Levora levonorgestrel and ethinyl estradiol Kit — NDC 51862-097-06 (Billing 51862-0097-06)

WARNINGS 1. Thromboembolic Disorders and Other Vascular Conditions Stop LEVORA 0.15/30-28 if an arterial or venous thrombotic/thromboembolic event occurs. Stop LEVORA 0.15/30-28 if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions and evaluate for retinal vein thrombosis immediately.

Discontinue LEVORA 0.15/30-28 during prolonged immobilization. If feasible, stop LEVORA 0.15/30-28 at least four weeks before and through two weeks after major surgery, or other surgeries known to have an elevated risk of thromboembolism. Start LEVORA 0.15/30-28 no earlier than four weeks after delivery in females who are not breast-feeding.

The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the likelihood of ovulation increases after the third postpartum week. Before starting LEVORA 0.15/30-28 evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy. LEVORA 0.15/30-28 is contraindicated in females with a high risk of arterial or venous thrombotic/thromboembolic diseases (see CONTRAINDICATIONS ).

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. LEVORA 0.15/30-28 is contraindicated in women over 35 years of age who smoke (see CONTRAINDICATIONS ).

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 COCs (see CONTRAINDICATIONS ). 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 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 COCs gradually disappears after COC 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. Figure 1: Likelihood of Developing a VTE Figure 1 2.

Liver Disease Elevated Liver Enzymes LEVORA 0.15/30-28 is contraindicated in females with acute viral hepatitis or severe (decompensated) cirrhosis of liver (see CONTRAINDICATIONS ). Discontinue LEVORA 0.15/30-28 if jaundice develops. Acute liver test abnormalities may necessitate the discontinuation of COC use until the liver tests return to normal and COC causation has been excluded.

Liver Tumors LEVORA 0.15/30-28 is contraindicated in females with benign or malignant liver tumors (see CONTRAINDICATIONS ). COCs increase the risk of hepatic adenomas. An estimate of the attributable risk is 3.3 cases/100,000 COC 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)… [Excerpted — this section continues on DailyMed.]

ADVERSE REACTIONS Post Marketing 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 - 1.12 (Figure 2). Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 2). 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 - 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 8-10 years of COC use. Figure 2: Risk of Breast Cancer with Combined Oral Contraceptive Use The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling: Serious cardiovascular adverse events [see BOXED WARNING and WARNINGS (1) ] Vascular events [see WARNINGS (1) ] Liver disease [see WARNINGS (2) ] Hypertension [see WARNINGS (4) ] Gallbladder disease [see WARNINGS (7) ] Carbohydrate and lipid effects [see WARNINGS (8) ] Headache [see WARNINGS (9) ] Carcinoma of the cervix [see WARNINGS (3) ] Adverse reactions reported by COC users and described elsewhere in the labeling are: Bleeding irregularities and amenorrhea [see WARNINGS (10) ] Mood changes, including depression [see WARNINGS (11) ] Melasma/chloasma which may persist [see WARNINGS (14) ] Edema/fluid retention [see PRECAUTIONS (2) ] Diminution in lactation when given immediately postpartum [see PRECAUTIONS (7) ] The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug-related: Breast tenderness, pain, enlargement, secretion; Nausea, vomiting and gastrointestinal symptoms (such as abdominal pain, cramps and bloating); Change in menstrual flow; Temporary infertility after discontinuation of treatment; Change in weight or appetite (increase or decrease); Change in cervical erosion and secretion; Cholestatic jaundice; Rash (allergic); Vaginitis, including candidiasis; Change in corneal curvature (steepening); Intolerance to contact lenses; Mesenteric thrombosis; Decrease in serum folate levels; Exacerbation of systemic lupus erythematosus; Exacerbation of porphyria; Exacerbation of chorea; Aggravation of varicose veins; Anaphylactic/anaphylactoid reactions, including urticaria, angioedema, and severe reactions with respiratory and circulatory symptoms.

The following adverse reactions have been reported in users of oral contraceptives, and the association has been neither confirmed nor refuted: Congenital anomalies; Premenstrual syndrome; Cataracts; Optic neuritis, which may lead to partial or complete loss of vision; Cystitis-like syndrome; Nervousness; Dizziness; Hirsutism; Loss of scalp hair; Erythema multiforme; Erythema nodosum; Hemorrhagic eruption; Impaired renal function; Hemolytic uremic syndrome; Budd-Chiari syndrome; Acne; Changes in libido; Colitis; Sickle-cell disease; Cerebral-vascular disease with mitral valve prolapse; Lupus-like syndromes; Pancreatitis; Dysmenorrhea.

Figure 2

4. 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 LEVORA 0.15/30-28.

4.1Effects of Other Drugs on Combined Oral Contraceptives Substances Decreasing the Plasma Concentrations of COCs and Potentially Diminishing the Efficacy of COCs Table 1 includes substances that demonstrated an important drug interaction with LEVORA 0.15/30-28. Table 1: 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 Induction potency of St. John's wort may vary widely based on preparation. , 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 COC. Prevention or management Administer 4 or more hours apart to attenuate this drug interaction.

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 systemic exposure of the estrogen and/or progestin have been noted when COCs 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).

4.2Effects of Combined Oral Contraceptives on Other Drugs Table 2 provides significant drug interaction inf… [Excerpted — this section continues on DailyMed.]

PRECAUTIONS 1. Lipid Disorders Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult [see WARNINGS (8) ].

In patients with familial defects of lipoprotein metabolism receiving estrogen-containing preparations, there have been case reports of significant elevations of plasma triglycerides leading to pancreatitis. 2. Fluid Retention Oral contraceptives may cause some degree of fluid retention.

They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention. 3. Gastrointestinal Motility Diarrhea and/or vomiting may reduce hormone absorption (see DOSAGE AND ADMINISTRATION ).

4. 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 LEVORA 0.15/30-28.

4.1Effects of Other Drugs on Combined Oral Contraceptives Substances Decreasing the Plasma Concentrations of COCs and Potentially Diminishing the Efficacy of COCs Table 1 includes substances that demonstrated an important drug interaction with LEVORA 0.15/30-28. Table 1: 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 Induction potency of St. John's wort may vary widely based on preparation. , 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 COC. Prevention or management Administer 4 or more hours apart to attenuate this drug interaction.

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 Significa… [Excerpted — this section continues on DailyMed.]