Ethinyl estradiol and norgestimate: uses, appearance and warnings

Norgestimate and ethinyl estradiol tablets are combinations of norgestimate, a progestin, and ethinyl estradiol, an estrogen, indicated for use by females of reproductive potential to prevent pregnancy. ( 1.1 ) Norgestimate and ethinyl estradiol tablets 0.18 mg/0.035 mg, 0.215 mg/0.035 mg, 0.25 mg/0.035 mg are indicated for the treatment of moderate acne vulgaris in females at least 15 years of age, who have no known contraindications to oral contraceptive therapy and have achieved menarche. Norgestimate and ethinyl estradiol tablets 0.18 mg/0.035 mg, 0.215 mg/0.035 mg, 0.25 mg/0.035 mg should be used for the treatment of acne only if the patient desires an oral contraceptive for birth control. ( 1.2 ) 1.1 Oral Contraceptive Norgestimate and Ethinyl Estradiol Tablets, 0.18 mg/0.035 mg, 0.215 mg/0.035 mg, 0.25 mg/0.035 mg and Norgestimate and Ethinyl Estradiol Tablets, 0.25 mg/0.035 mg are indicated for use by females of reproductive potential to prevent pregnancy [see Clinical Studies ( 14 )]. 1.2 Acne Norgestimate and Ethinyl Estradiol Tablets, 0.18 mg/0.035 mg, 0.215 mg/0.035 mg, 0.25 mg/0.035 mg are indicated for the treatment of moderate acne vulgaris in females at least 15 years of age, who have no known contraindications to oral contraceptive therapy and have achieved menarche. Norgestimate and Ethinyl Estradiol Tablets, 0.18 mg/0.035 mg, 0.215 mg/0.035 mg, 0.25 mg/0.035 mg should be used for the treatment of acne only if the patient desires an oral contraceptive for birth control [see Clinical Studies ( 14 )].

Norgestimate and Ethinyl Estradiol Tablets, USP 0.25 mg/0.035 mg are available in blister packs containing 28 tablets, in the following order: • 21 blue, round, flat faced beveled edged, uncoated tablets, debossed with ‘A7’ on one side and plain on the other. Each blue tablet contains 0.25 mg of norgestimate, USP and 0.035 mg of ethinyl estradiol, USP. • 7 light green, round, flat faced beveled edged, uncoated tablets debossed with ‘A2’on one side and plain on the other. Each light green tablet contains inert ingredients. Norgestimate and Ethinyl Estradiol Tablets, USP 0.18 mg/0.035 mg, 0.215 mg/0.035 mg, 0.25 mg/0.035 mg are available in blister cards. Each blister card contains 28 tablets in the following order: • 7 white to off-white, round, flat faced beveled edge, uncoated tablets, debossed with ‘A9’ on one side and plain on the other. Each white to off-white tablet contains 0.18 mg of norgestimate, USP and 0.035 mg of ethinyl estradiol, USP. • 7 light blue, round, flat faced beveled edge, uncoated tablets, debossed with ‘A8’ on one side and plain on the other. Each light blue tablet contains 0.215 mg norgestimate, USP and 0.035 mg of ethinyl estradiol, USP. • 7 blue, round, flat faced beveled edge, uncoated tablets, debossed with ‘A7’ on one side, and plain on the other. Each blue tablet contains 0.25 mg of norgestimate, USP and 0.035 mg of ethinyl estradiol, USP. …

16.1 How Supplied Norgestimate and Ethinyl Estradiol Tablets, USP 0.25 mg/0.035 mg are available in blister packs containing 28 tablets, as follows: • 21 blue, round, flat faced beveled edged, uncoated tablets, debossed with ‘A7’ on one side and plain on the other. Each blue tablet contains 0.25 mg of norgestimate, USP and 0.035 mg of ethinyl estradiol, USP. • 7 light green, round, flat faced beveled edged, uncoated tablets debossed with ‘A2’on one side and plain on the other. Each light green tablet contains inert ingredients. NDC 68462-309-29 1 carton containing 3 blister cards of 28 tablets Norgestimate and Ethinyl Estradiol Tablets, USP 0.18 mg/0.035 mg, 0.215 mg/0.035 mg, 0.25 mg/0.035 mg are available in blister packs containing 28 tablets, as follows: • 7 white to off-white, round, flat faced beveled edge, uncoated tablets, debossed with ‘A9’ on one side and plain on the other. Each white to off-white tablet contains 0.18 mg of norgestimate, USP and 0.035 mg of ethinyl estradiol, USP. • 7 light blue, round, flat faced beveled edge, uncoated tablets, debossed with ‘A8’ on one side and plain on the other. Each light blue tablet contains 0.215 mg norgestimate, USP and 0.035 mg of ethinyl estradiol, USP. • 7 blue, round, flat faced beveled edge, uncoated tablets, debossed with ‘A7’ on one side, and plain on the other. Each blue tablet contains 0.25 mg of norgestimate, USP and 0.035 mg of ethinyl estradiol, USP. • 7 light green, round, flat faced beveled edge, uncoated tablets, debossed with ‘A2’ on one side and plain on the other. Each light green tablet contains inert ingredients. NDC 68462-565-29 1 carton containing 3 blister cards of 28 tablets 16.2 Storage Conditions • Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. • Protect from light. • Keep out of the reach of children.

Norgestimate and ethinyl estradiol tablets are 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: o Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions ( 5.1 )] o Have deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings and Precautions ( 5.1 )] o Have inherited or acquired hyper coagulopathies [see Warnings and Precautions ( 5.1 )] o Have cerebrovascular disease [see Warnings and Precautions ( 5.1 )] o Have coronary artery disease [see Warnings and Precautions ( 5.1 )] o 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 )] o Have uncontrolled hypertension [see Warnings and Precautions ( 5.4 )] o Have diabetes mellitus with vascular disease [see Warnings and Precautions ( 5.6 )] o Have headaches with focal neurological symptoms or 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 )] • Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive [see Warnings and Precautions ( 5.10 )] • 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 ) • Breast cancer ( 4 ) • Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabu …

• Thromboembolic Disorders and Other Vascular Problems: Stop norgestimate and ethinyl estradiol tablets 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 norgestimate and ethinyl estradiol tablets if jaundice occurs. ( 5.2 ) • High blood pressure: If used in women with well-controlled hypertension, monitor blood pressure and stop norgestimate and ethinyl estradiol tablets if blood pressure rises significantly. ( 5.4 ) • Carbohydrate and lipid metabolic effects: Monitor prediabetic and diabetic women taking norgestimate and ethinyl estradiol tablets. Consider an alternate contraceptive method for women with uncontrolled dyslipidemia. ( 5.6 ) • Headache: Evaluate significant change in headaches and discontinue norgestimate and ethinyl estradiol tablets if indicated. ( 5.7 ) • Bleeding Irregularities and Amenorrhea: Evaluate irregular bleeding or amenorrhea. ( 5.8 ) 5.1 Thromboembolic Disorders and Other Vascular Problems • Stop norgestimate and ethinyl estradiol tablets if an arterial thrombotic event or venous thromboembolic (VTE) event occurs. • Stop norgestimate and ethinyl estradiol tablets 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 norgestimate and ethinyl estradiol 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 and following prolonged immobilization. • Start norgestimate and ethinyl estradiol 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 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. 5.2 Liver Disease Impaired Liver Function Norgestimate and ethinyl estradiol tablets are contraindicated 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 norgestimate and ethinyl estradiol tablets if jaundice develops. Liver Tumors Norgestimate and ethinyl estradiol 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 norgestimate and ethinyl estradiol tablets prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications ( 4 )]. Norgestimate and ethinyl estradiol tablets can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen. 5.4 High Blood Pressure Norgestimate and ethinyl estradiol 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 norgestimate and ethinyl estradiol 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 norgestimate and ethinyl estradiol tablets. COCs may decrease glucose tolerance. Consider alternative contraception for women with uncontrolled dyslipidemia. …

The following serious adverse reactions with the use of COCs are discussed elsewhere in 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 )] The most common adverse reactions reported during clinical trials (≥2%) were: Norgestimate and ethinyl estradiol tablets, 0.25 mg/0.035 mg: 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. …

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 norgestimate and ethinyl estradiol 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 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 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. …