Microgestin 24 Fe Norethindrone acetate/Ethinyl Estradiol and Ferrous Fumarate Kit — NDC 51862-648-06 (Billing 51862-0648-06)

5 WARNINGS AND PRECAUTIONS Thrombotic Disorders and Other Vascular Problems: Stop Microgestin 24 Fe 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 Microgestin 24 Fe if jaundice occurs. (5.2) High blood pressure: If used in women with well-controlled hypertension, monitor blood pressure and stop Microgestin 24 Fe if blood pressure rises significantly. (5.4) Carbohydrate and lipid metabolic effects: Monitor prediabetic and diabetic women taking Microgestin 24 Fe.

Consider an alternative contraceptive method for women with uncontrolled dyslipidemia. (5.6) Headache: Evaluate significant change in headaches and discontinue Microgestin 24 Fe if indicated. (5.7) Bleeding Irregularities and Amenorrhea: Evaluate irregular bleeding or amenorrhea.

(5.8)

5.1Thrombotic Disorders and Other Vascular Problems Stop Microgestin 24 Fe if an arterial thrombotic event or venous thromboembolic (VTE) event occurs. Stop Microgestin 24 Fe if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately [see Adverse Reactions (6.2) ].

If feasible, stop Microgestin 24 Fe 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 Microgestin 24 Fe 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 cases per 10,000 woman-years.

The risk of VTE is highest during the first year of use of a COCs and when restarting oral contraception after a break of 4 weeks or longer. The risk of thromboembolic disease due to COCs gradually disappears after COC 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). This 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.

5.2Liver Disease Impaired Liver Function Do not use Microgestin 24 Fe 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 Microgestin 24 Fe if jaundice develops.

Liver Tumors Microgestin 24 Fe is 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 (>8 years) COC users. However, the risk of liver cancers in COC users is less than one case per million users.

5.3Risk 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…

6 ADVERSE REACTIONS The most common adverse reactions (≥2%) were: headache, vaginal candidiasis, nausea, menstrual cramps, breast tenderness, mood changes, bacterial vaginitis, acne, and weight gain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Mayne Pharma Toll-Free at 1-844-825-8500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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

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 safety of norethindrone acetate and ethinyl estradiol tablets was evaluated in 743 subjects who participated in an open- label, randomized, active-controlled, multicenter clinical trial of norethindrone acetate and ethinyl estradiol tablets for contraception.

This trial examined healthy, non-pregnant volunteers aged 18 to 45 years, who were sexually active and had a body mass index of ≤35 kg/m 2 . Subjects were followed for up to six 28-day cycles providing a total of 3,823 treatment-cycles of exposure. Common Adverse Reactions (≥2% of all subjects) : The most common adverse reactions reported by at least 2% of the 743 women using norethindrone acetate and 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%), mood changes (including mood swings (2.2%) and depression (1.1%)), bacterial vaginitis (3.1%), acne (2.7%), and weight gain (2.0%).

Adverse Reactions Leading to Study Discontinuation : Among the 743 women using norethindrone acetate and 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 bleeding (0.9%), nausea (0.8%), mood changes (0.8%), menstrual cramps (0.4%), increased blood pressure (0.4%), and irregular bleeding (0.4%).

6.2Postmarketing Experience The following adverse reactions have been identified during post approval use of norethindrone acetate and ethinyl estradiol tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure. Cardiovascular: chest pain, palpitations, tachycardia, angina pectoris, myocardial infarction.

Endocrine disorders: hypothyroidism, hyperthyroidism. Eye disorders: blurred vision, visual impairment, transient blindness, corneal thinning, change in corneal curvature (steepening). GI disorders : nausea, vomiting, abdominal pain, constipation, pancreatitis.

Hepatobiliary disorders: cholelithiasis, cholecystitis, hepatic adenoma, hemangioma of liver. Immune system disorders: anaphylactic reactions, including urticaria, angioedema, and severe reactions with respiratory and circulatory symptoms. Infections: vaginal infection.

Metabolism and nutrition disorders : change in weight or appetite (increase or decrease). hypoglycemia, diabetes mellitus, anemia. Musculoskeletal and connective tissue disorders: myalgia. Skin and subcutaneous disorders: alopecia, rash (generalized and allergic), pruritus, skin discoloration, night sweats, swelling face or lips, hirsutism, skin burning sensation, erythema multiforme, erythema nodosum, hemorrhagic eruption.

Nervous system disorders: headache, dizziness, migraine, hyperesthesia, paraesthe…

7 DRUG INTERACTIONS 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 method or alternative method of contraception when enzyme inducers are used with COCs. (7.1) Consult the labeling of concurrently used drugs to obtain further information about interactions with oral contraceptives or the potential for enzyme alterations.

7.1Effects 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 oral contraceptives including phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, and products containing St.

John's wort. Interactions between COCs 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 or rosuvastatin and certain COCs containing ethinyl estradiol (EE) increase AUC values for EE by approximately 20-25%. 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 protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritnoavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir])/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine] or increase [e.g., etravirine]).

7.2Effects of Combined Oral Contraceptives on Other Drugs COCs containing EE may inhibit the metabolism of other compounds (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma concentrations. COCs have been shown to decrease plasma concentrations of acetaminophen, clofibric acid, morphine, salicylic acid, and temazepam. 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) ].

7.3Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation Do not co-administer Microgestin 24 Fe with HCV drug combinations containing ombitasvir/ paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Warnings and Precautions (5.3) ].

7.4Interactions 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.