Norgestimate and ethinyl estradiol

Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs are contraindicated in women who are over 35 years of age and smoke [see CONTRAINDICATIONS ( 4)].

Norgestimate and ethinyl estradiol tablets USP are indicated for use by females of reproductive potential to prevent pregnancy [see CLINICAL STUDIES ( 14)].

Norgestimate and ethinyl estradiol tablets USP 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 USP should be used for the treatment of acne only if the patient desires an oral contraceptive for birth control [see CLINICAL STUDIES ( 14)].

Take one tablet by mouth at the same time each day with or without food. Table 1 provides the recommended dosage and administration instructions for Norgestimate and Ethinyl Estradiol Tablets USP.

Starting Norgestimate and Ethinyl Estradiol Tablets USP after Abortion or Miscarriage

First-trimester:

• After a first-trimester abortion or miscarriage, norgestimate and ethinyl estradiol tablets USP may be started immediately. An additional method of contraception is not needed if norgestimate and ethinyl estradiol tablets USP is started immediately.

• If norgestimate and ethinyl estradiol tablets USP is not started within 5 days after termination of the pregnancy, the patient should use additional non-hormonal contraception (such as condoms and spermicide) for the first seven days of her first cycle pack of norgestimate and ethinyl estradiol tablets USP.

Second-trimester:

• Do not start until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. Start norgestimate and ethinyl estradiol tablets USP, following the instructions in Table 1 for Day 1 or Sunday start, as desired. If using Sunday start, use additional non-hormonal contraception (such as condoms and spermicide) for the first seven days of the patient's first cycle pack of norgestimate and ethinyl estradiol tablets USP. [see CONTRAINDICATIONS ( 4), WARNINGS AND PRECAUTIONS ( 5.1), AND FDA-APPROVED PATIENT LABELING.]

Starting Norgestimate and Ethinyl Estradiol Tablets USP after Childbirth

• Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. Start contraceptive therapy with norgestimate and ethinyl estradiol tablets USP following the instructions in Table 1 for women not currently using hormonal contraception.

• Norgestimate and ethinyl estradiol tablets USP are not recommended for use in lactating women [see USE IN SPECIFIC POPULATIONS ( 8.2)].

• If the woman has not yet had a period postpartum, consider the possibility of ovulation and conception occurring prior to use of norgestimate and ethinyl estradiol tablets USP [see CONTRAINDICATIONS ( 4), WARNINGS AND PRECAUTIONS ( 5.1), USE IN SPECIFIC POPULATIONS ( 8.1 AND 8.2),].

Contraceptive failure may occur when active tablets are missed. Table 2 describes instructions for Norgestimate and Ethinyl Estradiol Tablets USP dosing and use of additional non-hormonal contraception (such as condoms) when active tablets are missed.

In case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken. If vomiting or diarrhea occurs within 3 to 4 hours after taking an active tablet, handle this as a missed tablet [see FDA-APPROVED PATIENT LABELING].

The timing of initiation of dosing with norgestimate and ethinyl estradiol tablets USP for acne should follow the guidelines for use of norgestimate and ethinyl estradiol tablets USP as an oral contraceptive. Consult the DOSAGE AND ADMINISTRATION section ( 2.1) for instructions.

Norgestimate and ethinyl estradiol tablets are available in blister cards. Each blister card contains 28 tablets in the following order:

• 7 light blue unscored round tablets debossed on one side with “12”; the tablet contains 0.18 mg Norgestimate and 0.035 mg ethinyl estradiol

• 7 medium blue unscored round tablets debossed on one side with “13”; the tablet contains 0.215 mg Norgestimate and 0.035 mg ethinyl estradiol

• 7 dark blue unscored round tablet debossed on one side with “14”; the tablet contains 0.25 mg Norgestimate and 0.035 mg ethinyl estradiol

• 7 white unscored round tablets (non-hormonal placebo) debossed on one side with “11”; the tablet contains inert ingredients

    •    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.

Impaired Liver Function

Norgestimate and Ethinyl Estradiol Tablets USP 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 USP 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.

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.

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.

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.

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.

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).

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, 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 USP (0.250 mg/0.035 mg) and 231 (4.8%) women discontinued Norgestimate and Ethinyl Estradiol Tablets USP, at least in part, due to bleeding or spotting. Based on data from the clinical trials, 14-34% of women using Norgestimate and Ethinyl Estradiol Tablets USP (0.250 mg/0.035 mg) experienced unscheduled bleeding per cycle in the first year; for Norgestimate and Ethinyl Estradiol Tablets USP, the respective numbers were 13-38%. The percent of women who experienced breakthrough/unscheduled bleeding tended to decrease over time.

Amenorrhea and Oligomenorrhea

Women who use norgestimate and ethinyl estradiol tablets may experience amenorrhea. Some women may experience amenorrhea or oligomenorrhea after discontinuation of COCs, especially when such a condition was pre-existent.

If scheduled (withdrawal) bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one or more active tablets or started taking them on a day later than she should have), consider the possibility of pregnancy at the time of the first missed period and take appropriate diagnostic measures. If the patient has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy.

Carefully observe women with a history of depression and discontinue norgestimate and ethinyl estradiol tablets if depression recurs to a serious degree.

Breast Cancer

Norgestimate and Ethinyl Estradiol Tablets USP is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications (4)].

Epidemiology studies have not found a consistent association between use of combined oral contraceptives (COCs) and breast cancer risk. Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer. However, some studies report a small

increase in the risk of breast cancer among current or recent users (<6 months since last use) and current users with longer duration of COC use [see Postmarketing Experience (6.2)].

Cervical Cancer

Some studies suggest that COC use has been associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.

The estrogen component of COCs may raise the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin. The dose of replacement thyroid hormone or cortisol therapy may need to be increased.

A woman who is taking COCs should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare.

In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while taking norgestimate and ethinyl estradiol tablets.

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)]

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 USP (0.250 mg/0.035 mg)

The safety of Norgestimate and Ethinyl Estradiol Tablets USP (0.250 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 USP (0.250 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 USP

The safety of Norgestimate and Ethinyl Estradiol Tablets USP 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 USP 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).

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 - 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 - 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 8-10 years of COC use.

Figure 1: Risk of Breast Cancer with Combined Oral Contraceptive Use

figure

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

Chest pain, asthenic conditions.

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.

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 and 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

    •    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.

The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

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)] .

Risk Summary

There is no use for contraception in pregnancy, therefore, Norgestimate and Ethinyl Estradiol Tablets USP 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.

Risk Summary

Contraceptive hormones and/or metabolites are present in human milk. CHCs can reduce milk production in breastfeeding females. This reduction can occur at any time but is less likely to occur once breastfeeding is well-established. When possible, advise the nursing female to use other forms of contraception until she discontinues breast-feeding. The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for Norgestimate and Ethinyl Estradiol Tablets USP and any potential adverse effects on the breast-fed child from Norgestimate and Ethinyl Estradiol Tablets USP or from the underlying maternal condition.

Safety and efficacy of norgestimate and ethinyl estradiol tablets have been established in women of reproductive age. Efficacy is expected to be the same for post  pubertal adolescents under the age of 18 and for users 18 years and older. Use of this product before menarche is not indicated.

There was no significant difference between norgestimate and ethinyl estradiol tablets and placebo in mean change in total lumbar spine (L1 to L4) and total hip bone mineral density between baseline and Cycle 13 in 123 adolescent females with anorexia nervosa in a double-blind, placebo-controlled, multicenter, one-year treatment duration clinical trial for the Intent To Treat (ITT) population.

Norgestimate and ethinyl estradiol tablets have not been studied in postmenopausal women and are not indicated in this population.

The pharmacokinetics of norgestimate and ethinyl estradiol tablets have not been studied in subjects with hepatic impairment. However, steroid hormones may be poorly metabolized in patients with hepatic impairment. 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. [see CONTRAINDICATIONS ( 4) AND WARNINGS AND PRECAUTIONS ( 5.2).]

The pharmacokinetics of norgestimate and ethinyl estradiol tablets has not been studied in women with renal impairment.

There have been no reports of serious ill effects from overdosage of oral contraceptives, including ingestion by children. Overdosage may cause withdrawal bleeding in females and nausea.

Each of the following products is a combination oral contraceptive containing the progestational compound norgestimate and the estrogenic compound ethinyl estradiol. Norgestimate is designated as (18,19-Dinor-17-pregn-4-en-20-yn-3-one,17-(acetyloxy)-13-ethyl, oxime,(17α) (+)-) and ethinyl estradiol is designated as (19-nor-17α-pregna,1,3,5(10)-trien-20-yne-3,17-diol).

• Each active light blue tablet contains 0.18 mg of norgestimate and 0.035 mg of ethinyl estradiol. Inactive ingredients include colloidal silicon dioxide, FD & C Blue No. 2 Aluminum Lake, lactose, magnesium stearate and pregelatinized corn starch.

• Each active medium blue tablet contains 0.215 mg of norgestimate and 0.035 mg of ethinyl estradiol. Inactive ingredients include colloidal silicon dioxide, FD & C Blue No. 2 Aluminum Lake, lactose, magnesium stearate and pregelatinized corn starch.

• Each active dark blue tablet contains 0.25 mg of norgestimate and 0.035 mg of ethinyl estradiol. Inactive ingredients include colloidal silicon dioxide, FD & C Blue No. 2 Aluminum Lake, lactose, magnesium stearate and pregelatinized corn starch.

• Each white placebo tablet contains only inert ingredients, as follows: lactose, magnesium stearate, microcryatalline cellulose and pre gelatinized corn starch.

structure

• Oral Contraception

COCs lower the risk of becoming pregnant primarily by suppressing ovulation.

• Acne

Acne is a skin condition with a multifactorial etiology, including androgen stimulation of sebum production. While the combination of ethinyl estradiol and norgestimate increases sex hormone-binding globulin (SHBG) and decreases free testosterone, the relationship between these changes and a decrease in the severity of facial acne in otherwise healthy women with this skin condition has not been established.

No specific pharmacodynamic studies were conducted with norgestimate and ethinyl estradiol tablets.

Absorption

Norgestimate (NGM) and EE are rapidly absorbed following oral administration. NGM is rapidly and completely metabolized by first pass (intestinal and/or hepatic) mechanisms to norelgestromin (NGMN) and norgestrel (NG), which are the major active metabolites of norgestimate.

Peak serum concentrations of NGMN and EE are generally reached by 2 hours after administration of norgestimate and ethinyl estradiol tablets. Accumulation following multiple dosing of the 250 mcg NGM / 35 mcg EE dose is approximately 2-fold for NGMN and EE compared with single dose administration. The pharmacokinetics of NGMN is dose-proportional following NGM doses of 180 mcg to 250 mcg. Steady-state concentration of EE is achieved by Day 7 of each dosing cycle. Steady-state concentrations of NGMN and NG are achieved by Day 21. Non-linear accumulation (approximately 8 fold) of NG is observed as a result of high-affinity binding to SHBG, which limits its biological activity (Table 3).

Food Effect:

The effect of food on the pharmacokinetics of norgestimate and ethinyl estradiol tablets has not been studied.

Distribution

NGMN and NG are highly bound (>97%) to serum proteins. NGMN is bound to albumin and not to SHBG, while NG is bound primarily to SHBG. EE is extensively bound (>97%) to serum albumin and induces an increase in the serum concentrations of SHBG.

Metabolism

NGM is extensively metabolized by first-pass mechanisms in the gastrointestinal tract and/or liver. NGM's primary active metabolite is NGMN. Subsequent hepatic metabolism of NGMN occurs and metabolites include NG, which is also active, and various hydroxylated and conjugated metabolites. Although NGMN and its metabolites inhibit a variety of P450 enzymes in human liver microsomes, under the recommended dosing regimen, the in vivo concentrations of NGMN and its metabolites, even at the peak serum levels, are relatively low compared to the inhibitory constant (K _i). EE is also metabolized to various hydroxylated products and their glucuronide and sulfate conjugates.

Excretion

The metabolites of NGMN and EE are eliminated by renal and fecal pathways. Following administration of ¹⁴C-norgestimate, 47% (45 to 49%) and 37% (16 to 49%) of the administered radioactivity was eliminated in the urine and feces, respectively. Unchanged NGM was not detected in the urine. In addition to 17-deacetyl norgestimate, a number of metabolites of NGM have been identified in human urine following administration of radiolabeled NGM. These include 18, 19-Dinor-17-pregn-4-en-20-yn-3-one,17-hydroxy-13-ethyl,(17α)-(-);18,19-Dinor-5β  17-pregnan-20-yn,3α,17β-dihydroxy-13-ethyl,(17α), various hydroxylated metabolites and conjugates of these metabolites.

[see WARNINGS AND PRECAUTIONS ( 5.2, 5.10)

In four clinical trials with norgestimate and ethinyl estradiol tablets, 4,756 women aged 15 to 41 years were studied for 24 cycles, providing a total of 45,244 cycles of exposure. The racial demographic was about 87 to 90% Caucasian, 6 to 10% African-American, with the remainder Asian (≤1%) or Other (2 to 5%). There were no exclusions on the basis of weight; the weight range for women treated was 80 to 310 lbs, with a mean weight of about 132 lbs. The pregnancy rate was approximately 1 pregnancy per 100 women-years.

Norgestimate and ethinyl estradiol tablets were evaluated for the treatment of acne vulgaris in two randomized, double-blind, placebo-controlled, multicenter, six- (28 day) cycle studies. Two hundred twenty- one patients received norgestimate and ethinyl estradiol tablets and 234 patients received placebo. Mean age at enrollment for both groups was 28 years. At the end of 6 months, the mean total lesion count changed from 55 to 31 (42% reduction) in patients treated with norgestimate and ethinyl estradiol tablets and from 54 to 38 (27% reduction) in patients similarly treated with placebo. Table 4 summarizes the changes in lesion count for each type of lesion. Based on the investigator's global assessment conducted at the final visit, patients treated with norgestimate and ethinyl estradiol tablets showed a statistically significant improvement in total lesions compared to those treated with placebo.

Norgestimate and Ethinyl Estradiol Tablets USP, (0.18 mg/0.035 mg, 0.215 mg/0.035 mg and 0.25 mg/0.035 mg) are available in a blister card (NDC 79929-009-05).

Each blister (28 tablets) contains in the following order:

• 7 light blue unscored round tablets debossed on one side with “12”; the tablet contains 0.18 mg norgestimate and 0.035 mg ethinyl estradiol

• 7 medium blue unscored round tablets debossed on one side with “13”; the tablet contains 0.215 mg norgestimate and 0.035 mg ethinyl estradiol

• 7 dark blue unscored round tablet debossed on one side with “14”; the tablet contains 0.25 mg norgestimate and 0.035 mg ethinyl estradiol

• 7 white unscored round tablets (non-hormonal placebo) debossed on one side with “11”; the tablet contains inert ingredients

Norgestimate and Ethinyl Estradiol Tablets USP, (0.18 mg/0.035 mg, 0.215 mg/0.035 mg and 0.25 mg/0.035 mg) are packaged in a carton containing 3 blister cards. VERIDATE Tablet Dispenser is not applicable for the ANDA product.

• Store at 20–25°C (68–77°F); excursions permitted to 15° to 30°C (59° to 86°F).
• Protect from light.
• Keep out of the reach of children.

See FDA-approved patient labeling (Patient Information and Instructions for Use).

Counsel patients about the following information:

Cigarette smoking increases the risk of serious cardiovascular events from COC use, and that women who are over 35 years old and smoke should not use COCs [see Boxed Warning].
Increased risk of VTE compared to non-users of COCs is greatest after initially starting a COC or restarting (following a 4-week or greater pill-free interval) the same or a different COC [see Warnings and Precautions (5.1)].
Norgestimate and Ethinyl Estradiol Tablets USP do not protect against HIV infection (AIDS) and other sexually transmitted infections.
Norgestimate and Ethinyl Estradiol Tablets USP are not to be used during pregnancy; if pregnancy occurs during use of Norgestimate and Ethinyl Estradiol Tablets USP instruct the patient to stop further use [see Use in Specific Populations (8.1)]].
Take one tablet daily by mouth at the same time every day. Instruct patients what to do in the event tablets are missed [see Dosage and Administration (2.1, 2.2)].
Use a back-up or alternative method of contraception when enzyme inducers are used with Norgestimate and Ethinyl Estradiol Tablets USP [see Drug Interactions (7.1)].
COCs may reduce breast milk production; this is less likely to occur if breastfeeding is well established [see Use in Specific Populations (8.2)].
Women who start COCs postpartum, and who have not yet had a period, should use an additional method of contraception until they have taken an active tablet for 7 consecutive days [see Dosage and Administration (2.1)].
Amenorrhea may occur. Consider pregnancy in the event of amenorrhea at the time of the first missed period. Rule out pregnancy in the event of amenorrhea in two or more consecutive cycles [see Warnings and Precautions (5.8)].

Manufactured for:

Naari Pte Limited

36 Robinson Road, #13-06

City House, Singapore 068877

Instructions for Use

Norgestimate and Ethinyl Estradiol Tablets USP

(nor JES ti mate and ETH in il es tra DYE ole)

Important Information about taking Norgestimate and Ethinyl Estradiol Tablets USP

• Take 1 pill every day at the same time. Take the pills in the order directed on your pill dispenser.

• Do not skip your pills, even if you do not have sex often. If you miss pills (including starting the pack late) you could get pregnant. The more pills you miss, the more likely you are to get pregnant.

• If you have trouble remembering to take Norgestimate and Ethinyl Estradiol Tablets USP, talk to your healthcare provider. When you first start taking Norgestimate and Ethinyl Estradiol Tablets USP, spotting or light bleeding in between your periods may occur. Contact your healthcare provider if this does not go away after a few months.

• You may feel sick to your stomach (nauseous), especially during the first few months of taking Norgestimate and Ethinyl Estradiol Tablets USP. If you feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If your nausea does not go away, call your healthcare provider.

• Missing pills can also cause spotting or light bleeding, even when you take the missed pills later. On the days you take 2 pills to make up for missed pills (see What should I do if I miss any Norgestimate and Ethinyl Estradiol Tablets USP pills? below), you could also feel a little sick to your stomach.

• It is not uncommon to miss a period. However, if you miss a period and have not taken Norgestimate and Ethinyl Estradiol Tablets USP according to directions, or miss 2 periods in a row, or feel like you may be pregnant, call your healthcare provider. If you have a positive pregnancy test, you should stop taking Norgestimate and Ethinyl Estradiol Tablets USP.

• If you have vomiting or diarrhea within 3–4 hours of taking your pill, take another pill of the same color from your extra pill blister pack. If you do not have an extra pill blister pack, take the next pill in your pill blister pack. Continue taking all your remaining pills in order. Start the first pill of your next pill blister pack the day after finishing your current pill blister pack. This will be 1 day earlier than originally scheduled. Continue on your new schedule.

• If you have vomiting or diarrhea for more than 1 day, your birth control pills may not work as well. Use an additional birth control method, like condoms and a spermicide, until you check with your healthcare provider.

• Stop taking Norgestimate and Ethinyl Estradiol Tablets USP at least 4 weeks before you have major surgery and do not restart after the surgery without asking your healthcare provider. Be sure to use other forms of contraception (like condoms and spermicide) during this time period.

Before you start taking Norgestimate and Ethinyl Estradiol Tablets USP:

• Decide what time of day you want to take your pill. It is important to take it at the same time every day and in the order as directed on your pill dispenser.

• Have backup contraception (condoms and spermicide) available and if possible, an extra full pack of pills as needed.

When should I start taking Norgestimate and Ethinyl Estradiol Tablets USP? If you start taking Norgestimate and Ethinyl Estradiol Tablets USP and you have not used a hormonal birth control method before:

• There are 2 ways to start taking your birth control pills. You can either start on a Sunday (Sunday Start) or on the first day (Day 1) of your natural menstrual period (Day 1 Start). Your healthcare provider should tell you when to start taking your birth control pill.

• If you use the Sunday Start, use non-hormonal back-up contraception such as condoms and spermicide for the first 7 days that you take Norgestimate and Ethinyl Estradiol Tablets USP. You do not need back-up contraception if you use the Day 1 Start.

If you start taking Norgestimate and Ethinyl Estradiol Tablets USP and you are switching from another birth control pill:

• Start your new Norgestimate and Ethinyl Estradiol Tablets USP pack on the same day that you would start the next pack of your previous birth control method.

• Do not continue taking the pills from your previous birth control pack.

If you start taking Norgestimate and Ethinyl Estradiol Tablets USP and previously used a vaginal ring or transdermal patch:

• Start using Norgestimate and Ethinyl Estradiol Tablets USP on the day you would have reapplied the next ring or patch. If you start taking Norgestimate and Ethinyl Estradiol Tablets USP and you are switching from a progestin-only method such as an implant or injection:

• Start taking Norgestimate and Ethinyl Estradiol Tablets USP on the day of removal of your implant or on the day when you would have had your next injection.

If you start taking Norgestimate and Ethinyl Estradiol Tablets USP and you are switching from an intrauterine device or system (IUD or IUS):

• Start taking Norgestimate and Ethinyl Estradiol Tablets USP on the day of removal of your IUD or IUS.

• You do not need back-up contraception if your IUD or IUS is removed on the first day (Day 1) of your period. If your IUD or IUS is removed on any other day, use non hormonal back-up contraception such as condoms and spermicide for the first 7 days that you take Norgestimate and Ethinyl Estradiol Tablets USP.

Keep a calendar to track your period:

If this is the first time you are taking birth control pills, read, "When should I start taking Norgestimate and Ethinyl Estradiol Tablets USP?" above. Follow these instructions for either a Sunday Start or a Day 1 Start.

Sunday Start:

You will use a Sunday Start if your healthcare provider told you to take your first pill on a Sunday.

• Take pill 1 on the Sunday after your period starts.

• If your period starts on a Sunday, take pill "1" that day and refer to Day 1 Start instructions below.

• Take 1 pill every day in the order on the blister pack at the same time each day for 28 days.

• After taking the last pill on Day 28 from the blister pack, start taking the first pill from a new pack, on the same day of the week as the first pack (Sunday). Take the first pill in the new pack whether or not you are having your period

• Use non-hormonal back-up contraception such as condoms and spermicide for the first 7 days of the first cycle that you take Norgestimate and Ethinyl Estradiol Tablets USP. Day 1 Start: You will use a Day 1 Start if your doctor told you to take your first pill (Day 1) on the first day of your period.

• Take 1 pill every day in the order of the blister pack, at the same time each day, for 28 days.

• After taking the last pill on Day 28 from the blister pack, start taking the first pill from a new pack, on the same day of the week as the first pack. Take the first pill in the new pack whether or not you are having your period.

Norgestimate and Ethinyl Estradiol Tablets USP come in a blister pack. Read the instructions below for using the blister pack.

Instructions for using your blister pack:

Norgestimate and Ethinyl Estradiol Tablets USP, (0.18 mg/0.035 mg, 0.215 mg/0.035 mg and 0.25 mg/0.035 mg)

figure 1

• Norgestimate and Ethinyl Estradiol Tablets USP, (0.18 mg/0.035 mg, 0.215 mg/0.035 mg and 0.25 mg/0.035 mg)

o 7 light blue pills with hormones for Days 1 to 7.

o 7 medium blue pills with hormones Days 8 to 14. o 7 dark blue pills with hormones for Day 15 to 21.

o 7 white pills (without hormones) for Days 22 to 28.

Step 1. SET THE DAY TO START YOUR BLISTER PACK

Sunday Start:

o Norgestimate and Ethinyl Estradiol Tablets USP - the first light blue “active” tablet should be taken on the first Sunday after the patient’s menstrual period begins. If your period begins on Sunday, start the pack that same day.

Day 1 Start:

Pick the day label strip that starts with the first day of your period (this is the day you start bleeding or spotting, even it is almost midnight when the bleeding begins). Place this day label strip on the blister pack over the area that has the days of the week (starting with Sunday) printed on the blister. See Figure A.

blister 2

Step 2. You are ready to take pill “1”. You should always begin your pill cycle with pill “1” located in the top row of the blister. See Figure B. Take pills in the direction of the arrows (from left to right) each week.

blister 3

Step 3. Remove pill "1" by pushing down on the pill. The pill will come out through the foil in the back of the blister.

Step 4. Swallow the pill. You will take 1 pill every day, at the same time each day.

Step 5. Wait 24 hours to take your next pill. To take pill "2," push down on the next pill in the blister following the direction of the arrows. Continue to take 1 pill each day until all the pills have been taken.

Step 6. Take your pill at the same time every day. It is important to take the correct pill each day and not miss any pills. To help you remember, take your pill at the same time as another daily activity, like turning off your alarm clock or brushing your teeth.

Step 7. Start a new blister pack. You will start a new blister pack on the first day after pill "28".

Step 8. Remember to take your first pill in every blister pack on the same day of the week, no matter when your next period starts.

What should I do if I miss any Norgestimate and Ethinyl Estradiol Tablets USP pills? If you miss 1 pill in Weeks 1, 2, or 3, follow these steps:

• Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day.

• Then continue taking 1 pill every day until you finish the pack.

• You do not need to use a back-up birth control method if you have sex. If you miss 2 pills in Week 1 or Week 2 of your pack, follow these steps:

• Take the 2 missed pills as soon as possible and the next 2 pills the next day.

• Then continue to take 1 pill every day until you finish the pack.

• Use a non-hormonal birth control method (such as a condom and spermicide) as a back-up if you have sex during the first 7 days after missing your pills. If you miss 2 pills in a row in Week 3, or you miss 3 or more pills in a row during Weeks 1, 2, or 3 of the pack, follow these steps:

• If you are a Day 1 Starter:

o Throw out the rest of the pill pack and start a new pack that same day.

o You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare provider because you might be pregnant.

o You could become pregnant if you have sex during the first 7 days after you restart your pills. You MUST use a non-hormonal birth control method (such as a condom and spermicide) as a back-up if you have sex during the first 7 days after you restart your pills.

If you are a Sunday Starter:

o Keep taking 1 pill every day until Sunday. On Sunday, throw out the rest of the pack and start a new pack of pills that same day. o Use a non-hormonal birth control method (such as a condom and spermicide) as a backup if you have sex during the first 7 days after you restart your pills.

If you have any questions or are unsure about the information in this leaflet, call your healthcare provider.

Manufactured for:

Naari Pte Limited

36 Robinson Road,#13-06

City House, Singapore 068877

This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration.

Revised 06/2023