Natazia (estradiol valerate and estradiol valerate/dienogest) tablets provide an oral contraceptive regimen consisting of 26 active film-coated tablets that contain the active ingredients specified for each tablet below, followed by two inert film-coated tablets: • 2 dark yellow tablets each containing 3 mg estradiol valerate • 5 medium red tablets each containing 2 mg estradiol valerate and 2 mg dienogest • 17 light yellow tablets each containing 2 mg estradiol valerate and 3 mg dienogest • 2 dark red tablets each containing 1 mg estradiol valerate • 2 white tablets (inert) Natazia also contains the excipients lactose monohydrate, maize starch, maize starch pre-gelatinized, povidone 25, magnesium stearate, hypromellose, macrogol 6000, talc, titanium dioxide, and ferric oxide pigment, yellow, or ferric oxide pigment, red. The empirical formula of estradiol valerate is C 23 H 32 O 3 and the chemical structure is: Estradiol Valerate The chemical name of estradiol valerate is Estra-1,3,5(10)-triene-3,17-diol(17ß)-,17-pentanoate. The empirical formula of dienogest is C 20 H 25 NO 2 and the chemical structure is: Dienogest The chemical name of dienogest is (17α)-17-Hydroxy-3-oxo-19-norpregna-4,9-diene-21-nitrile. Chemical Strcuture EV Dienogest Chemical Structure

• Natazia is a combination of dienogest , a progestin, and estradiol valerate, an estrogen, indicated for use by females of reproductive potential to prevent pregnancy. • The efficacy of Natazia in females of reproductive potential with a body mass index (BMI) of >30 kg/m 2 has not been evaluated. • Treatment of heavy menstrual bleeding in females of reproductive potential without organic pathology who choose to use an oral contraceptive as their method of contraception

Oral Contraception Natazia ® is indicated for use by women to prevent pregnancy. The efficacy of Natazia in women with a body mass index (BMI) of > 30 kg/m 2 has not been evaluated

Heavy Menstrual Bleeding Natazia is also indicated for the treatment of heavy menstrual bleeding in women without organic pathology who choose to use an oral contraceptive as their method of contraception .

Natazia (estradiol valerate and estradiol valerate/dienogest) tablets are available in blister packs. Each blister pack contains 28 round, biconvex, film-coated tablets in the following order: • 2 dark yellow tablets, with an embossed “DD” in a regular hexagon on one side, each containing 3 mg estradiol valerate • 5 medium red tablets, with an embossed “DJ” in a regular hexagon on one side, each containing 2 mg estradiol valerate and 2 mg dienogest • 17 light yellow tablets, with an embossed “DH” in a regular hexagon on one side, each containing 2 mg estradiol valerate and 3 mg dienogest • 2 dark red tablets, with an embossed “DN” in a regular hexagon on one side, each containing 1 mg estradiol valerate • 2 white tablets (inert), with an embossed “DT” in a regular hexagon on one side Natazia consists of 28 film-coated, unscored tablets in the following order: • 2 dark yellow tablets each containing 3 mg estradiol valerate • 5 medium red tablets each containing 2 mg estradiol valerate and 2 mg dienogest • 17 light yellow tablets each containing 2 mg estradiol valerate and 3 mg dienogest • 2 dark red tablets each containing 1 mg estradiol valerate • 2 white tablets (inert)

• Take one tablet daily by mouth at the same time every day. • Tablets must be taken in the order directed on the blister pack. • Do not skip or delay intake by more than 12 hours

How to Take Natazia To achieve maximum contraceptive effectiveness, Natazia must be taken exactly as directed. Take one tablet by mouth at the same time every day. Tablets must be taken in the order directed on the blister pack. Tablets should not be skipped or intake delayed by more than 12 hours. For patient instructions for missed pills, see FDA-Approved Patient Labeling

How to Start Natazia Instruct the patient to begin taking Natazia on Day 1 of her menstrual cycle (that is, the first day of her menstrual bleeding). See FDA-Approved Patient Labeling . Instruct the patient to use a non-hormonal contraceptive as back-up during the first 9 days. For postpartum women who do not breastfeed or after a second trimester abortion, start Natazia no earlier than 4 weeks postpartum due to the increased risk of thromboembolism. If the patient starts on Natazia postpartum and has not yet had a period, evaluate for possible pregnancy, and instruct her to use an additional method of contraception until she has taken Natazia for 9 consecutive days. The possibility of ovulation and conception prior to initiation of medication should also be considered. If the patient is switching from a combination hormonal method such as: • Another pill • Vaginal ring • Patch • Instruct her to take the first dark yellow pill on the first day of her withdrawal bleed. She should not continue taking the pills from her previous birth control pack. If she does not have a withdrawal bleed, rule out pregnancy before starting Natazia. • If she previously used a vaginal ring or transdermal patch, she should start using Natazia on the day the ring or patch is removed. • Instruct the patient to use a non-hormonal back-up method such as a condom or spermicide for the first 9 days. If the patient is switching from a progestin-only method such as a: • Progestin-only pill • Implant • Intrauterine system • Injection • Instruct her to take the first dark yellow pill on the day she would have taken her next progestin-only pill or on the day of removal of her implant or intrauterine system or on the day when she would have had her next injection. • Instruct the patient to use a non-hormonal back-up method such as a condom or spermicide for the first 9 days

Advice in case of Gastrointestinal Disturbances In case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken. If vomiting or diarrhea occurs within 3-4 hours after taking a colored tablet, this can be regarded as a missed tablet.

• Vascular risks : Stop Natazia if a thrombotic event occurs. Stop Natazia at least 4 weeks before and through 2 weeks after major surgery. Start Natazia no earlier than 4 weeks after delivery, in women who are not breastfeeding. • Liver disease : Discontinue Natazia if jaundice occurs. • High blood pressure : Do not prescribe Natazia for women with uncontrolled hypertension or hypertension with vascular disease. • Carbohydrate and lipid metabolic effects : Monitor prediabetic and diabetic women taking Natazia. Consider an alternate contraceptive method for women with uncontrolled dyslipidemia. • Headache : Evaluate significant change in headaches and discontinue Natazia if indicated. • Uterine bleeding : Evaluate irregular bleeding or amenorrhea. • CYP3A4 induction : Women taking strong CYP3A4 inducers (for example, carbamazepine, phenytoin, rifampicin, and St. John’s wort) should not choose Natazia as their oral contraceptive due to the possibility of decreased contraceptive efficacy. ( 5.13 , 7.1 ) 5.1 Thromboembolic Disorders and Other Vascular Problems Stop Natazia if an arterial or venous thrombotic event (VTE) occurs. The use of COCs increases the risk of venous thromboembolism. However, pregnancy increases the risk of venous thromboembolism as much or more than the use of COCs. The risk of VTE in women using COCs has been estimated to be 3 to 9 per 10,000 woman-years. The risk of VTE is highest during the first year of use. Data from a large, prospective cohort safety study of various COCs suggest that this increased risk, as compared to that in non-COC users, is greatest during the first 6 months of COC use. Data from this safety study indicate that the greatest risk of VTE is present after initially starting a COC or restarting (following a 4 week or greater pill-free interval) the same or a different COC. Use of COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events. The risk of thromboembolic disease due to oral contraceptives gradually disappears after COC use is discontinued. If feasible, stop Natazia at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism. Start Natazia no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week. COCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years of age), hypertensive women who also smoke. COCs also increase the risk for stroke in women with other underlying risk factors. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors. Stop Natazia if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately. 5.2 Malignant Neoplasms Breast Cancer Natazia is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive . Epidemiology studies have not found a consistent association between use of combined oral contraceptives (COCs) and breast cancer risk. Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer. However, some studies report a small increase in the risk of breast cancer among current or recent users (<6 months since last use) and current users with longer duration of COC use . Cervical Cancer Some studies suggest that COCs 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 may be due to differences in sexual behavior and other factors

Liver Disease Discontinue Natazia if jaundice develops. Steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded. Hepatic adenomas are associated with COC use. An estimate of the attributable risk is 3.3 cases/100,000 COC 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) COC users. However, the attributable risk of liver cancers in COC users is less than one case per million users. Oral contraceptive-related cholestasis may occur in women with a history of pregnancy-related cholestasis. Women with a history of COC-related cholestasis may have the condition recur with subsequent COC use

High Blood Pressure For women with well-controlled hypertension, monitor blood pressure and stop Natazia if blood pressure rises significantly. Women with uncontrolled hypertension or hypertension with vascular disease should not use COCs. An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use. The incidence of hypertension increases with increasing concentration of progestin

Gallbladder Disease Studies suggest a small increased relative risk of developing gallbladder disease among COC users

Carbohydrate and Lipid Metabolic Effects Carefully monitor prediabetic and diabetic women who are taking Natazia. COCs may decrease glucose tolerance in a dose-related fashion. Consider alternative contraception for women with uncontrolled dyslipidemia. A small proportion of women will have adverse lipid changes while on COCs. Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs

Headache If a woman taking Natazia develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Natazia if indicated. An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC

Bleeding Irregularities Breakthrough bleeding and spotting sometimes occur in patients on COCs, especially during the first three months of use. If bleeding persists or occurs after previously regular cycles, 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 COC. Women who are not pregnant and use Natazia, may experience amenorrhea. Based on patient diaries, amenorrhea occurs in approximately 16% of cycles in women using Natazia. Pregnancy should be ruled out in the event of amenorrhea occurring in two or more consecutive cycles. Some women may encounter amenorrhea or oligomenorrhea after stopping COCs, especially when such a condition was pre-existent. Based on patient diaries from three clinical trials evaluating the safety and efficacy of Natazia for contraception, 10-23% of women experienced intracyclic bleeding per cycle

Depression Women with a history of depression should be carefully observed and Natazia discontinued if depression recurs to a serious degree

Interference with Laboratory Tests The use of COCs may change the results of some laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid-binding globulin increase with use of COCs

Monitoring A woman who is taking COCs should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare

Drug Interactions Women who take medications that are strong cytochrome P450 3A4 (CYP3A4) inducers (for example, carbamazepine, phenytoin, rifampicin, and St. John’s wort) should not choose Natazia as their oral contraceptive while using these inducers and for at least 28 days after discontinuation of these inducers due to the possibility of decreased contraceptive efficacy

Other Conditions In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while taking COCs.

Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations . Drugs or herbal products that induce certain enzymes (for example, CYP3A4) may decrease the effectiveness of COCs or increase breakthrough bleeding. Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with COCs

Effects of Other Drugs on Combined Oral Contraceptives Substances diminishing the efficacy of COCs: Dienogest is a substrate of CYP3A4. Women who take medications that are strong CYP3A4 inducers should not choose Natazia as their oral contraceptive while using these inducers and for at least 28 days after discontinuation of these inducers due to the possibility of increased breakthrough bleeding and/or decreased contraceptive efficacy. Drugs or herbal products that induce certain enzymes, including CYP3A4, may decrease the effectiveness of COCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampin, topiramate and products containing St. John’s wort. Interactions between oral contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with COCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability. Multiple dose co-administration of the strong CYP3A4 inducer rifampin with estradiol valerate/dienogest tablets in healthy postmenopausal women led to a decrease in dienogest and estradiol systemic exposure at steady state. Substances Increasing the Systemic Exposure of COCs (enzyme inhibitors): Concomitant administration of moderate or strong CYP3A4 inhibitors like azole antifungals (for example, ketoconazole, itraconazole, voriconazole, fluconazole), verapamil, macrolides (for example, clarithromycin, erythromycin), diltiazem, and grapefruit increase the serum concentrations of both estradiol and dienogest. In a multiple dose study investigating the effect of CYP3A4 inhibitors (ketoconazole and erythromycin) on Natazia, steady state estradiol and dienogest exposures were increased when co-administered with ketoconazole or erythromycin . Human Immunodeficiency Virus (HIV)/Hepatitis C Virus (HCV) Protease Inhibitors and Non-Nucleoside Reverse Transcriptase Inhibitors : Significant changes (increase and decrease) in plasma concentrations of estrogen and progestin have been noted in some cases of co-administration of HIV/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors. Antibiotics : There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids

Effects of Combined Oral Contraceptives on Other Drugs COCs containing ethinyl estradiol may inhibit the metabolism of other compounds. COCs have been shown to significantly decrease plasma concentrations of lamotrigine, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Consult the labeling of the concurrently-used drug to obtain further information about interactions with COCs or the potential for enzyme alterations. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid-binding globulin increase with use of COCs

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 .