1.1 Oral Contraceptive

2.1 How to Start Mono-Linyah

2.2 How to Take Mono-Linyah

First-trimester

• After a first-trimester abortion or miscarriage, Mono-Linyah may be started immediately. An additional method of contraception is not needed if Mono-Linyah is started immediately.
• If Mono-Linyah 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 Mono-Linyah.

• Do not start until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. Start Mono-Linyah, 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 Mono-Linyah.[see Contraindications (4), Warnings and Precautions (5.1), and FDA-Approved Patient Labeling.]

• Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. Start contraceptive therapy with Mono-Linyah following the instructions in Table 1 for women not currently using hormonal contraception.
• Mono-Linyah is not recommended for use in lactating women[see Use in Specific Populations (8.3)] .
• If the woman has not yet had a period postpartum, consider the possibility of ovulation and conception occurring prior to use of Mono-Linyah.[See Contraindications (4), Warnings and Precautions (5.1), Use in Specific Populations (8.1and8.3), and FDA-Approved Patient Labeling].

If the patient starts pill-taking on Sunday, the first active pill should be taken on the first Sunday after the patient's menstrual period begins. Remove the first active pill at the top of the dispenser (Sunday) by pressing the pill through the blister foil.

If the patient will start pill-taking on "Day 1", place a day-label sticker on the compact which starts with the day of the week the patient will take the first pill. Remove the first active pill at the top of the dispenser (Day 1) by pressing the pill through the blister foil.

2.3 Missed Tablets

2.4 Advice in Case of Gastrointestinal Disturbances

• 21 blue, round, biconvex, coated tablet imprinted "C3" on one side of the tablet and contains 0.250 mg norgestimate and 0.035 mg ethinyl estradiol
• 7 white, round, biconvex tablets (non-hormonal placebo) imprinted "P" on one side and "N" on the other side contains inert ingredients

• 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 have 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)]

5.1 Thrombotic Disorders and Other Vascular Problems

• Stop Mono-Linyah if an arterial thrombotic event or venous thromboembolic (VTE) event occurs.
• Stop Mono-Linyah 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 Mono-Linyah 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 Mono-Linyah 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

Do not use Mono-Linyah 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 Mono-Linyah if jaundice develops.

Liver Tumors

Mono-Linyah is contraindicated in women with benign and malignant liver tumors [see Contraindications (4)]. Hepatic adenomas are associated with COC use. An estimate of the attributable risk is 3.3 cases per 100,000 COC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage.

Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) COC users. However, the risk of liver cancers in COC users is less than one case per million users.

5.3 Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment

5.4 High Blood Pressure

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

5.6 Carbohydrate and Lipid Metabolic Effects

Consider alternative contraception for women with uncontrolled dyslipidemias. 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

Consider discontinuation of Mono-Linyah 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 (breakthrough or intracyclic) bleeding and spotting sometimes occur in patients on COCs, especially during the first three months of use. If bleeding persists or occurs after previously regular cycles, check for causes such as pregnancy or malignancy. If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different contraceptive product.

In clinical trials of norgestimate and ethinyl estradiol Tablets 0.25mg/0.035mg, the frequency and duration of breakthrough bleeding and/or spotting was assessed in 1,647 patients (21,275 evaluable cycles) and 4,826 patients (35,546 evaluable cycles), respectively. A total of 100 (7.5%) women discontinued norgestimate and ethinyl estradiol Tablets 0.25mg/0.035mg, 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 0.25mg/0.035mg experienced unscheduled bleeding per cycle in the first year. The percent of women who experienced breakthrough/unscheduled bleeding tended to decrease over time.

Amenorrhea and Oligomenorrhea

Women who use Mono-Linyah 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

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

5.11 Carcinoma of the Breast and Cervix

• Mono-Linyah is contraindicated in women who currently have or have had breast cancer because breast cancer may be hormonally sensitive[see Contraindications (4)] .

• 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

5.13 Monitoring

5.14 Hereditary Angioedema

5.15 Chloasma

• Serious cardiovascular events and stroke[ see Boxed Warningand Warnings and Precautions (5.1)]
• Vascular events[ see Warnings and Precautions (5.1)]
• Liver disease[ see Warnings and Precautions (5.2)]

• Irregular uterine bleeding
• Nausea
• Breast tenderness
• Headache

6.1 Clinical Trial Experience

The safety of norgestimate and ethinyl estradiol 0.25mg/0.035mg tablets was evaluated in 1,647 healthy women of child-bearing potential who participated in 3 clinical trials and received at least 1 dose of norgestimate and ethinyl estradiol 0.25mg/0.035mg tablets for contraception. Two trials were randomized active-controlled trials and 1 was an uncontrolled open-label trial. In all 3 trials, subjects were followed for up to 24 cycles.

Common Adverse Reactions ( 2% of all subjects): The most common adverse reactions reported by at least 2% of the 1,647 women were the following in order of decreasing incidence: headache/migraine (32.9%), abdominal/gastrointestinal pain (7.8%), vaginal infection (8.4%), genital discharge (6.8%), breast issues (including breast pain, discharge,and enlargement) (6.3%), mood disorders (including depression and mood altered) (5.0%), flatulence (3.2%), nervousness (2.9%), and rash (2.6%).

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

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

6.2 Postmarketing Experience

Infections and Infestations: Urinary tract infection;

Neoplasms Benign, Malignant and Unspecified (Incl. Cysts and Polyps): Breast cancer, benign breast neoplasm, hepatic adenoma, focal nodular hyperplasia, breast cyst;

Immune System Disorders: Hypersensitivity;

Metabolism and Nutrition Disorders: Dyslipidemia;

Psychiatric Disorders: Anxiety, insomnia;

Nervous System Disorders: Syncope, convulsion, paresthesia, dizziness;

Eye Disorders: Visual impairment, dry eye, contact lens intolerance;

Ear and Labyrinth Disorders: Vertigo;

Cardiac Disorders: Tachycardia, palpitations;

Vascular Events: Deep vein thrombosis, pulmonary embolism, retinal 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.

No drug-drug interaction studies were conducted with Mono-Linyah.

7.1 Effects of Other Drugs on Combined Oral Contraceptives

Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the plasma concentrations of COCs and potentially diminish the effectiveness of COCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, and products containing St. John's wort. Interactions between hormonal contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with COCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability.

Colesevelam: Colesevelam, a bile acid sequestrant, given together with a COC, has been shown to significantly decrease the AUC of EE. The drug interaction between the contraceptive and colesevelam was decreased when the two drug products were given 4 hours apart.

Substances increasing the plasma concentrations of COCs:

Co-administration of atorvastatin or rosuvastatin and certain COCs containing ethinyl estradiol (EE) increase AUC values for EE by approximately 20-25%. Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase plasma hormone concentrations.

Human immunodeficiency virus (HIV)/Hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors:

Significant changes (increase or decrease) in the plasma concentrations of estrogen and/or progestin have been noted in some cases of co-administration with HIV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir])/HCV protease inhibitors (decrease [e.g., boceprevir and telaprevir]) or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine] or increase [e.g., etravirine]).

7.2 Effects of Combined Oral Contraceptives on Other Drugs

7.2.2 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 Interactions with Laboratory Tests

7.4 Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevatio

8.1 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

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

8.7 Renal Impairment

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

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 Mono-Linyah. 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).

The effect of food on the pharmacokinetics of Mono-Linyah 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

The metabolites of NGMN and EE are eliminated by renal and fecal pathways. Following administration of 14C-norgestimate, 47% (45-49%) and 37% (16-49%) 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,(17 )-(-);18,19-Dinor-5 -17-pregnan-20-yn,3 ,17 -dihydroxy-13-ethyl,(17 ), various hydroxylated metabolites and conjugates of these metabolites.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Contraception

16.1 How Supplied

Mono-Linyah Tablets are available in the following configurations:

Carton of 1 blister card NDC 16714-360-02

Carton of 3 blister cards NDC 16714-360-03

Carton of 6 blister cards NDC 16714-360-04

Keep out of reach of children.

16.2 Storage Conditions

• Store at 20° to 25 (68° to 77H),[see USP Controlled Room Temperature].
• Protect from light.