Norethindrone Acetate and Ethinyl Estradiol and Ferrous Fumarate Kit — NDC 60219-1031-7 (Billing 60219-1031-07)

5 WARNINGS AND PRECAUTIONS Vascular risks: Stop norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets 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 if jaundice occurs (5.2) High blood pressure: Do not prescribe for women with uncontrolled hypertension or hypertension with vascular disease (5.4) Carbohydrate and lipid metabolic effects: Monitor prediabetic and diabetic women taking norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets.

Consider an alternative contraceptive method for women with uncontrolled dyslipidemia (5.6) Headache: Evaluate significant change in headaches and discontinue if indicated (5.7) Uterine bleeding: Evaluate irregular bleeding or amenorrhea (5.8)

5.1Thromboembolic Disorders and Other Vascular Problems Stop norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets if an arterial or deep venous thrombotic event (VTE) occurs. Stop norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately.

If feasible, stop norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of VTE. Start norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate 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 a COC. The risk of thromboembolic disease due to oral contraceptives gradually disappears after COC use is discontinued. Use of COCs also increases the risk of arterial thrombosis 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), although, in general, the risk is greatest in older (greater than 35 years of age), hypertensive women who also smoke. COCs also increase the risk for stroke in women with underlying risk factors. Use COCs with caution in women with cardiovascular disease risk factors.

5.2Liver Disease Impaired Liver Function Do not use norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets in women with acute viral hepatitis or severe (decompensated) cirrhosis of the 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 norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets if jaundice develops.

Liver Tumors Norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate 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 per 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 (greater than 8 years) COC users. However, the attributable risk of liver cancers in COC users is less than one case per million users.

5.3Risk of Liver… [Excerpted — this section continues on DailyMed.]

6 ADVERSE REACTIONS 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 The most common adverse reactions in clinical trials (greater than or equal to 2%) were: headache, vaginal candidiasis, nausea, menstrual cramps, breast tenderness, bacterial vaginitis, abnormal cervical smear, acne, mood swings, and weight gain.

(6.1) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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 data presented in Section 6.1 are from a clinical trial conducted with a 24-day regimen of norethindrone acetate 1 mg/ethinyl estradiol 0.020 mg tablets. Norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets is bioequivalent to these norethindrone acetate/ethinyl estradiol tablets.

Common Adverse Reactions (Greater Than or Equal to 2% of all Treated Subjects) : The most common adverse reactions reported by at least 2% of the 743 women using norethindrone acetate/ethinyl estradiol tablets were the following, in order of decreasing incidence: headache (6.3%), vaginal candidiasis (6.1%), nausea (4.6%), menstrual cramps (4.4%), breast tenderness (3.4%), bacterial vaginitis (3.1%), abnormal cervical smear (3.1%), acne (2.7%), mood swings (2.2%), and weight gain (2%). Adverse Reactions Leading to Study Discontinuation : Among the 743 women using norethindrone acetate/ethinyl estradiol tablets, 46 women (6.2%) withdrew because of an adverse event.

Adverse events occurring in 3 or more subjects leading to discontinuation of treatment were, in decreasing order: abnormal or irregular bleeding (1.3%), nausea (0.8%), menstrual cramps (0.5%), and increased blood pressure (0.4%).

6.2Post-marketing 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.

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 a 24-day regimen of norethindrone acetate 1 mg/ethinyl estradiol 0.020 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 evaluate a causal relationship to drug exposure.

Adverse reactions are grouped into System Organ Classes. Vascular disorders: thrombosis/embolism (coronary artery, pulmonary, cerebral, deep vein). Hepatobiliary disorders: cholelithiasis, cholecystitis, hepatic adenoma, hemangioma of liver.

Immune system disorders: hypersensiti… [Excerpted — this section continues on DailyMed.]

7 DRUG INTERACTIONS Consult the labeling of the concurrently-used drug to obtain further information about interactions with COCs or the potential for enzyme alterations. No drug-drug interaction studies were conducted with norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets. 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)

7.1Effects of Other Drugs on Combined Oral Contraceptives Substances diminishing the efficacy of COCs: Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (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, rifampicin, 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. Substances increasing the plasma concentrations of COCs: Co-administration of atorvastatin and certain COCs containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20%.

Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole 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 the estrogen and progestin have been noted in some cases of co-administration of HIV/HCV protease inhibitors or of 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.

7.2Effects 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.

Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentration of thyroid-binding globulin increases with use of COCs.

7.3Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation Do not co-administer norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate 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) ] .

7.4Interference 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.