Low-Ogestrel (Page 2 of 7)

WARNINGS

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, hypercholesterolemia, obesity and diabetes.^2–5

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 both 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. Relative risk, the ratio of the incidence of a disease among oral contraceptive users to that among non-users, cannot be assessed directly from case control studies, but the odds ratio obtained is a measure of relative risk. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide not only a measure of relative risk but a measure of attributable risk, which is the difference in the incidence of disease between the oral contraceptive users and non-users. The attributable risk does provide information about the actual occurrence of a disease in the population. (Adapted from ref. 12 and 13 with the author’s permission.) 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.^{2–5, 13} The relative risk of heart attack for current oral contraceptive users has been estimated to be 2 to 6.^{2, 14–19} 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 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.²⁰

Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and non-smokers over the age of 40 among women who use oral contraceptives (see Table II).¹⁶

TABLE II: CIRCULATORY DISEASE MORTALITY RATES PER 100,000 WOMAN YEARS BY AGE, SMOKING STATUS AND ORAL CONTRACEPTIVE USE

Adapted from P.M. Layde and V. Beral, Table V16

(click image for full-size original)

Oral contraceptives may compound the effects of well-known risk factors such as hypertension, diabetes, hyperlipidemias, hypercholesterolemia, age and obesity.^{3, 13, 21} In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism.^21–25 Oral contraceptives have been shown to increase blood pressure among users (see WARNINGS, section 10). 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 studies have found the relative risk of users compared to non-users 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.^{12, 13, 26–31} Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization.³² The risk of thromboembolic disease due to oral contraceptives is notrelated to length of use and disappears after pill use is stopped.¹²

A 2- to 6-fold increase in relative risk of post-operative thromboembolic complications has been reported with the use of oral contraceptives. The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions.⁸³ If feasible, oral contraceptives should be discontinued at least 4 weeks prior to and for 2 weeks after elective surgery and during and following prolonged immobilization. Since the immediate postpartum period also is 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 breast feed.³³

c. Cerebrovascular diseases

An increase in both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes) has been shown in users of oral contraceptives. In general, the risk is greatest among older (>35 years), hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and non-users for both types of strokes while smoking interacted to increase the risk for hemorrhagic strokes.³⁴

In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension.³⁵ The relative risk of hemorrhagic stroke is reported to be 1.2 for non-smokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users, and 25.7 for users with severe hypertension.³⁵ The attributable risk also is greater in women in their mid-thirties or older and among smokers.¹³

d. Dose-related risk of vascular disease from oral contraceptives

A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease.^36–38 A decline in serum high density lipoproteins (HDL) has been reported with many progestational agents.^22–24 A decline in serum high density lipoproteins has been associated with an increased incidence of ischemic heart disease.³⁹ Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestogen and the nature and absolute amount of progestogens used in the contraceptives. The amount of both hormones should be considered in the choice of an oral contraceptive.³⁷

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 which 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 contraceptive agents should be started on preparations containing the lowest estrogen content that produces satisfactory results for the individual.

e. Persistence of risk of vascular disease

There are three studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives.^{17, 34, 40} In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women 40–49 years who had used oral contraceptives for 5 or more years, but this increased risk was not demonstrated in other age groups.¹⁷ In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small.⁴⁰ There is a significantly increased relative risk of subarachnoid hemorrhage after termination of use of oral contraceptives.³⁴ However, these studies were performed with oral contraceptive formulations containing 50 µg or higher of estrogen.