Norethindrone - Warnings and Precautions

WARNINGS Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive use.

This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked.

For this reason, combination oral contraceptives, including Nortrel 0.5/35 and 1/35, should not be used by women who are over 35 years of age and smoke.

The use of oral contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease, 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 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 principally based 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 a 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 (adapted from refs.

2 and 3 with the author's permission).

For further information, the reader is referred to a text on epidemiological methods.

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.

4-10 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.

11 Mortality rates associated with circulatory disease have been shown to increase substantially in smokers, especially in those 35 years of age and older and in nonsmokers over the age of 40 among women who use oral contraceptives (see Figure 1).

Figure 1: Circulatory Disease Mortality Rates per 100,000 Woman-Years by Age, Smoking Status and Oral Contraceptive Use (Adapted from P.M.

Beral, ref. #12.) Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity.

13 In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism.