Tri-Linyah

Do not use birth control pills if you are pregnant or if you have recently had a baby.

You should not take birth control pills if you have any of the following conditions: unusual vaginal bleeding, chest pain, uncontrolled high blood pressure, an uncontrolled heart valve disorder, diabetic problems with your eyes or kidneys, liver cancer, severe migraine headaches, or if you have ever had breast or uterine cancer, jaundice caused by pregnancy or birth control pills, a heart attack, a stroke, or a blood clot.

Taking birth control pills can increase your risk of blood clots, stroke, or heart attack, especially if you have certain other conditions, or if you are overweight.

Smoking can greatly increase your risk of blood clots, stroke, or heart attack. You should not take birth control pills if you smoke and are over 35 years old.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using birth control pills and call your doctor at once if you have:

• signs of a stroke--sudden numbness or weakness (especially on one side of the body), sudden severe headache, slurred speech, problems with vision or balance;

• signs of a blood clot in the lung--chest pain, sudden cough, wheezing, rapid breathing, coughing up blood;

• signs of a blood clot in your leg--pain, swelling, warmth, or redness in one or both legs;

• heart attack symptoms--chest pain or pressure, pain spreading to your jaw or shoulder, nausea, sweating;

• liver problems--nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);

• a change in the pattern or severity of migraine headaches;

• swelling in your hands, ankles, or feet;

• a breast lump; or

• symptoms of depression--sleep problems, weakness, tired feeling, mood changes.

Common side effects may include:

• nausea, vomiting;

• breast tenderness;

• freckles or darkening of facial skin, loss of scalp hair;

• headache, dizziness, nervousness;

• problems with contact lenses;

• changes in weight or appetite;

• irregular menstrual bleeding or spotting;

• vaginal itching or discharge; or

• rash.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Some drugs can make birth control pills less effective, which may result in pregnancy. Other drugs may interact with ethinyl estradiol and desogestrel, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Weight gain.
• Headache.
• Upset stomach or throwing up.
• Gas.
• Feeling nervous and excitable.
• Belly pain.
• Enlarged breasts.
• Tender breasts.
• Period (menstrual) changes. These include spotting or bleeding between cycles.
• This medicine may cause dark patches of skin on your face. Avoid sun, sunlamps, and tanning beds. Use sunscreen and wear clothing and eyewear that protects you from the sun.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Oral Contraceptive

Tri-Linyah tablets are indicated for use by females of reproductive potential to prevent pregnancy [see Clinical Studies (14)].

Acne

Tri-Linyah is 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. Tri-Linyah should be used for the treatment of acne only if the patient desires an oral contraceptive for birth control [see Clinical Studies (14)].

How to Start Tri-Linyah

Tri-Linyah is dispensed in 28-tablet blister [see How Supplied/Storage and Handling (16)]. Tri-Linyah may be started using either a Day 1 start or a Sunday start (see Table 1). The plastic compact is pre-set for a Sunday start. Day 1 Start day-label stickers are available. 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.

How to Take Tri-Linyah

Starting Tri-Linyah after Abortion or Miscarriage

First-trimester

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

● If Tri-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 Tri-Linyah.

Second-trimester

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

Starting Tri-Linyah after Childbirth

● Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. Start contraceptive therapy with Tri-Linyah following the instructions in Table 1 for women not currently using hormonal contraception.

● Tri-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 Tri-Linyah. [See Contraindications (4), Warnings and Precautions (5.1), Use in Specific Populations(8.1 and 8.3), and FDA-Approved Patient Labeling].

Compact Blister Dispenser

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 pa tient 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 a t the top of the dispenser (Day 1) by pressing the pill through the blister foil.

Missed Tablets

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].

Tri-Linyah Use for Acne

The timing of initiation of dosing with Tri-Linyah for acne should follow the guidelines for use of Tri-Linyah as an oral contraceptive. Consult the DOSAGE AND ADMINISTRATION section (2.1) for instructions.

Thromboembolic Disorders and Other Vascular Problems

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

● Stop Tri-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 Tri-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 Tri-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.

Liver Disease

Impaired Liver Function

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

Liver Tumors

Tri-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/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.

High Blood Pressure

Tri-Linyah is 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 Tri-Linyah 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.

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.

Carbohydrate and Lipid Metabolic Effects

Carefully monitor prediabetic and diabetic women who take Tri-Linyah. 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.

Headache

If a woman taking Tri-Linyah develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Tri-Linyah if indicated.

Consider discontinuation of Tri-Linyah in the case of increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event).

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 clinical trials of norgestimate and ethinyl estradiol tricycle tablets, the frequency and duration of breakthrough bleeding and/or spotting was assessed in 4,826 patients (35,546 evaluable cycles). A total of 231 (4.8%) women discontinued norgestimate and ethinyl estradiol tricycle tablets, at least in part, due to bleeding or spotting. Based on data from the clinical trials, 13-38% of women using norgestimate and ethinyl estradiol tricycle tablets 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 Tri-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.

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 Tri-Linyah 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)].

Depression

Carefully observe women with a history of depression and discontinue Tri-Linyah if depression recurs to a serious degree.

Carcinoma of Breast and Cervix

● Tri-Linyah is 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.

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.

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.

Hereditary Angioedema

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

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 Tri-Linyah.

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)]

Adverse reactions commonly reported by COC users are:

● Irregular uterine bleeding

● Nausea

● Breast tenderness

● Headache

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 tri-cycle norgestimate and ethinyl estradiol Tablets was evaluated in 4,826 healthy women of child-bearing potential who participated in 6 clinical trials and received at least 1 dose of tri-cycle norgestimate and ethinyl estradiol Tablets for contraception. Two trials were randomized activecontrolled 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).

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 (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.

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 Tri-Linyah.

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 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]).

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.

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

[See Warnings and Precautions (5.2, 5.10) and Use in Specific Populations (8.1).]