Ashlyna Levonorgestrel and Ethinyl Estradiol Kit, 2 pouches — NDC 68462-646-93 (Billing 68462-0646-93)

5 WARNINGS AND PRECAUTIONS • Vascular risks: Stop if a thrombotic or thromboembolic 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.

Consider cardiovascular risk factors before initiating in all females, particularly those over 35 years. ( 5.1 , 5.5 ) • Liver disease: Discontinue if jaundice occurs. ( 5.2 ) • Hypertension: If used in females with well-controlled hypertension, monitor blood pressure and stop if blood pressure rises significantly.

( 5.3 ) • Gallbladder disease: May cause or worsen gallbladder disease. ( 5.6 ) • Adverse carbohydrate and lipid metabolic effects: Monitor glucose in prediabetic and diabetic women taking Ashlyna. Consider an alternate contraceptive method for women with uncontrolled dyslipidemias.

( 5.7 ) • Headache: Evaluate significant change in headaches and discontinue if indicated. ( 5.8 ) • Uterine bleeding: May cause irregular bleeding or amenorrhea. Evaluate for other causes if symptoms persist.

( 5.9 )

5.1Thromboembolic Disorders and Other Vascular Conditions • Stop levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets if an arterial or deep venous thrombotic/ thrombembolic event occurs. • Stop levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions and evaluate for retinal vein thrombosis immediately. • Discontinue levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets during prolonged immobilization.

If feasible, stop levonorgestrel and ethinyl estradiol tablets 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 thromboembolism. • Start levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week. • Before starting levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy.

Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets are contraindicated in women with a high risk of arterial or venous/thromboembolic diseases [see Contraindications ( 4 )] . Arterial Events COCs 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. levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets are contraindicated in women over 35 years of age who smoke [see Contraindications ( 4 )] .

Cigarette smoking increases the risk of serious cardiovascular events from COC 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 COCs 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 COCs 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 COC and when restarting hormonal contraception aft… [Excerpted — this section continues on DailyMed.]

6 ADVERSE REACTIONS The following serious adverse reactions with the use of COCs are discussed elsewhere in the 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 )] The most common adverse reactions (≥5%) in clinical trials for Ashlyna are irregular and/or heavy uterine bleeding, weight gain, and acne. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 the rates in the clinical trials of another drug and may not reflect the rates observed in practice. The clinical trial that evaluated the safety and efficacy of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets was a 12-month, randomized, multicenter, open-label study, which enrolled women aged 18 to 40, of whom 1,006 took at least one dose of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets.

Adverse Reactions Leading to Study Discontinuation: 16.3% of the women discontinued from the clinical trial due to an adverse reaction; the most common adverse reactions (≥ 1% of women) leading to discontinuation were irregular and/or heavy uterine bleeding (5.9%), weight gain (2.4%), mood changes (1.5%), and acne (1%). Common Treatment-Emergent Adverse Reactions (≥ 5% of women): irregular and/or heavy uterine bleeding (17%), weight gain (5%), acne (5%). Serious Adverse Reactions: migraine, cholecystitis, cholelithiasis, pancreatitis, abdominal pain, and major depressive disorder.

6.2Postmarketing Experience Five studies that compared breast cancer risk between ever-users (current or past use) of COCs and never-users of COCs reported no association between ever use of COCs and breast cancer risk, with effect estimates ranging from 0.90 to 1.12 (Figure 3). Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 3). One of these studies reported no association between breast cancer risk and COC use.

The other two studies found an increased relative risk of 1.19 to 1.33 with current or recent use. Both of these studies found an increased risk of breast cancer with current use of longer duration, with relative risks ranging from 1.03 with less than one year of COC use to approximately 1.4 with more than 8 to 10 years of COC use. Figure 3: Relevant Studies of Risk of Breast Cancer with Combined Oral Contraceptives RR = relative risk; OR = odds ratio; HR = hazard ratio. “ever COC” are females with current or past COC use; “never COC use” are females that never used COCs.

The following adverse reactions have been identified during post-approval use of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency of establish a causal relationship to drug exposure. Gastrointestinal disorders : abdominal distension, vomiting General disorders and administration site conditions : chest pain, fatigue, malaise, edema peripheral, pain Immune system disorders : hypersensitivity reaction Investigations: blood pressure increased Musculoskeletal and connective tissue disorders : muscle spasms, pain in extremity Nervous system disorders : dizziness, loss of consciousness Psychiatric disorders : insomnia Reproductive and breast disorders : dysmenorrhea Respiratory, thoracic and mediastinal disorders: pulmonary embolism, pulmonary thrombosis Skin and subcutaneous tissue disorders : alopecia Vascular disorders : thrombosis figure3

7 DRUG INTERACTIONS The sections below provide information on substances for which data on drug interactions with COCs are available. There is little information available about the clinical effect of most drug interactions that may affect COCs. 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 COCs or the potential for metabolic enzyme or transporter system alterations. No drug-drug interaction studies were conducted with levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets. Enzyme inducers (e.g., CYP3A4): May decrease the effectiveness of Ashlyna or increase breakthrough bleeding.

Counsel patients to use a back-up method or alternative method of contraception when enzyme inducers are used with Ashlyna. ( 7.1 )

7.1Effects of Other Drugs on Combined Oral Contraceptives Substances Decreasing the Plasma Concentrations of COCs and Potentially Diminishing the Efficacy of COCs: Table 4 includes substances that demonstrated an important drug interaction with levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets. Table 4: Significant Drug Interactions Involving Substances That Affect COCs Metabolic Enzyme Inducers Clinical effect • Concomitant use of COCs with metabolic enzyme inducers may decrease the plasma concentrations of the estrogen and/or progestin component of COCs. • Decreased exposure of the estrogen and/or progestin component of COCs may potentially diminish the effectiveness of COCs 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 COCs. • 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, rifabutin, rufinamide, topiramate, products containing St. John’s wort a , and certain protease inhibitors (see separate section on protease inhibitors below).

Colesevelam Clinical effect • Concomitant use of COCs with colesevelam significantly decreases systemic exposure of ethinyl estradiol. • Decreased exposure of the estrogen component of COCs 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. a Induction potency of St. John’s wort may vary widely based on preparation.

Substances increasing the systemic exposure of COCs: Co-administration of atorvastatin or rosuvastatin and COCs 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, or ketoconazole may increase systemic exposure of the estrogen and/or progestin component of COCs.

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 COCs 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 sys… [Excerpted — this section continues on DailyMed.]