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Progestogens and estrogens, fixed combinations

Norgestimate and Ethinyl Estradiol

Approved 25 Jun 2012OralTablet

The FDA lists this product in 17 strengths and forms.

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Indications

Tri-Lo-Marzia is an estrogen/progestin COC, indicated for use by women to prevent pregnancy. ( 1.1 )

1.1Oral Contraception Tri-Lo-Marzia™

Tablets are indicated for use by females of reproductive potential to prevent pregnancy [see CLINICAL STUDIES ( 14 )].

Contraindications

A high risk of arterial or venous thrombotic diseases ( 4 )
Liver tumors or liver disease ( 4 )
Undiagnosed abnormal uterine bleeding ( 4 )
Pregnancy ( 4 )
Breast cancer or other estrogen- or progestin-sensitive cancer ( 4 ) Do not prescribe Tri-Lo-Marzia 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: o Smoke, if over age 35 [see BOXED WARNING and WARNINGS AND PRECAUTIONS ( 5.1 )] o Have deep vein thrombosis or pulmonary embolism, now or in the past [see WARNINGS AND PRECAUTIONS ( 5.1 )] o Have inherited or acquired hypercoagulopathies [see WARNINGS AND PRECAUTIONS ( 5.1 )] o Have cerebrovascular disease [see WARNINGS AND PRECAUTIONS ( 5.1 )] o Have coronary artery disease [see WARNINGS AND PRECAUTIONS ( 5.1 )] o Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see WARNINGS AND PRECAUTIONS ( 5.1 )] o Have uncontrolled hypertension [see WARNINGS AND PRECAUTIONS ( 5.3 )] o Have diabetes mellitus with vascular disease [see WARNINGS AND PRECAUTIONS ( 5.5 )] o Have headaches with focal neurological symptoms or migraine headaches with aura [see WARNINGS AND PRECAUTIONS ( 5.6 )] o Women over age 35 with any migraine headaches [see WARNINGS AND PRECAUTIONS ( 5.6 )]
Liver tumors, benign or malignant, or liver disease [see WARNINGS AND PRECAUTIONS ( 5.2 )]
Undiagnosed abnormal uterine bleeding [see WARNINGS AND PRECAUTIONS ( 5.7 )]
Pregnancy, because there is no reason to use COCs during pregnancy [see WARNINGS AND PRECAUTIONS ( 5.8 ) and USE IN SPECIFIC POPULATIONS ( 8.1 )]

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Warnings and precautions

Thromboembolic Disorders and Other Vascular Problems: Stop Tri-Lo-Marzia if a thrombotic event occurs. Stop at least 4 weeks before and through 2 weeks after major surgery. Start no earlier than 4 weeks after delivery, in women who are not breastfeeding. ( 5.1 )
Liver Disease: Discontinue Tri-Lo-Marzia if jaundice occurs. ( 5.2 )
High Blood Pressure: If used in women with well-controlled hypertension, monitor blood pressure and stop Tri-Lo-Marzia if blood pressure rises significantly. ( 5.3 )
Carbohydrate and Lipid Metabolic Effects: Monitor prediabetic and diabetic women taking Tri-Lo-Marzia. Consider an alternate contraceptive method for women with uncontrolled dyslipidemia. ( 5.5 )
Headache: Evaluate significant change in headaches and discontinue Tri-Lo-Marzia if indicated. ( 5.6 )
Bleeding Irregularities and Amenorrhea: Evaluate irregular bleeding or amenorrhea. ( 5.7 )

5.1Thromboembolic Disorders and Other Vascular

Problems

Stop Tri-Lo-Marzia if an arterial thrombotic event or venous thrombotic (VTE) event occurs.
Stop Tri-Lo-Marzia 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-Lo-Marzia 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-Lo-Marzia no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum VTE decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week.
The use of COCs increases the risk of VTE. However, pregnancy increases the risk of VTE as much or more than the use of COCs. The risk of VTE in women using COCs is 3 to 9 cases per 10,000 woman-years. The risk of VTE is highest during the first year of use of COCs and when restarting hormonal contraception after a break of 4 weeks or longer. The risk of thromboembolic disease due to COCs gradually disappears after use is discontinued.
Use of COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events. COCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes). This risk increases with age, particularly in women over 35 years of age who smoke.
Use COCs with caution in women with cardiovascular disease risk factors.

5.2Liver Disease Impaired Liver Function Do

not use Tri-Lo-Marzia 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-Lo-Marzia if jaundice develops. Liver Tumors Tri-Lo-Marzia 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.

5.3High Blood Pressure

Tri-Lo-Marzia 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-Lo-Marzia 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.

5.4Gallbladder 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.

5.5Carbohydrate and Lipid Metabolic Effects

Carefully monitor prediabetic and diabetic women who take Tri-Lo-Marzia. 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.

5.6Headache If

a woman taking Tri-Lo-Marzia develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Tri-Lo-Marzia if indicated. Consider discontinuation of Tri-Lo-Marzia in the case of increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event).

5.7Bleeding 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 Tri-Lo-Marzia, 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 Tri-Lo-Marzia, at least in part, due to bleeding or spotting. Based on data from the clinical trials, 7 to 17% of women using Tri-Lo-Marzia 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 Tri-Lo-Marzia 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.

5.8COC 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-Lo-Marzia 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 )].

5.9Depression

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

5.10 Carcinoma of Breast and Cervix

Tri-Lo-Marzia 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 pa

Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA

Interactions

Drugs or herbal products that induce certain enzymes including CYP3A4, may decrease the effectiveness of COCs or increase breakthrough bleeding. Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with COCs. ( 7.1 ) 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-Lo-Marzia.

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]).

7.2Effects of Combined Oral Contraceptives on Other

Drugs

COCs containing EE may inhibit the metabolism of other compounds (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma concentrations.
COCs have been shown to decrease plasma concentrations of acetaminophen, clofibric acid, morphine, salicylic acid, temazepam and lamotrigine. Significant decrease in plasma concentration of lamotrigine has been shown, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because the serum concentration of thyroid-binding globulin increases with use of COCs.

7.3Interference with Laboratory Tests

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

Adverse reactions

The most common adverse reactions reported during clinical trials (≥2%) were: headache/migraine, nausea/vomiting, breast issues, abdominal pain, menstrual disorders, mood disorders, acne, vulvovaginal infection, abdominal distension, weight increased, fatigue. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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

6.1Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of Tri-Lo-Marzia was evaluated in 1,723 subjects who participated in a randomized, partially blinded, multicenter, active-controlled clinical trial of Tri-Lo-Marzia 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 Tri-Lo-Marzia 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).

6.2Postmarketing 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.