These highlights do not include all the information needed to use NORGESTIMATE AND ETHINYL ESTRADIOL TABLETS safely and effectively. See full prescribing information for NORGESTIMATE AND ETHINYL ESTRADIOL TABLETS.NORGESTIMATE and ETHINYL ESTRADIOL tablets, for oral useInitial U.S. Approval: 1989

WARNING: CIGARETTE SMOKING and SERIOUS CARDIOVASCULAR EVENTS

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)].

1 INDICATIONS AND USAGE

1.1 Oral Contraception

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

2 DOSAGE AND ADMINISTRATION

2.1 How to Start Norgestimate and Ethinyl Estradiol Tablets

Norgestimate and ethinyl estradiol tablets are dispensed in a blister pack [see How Supplied/Storage and Handling (16)]. Norgestimate and ethinyl estradiol tablets may be started using either a Day 1 start or a Sunday start (see Table 1). For the first cycle of a Sunday Start regimen, an additional method of contraception should be used until after the first 7 consecutive days of administration.

2.2 How to Take Norgestimate and Ethinyl Estradiol Tablets

Table 1: Instructions for Administration of norgestimate and ethinyl estradiol tablets

Complete instructions to facilitate patient counseling on proper tablet usage are located in the FDA-Approved Patient Labeling.

Starting Norgestimate and Ethinyl Estradiol Tablets after Abortion or Miscarriage

First-trimester

Second-trimester

Starting Norgestimate and Ethinyl Estradiol Tablets after Childbirth

Blister Card Tablet Dispenser

SET THE DAY:Day 1 Start

Sunday Start

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

2.3 Missed Tablets

Table 2: Instructions for Missed Norgestimate and Ethinyl Estradiol Tablets

2.4 Advice in Case of Gastrointestinal Disturbances

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].

3 DOSAGE FORMS AND STRENGTHS

Norgestimate and Ethinyl Estradiol Tablets USP are available in a blister card. Each blister card contains 28 tablets in the following order:

• •7 white to off-white, round, biconvex, film coated tablets, debossed with ‘C8’ on one side. Each tablet contains 0.18 mg norgestimate, USP and 0.025 mg ethinyl estradiol, USP.
• •7 light blue, round, biconvex, film coated tablets, debossed with ‘C7’ on one side. Each tablet contains 0.215 mg norgestimate, USP and 0.025 mg ethinyl estradiol, USP
• •7 blue, round, biconvex, film coated tablets, debossed with ‘C6’ on one side. Each tablet contains 0.25 mg norgestimate, USP and 0.025 mg ethinyl estradiol, USP.
• •7 green to dark green, round, biconvex, film coated tablets, debossed with ‘C9’ on one side. Each tablet contains inert ingredients.

4 CONTRAINDICATIONS

Do not prescribe norgestimate and ethinyl estradiol tablets to women who are known to have the following conditions:

• •A high risk of arterial or venous thrombotic diseases. Examples include women who are known to:∘Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions (5.1)]∘Have deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings and Precautions (5.1)]∘Have inherited or acquired hypercoagulopathies [see Warnings and Precautions (5.1)]∘Have cerebrovascular disease [see Warnings and Precautions (5.1)]∘Have coronary artery disease [see Warnings and Precautions (5.1)]∘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)]∘Have uncontrolled hypertension [see Warnings and Precautions (5.4)]∘Have diabetes mellitus with vascular disease [see Warnings and Precautions (5.6)]∘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)]
• •Pregnancy, because there is no reason to use COCs during pregnancy [see Warnings and Precautions (5.9) and Use in Specific Populations (8.1)]
• •Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past [see Warnings and Precautions (5.11)]
• •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)]

5 WARNINGS AND PRECAUTIONS

5.1 Thromboembolic Disorders and Other Vascular Problems

• •Stop norgestimate and ethinyl estradiol tablets if an arterial thrombotic event or venous thrombotic (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

Do not use norgestimate and ethinyl estradiol tablets 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. 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.

5.7 Headache

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).

5.8 Bleeding 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 the clinical trial of norgestimate and ethinyl estradiol tablets, the frequency and duration of unscheduled bleeding and/or spotting was assessed in 1,673 women (11,015 evaluable cycles). A total of 3 (0.2%) women discontinued norgestimate and ethinyl estradiol tablets, at least in part, due to bleeding or spotting. Based on data from the clinical trials, 7 to 17% of women using norgestimate and ethinyl estradiol tablets experienced unscheduled bleeding per cycle in the first year. The percent of women who experienced 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.

5.9 COC Use Before or During Early Pregnancy

Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned, when oral contraceptives are taken inadvertently during early pregnancy. Discontinue norgestimate and ethinyl estradiol tablets use if pregnancy is confirmed.

Administration of COCs to induce withdrawal bleeding should not be used as a test for pregnancy [see Use in Specific Populations (8.1)].

5.10 Depression

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

5.11 Carcinoma of Breast and Cervix

• •Norgestimate and ethinyl estradiol tablets are contraindicated in women who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications (4)].There is substantial evidence that COCs do not increase the incidence of breast cancer. Although some past studies have suggested that COCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings.
• •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.

5.12 Effect on Binding Globulins

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.

5.13 Monitoring

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.

5.14 Hereditary Angioedema

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

5.15 Chloasma

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.

6 ADVERSE REACTIONS

The following serious adverse reactions with the use of COCs are discussed elsewhere in labeling:

Adverse reactions commonly reported by COC users are:

• •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)]

6.1 Clinical 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 tablets was evaluated in 1,723 subjects who participated in a randomized, partially blinded, multicenter, active-controlled clinical trial of norgestimate and ethinyl estradiol tablets for contraception. This trial examined healthy, nonpregnant, volunteers aged 18 to 45 (nonsmoker if 35 to 45 years of age), who were sexually active with regular coitus. Subjects were followed for up to 13 28-day cycles.

Common Adverse Reactions (≥ 2% of subjects): The most common adverse reactions reported by at least 2% of the 1,723 women using the 28-day regimen were the following in order of decreasing incidence: headache/migraine (30.5%), nausea/vomiting (16.3%); breast issues (including tenderness, pain, enlargement, swelling, discharge, discomfort, cyst, and nipple pain) (10.3%), abdominal pain (9.2%), menstrual disorders (including dysmenorrhea, menstrual discomfort, menstrual disorder) (9.2%), mood disorders (including depression, mood altered, mood swings and depressed mood) (7.6%); acne (5.1%), vulvovaginal infection (3.5%), abdominal distension (2.8%), weight increased (2.4%), fatigue (2.1%).

Adverse Reactions Leading to Study Discontinuation: In the clinical trial of norgestimate and ethinyl estradiol tablets 4% of subjects discontinued the trial due to an adverse reaction. The most common adverse reactions leading to discontinuation were headache/migraine (1.2%), nausea/vomiting (0.7%), cervical dysplasia (0.7%), abdominal pain (0.4%), ovarian cyst (0.3%), acne (0.2%), flatulence (0.2%) and depression (0.2%).

Serious Adverse Reactions: carcinoma of the cervix in situ (1 subject) and cervical dysplasia (1 subject).

6.2 Postmarketing 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 (Including 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 vascular thrombosis, hot flush

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

7 DRUG 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.

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. Some drugs or herbal products that may decrease the effectiveness of COCs include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant and products containing St. John’s wort. Interactions between COCs and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with COCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability.

Colesevelam: Colesevelam, a bile acid sequestrant, given together with a COC, has been shown to significantly decrease the AUC of ethinyl estradiol (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 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

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]).

7.2 Effects 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.

7.3 Interference 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.

7.4 Concomitant 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)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

There is little or no increased risk of birth defects in women who inadvertently use COCs during early 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 low dose COCs prior to conception or during early pregnancy.

Do not administer COCs to induce withdrawal bleeding as a test for pregnancy. Do not use COCs during pregnancy to treat threatened or habitual abortion.

8.3 Nursing Mothers

Advise the nursing mother to use other forms of contraception, when possible, until she has weaned her child. COCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk.

8.4 Pediatric Use

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.

8.5 Geriatric Use

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

8.6 Hepatic Impairment

The pharmacokinetics of norgestimate and ethinyl estradiol tablets has 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)].

8.7 Renal Impairment

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

10 OVERDOSAGE

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.

11 DESCRIPTION

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

• •Each active white to off-white tablet contains 0.18 mg of norgestimate, USP and 0.025 mg of ethinyl estradiol, USP. Inactive ingredients include croscarmellose sodium, hypromellose, lactose monohydrate, microcrystalline cellulose, magnesium stearate, povidone K-30, polyethylene glycol, polusorbate 80, talc, titanium dioxide and vitamin E.
• •Each active light blue tablet contains 0.215 mg of norgestimate, USP and 0.025 mg of ethinyl estradiol, USP. Inactive ingredients include croscarmellose sodium, FD & C blue #2, FD & C blue #1, FD & C red #40, hypromellose, lactose monohydrate, microcrystalline cellulose, magnesium stearate, povidone K-30, polyethylene glycol, polusorbate 80, talc, titanium dioxide and vitamin E.
• •Each active blue tablet contains 0.25 mg of norgestimate, USP and 0.025 mg of ethinyl estradiol, USP. Inactive ingredients include croscarmellose sodium, FD & C Blue #2, FD & C blue #1, FD & C red #40, hypromellose, lactose monohydrate, microcrystalline cellulose, magnesium stearate, povidone K-30, polyethylene glycol, polysorbate 80, talc, titanium dioxide and vitamin E.
• •Each green to dark green placebo tablet contains only inert ingredients, as follows: anhydrous lactose, FD&C Blue #2, hypromellose, iron oxide yellow, lactose monohydrate, microcrystalline cellulose, magnesium stearate, polacrilin potassium, polyethylene glycol, polysorbate 80, talc, and titanium dioxide.
•  

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

COCs lower the risk of becoming pregnant primarily by suppressing ovulation. Other possible mechanisms may include cervical mucus changes that inhibit sperm penetration and endometrial changes that reduce the likelihood of implantation.

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

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 NGM.

Mean pharmacokinetic parameters for NGMN, NG and EE during three cycles of administration of norgestimate and ethinyl estradiol tablets are summarized in Table 3.

Peak serum concentrations of NGMN and EE were generally reached by 2 hours after administration of norgestimate and ethinyl estradiol tablets. Accumulation following multiple dosing of the 0.18 mg NGM / 0.025 mg EE dose is approximately 1.5 to 2 fold for NGMN and approximately 1.5 fold for EE compared with single dose administration, in agreement with that predicted based on linear kinetics of NGMN and EE. The pharmacokinetics of NGMN is dose proportional following NGM doses of 0.18 to 0.25 mg. Steady-state conditions for NGMN following each NGM dose and for EE were achieved during the three cycle study. Non-linear accumulation (4.5 to 14.5 fold) of NG was observed as a result of high affinity binding to SHBG, which limits its biological activity.

Table 3 Summary of NGMN, NG and EE pharmacokinetic parameters.

1 NGMN = Norelgestromin, NG = norgestrel, EE = ethinyl estradiol

2 Cmax = peak serum concentration, tmax = time to reach peak serum concentration, AUC0-24h = area under serum concentration vs. time curve from 0 to 24 hours, t1/2 = elimination half-life.

3 units for all analytes; h = hours

4 units for NGMN and NG – Cmax = ng/mL, AUC0-24h = h•ng/mL

5 units for EE only – Cmax = pg/mL, AUC0-24h = h•pg/mL

NC = not calculated

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 (Ki). EE is also metabolized to various hydroxylated products and their glucuronide and sulfate conjugates.

Excretion

Following 3 cycles of administration of norgestimate and ethinyl estradiol tablets, the mean (± SD) elimination half-life values, at steady-state, for NGMN, NG and EE were 28.1 (± 10.6) hours, 36.4 (± 10.2) hours and 17.7 (± 4.4) hours, respectively (Table 2). The metabolites of NGMN and EE are eliminated by renal and fecal pathways.

Use in Specific Populations

Effects of Body Weight, Body Surface Area, and Age

The effects of body weight, body surface area, age and race on the pharmacokinetics of NGMN, NG and EE were evaluated in 79 healthy women using pooled data following single dose administration of NGM 0.18 or 0.25 mg / EE 0.025 mg tablets in four pharmacokinetic studies. Increasing body weight and body surface area were each associated with decreases in Cmax and AUC0-24h values for NGMN and EE and increases in CL/F (oral clearance) for EE. Increasing body weight by 10 kg is predicted to reduce the following parameters: NGMN Cmax by 9% and AUC0-24h by 19%, NG Cmax by 12% and AUC0-24h by 46%, EE Cmax by 13% and AUC0-24h by 12%. These changes were statistically significant. Increasing age was associated with slight decreases (6% with increasing age by 5 years) in Cmax and AUC0-24h for NGMN and were statistically significant, but there was no significant effect for NG or EE. Only a small to moderate fraction (5 to 40%) of the overall variability in the pharmacokinetics of NGMN and EE following norgestimate and ethinyl estradiol tablets may be explained by any or all of the above demographic parameters.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

[See Warnings and Precautions (5.2, 5.11) and Use in Specific Populations (8.1).]

14 CLINICAL STUDIES

In an active controlled clinical trial lasting 12 months, 1,673 women, 18 to 45 years old completed 11,003 cycles of norgestimate and ethinyl estradiol tablets use and a total of 20 pregnancies were reported in norgestimate and ethinyl estradiol tablets users. The racial demographic of those treated with norgestimate and ethinyl estradiol tablets was: Caucasian (86%), African-American (6%), Asian (2%), and Other (6%). There were no exclusions on the basis of weight; the weight range for women treated was 90 to 240 lbs, with a mean weight of about 142 lbs. The pregnancy rate in women aged 18 to 35 years was approximately 2.6 pregnancies per 100 woman-years of use.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Norgestimate and Ethinyl Estradiol Tablets USP are available as blister card pill dispensers (NDC 68462-719-84). Each blister card contains 28 tablets in the following order:

NDC 68462-719-29 1 carton containing 3 blister cards of 28 tablets

• •7 white to off-white, round, biconvex, film coated tablets (active), debossed with ‘C8’ on one side. Each tablet contains 0.18 mg norgestimate, USP and 0.025 mg ethinyl estradiol, USP.
• •7 light blue, round, biconvex, film coated tablets (active), debossed with ‘C7’ on one side. Each tablet contains 0.215 mg norgestimate, USP and 0.025 mg ethinyl estradiol, USP.
• •7 blue, round, biconvex, film coated tablets (active), debossed with ‘C6’ on one side. Each tablet contains 0.25 mg norgestimate, USP and 0.025 mg ethinyl estradiol, USP.
• •7 green to dark green, round, biconvex, film coated tablets (non-hormonal placebo), debossed with ‘C9’ on one side. Each tablet contains inert ingredients.

16.2 Storage Conditions

• •Store at 20 to 25°C (68 to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]
• •Keep out of reach of children.

17 PATIENT COUNSELING INFORMATION

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

Counsel patients about the following information:

Manufactured by:

Glenmark Pharmaceuticals Ltd.Colvale-Bardez, Goa 403 513, India

Manufactured for:

Glenmark Pharmaceuticals Inc., USAMahwah, NJ 07430

Questions? 1 (888)721-7115www.glenmarkpharma.com/usa

September 2017

• •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 do not protect against HIV infection (AIDS) and other sexually transmitted infections.
• •Norgestimate and ethinyl estradiol tablets are not to be used during pregnancy; if pregnancy occurs during use of norgestimate and ethinyl estradiol tablets instruct the patient to stop further use [see Warnings and Precautions (5.9)].
• •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 (2.2)].
• •Use a back-up or alternative method of contraception when enzyme inducers are used with norgestimate and ethinyl estradiol tablets [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 (8.3)].
• •Women who start COCs postpartum; and who have not yet had a period, should use an additional method of contraception until they have taken a white to off-white tablet for 7 consecutive days [see Dosage and Administration (2.2)].
• •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)].

Patient Information

Norgestimate and Ethinyl Estradiol (nor eth IN drone/ETH in il ess tra DYE ole) Tablets

What is the most important information I should know about norgestimate and ethinyl estradiol tablets?

Do not use norgestimate and ethinyl estradiol tablets if you smoke cigarettes and are over 35 years old. Smoking increases your risk of serious cardiovascular side effects from hormonal birth control pills, including death from heart attack, blood clots or stroke. This risk increases with age and the number of cigarettes you smoke.

What are norgestimate and ethinyl estradiol tablets?

Norgestimate and ethinyl estradiol tablets are birth control pills (oral contraceptive) used by women to prevent pregnancy.

How do norgestimate and ethinyl estradiol tablets work for contraception?

Your chance of getting pregnant depends on how well you follow the directions for taking your birth control pills. The better you follow the directions, the less chance you have of getting pregnant.

Based on the results from the clinical study, about 3 out of 100 women may get pregnant during the first year they use norgestimate and ethinyl estradiol tablets.

The following chart shows the chance of getting pregnant for women who use different methods of birth control. Each box on the chart contains a list of birth control methods that are similar in effectiveness. The most effective methods are at the top of the chart. The box on the bottom of the chart shows the chance of getting pregnant for women who do not use birth control and are trying to get pregnant.

Who should not take norgestimate and ethinyl estradiol tablets?

Do not take norgestimate and ethinyl estradiol tablets if you:

If any of these conditions happen while you are taking norgestimate and ethinyl estradiol tablets, stop taking norgestimate and ethinyl estradiol tablets right away and talk to your healthcare provider. Use non-hormonal contraception when you stop taking norgestimate and ethinyl estradiol tablets.

What should I tell my healthcare provider before taking norgestimate and ethinyl estradiol tablets?

Tell your healthcare provider if you:

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements.

Norgestimate and ethinyl estradiol tablets may affect the way other medicines work, and other medicines may affect how well norgestimate and ethinyl estradiol tablets work.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

How should I take norgestimate and ethinyl estradiol tablets?

Read the Instructions for Use at the end of this Patient Information.

What are the possible serious side effects of norgestimate and ethinyl estradiol tablets?

Serious blood clots can happen especially if you smoke, are obese, or are older than 35 years of age. Serious blood clots are more likely to happen when you:

Call your healthcare provider or go to a hospital emergency room right away if you have:

Other serious side effects include:

What are the most common side effects of norgestimate and ethinyl estradiol tablets?

These are not all the possible side effects of norgestimate and ethinyl estradiol tablets. For more information, ask your healthcare provider or pharmacist.

You may report side effects to the FDA at 1-800-FDA-1088.

What else should I know about taking norgestimate and ethinyl estradiol tablets?

How should I store norgestimate and ethinyl estradiol tablets?

General information about the safe and effective use of norgestimate and ethinyl estradiol tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use norgestimate and ethinyl estradiol tablets for a condition for which they were not prescribed. Do not give norgestimate and ethinyl estradiol tablets to other people, even if they have the same symptoms that you have.

This Patient Information summarizes the most important information about norgestimate and ethinyl estradiol tablets. You can ask your pharmacist or healthcare provider for information about norgestimate and ethinyl estradiol tablets that is written for health professionals.

For more information, call Glenmark Pharmaceuticals Inc., USA at 1(888)721-7115.

Do birth control pills cause cancer?

Birth control pills do not seem to cause breast cancer. However, if you have breast cancer now, or have had it in the past, do not use birth control pills because some breast cancers are sensitive to hormones. Women who use birth control pills may have a slightly higher chance of getting cervical cancer. However, this may be due to other reasons such as having more sexual partners.

What if I want to become pregnant?

You may stop taking the pill whenever you wish. Consider a visit with your healthcare provider for a pre-pregnancy checkup before you stop taking the pill.

What should I know about my period when taking norgestimate and ethinyl estradiol tablets?

Your periods may be lighter and shorter than usual. Some women may miss a period. Irregular vaginal bleeding or spotting may happen while you are taking norgestimate and ethinyl estradiol tablets, especially during the first few months of use. This usually is not a serious problem. It is important to continue taking your pills on a regular schedule to prevent a pregnancy.

What are the ingredients in norgestimate and ethinyl estradiol tablets?

Active ingredients: Each white to off-white, light blue, and blue pill contains norgestimate and ethinyl estradiol

Inactive ingredients:White to off-white pills: croscarmellose sodium, hypromellose, lactose monohydrate, microcrystalline cellulose, magnesium stearate, povidone K-30, polyethylene glycol, polysorbate 80, talc, titanium dioxide and vitamin E

Light blue pills: croscarmellose sodium, FD&C blue #2, FD&C blue #1, FD&C red #40, hypromellose, lactose monohydrate, microcrystalline cellulose, magnesium stearate, povidone K-30, polyethylene glycol, polysorbate 80, talc, titanium dioxide and vitamin E.

Blue pills: croscarmellose sodium, FD&C blue #2, FD&C blue #1, FD&C red #40, hypromellose, lactose monohydrate, microcrystalline cellulose, magnesium stearate, povidone K-30, polyethylene glycol, polysorbate 80, talc, titanium dioxide and vitamin E.

Green to dark green pills: anhydrous lactose, FD&C blue #2, hypromellose, iron oxide yellow, lactose monohydrate, microcrystalline cellulose, magnesium stearate, polacrilin potassium, polyethylene glycol, polysorbate 80, talc, and titanium dioxide.

Instructions For UseNorgestimate and Ethinyl Estradiol (nor eth IN drone/ETH in il ess tra DYE ole) Tablets

Important Information about taking norgestimate and ethinyl estradiol tablets

Before you start taking norgestimate and ethinyl estradiol tablets:

When should I start taking norgestimate and ethinyl estradiol tablets?

If you start taking norgestimate and ethinyl estradiol tablets and you have not used a hormonal birth control method before:

If you start taking norgestimate and ethinyl estradiol tablets and you are switching from another birth control pill:

If you start taking norgestimate and ethinyl estradiol tablets and previously used a vaginal ring or transdermal patch:

If you start taking norgestimate and ethinyl estradiol tablets and you are switching from a progestin-only method such as an implant or injection:

If you start taking norgestimate and ethinyl estradiol tablets and you are switching from an intrauterine device or system (IUD or IUS):

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?” 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.

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.

Norgestimate and ethinyl estradiol tablets come in a blister card pill dispenser. Read the instructions below for using your blister card pill dispenser.

Instructions for using your blister card pill dispenser:

Step 1. Starting your pills

Sunday Start:Remove the first white to off-white pill at the top of the dispenser (Sunday) by pressing the pill through the hole in the bottom of the dispenser. See Figure B. The pill will come out through a hole in the back of the blister card.

Day 1 Start:

Step 2. Wait 24 hours to take your next pill. Continue taking 1 pill every day from the blister card as indicated by the arrows and week numbers on the blister card until no pills remain in the first 3 rows of the blister card.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 3. The next day take a green to dark green pill from the last row of the blister card. See Figure E.

What should I do if I miss any norgestimate and ethinyl estradiol tablets pills?

If you miss 1 pill in Weeks 1, 2, or 3, follow these steps:

If you miss 2 pills in Week 1 or Week 2 of your pack, follow these steps:

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

Manufactured by:

Glenmark Pharmaceuticals Ltd.Colvale-Bardez, Goa 403 513, India

Manufactured for:

Glenmark Pharmaceuticals Inc., USAMahwah, NJ 07430

Questions? 1 (888)721-7115www.glenmarkpharma.com/usa

August 2017

• •smoke and are over 35 years of age
• •had blood clots in your arms, legs, lungs, or eyes
• •had a problem with your blood that makes it clot more than normal
• •have certain heart valve problems or irregular heart beat that increases your risk of having blood clots
• •had a stroke
• •had a heart attack
• •have high blood pressure that cannot be controlled by medicine
• •have diabetes with kidney, eye, nerve, or blood vessel damage
• •have certain kinds of severe migraine headaches with aura, numbness, weakness or changes in vision, or any migraine headaches if you are over 35 years of age
• •have liver problems, including liver tumors
• •have any unexplained vaginal bleeding
• •are pregnant
• •had breast cancer or any cancer that is sensitive to female hormones

norgestimate and ethinyl estradiol