Levonorgestrel and Ethinyl Estradiol and Ferrous Bisglycinate

Minzoya™ is indicated for use by females of reproductive potential to prevent pregnancy. Minzoya is a progestin/estrogen COC indicated for use by females of reproductive potential to prevent pregnancy.

Minzoya (levonorgestrel and ethinyl estradiol tablets USP and ferrous bisglycinate tablets) is available in a 28-tablets compact blister card with: 21 White to off-white round biconvex tablets (active), debossed with "J3" on one side and plain on other side; and each containing levonorgestrel 0.1 mg and ethinyl estradiol 0.02 mg 7 Blue colored round biconvex film coated tablets (inactive), debossed with "J4" on one side and plain on the other side containing ferrous bisglycinate 36.5 mg. The ferrous bisglycinate tablets do not serve any therapeutic purpose. Minzoya consists of 28 tablets in the following order: 21 white to off-white tablets (active), each containing 0.1 mg levonorgestrel and 0.02 mg ethinyl estradiol. 7 blue tablets (inactive placebo) each containing ferrous bisglycinate 36.5 mg. The ferrous bisglycinate tablets do not serve any therapeutic purpose. ( 3 )

Minzoya is contraindicated in females who are known to have or develop the following conditions:

• A high risk of arterial or venous thrombotic disease. 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 inherited or acquired hypercoagulopathies [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 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 aura [see Warnings and Precautions ( 5.7 )] .
• Women over age 35 with any migraine headaches [see Warnings and Precautions ( 5.7 )] .
• Liver tumors, benign or malignant, or liver disease [see Warnings and Precautions ( 5.2 )]
• Undiagnosed abnormal uterine bleeding [see Warnings and Precautions ( 5.8 )] .
• Pregnancy, because there is no reason to use COCs during pregnancy [see Warnings and Precautions ( 5.10 ) and Use in Specific Populations ( 8.1 )] .
• Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive [see Warnings and Precautions ( 5.11 )] .
• Hypersensitivity to any of the components.
• Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations [see Warnings and Precautions ( 5.3 )] . A high risk of arterial or venous thrombotic diseases ( 4 ) Liver tumors or liver disease ( 4 ) Undiagnosed abnormal uterine bleeding ( 4 ) Pregnancy ( 4 ) Breast cancer ( 4 ) Hypersensitivity of any of the components ( 4 ) Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir ( 4 )

Thrombotic Disorders and Other Vascular Problems : Stop Minzoya if a thrombotic event occurs. Stop at least 4 weeks before through 2 weeks after major surgery. Start no earlier than 4 weeks after delivery, in women who are not breastfeeding ( 5.1 ) Liver disease : Discontinue Minzoya if jaundice occurs ( 5.2 ) High Blood Pressure : If used in women with well- controlled hypertension, monitor blood pressure and stop Minzoya if blood pressure rises significantly. ( 5.4 ) Carbohydrate and Lipid Metabolic Effects : Monitor prediabetic and diabetic women taking Minzoya. Consider an alternative contraceptive method for women with uncontrolled dyslipidemia ( 5.6 ) Headache : Evaluate significant change in headaches and discontinue Minzoya if indicated ( 5.7 ) Bleeding Irregularities and Amenorrhea : Evaluate irregular bleeding or amenorrhea ( 5.8 )

5.1 Thrombotic Disorders and Other Vascular Problems Stop levonorgestrel and ethinyl estradiol tablets and ferrous bisglycinate tablets if an arterial thrombotic event or venous thromboembolic (VTE) event occurs. Stop levonorgestrel and ethinyl estradiol tablets and ferrous bisglycinate tablets if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately. If feasible, stop levonorgestrel and ethinyl estradiol tablets and ferrous bisglycinate tablets at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of VTE as well as during the following prolonged immobilization. Start levonorgestrel and ethinyl estradiol tablets and ferrous bisglycinate tablets no earlier than 4 weeks after delivery, in women 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. The use of COCs increases the risk of VTE. However, pregnancy increases the risk of VTE as much or more than the use of COCs. The risk of VTE in women using COCs is 3 to 9 per 10,000 woman-years. The risk of VTE is highest during the first year of use of COCs and when restarting hormonal contraception after a break of 4 weeks or longer. The risk of thromboembolic disease due to COCs gradually disappears after use is discontinued. 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. COCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes). The risk increases with age, particularly in women over 35 years of age who smoke. Use COCs with caution in women with cardiovascular disease risk factors.

5.2 Liver Disease Impaired Liver Function Do not use levonorgestrel and ethinyl estradiol tablets and ferrous bisglycinate tablets in women with liver disease, such as acute viral hepatitis or severe (decompensated) cirrhosis of liver [see Contraindications ( 4 )] . 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. Discontinue levonorgestrel and ethinyl estradiol tablets and ferrous bisglycinate tablets if jaundice develops. Liver Tumors Levonorgestrel and ethinyl estradiol tablets and ferrous bisglycinate tablets are contraindicated in women with benign and malignant liver tumors [see Contraindications ( 4 )] . 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 risk of liver cancers in COC users is less than one case per million users.

5.3 Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment During clinical trials with the Hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or 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 women using ethinyl estradiol-containing medications, such as COCs. Discontinue levonorgestrel and ethinyl estradiol tablets USP and ferrous bisglycinate tablets prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications ( 4 )] . Levonorgestrel and ethinyl estradiol tablets and ferrous bisglycinate tablets can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.

5.4 High Blood Pressure Levonorgestrel and ethinyl estradiol tablets and ferrous bisglycinate tablets are contraindicated in women with uncontrolled hypertension or hypertension with vascular disease [see Contraindications ( 4 )] . For women with well-controlled hypertension, monitor blood pressure and stop levonorgestrel and ethinyl estradiol tablets and ferrous bisglycinate tablets if blood pressure rises significantly. An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women with extended duration of use. The incidence of hypertension increases with increasing concentrations of progestin.

5.5 Gallbladder Disease Studies suggest a small increased relative risk of developing gallbladder disease among COC users. Use of COCs may worsen existing gallbladder disease. A past history of COC-related cholestasis predicts an increased risk with subsequent COC use. Women with a history of pregnancy-related cholestasis may be at an increased risk for COC related cholestasis.

5.6 Carbohydrate and Lipid Metabolic Effects Carefully monitor prediabetic and diabetic women who take levonorgestrel and ethinyl estradiol tablets and ferrous bisglycinate tablets. COCs may decrease glucose tolerance. 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 levonorgestrel and ethinyl estradiol tablets and ferrous bisglycinate tablets develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue levonorgestrel and ethinyl estradiol tablets and ferrous bisglycinate tablets if indicated. Consider discontinuation of levonorgestrel and ethinyl estradiol tablets and ferrous bisglycinate tablets in the case of increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event).

5.8 Bleeding Irregularities and Amenorrhea Unscheduled Bleeding and Spotting Unscheduled (breakthrough or intracyclic) 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 contraceptive product. In the clinical trial with levonorgestrel 0.1 mg and ethinyl estradiol 0.02 mg tablets breakthrough bleeding and spotting was reported in 4% and 12% of cycles, respectively. Breakthrough bleeding and spotting occurred together during 11% of the cycles. Amenorrhea and Oligomenorrhea Women who use levonorgestrel and ethinyl estradiol tablets and ferrous bisglycinate tablets may experience amenorrhea. In the clinical trial, 2.6% of the evaluable cycles were amenorrheic. Some women may experience amenorrhea or oligomenorrhea after discontinuation of COCs, especially when such a condition was preexistent. […]

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 ( 5.2 )] Adverse reactions commonly reported by COC users are: Irregular uterine bleeding Nausea Breast tenderness Headache Common adverse reactions (≥2% of women): headache (14%), metrorrhagia (8%), dysmenorrhea and nausea (7% each), abdominal pain and breast pain (4% each), emotional lability and acne (3% each), and depression, amenorrhea, and vaginal moniliasis (2% each) ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 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 the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In a clinical trial with levonorgestrel 0.1 mg and ethinyl estradiol 0.02 mg tablets, a total of 1477 healthy women of child-bearing potential were enrolled and had 7870 cycles of exposure. Of these, 792 subjects had completed 6 cycles of treatment. The women ranged in age from 17 to 49 years and 87% were Caucasian. Common Adverse Reactions (≥ 2% of women) headache (14%) metrorrhagia (8%) dysmenorrhea (7%) nausea (7%) abdominal pain (4%) breast pain (4%) emotional lability (3%) acne (3%) depression (2%) amenorrhea (2%) vaginal moniliasis (2%) At the time of the report, 133 (9%) subjects had withdrawn from the study due to adverse events. The most frequent were due to headache and metrorrhagia (1% each). Other adverse events occurring in <1% of those who discontinued included amenorrhea, depression, emotional lability, hypertension, acne, menorrhagia, nausea, hypercholesterolemia, weight gain, dysmenorrhea, and flatulence. All other reasons for discontinuation were reported by 3 or fewer subjects.

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 to 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 to 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 to 10 years of COC use. Figure 1. Relevant Studies of Risk of Breast Cancer with Combined Oral Contraceptives The following additional adverse drug reactions have been reported from worldwide postmarketing experience with levonorgestrel 0.1 mg and ethinyl estradiol 0.02 mg tablets. 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. Cardiac Disorder : chest pain, dyspnea, palpitations Gastrointestinal Disorders : abdominal pain, nausea, vomiting, diarrhea General Disorders and Administration Site Conditions : chest pain, fatigue, pain, malaise, injection site pain or erythema, feeling abnormal, pyrexia, condition aggravated, asthenia Immune System Disorders : hypersensitivity reactions, including pruritus, rash, urticaria, erythema Injury, Poisoning and Procedural Complications : injury Investigations : weight decreased Musculoskeletal and Connective Tissue Disorders : pain in extremity, arthralgia, back pain, muscle spasm Nervous System Disorders : headache, migraine, dizziness, hypoesthesia, paresthesia Psychiatric Disorders : depression, insomnia, anxiety Reproductive System and Breast Disorders : metrorrhagia, menorrhagia, hot flush, vaginal hemorrhage Respiratory, Thoracic and Mediastinal Disorders : nasopharyngitis, cough Sleep Disorders and Disturbances : somnolence Vascular Disorders : deep vein thrombosis, pulmonary embolism Figure 1

Consult the labeling of 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, including CYP3A4, may decrease the effectiveness of COCs or increase breakthrough bleeding. Counsel patients to use a back-up method 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 Decreasing the Plasma Concentrations of COCs and Potentially Diminishing the Efficacy of COCs Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the plasma concentrations of COCs and potentially diminish 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, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, and products containing St. John's wort. Interactions between hormonal 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. Colesevelam: Colesevelam, a bile acid sequestrant, given together with a COC, has been shown to significantly decrease the AUC of ethinyl estradiol (EE). The drug interaction between the contraceptive and colesevelam was decreased when the two drug products were given 4 hours apart. Substances Increasing the Plasma Concentrations of COCs Co-administration of atorvastatin or rosuvastatin and certain COCs containing EE increase AUC values for EE by approximately 20 to 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 plasma hormone concentrations. Human Immunodeficiency Virus (HIV)/ Hepatitis C Virus (HCV) Protease Inhibitors and Non-nucleoside Reverse Transcriptase Inhibitors Significant changes (increase or decrease) in the plasma concentrations of estrogen and/or progestin have been noted in some cases of co-administration with HIV/HCV protease inhibitors and non- nucleoside reverse transcriptase inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos) amprenavir/ritonavir, lopinavir/ritonavir, tipranavir/ritonavir, boceprevir, telaprevir, nevirapine and efavirenz] or increase [e.g., indinavir, atazanavir/ritonavir and etravirine]).

7.2 Effects of Combined Oral Contraceptives on Other Drugs Combined oral contraceptives containing EE may inhibit the metabolism of other compounds (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma concentrations. Combined oral contraceptives have been shown to decrease plasma concentrations of acetaminophen, clofibric acid, morphine, salicylic acid, temazepam and lamotrigine. Significant decrease in plasma concentration of lamotrigine has been shown, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because the serum concentration of thyroid-binding globulin increases with use of COCs [see Warnings and Precautions ( 5.12 )] .

7.3 Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation Do not co-administer levonorgestrel and ethinyl estradiol tablets and ferrous bisglycinate tablets with HCV drug combinations containing ombitasvir/ paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Warnings and Precautions ( 5.3 )] .

7.4 Interactions 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.

Nursing mothers: Advise use of another contraceptive method. Minzoya can decrease milk production. ( 8.2 )

8.1 Pregnancy Risk Summary Levonorgestrel and ethinyl estradiol tablets and ferrous bisglycinate tablets are contraindicated in pregnancy because there is no reason to use combined hormonal contraceptives (CHCs) in pregnancy. Discontinue levonorgestrel and ethinyl estradiol tablets and ferrous bisglycinate tablets if pregnancy occurs. Based on epidemiologic studies and meta-analyses, there is little or no increased risk of birth defects in the children of females who inadvertently use COCs during early pregnancy (See Data) . 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. Human Data 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 COCs before conception or during early pregnancy.

8.2 Lactation Risk Summary Combined hormonal contraceptives (CHCs) and/or metabolites are present in human milk and in breast-fed infants. CHCs, including levonorgestrel and ethinyl estradiol tablets and ferrous bisglycinate tablets, can reduce milk production in breast-feeding females. This reduction can occur at any time but is less likely to occur once breast-feeding is well-established. When possible, advise the nursing female to use other methods of contraception until she discontinues breast-feeding. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for levonorgestrel and ethinyl estradiol tablets and ferrous bisglycinate tablets and any potential adverse effects on the breast-fed child from levonorgestrel and ethinyl estradiol tablets and ferrous bisglycinate tablets or from the underlying maternal condition.

8.4 Pediatric Use Safety and efficacy of levonorgestrel and ethinyl estradiol tablets and ferrous bisglycinate tablets have been established in women of reproductive age. Efficacy is expected to be the same in post-pubertal adolescents under the age of 18 years as for users 18 years and older. Use of this product before menarche is not indicated.

8.5 Geriatric Use Levonorgestrel and ethinyl estradiol tablets and ferrous bisglycinate tablets has not been studied in postmenopausal women and is not indicated in this population.

8.7 Hepatic Impairment The pharmacokinetics of levonorgestrel and ethinyl estradiol tablets and ferrous bisglycinate tablets have not been studied in women with hepatic impairment. However, steroid hormones may be poorly metabolized in patients with hepatic impairment. 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 [see Contraindications ( 4 ) and Warnings and Precautions ( 5.2 )] .

COCs lower the risk of becoming pregnant primarily by suppressing ovulation. Other possible mechanisms may include cervical mucus changes that inhibit sperm penetration and endometrial changes that reduce the likelihood of implantation.