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.

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.

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.

Layde and V.

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.

14-18 Oral contraceptives have been shown to increase blood pressure among users (see Section 10 in ).

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.

Table II 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 nonusers 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.

2,3,19-24 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.

25 The risk of thromboembolic disease associated with oral contraceptives gradually disappears after combined oral contraceptive (COC) use is stopped.

2 VTE risk is highest in the first year of use and when restarting hormonal contraception after a break of four weeks or longer.

A two- to four-fold increase in relative risk of post-operative thromboembolic complications has been reported with the use of oral contraceptives.

9 The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions.

26 If feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and 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 four weeks after delivery in women who elect not to breast feed.

c.

Cerebrovascular Diseases Oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, 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 nonusers, for both types of strokes, and smoking interacted to increase the risk of stroke.

27-29 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.

30 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.

30 The attributable risk is also greater in older women.

3 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.

31-33 A decline in serum high density lipoproteins (HDL) has been reported with many progestational agents.

14-16 A decline in serum high density lipoproteins has been associated with an increased incidence of ischemic heart disease.

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 activity of the progestogen used in the contraceptives.

The activity and amount of both hormones 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 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 which is judged appropriate for the individual patient.

e.

Persistence of Risk of Vascular Disease There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives.

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 five or more years, but this increased risk was not demonstrated in other age groups.

8 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.

34 However, both studies were performed with oral contraceptive formulations containing 50 micrograms or higher of estrogens.

2.

Estimates of Mortality from Contraceptive Use One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table 2).

These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure.

Each method of contraception has its specific benefits and risks.

The study concluded that with the exception of oral contraceptive users 35 and older who smoke, and 40 and older who do not smoke, mortality associated with all methods of birth control is low and below that associated with childbirth.

The observation of an increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970’s.

35 Current clinical recommendation involves the use of lower estrogen dose formulations and a careful consideration of risk factors.

In 1989, the Fertility and Maternal Health Drugs Advisory Committee was asked to review the use of oral contraceptives in women 40 years of age and over.

The Committee concluded that although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy non-smoking women (even with the newer low-dose formulations), there are also greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception.

The Committee recommended that the benefits of low-dose oral contraceptive use by healthy non-smoking women over 40 may outweigh the possible risks.

Of course, older women, as all women who take oral contraceptives, should take an oral contraceptive which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and individual patient needs.

TABLE 2: ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN, BY FERTILITY CONTROL METHOD ACCORDING TO AGE Method of control and outcome 15-19 20-24 25-29 30-34 35-39 40-44 No fertility control methods 1 7.0 7.4 9.1 14.8 25.7 28.2 Oral contraceptives non-smoker 2 0.3 0.5 0.9 1.9 13.8 31.6 Oral contraceptives smoker 2 2.2 3.4 6.6 13.5 51.1 117.2 IUD 2 0.8 0.8 1.0 1.0 1.4 1.4 Condom 1 1.1 1.6 0.7 0.2 0.3 0.4 Diaphragm/spermicide 1 1.9 1.2 1.2 1.3 2.2 2.8 Periodic abstinence 1 2.5 1.6 1.6 1.7 2.9 3.6 Adapted from H.W.

Ory, ref.

#35.

1.

Deaths are birth-related 2.

Deaths are method-related 3.

Malignant Neoplasms Breast Cancer Nortrel 0.5/35 and 1/35 is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive (see CONTRAINDICATIONS ).

Epidemiology studies have not found a consistent association between use of combined oral contraceptives (COCs) and breast cancer risk.

Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer.

However, some studies report a small increase in the risk of breast cancer among current or recent users (<6 months since last use) and current users with longer duration of COC use (see Postmarketing Experience ).

Cervical Cancer Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women.

45-48 However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.

In spite of many studies of the relationship between oral contraceptive use and breast and cervical cancers, a cause-and-effect relationship has not been established.

4.

Hepatic Neoplasia Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of benign tumors is rare in the United States.

Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use especially with oral contraceptives of higher dose.

49 Rupture of benign, hepatic adenomas may cause death through intra-abdominal hemorrhage.

50, 51 Studies from Britain have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) oral contraceptive users.

However, these cancers are extremely rare in the U.S.

and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users.

5.

Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment During clinical trials with the Hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in women using ethinyl estradiol-containing medications such as COCs.

Discontinue Nortrel prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir (see CONTRAINDICATIONS ).

Nortrel can be restarted approximately 2 weeks following completion of treatment with the combination drug regimen.

6.

Ocular Lesions There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives.

Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions.

Appropriate diagnostic and therapeutic measures should be undertaken immediately.

7.

Oral Contraceptive Use Before or During Early Pregnancy Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy.

56,57 The majority of recent studies also do not indicate a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned, 55,56,58,59 when taken inadvertently during early pregnancy.

The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy.

Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion.

It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out.

If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period.

Oral contraceptive use should be discontinued if pregnancy is confirmed.

8.

Gallbladder Disease Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens.

60,61 More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal.

62-64 The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens.

9.

Carbohydrate and Lipid Metabolic Effects Oral contraceptives have been shown to cause a decrease in glucose tolerance in a significant percentage of users.

17 This effect has been shown to be directly related to estrogen dose.

65 Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents.

17,66 However, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose.

67 Because of these demonstrated effects, prediabetic and diabetic women in particular should be carefully monitored while taking oral contraceptives.

A small proportion of women will have persistent hypertriglyceridemia while on the pill.

As discussed earlier (see 1a and 1d), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users.

10.

Elevated Blood Pressure Women with significant hypertension should not be started on hormonal contraception.

92 An increase in blood pressure has been reported in women taking oral contraceptives 68 and this increase is more likely in older oral contraceptive users 69 and with extended duration of use.

61 Data from the Royal College of General Practitioners 12 and subsequent randomized trials have shown that the incidence of hypertension increases with increasing progestational activity.

Women with a history of hypertension or hypertension-related diseases, or renal disease 70 should be encouraged to use another method of contraception.

If these women elect to use oral contraceptives, they should be monitored closely and if a clinically significant persistent elevation of blood pressure (BP) occurs (≥ 160 mm Hg systolic or ≥ 100 mm Hg diastolic) and cannot be adequately controlled, oral contraceptives should be discontinued.

In general, women who develop hypertension during hormonal contraceptive therapy should be switched to a non-hormonal contraceptive.

If other contraceptive methods are not suitable, hormonal contraceptive therapy may continue combined with antihypertensive therapy.

Regular monitoring of BP throughout hormonal contraceptive therapy is recommended.

96 For most women, elevated blood pressure will return to normal after stopping oral contraceptives, and there is no difference in the occurrence of hypertension between former and never users.

68-71 11.

Headache The onset or exacerbation of migraine or development of headache with a new pattern which is recurrent, persistent or severe requires discontinuation of oral contraceptives and evaluation of the cause.

12.

Bleeding Irregularities Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use.

Nonhormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding.

If pathology has been excluded, time or a change to another formulation may solve the problem.

In the event of amenorrhea, pregnancy should be ruled out.

Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was preexistent.

13.

Ectopic Pregnancy Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.