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 )
1.1Oral 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 )].
1.2Acne 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 )].
Contraindications
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 )]
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 dasabuvir ( 4 )
Warnings and precautions
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 )
5.1Thromboembolic 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.
5.2Liver 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.
5.3Risk 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 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.
5.4High 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.
5.5Gallbladder 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.
5.6Carbohydrate 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. 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.
5.7Headache If
a woman taking norgestimate and ethinyl estradiol tablets develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue norgestimate and ethinyl estradiol tablets if indicated. Consider discontinuation of norgestimate and ethinyl estradiol tablets in the case of increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event).
5.8Bleeding 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 clinical trials of norgestimate and ethinyl estradiol tablets, 0.25 mg/0.035 mg, and norgestimate and ethinyl estradiol tablets, 0.18 mg/0.035 mg, 0.215 mg/0.035 mg, 0.25 mg/0.035 mg, the frequency and duration of breakthrough bleeding and/or spotting was assessed in 1,647 patients (21,275 evaluable cycles) and 4,826 patients (35,546 evaluable cycles), respectively.
A total of 100 (7.5%) women discontinued norgestimate and ethinyl estradiol tablets, 0.25 mg/0.035 mg and 231 (4.8%) women discontinued norgestimate and ethinyl estradiol tablets, 0.18 mg/0.035 mg, 0.215 mg/0.035 mg, 0.25 mg/0.035 mg, at least in part, due to bleeding or spotting. Based on data from the clinical trials, 14 to 34% of women using norgestimate and ethinyl estradiol tablets, 0.25 mg/0.035 mg, experienced unscheduled bleeding per cycle in the first year; for norgestimate and ethinyl estradiol tab
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Interactions
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 )
7.1Effects 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 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, non-nucleoside reverse transcriptase inhibitors, and HIV/AIDS medications containing strong inhibitors or inducers of CYP3A 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]) or with HIV/AIDS medications containing strong inhibitors (e.g., cobicistat and ritonavir) or inducers of CYP3A.
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.
7.3Interference 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 – Liver Enzyme Elevation Do not co-administer norgestimate and ethinyl estradiol 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 )].
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary
There is no use for contraception in pregnancy, therefore, norgestimate and ethinyl estradiol tablets should be discontinued during pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb reduction defects) following exposure to CHCs before conception or during early pregnancy. 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.
Adverse reactions
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. ( 6.1 ) Norgestimate and ethinyl estradiol tablets, 0.18 mg/0.035 mg, 0.215 mg/0.035 mg, 0.25 mg/0.035 mg: headache/migraine, breast issues (including breast pain, enlargement, and discharge), vaginal infection, abdominal/gastrointestinal pain, mood disorders (including mood alteration and depression), genital discharge, changes in weight (including weight increased or decreased). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 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 rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Norgestimate and Ethinyl Estradiol Tablets, 0.25 mg/0.035 mg The safety of norgestimate and ethinyl estradiol tablets, 0.25 mg/0.035 mg, 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 tablets, 0.25 mg/0.035 mg, 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 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). Norgestimate and Ethinyl Estradiol Tablets, 0.18 mg/0.035 mg, 0.215 mg/0.035 mg, 0.25 mg/0.035 mg The safety of norgestimate and ethinyl estradiol tablets, 0.18 mg/0.035 mg, 0.215 mg/0.035 mg, 0.25 mg/0.035 mg, was evaluated in 4,826 healthy women of child-bearing potential who participated in 6 clinical trials and received at least 1 dose of norgestimate and ethinyl estradiol tablets, 0.18 mg/0.035 mg, 0.215 mg/0.035 mg, 0.25 mg/0.035 mg, for contraception.
Two trials were randomized active-controlled trials and 4 were uncontrolled open-label trials. In 3 trials, subjects were followed for up to 24 cycles; in 2 trials, subjects were followed for up to 12 cycles; and in 1 trial, subjects were followed for up to 6 cycles. Common Adverse Reactions (≥ 2% of subjects): The most common adverse reactions reported by at least 2% of the 4,826 women were the following in order of decreasing incidence: headache/migraine (33.6%), breast issues (including breast pain, enlargement, and discharge) (8.0%), vaginal infection (7.1%), abdominal/gastrointestinal pain (5.6%), mood disorders (including mood alteration and depression) (3.8%), genital discharge (3.2%), and changes in weight (including weight fluctuation, increased or decreased) (2.5%).
Adverse Reactions Leading to Study Discontinuation: Over the trials, between 9 to 27% of subjects discontinued the trial due to an adverse reaction. The most common adverse reactions (≥1%) leading to discontinuation were: metrorrhagia (4.3%), nausea/vomiting (2.8%), headache/migraine (2.4%), mood disorders (including depression and mood altered) (1.1%), and weight increased (1.1%). Serious Adverse Reactions: breast cancer (1 subject), carcinoma of the cervix in situ (1 subject), hypertension (1 subject), and migraine (2 subjects).
6.2Postmarketing 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. 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 additional adverse 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 : Anaphylactic reaction, 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 vascular thrombosis, hot flush, venous thrombosis (including Budd Chiari Syndrome and hepatic vein thrombosis); Arterial Events :Arterial thromboembolism, myocardial infarction, cerebrovascular accident; Respiratory, Thoracic and Mediastinal Disorders :Dyspnea; Gastrointestinal Disorders : Pancreatitis, abdominal distension, diarrhea, constipation; Hepatobiliary Disorders : Hepatitis; Skin and Subcutaneous Tissue Disorders : Angioedema, erythema nodosum, hirsutism, night sweats, hyperhidrosis, photosensitivity reaction, urticaria, pruritus, acne; Musculoskeletal, Connective Tissue, and Bone Disorders :Muscle spasms, pain in extremity, myalgia, back pain; Reproductive System and Breast Disorders :Ovarian cyst, suppressed lactation, vulvovaginal dryness; General Disorders and Administration Site Conditions
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Composition
Active ingredients
ETHINYL ESTRADIOL 0.035MG; NORGESTIMATE 0.25MG
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
At a glance
Brand name
Norgestimate and Ethinyl Estradiol
Active substance
ethinyl estradiol
Drug class
Progestogens and estrogens, fixed combinations, Progestogens and estrogens, sequential preparations
