding affinity for sex hormone-binding globulin (SHBG). EE is highly protein bound but not specifically bound to serum albumin (98.5%) and induces an increase in the serum concentrations of SHBG.

Metabolism

In vitro data show that both SA and EE are metabolized by the cytochrome P450 (CYP) 3A4 isoenzyme. In human serum, two oxidative metabolites (5α-dihydro-and 17α-hydroxy-5αdihydro metabolites) constitute 50% of exposure relative to SA. Both metabolites are not considered as active metabolites with EC₅₀ to progesterone receptor 10-fold higher than that of SA. EE is primarily metabolized by aromatic hydroxylation, but a wide variety of hydroxylated and methylated metabolites are formed. These are present as free metabolites and as sulfate and glucuronide conjugates. The hydroxylated EE metabolites have weak estrogenic activity.

Excretion

The mean (SD) half-life of SA is 4.5 (3.4) hours. EE is known to be excreted in the urine and feces as glucuronide and sulfate conjugates, and it undergoes enterohepatic recirculation. The mean (SD) half-life of EE is 15.1 (7.5) hours.

Specific Populations

Body Mass Index (BMI)

Higher body weight associates with lower systemic exposure of SA and EE. In a PK study conducted in 18 females with BMI <25 (16.89 -24.34) kg/m² and 21 females with BMI >25 (25.15 -37.46) kg/m², up to 16% and 33% decreases in the systemic exposure (AUC 0-21day) of SA and EE, respectively, were observed between the two BMI groups.

Interaction With Vaginal Medications

A clinical drug-drug interaction (DDI) study was conducted to evaluate the effect of vaginal antimycotic medication (miconazole nitrate) on the PK of SA and EE in 29 females using ANNOVERA™. The results showed that a single-dose vaginal administration of 1,200 mg miconazole suppository on Day 8 of ANNOVERA™ use increased the systemic exposure of EE (AUCDay8-21) by approximately 67%. A similar trend was observed with SA with AUC Day8-9, AUCDay8-10, and AUCDay8-21 increasing by approximately 30%, 32%, and 19%, respectively. When 200 mg miconazole vaginal suppositories were administered on Day 8, Day 9, and Day 10 of ANNOVERA™ use, EE AUCDay8-11 and AUCDay8-21 were increased by 9% and 42%, respectively. SA AUCDay8-11 and AUC Day8-21 were increased by 28% and 27%, respectively. Water-based vaginal miconazole cream had no effect on ANNOVERA™ [(see DRUG INTERACTIONS].

The in vitro studies suggest that SA is unlikely to inhibit or induce CYP enzymes at the therapeutic dose.

Clinical Studies

The efficacy of ANNOVERA™ was evaluated in two 1-year multicenter trials enrolling 2,265 females, age 18–40 years, who were healthy and sexually active with regular menstrual cycles. The trials were conducted in the U.S., Dominican Republic, Brazil, Chile, Finland, Hungary, Sweden, and Australia, with 67.1% of females from the U.S. The racial/ethnic distribution was Caucasian (71.2%), African-American (14.1%), Asian (3.5%), other/multiple races (11.2%); 28.7% of the study population was Hispanic. The mean age was 26.7 years and the mean (range) BMI was 24.1 (16.0, 41.5) kg/m². At approximately 50% enrollment, women with BMI >29.0 kg/m² were no longer enrolled in the two trials and all women with a BMI >29.0 kg/m² were discontinued from the trials.

Based on pooled data from the two trials, 2,111 females ≤35 years of age completed 17,427 evaluable 28-day cycles (cycles in which no back-up contraception was used). The pooled pregnancy rate, evaluated by the Pearl Index (PI), was 2.98 (95% Confidence Interval [2.13, 4.06]) per 100 woman-years of ANNOVERA™ use.

Return to fertility was assessed in 290 of the subjects in the two trials who either desired pregnancy or switched to a nonhormonal method after the trials, and all 290 subjects reported a return to fertility during the 6-month follow-up period (defined as a return of menses or pregnancy).