BRIEF SUMMARY

SEGESTERONE- (Aug 2018)

Indn-    New vaginal ring used to prevent pregnancy for an entire year

Comp-  ANNOVERA™ is a silicone elastomer vaginal system containing 103 mg segesterone acetate (SA) and 17.4 mg ethinyl estradiol (EE), which releases on average 0.15 mg/day of segesterone acetate and 0.013 mg/day of ethinyl estradiol.

 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).

ADR- The most common adverse reactions (>5%) are headache/migraine, nausea/vomiting, vulvovaginal mycotic infection/candidiasis, abdominal pain lower/upper, dysmenorrhea, vaginal discharge, urinary tract infection, breast tenderness/pain/discomfort, bleeding irregularities

CI-   • A high risk of arterial or venous thrombotic diseases

Pat Infm-  

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 Boxed Warning and Warnings and Precautions (5.1)].

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 (5.1)].

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U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  29

ADVERSE REACTIONS-

 The most common adverse reactions (>5%) are headache/migraine, nausea/vomiting, vulvovaginal mycotic infection/candidiasis, abdominal pain lower/upper, dysmenorrhea, vaginal discharge, urinary tract infection, breast tenderness/pain/discomfort, bleeding irregularities in

ANNOVERA™ no earlier than 4 weeks after delivery, in females who are not breastfeeding. Consider cardiovascular risk factors before initiating in all females, particularly those over 35 years.

 • Liver Disease: Discontinue if jaundice occurs.

 • Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment: Stop ANNOVERA™ prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir. ANNOVERA™ can be restarted 2 weeks following completion of this regimen

 • Hypertension: Do not prescribe ANNOVERA™ for females with uncontrolled hypertension or hypertension with vascular disease. If used in females with well-controlled hypertension, monitor blood pressure and stop use if blood pressure rises significantly.

 • Carbohydrate and lipid metabolic effects: Monitor glucose in prediabetic and diabetic females taking ANNOVERA™. Consider an alternate contraceptive method for females with uncontrolled dyslipidemias

 • Headache: Evaluate significant change in headaches and discontinue ANNOVERA™ if indicated.

 • Bleeding Irregularities and Amenorrhea: May cause irregular bleeding or amenorrhea. Evaluate for other causes if irregular bleeding or amenorrhea persists. (5.9)

PATIENT COUNSELING INFORMATION-

Advise the patient to read the FDA-approved Patient Information .

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™ 

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 

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

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 (2) 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 (16.1)].

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 (7.3)].

Need for Additional Contraception Use a back-up or alternative method of contraception when: Enzyme inducers are used with CHCs [see Drug Interactions (7.1)]. 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 (2.3)].

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 (2.2)].

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 (8.2)].

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 (5.9)].

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 (14)]. 25 Reference ID: 4305085

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

CLINICAL PHARMACOLOGY

1. Mechanism of Action -CHCs lower the risk of becoming pregnant primarily by suppressing ovulation.

.2. 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.

3. Pharmacokinetics Absorption The pharmacokinetics (PK) of ANNOVERA™ were determined in 39 women who used ANNOVERA™ for up to 13 cycles.

 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 (5a-dihydro- and 17a-hydroxy-5adihydro 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 21 Reference ID: 4305085 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.

USE IN SPECIFIC POPULATIONS-

1. 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.

2. 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.

3.. 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.

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

5. 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.

6. Renal Impairment-                                                                                                       No studies were conducted in subjects with renal impairment; ANNOVERA™ is not recommended in patients with renal impairment.

7. 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 

Higher body weight is associated with lower systemic exposure of SA and EE 

 OVERDOSAGE -

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.