LEVONORGESTREL AND ETHINYL ESTRADIOL

LEVONORGESTREL AND ETHINYL ESTRADIOL-
Mylan Pharmaceuticals Inc.

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS

Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs, including levonorgestrel and ethinyl estradiol tablets, are contraindicated in women who are over 35 years of age and smoke [see CONTRAINDICATIONS and WARNINGS (1)].

DESCRIPTION

Levonorgestrel and ethinyl estradiol tablets USP, 0.15 mg/30 mcg are combination oral contraceptives (COC) consisting of 21 white to off-white active tablets, each containing 0.15 mg of levonorgestrel, a synthetic progestin and 30 mcg of ethinyl estradiol, an estrogen, and 7 green inert tablets (without hormones).

The structural formulas for the active components are:

Structural formula -- Levonorgestrel

Levonorgestrel

C21 H28 O2 MW: 312.45

Levonorgestrel is chemically 18,19-Dinorpregn-4-en-20-yn-3-one, 13-ethyl-17-hydroxy-,(17α)-(-)-.

Structural formula -- Ethinyl Estradiol

Ethinyl Estradiol

C20 H24 O2 MW: 296.40

Ethinyl Estradiol is 19-Nor-17α-pregna-1,3,5(10)-trien-20-yne-3, 17-diol.

Each white to off-white active tablet contains the following inactive ingredients: lactose monohydrate, magnesium stearate, and polacrilin potassium.

Each green inert tablet contains the following inactive ingredients: FD&C Blue No. 1 aluminum lake, lactose monohydrate, magnesium stearate, polacrilin potassium, and yellow oxide of iron.

CLINICAL PHARMACOLOGY

Combination oral contraceptives prevent pregnancy primarily by suppressing ovulation.

INDICATIONS AND USAGE

Levonorgestrel and ethinyl estradiol tablets, 0.15 mg/30 mcg are indicated for use by females of reproductive potential to prevent pregnancy.

CONTRAINDICATIONS

Levonorgestrel and ethinyl estradiol tablets are contraindicated in females 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 (1)].
o
Have current or history of deep vein thrombosis or pulmonary embolism [see WARNINGS (1)].
o
Have cerebrovascular disease [see WARNINGS (1)].
o
Have coronary artery disease [see WARNINGS (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 (1)].
o
Have inherited or acquired hypercoagulopathies [see WARNINGS (1)].
o
Have uncontrolled hypertension or hypertension with vascular disease [see WARNINGS (3)].
o
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 (7)].
o
Have headaches with focal neurological symptoms, migraine headaches with aura, or over age 35 with any migraine headaches [see WARNINGS (8)].
Current or history of breast cancer or other estrogen-or progestin-sensitive cancer.
Liver tumors, acute viral hepatitis, or severe (decompensated) cirrhosis [see WARNINGS (2)].
Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations [see WARNINGS (5)].
Undiagnosed abnormal uterine bleeding [see WARNINGS (9)].

WARNINGS

1. Thromboembolic Disorders and Other Vascular Conditions

Stop levonorgestrel and ethinyl estradiol tablets if an arterial or venous thrombotic/thromboembolic event occurs.
Stop levonorgestrel 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 during prolonged immobilization. If feasible, stop levonorgestrel and ethinyl estradiol tablets at least four weeks before and through two weeks after major surgery, or other surgeries known to have an elevated risk of thromboembolism.
Start levonorgestrel and ethinyl estradiol tablets 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 levonorgestrel 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 are 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.

Levonorgestrel and ethinyl estradiol tablets are 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

Fig 01
(click image for full-size original)

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