Levonorgestrel and Ethinyl Estradiol

TYBLUME is indicated for use by females of reproductive potential to prevent pregnancy. TYBLUME (levonorgestrel and ethinyl estradiol tablets) is a combination of levonorgestrel, a progestin, and ethinyl estradiol, an estrogen, indicated for use by females of reproductive potential to prevent pregnancy. ( 1 )

One pack of TYBLUME consists of 28 tablets: 21 active tablets are white, round, and debossed with 30 on one side and L2 on the other side. Each active tablet contains levonorgestrel 0.1 mg and ethinyl estradiol 0.02 mg. 7 inactive tablets (placebo) are peach-colored, round, and debossed with 1 on one side and L2 on the other side. A TYBLUME pack consists of 28 tablets: 21 white tablets (active), each containing levonorgestrel 0.1 mg and ethinyl estradiol 0.02 mg. 7 peach-colored tablets (inactive placebo).

TYBLUME is contraindicated in females who are known to have the following conditions: A high risk of arterial or venous thrombotic diseases. Examples include females who are known to: Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions (5.1) ] Have current or history of deep vein thrombosis or pulmonary embolism [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 inherited or acquired hypercoagulopathies [see Warnings and Precautions (5.1) ] Have uncontrolled hypertension or hypertension with vascular disease [see Warnings and Precautions (5.3) ] Have diabetes mellitus and are over age 35, diabetes mellitus with hypertension or vascular disease or other end-organ damage, or diabetes mellitus of > 20 years duration [see Warnings and Precautions (5.6) ] Have headaches with focal neurological symptoms, migraine headaches with aura, or over age 35 with any migraine headaches [see Warnings and Precautions (5.7) ] Current or history of breast cancer or other estrogen- or progestin-sensitive cancer Liver tumors, acute viral hepatitis, or severe (decompensated) cirrhosis [see Warnings and Precautions (5.2) ] Undiagnosed abnormal uterine bleeding [see Warnings and Precautions (5.8) ] 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 (5.14) ] High risk of arterial or venous thrombotic diseases. ( 4 ) Breast cancer or other estrogen- or progestin-sensitive cancer. ( 4 ) Liver tumors, acute viral hepatitis or decompensated cirrhosis. ( 4 ) Undiagnosed abnormal uterine bleeding. ( 4 ) Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. ( 4 )

Vascular risks : Stop if a thrombotic or thromboembolic event occurs. Stop TYBLUME at least 4 weeks before and through 2 weeks after major surgery. Start no earlier than 4 weeks after delivery, in females who are not breast-feeding. Consider cardiovascular risk factors before initiating in all females, particularly those over 35 years. ( 5.1 , 5.4 ) Liver disease : Discontinue TYBLUME if jaundice occurs. ( 5.2 ) Hypertension : If used in females with well-controlled hypertension, monitor blood pressure. Stop use of TYBLUME if blood pressure rises significantly. ( 5.3 ) Gallbladder disease : May cause or worsen gallbladder disease. ( 5.5 ) Adverse carbohydrate and lipid effect : Monitor glucose in prediabetic and diabetic females using TYBLUME. Consider an alternate contraceptive method for females with uncontrolled dyslipidemia. ( 5.6 ) Headache : Evaluate significant change in headaches and discontinue TYBLUME if indicated. ( 5.7 ) Uterine bleeding : May cause irregular bleeding or amenorrhea. Evaluate for other causes if symptoms persist. ( 5.8 )

5.1 Thromboembolic Disorders and Other Vascular Problems Before starting TYBLUME evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy. TYBLUME is contraindicated in females with a high risk of arterial or venous thrombotic/thromboembolic diseases [see Contraindications (4) ]. Stop TYBLUME if an arterial or venous thrombotic/thromboembolic event occurs. Stop TYBLUME if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions and evaluate for retinal vein thrombosis immediately. Discontinue TYBLUME during prolonged immobilization. If feasible, stop TYBLUME at least four weeks before and through two weeks after major surgery, or other surgeries known to have an elevated risk of thromboembolism. Start TYBLUME no earlier than four weeks after delivery in females who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the likelihood of ovulation increases after the third postpartum week. Arterial Events CHCs increase the risk of cardiovascular events and cerebrovascular events, such as myocardial infarction and stroke. The risk is greater among older women (> 35 years of age), smokers, and females with hypertension, dyslipidemia, diabetes, or obesity. TYBLUME is contraindicated in women over 35 years of age who smoke [see Contraindications (4) ] . Cigarette smoking increases the risk of serious cardiovascular events from CHC use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. Venous Events Use of CHCs increases the risk of venous thromboembolic events (VTEs), such as deep vein thrombosis and pulmonary embolism. Risk factors for VTEs include smoking, obesity, and family history of VTE, in addition to other factors that contraindicate use of CHCs [see Contraindications (4) ] . While the increased risk of VTE associated with use of CHCs is well-established, the rates of VTE are even greater during pregnancy, and especially during the postpartum period (see Figure 1 ). The rate of VTE in females using COCs has been estimated to be 3 to 9 cases per 10,000 woman-years. The risk of VTE is highest during the first year of use of a CHC and when restarting hormonal contraception after a break of four weeks or longer. Based on results from a few studies, there is some evidence that this is true for non-oral products as well. The risk of thromboembolic disease due to CHCs gradually disappears after CHC use is discontinued. Figure 1 shows the risk of developing a VTE for females who are not pregnant and do not use oral contraceptives, for females who use oral contraceptives, for pregnant females, and for females in the postpartum period. To put the risk of developing a VTE into perspective: If 10,000 females who are not pregnant and do not use oral contraceptives are followed for one year, between 1 and 5 of these females will develop a VTE. *Pregnancy data based on actual duration of pregnancy in the reference studies. Based on a model assumption that pregnancy duration is nine months, the rate is 7 to 27 per 10,000 WY. Figure 1 Likelihood of Developing a VTE Figure 1

5.2 Liver Disease Elevated Liver Enzymes TYBLUME is contraindicated in females with acute viral hepatitis or severe (decompensated) cirrhosis of the liver [see Contraindications (4) ]. Discontinue TYBLUME if jaundice develops. Acute liver test abnormalities may necessitate the discontinuation of CHC use until the liver tests return to normal and CHC causation has been excluded. Liver Tumors TYBLUME is contraindicated in females with benign or malignant liver tumors [see Contraindications (4) ] . CHCs increase the risk of hepatic adenomas. An estimate of the attributable risk is 3.3 cases/100,000 CHC users. Rupture of hepatic adenomas may cause death from abdominal hemorrhage. Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (> 8 years) CHC users. The attributable risk of liver cancers in CHC users is less than one case per million users.

5.3 Hypertension TYBLUME is contraindicated in females with uncontrolled hypertension or hypertension with vascular disease [see Contraindications (4) ] . For all females, including those with well-controlled hypertension, monitor blood pressure at routine visits and stop TYBLUME if blood pressure rises significantly. An increase in blood pressure has been reported in females using CHCs, and this increase is more likely in older women with extended duration of use. The effect of CHCs on blood pressure may vary according to the progestin in the CHC.

5.4 Age-related Considerations The risk for cardiovascular disease and prevalence of risk factors for cardiovascular disease increase with age. Certain conditions, such as smoking and migraine headache without aura, that do not contraindicate CHC use in younger females, are contraindications to use in women over 35 years of age [see Contraindications (4) and Warnings and Precautions (5.1) ]. Consider the presence of underlying risk factors that may increase the risk of cardiovascular disease or VTE, particularly before initiating a CHC for women over 35 years, such as: Hypertension Diabetes Dyslipidemia Obesity

5.5 Gallbladder Disease Studies suggest an increased risk of developing gallbladder disease among CHC users. Use of CHCs may also worsen existing gallbladder disease. A past history of CHC-related cholestasis predicts an increased risk with subsequent CHC use. Females with a history of pregnancy-related cholestasis may be at an increased risk for CHC related cholestasis.

5.6 Adverse Carbohydrate and Lipid Metabolic Effects Hyperglycemia TYBLUME is contraindicated in diabetic women over age 35, or females who have diabetes with hypertension, nephropathy, retinopathy, neuropathy, other vascular disease, or females with diabetes of > 20 years duration [see Contraindications (4) ]. TYBLUME may decrease glucose tolerance. Carefully monitor prediabetic and diabetic females who are using TYBLUME. Dyslipidemia Consider alternative contraception for females with uncontrolled dyslipidemia. TYBLUME may cause adverse lipid changes. Females with hypertriglyceridemia, or a family history thereof, may have an increase in serum triglyceride concentrations when using TYBLUME, which may increase the risk of pancreatitis.

5.7 Headache TYBLUME is contraindicated in females who have headaches with focal neurological symptoms or have migraine headaches with aura, and in women over age 35 years who have migraine headaches with or without aura [see Contraindications (4) ]. If a woman using TYBLUME develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue TYBLUME if indicated. […]

The following serious adverse reactions with the use of CHCs are discussed elsewhere in labeling: Serious cardiovascular events [see Boxed Warning and Warnings and Precautions (5.1 and 5.4) ] Vascular events [see Warnings and Precautions (5.1) ] Liver disease [see Warnings and Precautions (5.2) ] Hypertension [see Warnings and Precautions (5.3) ] Gallbladder disease [see Warnings and Precautions (5.5) ] Adverse carbohydrate and lipid metabolic effects [see Warnings and Precautions (5.6) ] Headache [see Warnings and Precautions (5.7) ] Bleeding irregularities and amenorrhea [see Warnings and Precautions (5.8) ] Depression [see Warnings and Precautions (5.9) ] Cervical cancer [see Warnings and Precautions (5.10) ] Effect on binding globulins [see Warnings and Precautions (5.11) ] Hereditary angioedema [see Warnings and Precautions (5.12) ] Chloasma [see Warnings and Precautions (5.13) ] Risk of liver enzyme elevations with concomitant hepatitis C treatment [see Warnings and Precautions (5.14) ] The following adverse reactions associated with the use of oral CHCs were identified in clinical studies or postmarketing reports. Because some of these reactions were 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. Common adverse reactions associated with oral CHCs are headache, abdominal pain, nausea, metrorrhagia, vaginal moniliasis and pain, acne, and vaginitis. Additional adverse reactions that have been reported include the following: Eye disorder: intolerance to contact lenses, steepening of corneal curvature Gastrointestinal disorders: Abdominal bloating, vomiting General disorders and administration site condition: Edema, fluid retention Hepatobiliary disorders: Cholestatic jaundice Psychiatric disorders: Change in libido, mood changes Reproductive system and breast disorders: Amenorrhea, breast tenderness, breast pain, breast enlargement, increased cervical mucous, change in menstrual flow, unscheduled bleeding Skin and subcutaneous tissue disorders: Acne, melasma [see Warnings and Precautions (5.13) ] Vascular disorders: Budd-Chiari syndrome, aggravation of varicose veins Common adverse reactions are: headache, abdominal pain, nausea, metrorrhagia, vaginal moniliasis and pain, acne, and vaginitis. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Exeltis USA, Inc. at 1-877-324-9349 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

The sections below provide information on substances for which data on drug interactions with CHCs are available. There is little information available about the clinical effect of most drug interactions that may affect CHCs. However, based on the known pharmacokinetic effects of these drugs, clinical strategies to minimize any potential adverse effect on contraceptive effectiveness or safety are suggested. Consult the approved product labeling of all concurrently used drugs to obtain further information about interactions with CHCs or the potential for metabolic enzyme or transporter system alterations. No drug-drug interaction studies were conducted with TYBLUME. Enzyme inducers (e.g., CYP3A4) : May decrease the effectiveness of TYBLUME or increase breakthrough bleeding. Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with TYBLUME. ( 7.1 , 7.2 )

7.1 Effects of Other Drugs on Combined Hormonal Contraceptives Substances decreasing the Plasma Concentration of CHCs and Potentially Diminishing the Efficacy of CHCs Table 3 Significant Drug Interactions Involving Substances That Affect CHCs a Induction potency of St. John's wort may vary widely based on preparation. Metabolic Enzyme Inducers Clinical effect Concomitant use of CHCs with metabolic enzyme inducers may decrease the plasma concentrations of the estrogen and/or progestin component of CHCs [see Clinical Pharmacology (12.3) ] . Decreased exposure of the estrogen and/or progestin component of CHCs may potentially diminish the effectiveness of CHCs and may lead to contraceptive failure or an increase in breakthrough bleeding. Prevention or management Counsel females to use an alternative method of contraception or a backup method when enzyme inducers are used with CHCs. Continue backup contraception for 28 days after discontinuing the enzyme inducer to maintain contraceptive reliability. Examples Aprepitant, barbiturates, bosentan, carbamazepine, efavirenz, felbamate, griseofulvin, oxcarbazepine, phenytoin, rifampin, primidone, phenylbutazone, rifabutin, rufinamide, topiramate, products containing St. John's wort, and certain protease inhibitors (see separate section on protease inhibitors below). Colesevelam Clinical effect Concomitant use of CHCs with colesevelam significantly decreases systemic exposure of ethinyl estradiol [see Clinical Pharmacology (12.3) ]. Decreased exposure of the estrogen component of CHCs may potentially reduce contraceptive efficacy or result in an increase in breakthrough bleeding, depending on the strength of ethinyl estradiol in the CHC. Prevention or management Administer 4 or more hours apart to attenuate this drug interaction. Substances increasing the systemic exposure of CHCs: Co-administration of atorvastatin or rosuvastatin and CHCs containing ethinyl estradiol increase systemic exposure of ethinyl estradiol by approximately 20 to 25 percent. Ascorbic acid and acetaminophen may increase systemic exposure of ethinyl estradiol, possibly by inhibition of conjugation. CYP3A inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice The effect of grapefruit juice on CYP3A4 enzymes (e.g., strong vs. moderate inhibition) depends on its brand, concentration, and preparation. , or ketoconazole may increase systemic exposure of the estrogen and/or progestin component of CHCs. Human immunodeficiency virus (HIV)/hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant decreases in systemic exposure of the estrogen and/or progestin have been noted when CHCs are co-administered with some HIV protease inhibitors (e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir), some HCV protease inhibitors (e.g., boceprevir and telaprevir), and some non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine). In contrast, significant increases in systemic exposure of the estrogen and/or progestin have been noted when CHCs are co-administered with certain other HIV protease inhibitors (e.g., indinavir and atazanavir/ritonavir) and with other non-nucleoside reverse transcriptase inhibitors (e.g., etravirine).

7.2 Effects of Combined Hormonal Contraceptives on Other Drugs Table 4 provides significant drug interaction information for drugs co-administered with TYBLUME. Table 4 Significant Drug Interaction Information for Drugs Co-Administered with CHCs Lamotrigine Clinical effect Concomitant use of CHCs with lamotrigine may significantly decrease systemic exposure of lamotrigine due to induction of lamotrigine glucuronidation [see Clinical Pharmacology (12.3) ]. Decreased systemic exposure of lamotrigine may reduce seizure control. Prevention or management Dose adjustment may be necessary. Consult the approved product labeling for lamotrigine. Thyroid Hormone Replacement Therapy or Corticosteroid Replacement Therapy Clinical effect Concomitant use of CHCs with thyroid hormone replacement therapy or corticosteroid replacement therapy may increase systemic exposure of thyroid-binding and cortisol-binding globulin [see Warnings and Precautions (5.11) ]. Prevention or management The dose of replacement thyroid hormone or cortisol therapy may need to be increased. Consult the approved product labeling for the therapy in use. [See Warnings and Precautions (5.11) ]. Other Drugs Clinical effect Concomitant use of CHCs may decrease systemic exposure of acetaminophen, morphine, salicylic acid, and temazepam. Concomitant use with ethinyl estradiol-containing CHCs may increase systemic exposure of other drugs (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole). Prevention or management The dosage of drugs that can be affected by this interaction may need to be increased. Consult the approved product labeling for the concomitantly used drug.

7.3 Effect on Laboratory Tests The use of CHCs 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 CHCs are contraindicated for use with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications (4) ]. Discontinue TYBLUME prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. TYBLUME can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.

Lactation : Advise use of another method; TYBLUME can decrease milk production. ( 8.2 )

8.1 Pregnancy Risk Summary There is no use for contraception in pregnancy; therefore, TYBLUME should be discontinued during pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to CHCs before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 percent and 15 to 20 percent, respectively.

8.2 Lactation Risk Summary Contraceptive hormones and/or metabolites are present in human milk. CHCs can reduce milk production in breast-feeding females. This reduction can occur at any time but is less likely to occur once breast-feeding is well established. When possible, advise the nursing female to use other methods of contraception until she discontinues breast-feeding [see Dosage and Administration (2.2) ]. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for TYBLUME and any potential adverse effects on the breast-fed child from TYBLUME or from the underlying maternal condition. Data Small amounts of oral-contraceptive steroids and/or metabolites have been identified in the milk of nursing mothers, and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, combination oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk.

8.4 Pediatric Use The safety and effectiveness of TYBLUME have been established in females of reproductive potential. Efficacy is expected to be the same for post-menarchal females under the age of 17 as for users 17 years and older. The use of TYBLUME before menarche is not indicated.

8.5 Geriatric Use TYBLUME has not been studied in postmenopausal women and is not indicated in this population.

8.6 Hepatic Impairment The pharmacokinetics of TYBLUME have not been studied in women 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 Body Mass Indexes Data on differences in safety and effectiveness (if any) of TYBLUME between patients with high BMI and lower BMI are not available.

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