Estradiol Valerate and Estradiol Valerate/Dienogest

• Natazia is a combination of dienogest , a progestin, and estradiol valerate, an estrogen, indicated for use by females of reproductive potential to prevent pregnancy. ( 1 )
• The efficacy of Natazia in females of reproductive potential with a body mass index (BMI) of >30 kg/m 2 has not been evaluated. ( 1 , 8.8 )
• 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. ( 1.2 )

1.1 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.

1.2 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 [see Clinical Studies ( 14.2 )].

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 ( 3 ):
• 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 is contraindicated in females who are known to have or develop the following conditions:

• A high risk of arterial or venous thrombotic diseases. Examples include women who are known to:
• Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions ( 5.1 )]
• Have deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings and Precautions ( 5.1 )]
• Have cerebrovascular disease [see Warnings and Precautions ( 5.1 )]
• Have coronary artery disease [see Warnings and Precautions ( 5.1 )]
• 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 ( 5.1 )]
• Have inherited or acquired hypercoagulopathies [see Warnings and Precautions ( 5.1 )]
• Have uncontrolled hypertension [see Warnings and Precautions ( 5.4 )]
• Have diabetes mellitus with vascular disease [see Warnings and Precautions ( 5.6 )]
• Have headaches with focal neurological symptoms or have migraine headaches with or without aura if over age 35 [see Warnings and Precautions ( 5.7 )]
• Undiagnosed abnormal uterine bleeding [see Warnings and Precautions ( 5.8 )]
• Current diagnosis of, or history of, breast cancer, which may be hormone sensitive [see Warnings and Precautions ( 5.2 )]
• Liver tumors, benign or malignant, or liver disease [see Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.7 ) and Clinical Pharmacology ( 12.3 ])].
• A high risk of arterial or venous thrombotic diseases ( 4 )
• Undiagnosed abnormal uterine bleeding ( 4 )
• Breast cancer ( 4 )
• Liver tumors or liver disease ( 4 )

• 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. ( 5.1 )
• Liver disease : Discontinue Natazia if jaundice occurs. ( 5.3 )
• High blood pressure : Do not prescribe Natazia for women with uncontrolled hypertension or hypertension with vascular disease. ( 5.4 )
• Carbohydrate and lipid metabolic effects : Monitor prediabetic and diabetic women taking Natazia. Consider an alternate contraceptive method for women with uncontrolled dyslipidemia. ( 5.6 )
• Headache : Evaluate significant change in headaches and discontinue Natazia if indicated. ( 5.7 )
• Uterine bleeding : Evaluate irregular bleeding or amenorrhea. ( 5.8 )
• 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. [See Adverse Reactions ( 6 ).]

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 [see Contraindications ( 4 )]. 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 [see Adverse Reactions ( 6.2 )] . 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.

5.3 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.

5.4 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.

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

5.6 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.

5.7 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.

5.8 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.

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

5.10 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 [see Clinical Pharmacology ( 12.3 )] . […]

The following serious adverse reactions with the use of COCs are discussed elsewhere in 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 ( 5.3 )] Adverse reactions commonly reported by COC users are:
• Irregular uterine bleeding
• Nausea
• Breast tenderness
• Headache The most common adverse reactions (≥ 2%) in clinical trials for Natazia are headache (including migraines) 13%, breast pain 7%, menstrual disorders 7%, nausea/vomiting 6%, acne 4%, mood changes (3%) and increased weight 3%. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trials 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 rates in the clinical trials of another drug and may not reflect the rates observed in practice. Contraception and Heavy Menstrual Bleeding Studies A total of 2,131 women, 18 to 54 years of age, who took at least one dose of Natazia were enrolled in four clinical phase 3 trials. A total of 1,867 subjects were included in two clinical phase 3 studies with a treatment duration up to 28 cycles with Natazia as an oral contraceptive and 264 subjects in the two phase 3 clinical trials with a treatment duration of 7 cycles evaluating Natazia in the treatment of heavy, prolonged, and/or frequent menstrual bleeding in women without organic pathology [see Clinical Studies ( 14.1 , 14.2 )]. Adverse Reactions Leading to Study Discontinuation : 11.4% of the women discontinued from the clinical trials due to an adverse reaction; the most frequent adverse reactions leading to discontinuation were menstrual disorder (metrorrhagia, menorrhagia, menstruation irregular, genital hemorrhage, vaginal hemorrhage, dysfunctional uterine bleeding) (2.3%); mood changes (depression, mood swings, mood altered, depressed mood, dysthymic disorder, crying) (1.2%); acne (1.1%), headache (including migraines) (1.1%), and weight increased (0.7 %). Common Adverse Reactions (≥ 2%): headache (including migraines) (12.7%), breast pain, discomfort or tenderness (7.0%), menstrual disorders (metrorrhagia, menstruation irregular, menorrhagia, vaginal hemorrhage, dysfunctional uterine bleeding, genital hemorrhage, abnormal withdrawal bleeding, uterine hemorrhage) (6.9%), nausea or vomiting (6.0%), acne (3.9%), mood changes (depression, mood swings, depressed mood, mood altered, affect lability, dysthymic disorder, crying) (3.0%) and increased weight (2.9%). Serious Adverse Reactions: myocardial infarction (2 cases), ruptured ovarian cyst (2 cases), deep vein thrombosis, focal nodular hyperplasia of the liver, uterine leiomyoma, acute cholecystitis, and chronic acalculous cholecystitis.

6.2 Postmarketing Experience Five studies that compared breast cancer risk between ever-users (current or past use) of COCs and never-users of COCs reported no association between ever use of COCs and breast cancer risk, with effect estimates ranging from 0.90 – 1.12 (Figure 1). Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 1). One of these studies reported no association between breast cancer risk and COC use. The other two studies found an increased relative risk of 1.19–1.33 with current or recent use. Both of these studies found an increased risk of breast cancer with current use of longer duration, with relative risks ranging from 1.03 with less than one year of COC use to approximately 1.4 with more than 8–10 years of COC use. Figure 1: Relative Studies of Risk of Breast Cancer with Combined Oral Contraceptives. RR = relative risk; OR = odds ratio; HR = hazard ratio. “ever COC” are females with current or past COC use; “never COC use” are females that never used COCs. The following adverse reactions have been identified during post-approval use of Natazia. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Vascular disorders: Venous and arterial thromboembolic events (including pulmonary emboli, deep vein thrombosis, cerebral thrombosis, myocardial infarction and stroke), hypertension Hepatobiliary disorders: Gallbladder disease, hepatitis Immune system disorders: Hypersensitivity Metabolism and nutrition disorders: Fluid retention, hypertriglyceridemia Nervous system disorders: Dizziness Skin and subcutaneous tissue disorders: Chloasma, angioedema, erythema nodosum, erythema multiforme Gastrointestinal disorders: Gastrointestinal symptoms (for example, abdominal pain) Infections and infestations: Vulvovaginal candidiasis Figure 1

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. ( 7.1 )

7.1 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. [See Clinical Pharmacology (12.3).] 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 [see Clinical Pharmacology ( 12.3 )] . 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.

7.2 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. [See Clinical Pharmacology ( 12.3 ).] 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.

7.3 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 [see Warnings and Precautions ( 5.11 ) and Drug Interactions ( 7.2 )].

• Lactation: can decrease milk production. ( 8.2 )
• Body Mass Index: The safety and efficacy of Natazia in women with a body mass index (BMI) of >30 kg/m 2 has not been evaluated. ( 8.8 )

8.1 Pregnancy Risk Summary There is no reason to use COCs in pregnancy Discontinue Natazia if pregnancy occurs. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to COCs prior to 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 to 4 percent and 15 to 20 percent, respectively.

8.2 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. When possible, advise the nursing female to use other forms of contraception until she discontinues breastfeeding. [See also Dosage and Administration ( 2.2 )]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Natazia and any potential adverse effects on the breast-fed child from Natazia or from the underlying maternal condition.

8.4 Pediatric Use Safety and efficacy of Natazia have been established in women of reproductive age. Efficacy is expected to be the same for postpubertal adolescents under the age of 18 and for users 18 years and older. Use of this product before menarche is not indicated.

8.5 Geriatric Use Natazia has not been studied in postmenopausal women and is not indicated in this population.

8.6 Patients with Renal Impairment The pharmacokinetics of Natazia has not been studied in subjects with renal impairment, but an effect requiring dose adjustment is unlikely to be present [see Clinical Pharmacology ( 12.3 )] .

8.7 Patients with Hepatic Impairment The pharmacokinetics of Natazia has not been studied in subjects with hepatic impairment. 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. [See Contraindications ( 4 ) and Warnings and Precautions ( 5.3 )].

8.8 Body Mass Index The safety and efficacy of Natazia in women with a BMI of > 30 kg/m 2 has not been evaluated.

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