Kelnor 1/50 (Page 2 of 8)

CONTRAINDICATIONS

Kelnor 1/50 is contraindicated in females who are known to have or develop the following conditions:

• Thrombophlebitis or thromboembolic disorders
• A past history of deep vein thrombophlebitis or thromboembolic disorders
• Cerebral vascular disease, myocardial infarction, or coronary artery disease, or a past history of these conditions
• Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive
• Known or suspected carcinoma of the female reproductive organs or suspected estrogen-dependent neoplasia, or a history of these conditions
• Undiagnosed abnormal genital bleeding
• History of cholestatic jaundice of pregnancy or jaundice with prior oral contraceptive use
• Past or present, benign or malignant liver tumors
• Known or suspected pregnancy
• Are receiving Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations (see WARNINGS, Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment).

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 risk of several serious conditions including venous and arterial thromboembolism, thrombotic and hemorrhagic stroke, myocardial infarction, liver tumors or other liver lesions, and gallbladder disease. The risk of morbidity and mortality increases significantly in the presence of other risk factors such as hypertension, hyperlipidemia, obesity, and diabetes mellitus.

Practitioners prescribing oral contraceptives should be familiar with the following information relating to these and other risks.

The information contained herein is principally based on studies carried out in patients who used oral contraceptives with formulations containing higher amounts of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lesser amounts of both estrogens and progestogens remains to be determined.

Throughout this labeling, epidemiological studies reported are of two types: retrospective case-control studies and prospective cohort studies. Case-control studies provide an estimate of the relative risk of a disease, which is defined as the ratio of the incidence of a disease among oral contraceptive users to that among nonusers. The relative risk (or odds ratio) does not provide information about the actual clinical occurrence of a disease. Cohort studies provide a measure of both the relative risk and the attributable risk. The latter is the difference in the incidence of disease between oral contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence or incidence of a disease in the subject 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 associated with oral contraceptive use.^2-21 This increased risk is primarily in smokers or in women with other underlying risk factors for coronary artery disease such as hypertension, obesity, diabetes, and hypercholesterolemia. The relative risk for myocardial infarction in current oral contraceptive users has been estimated to be 2 to 6. The risk is very low under the age of 30. However, there is the possibility of a risk of cardiovascular disease even in very young women who take oral contraceptives.

Smoking in combination with oral contraceptive use has been reported to contribute substantially to the risk of myocardial infarction in women in their mid-thirties or older, with smoking accounting for the majority of excess cases.²² Mortality rates associated with circulatory disease have been shown to increase substantially in smokers, especially in those 35 years of age and older among women who use oral contraceptives (see Figure 1 , Table 2).

Figure 1. Circulatory disease mortality rates per 100,000 woman-years by age, smoking status, and oral contraceptive use.¹⁴

Oral contraceptives may compound the effects of well-known cardiovascular risk factors such as hypertension, diabetes, hyperlipidemias, hypercholesterolemia, age, cigarette smoking, and obesity. In particular, some progestogens decrease HDL cholesterol^23-31 and cause glucose intolerance, while estrogens may create a state of hyperinsulinism.³² Oral contraceptives have been shown to increase blood pressure among some users (see WARNINGS , No. 10). Similar effects on risk factors have been associated with an increased risk of heart disease.

b. Thromboembolism

An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established.^{17, 33-51} Case-control studies have estimated the relative risk to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease.^{34-37, 45, 46} Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases (subjects with no past history of venous thrombosis or varicose veins) and about 4.5 for new cases requiring hospitalization.^{42, 47, 48} The risk of venous thromboembolic disease associated with oral contraceptives is not related to duration of use.

A two- to seven-fold increase in relative risk of postoperative thromboembolic complications has been reported with the use of oral contraceptives.^{38, 39} The relative risk of venous thrombosis in women who have predisposing conditions is about twice that of women without such medical conditions.⁴³ If feasible, oral contraceptives should be discontinued at least 4 weeks prior to and for 2 weeks after elective surgery of a type associated with an increased risk of thromboembolism, and also during and following prolonged immobilization. Since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than 4 to 6 weeks after delivery in women who elect not to breastfeed.

c. Cerebrovascular Diseases

Both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes) have been reported to be increased with oral contraceptive use,^{14, 17, 18, 34, 42, 46, 52-59} although, in general, the risk was greatest among older (over 35 years), hypertensive women who also smoked. Hypertension was reported to be a risk factor for both users and nonusers, for both types of strokes, while smoking increased the risk for hemorrhagic strokes.

In one large study,⁵² the relative risk for thrombotic stroke was reported as 9.5 times greater in users than in nonusers. It ranged from 3 for normotensive users to 14 for users with severe hypertension.⁵⁴ The relative risk for hemorrhagic stroke was reported to be 1.2 for nonsmokers who used oral contraceptives, 1.9 to 2.6 for smokers who did not use oral contraceptives, 6.1 to 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users, and 25.7 for users with severe hypertension. The risk is also greater in older women and among smokers.

d. Dose-Related Risk of Vascular Disease With Oral Contraceptives

A positive association has been reported between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease.^{41, 43, 53, 59-64} A decline in serum high density lipoproteins (HDL) has been reported with many progestogens.^23-31 A decline in serum high density lipoproteins has been associated with an increased incidence of ischemic heart disease.⁶⁵ Because estrogens increase HDL-cholesterol, the net effect of an oral contraceptive depends on the balance achieved between doses of estrogen and progestogen and the nature and absolute amount of progestogens used in the contraceptives. The amount of both steroids should be considered in the choice of an oral contraceptive.

Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular estrogen-progestogen combination, the dosage regimen prescribed should be one that contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient. New acceptors of oral contraceptives should be started on preparations containing the lowest estrogen content that produces satisfactory results in the individual.

Products containing 50 mcg estrogen should be used only when medically indicated.