Nymyo norgestimate and ethinyl estradiol Kit — NDC 51862-645-03 (Billing 51862-0645-03)

5 WARNINGS AND PRECAUTIONS Thromboembolic Disorders and Other Vascular Problems: Stop Nymyo if a thrombotic event occurs. Stop at least 4 weeks before and 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 Nymyo if jaundice occurs. ( 5.2 ) High blood pressure: If used in women with well-controlled hypertension, monitor blood pressure and stop Nymyo if blood pressure rises significantly. ( 5.4 ) Carbohydrate and lipid metabolic effects: Monitor prediabetic and diabetic women taking Nymyo.

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

( 5.8 )

5.1Thrombotic Disorders and Other Vascular Problems Stop Nymyo if an arterial thrombotic event or venous thromboembolic (VTE) event occurs. Stop Nymyo 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 Nymyo 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 and following prolonged immobilization. Start Nymyo 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 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). 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 Nymyo 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 Nymyo if jaundice develops.

Liver Tumors Nymyo 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 estradiol-containing medications, such as COCs. Discontinue Nymyo prior to starting therapy with the combination drug regimen… [Excerpted — this section continues on DailyMed.]

6 ADVERSE REACTIONS The most common adverse reactions reported during clinical trials (≥2%) were: headache/migraine, abdominal/gastrointestinal pain, vaginal infection, genital discharge, breast issues (including breast pain, discharge, and enlargement), mood disorders (including depression and mood altered), flatulence, nervousness, rash. ( 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 rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of norgestimate and ethinyl estradiol 0.25mg/0.035mg tablets was evaluated in 1,647 healthy women of child-bearing potential who participated in 3 clinical trials and received at least 1 dose of norgestimate and ethinyl estradiol 0.25mg/0.035mg tablets for contraception.

Two trials were randomized active-controlled trials and 1 was an uncontrolled open-label trial. In all 3 trials, subjects were followed for up to 24 cycles. Common Adverse Reactions (≥2% of all subjects) : The most common adverse reactions reported by at least 2% of the 1,647 women were the following in order of decreasing incidence: headache/migraine (32.9%), abdominal/gastrointestinal pain (7.8%), vaginal infection (8.4%), genital discharge (6.8%), breast issues (including breast pain, discharge,and enlargement) (6.3%), mood disorders (including depression and mood altered) (5.0%), flatulence (3.2%), nervousness (2.9%), and rash (2.6%).

Adverse Reactions Leading to Study Discontinuation : Over the three trials, between 11 to 21% of subjects discontinued the trial due to an adverse reaction. The most common adverse reactions (≥1%) leading to discontinuation were: metrorrhagia (6.9%), nausea/vomiting (5.0%), headache (4.1%), mood disorders (including depression and mood altered) (2.4%), premenstrual syndrome (1.7%), hypertension (1.4%), breast pain (1.4%), nervousness (1.3%), amenorrhea (1.1%), dysmenorrhea (1.1%), weight increased (1.1%), and flatulence (1.1%).

Serious Adverse Reactions : breast cancer (1 subject), mood disorders including depression, irritability, and mood swings (1 subject), myocardial infarction (1 subject), and venous thromboembolic events including pulmonary embolism (1 subject) and deep vein thrombosis (DVT) (1 subject).

6.2Postmarketing Experience The following additional adverse drug reactions have been reported from worldwide postmarketing experience with norgestimate/ethinyl estradiol. 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. Infections and Infestations : Urinary tract infection; Neoplasms Benign, Malignant and Unspecified (Incl.

Cysts and Polyps) : Breast cancer, benign breast neoplasm, hepatic adenoma, focal nodular hyperplasia, breast cyst; Immune System Disorders : Hypersensitivity; Metabolism and Nutrition Disorders : Dyslipidemia; Psychiatric Disorders : Anxiety, insomnia; Nervous System Disorders : Syncope, convulsion, paresthesia, dizziness; Eye Disorders : Visual impairment, dry eye, contact lens intolerance; Ear and Labyrinth Disorders : Vertigo; Cardiac Disorders : Tachycardia, palpitations; Vascular Events : Deep vein thrombosis, pulmonary embolism, retinal va… [Excerpted — this section continues on DailyMed.]

7 DRUG INTERACTIONS 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 ) Consult the labeling of concurrently used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.

No drug-drug interaction studies were conducted with Nymyo.

7.1Effects of Other Drugs on Combined Oral Contraceptives Substances decreasing the plasma concentrations 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 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 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/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir])/HCV protease inhibitors (decrease [e.g., boceprevir and telaprevir]) 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, 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.

7.3Interactions 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.

7.4Concomitant Use with HCV Combination Therapy… [Excerpted — this section continues on DailyMed.]