Levonorgestrel and Ethinyl Estradiol Kit — NDC 68180-857-73 (Billing 68180-0857-73)

Warnings Cigarette smoking increases the risk of serious cardiovascular side effects from oral- contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.

The use of oral contraceptives is associated with increased risks of several serious conditions including venous and arterial thrombotic and thromboembolic events (such as myocardial infarction, thromboembolism, and stroke), hepatic neoplasia, gallbladder disease, and hypertension, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as certain inherited or acquired thrombophilias, hypertension, hyperlipidemias, obesity, and diabetes.

Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks. The information contained in this package insert is based principally on studies carried out in patients who used oral contraceptives with higher formulations of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower formulations of both estrogens and progestogens remains to be determined.

Throughout this labeling, epidemiological studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of disease, namely, a ratio of the incidence of a disease among oral-contraceptive users to that among nonusers. The relative risk does not provide information on the actual clinical occurrence of a disease.

Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral-contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence of a disease in the population. For further information, the reader is referred to a text on epidemiological methods.

1. THROMBOEMBOLIC DISORDERS AND OTHER VASCULAR PROBLEMS a. Myocardial Infarction An increased risk of myocardial infarction has been attributed to oral-contraceptive use.

This risk is primarily in smokers or women with other underlying risk factors for coronary-artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral-contraceptive users has been estimated to be two to six. The risk is very low under the age of 30.

Smoking in combination with oral-contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting for the majority of excess cases. Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and nonsmokers over the age of 40 (Table III) among women who use oral contraceptives. CIRCULATORY DISEASE MORTALITY RATES PER 100,000 WOMAN YEARS BY AGE, SMOKING STATUS AND ORAL-CONTRACEPTIVE USE Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age, and obesity.

In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism. Oral contraceptives have been shown to increase blood pressure among users (see section 10 in "Warnings"). Similar effects on risk factors have been associated with an increased risk of heart disease.

Oral contraceptives must be used with caution in women with cardiovascular disease risk factors. b Thromboembolism An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Case control st… [Excerpted — this section continues on DailyMed.]

Adverse Reactions Postmarketing 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 1). Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 1). 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. 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.

An increased risk of the following serious adverse reactions has been associated with the use of oral- contraceptives (see "Warnings" section): Thrombophlebitis. Arterial thromboembolism. Pulmonary embolism.

Myocardial infarction. Cerebral hemorrhage. Cerebral thrombosis.

Hypertension. Gallbladder disease. Hepatic adenomas or benign liver tumors.

There is evidence of an association between the following conditions and the use of oral contraceptives, although additional confirmatory studies are needed: Mesenteric thrombosis. Retinal thrombosis. The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug related: Nausea.

Vomiting. Gastrointestinal symptoms (such as abdominal cramps and bloating). Breakthrough bleeding.

Spotting. Change in menstrual flow. Amenorrhea.

Temporary infertility after discontinuation of treatment. Edema. Melasma which may persist.

Breast changes: tenderness, enlargement, secretion. Change in weight (increase or decrease). Change in cervical erosion and secretion.

Diminution in lactation when given immediately postpartum. Cholestatic jaundice. Migraine.

Rash (allergic). Mental depression. Reduced tolerance to carbohydrates.

Vaginal candidiasis. Change in corneal curvature (steepening). Intolerance to contact lenses.

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. Changes in appetite. Cystitis-like syndrome.

Headache. Nervousness. Dizziness.

Hirsutism. Loss of scalp hair. Erythema multiforme.

Erythema nodosum. Hemorrhagic eruption. Vaginitis.

Porphyria. 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. Figure 1: Relevant Studies of Risk of Breast Cancer with Combined Oral Contraceptive Use

Precautions Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases. 1.PHYSICAL EXAMINATION AND FOLLOW-UP A periodic history and physical examination is appropriate for all women, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician.

The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent, or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care.

2.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," 1d.) 3.LIVER FUNCTION If jaundice develops in any woman receiving such drugs, the medication should be discontinued.

Steroid hormones may be poorly metabolized in patients with impaired liver function. 4.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.

5.EMOTIONAL DISORDERS Patients becoming significantly depressed while take oral contraceptives should stop the medication and use an alternative method of contraception in an attempt to determine whether the symptom is drug related. Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree. 6.HEREDITARY ANGIOEDEMA In females with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

7.CONTACT LENSES Contact-lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist. 8.DRUG INTERACTIONS Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation Do not co-administer levonorgestrel and ethinyl estradiol tablets with HCV drug combinations containing ombitasvir/ paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations (see WARNINGS, RISK OF LIVER ENZYME ELEVATIONS WITH CONCOMITANT HEPATITIS C TREATMENT). Reduced efficacy and increased incidence of breakthrough bleeding and menstrual irregularities have been associated with concomitant use of rifampin.

A similar association, though less marked, has been suggested with barbiturates, phenylbutazone, phenytoin sodium, and possibly with griseofulvin, ampicillin, and tetracyclines. 9.INTERACTIONS WITH LABORATORY TESTS Certain endocrine- and liver-function tests and blood components may be affected by oral contraceptives: a.Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability. b.Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay.

Free T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered. c.Other binding proteins may be elevated in serum. d.Sex-binding globulins are increased and result in elevated levels of total circulating sex steroids and corticoids; however, free or biologically active levels remain unchanged. e.Triglycerides may be increased. f.Glucose tolerance may be decreased. g.Serum folate levels may be depressed by oral-contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives.

10.CARCINOGENESIS See "Wa… [Excerpted — this section continues on DailyMed.]