VIORELE (Page 3 of 11)

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 to 49 years old 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 more of estrogen.

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 IV). 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 a possible increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970’s — but not reported until 1983 (35). However, current clinical practice involves the use of lower estrogen formulations combined with careful consideration of risk factors.

Because of these changes in practice and, also, because of some limited new data which suggest that the risk of cardiovascular disease with the use of oral contraceptives may now be less than previously observed (100,101), the Fertility and Maternal Health Drugs Advisory Committee was asked to review the topic in 1989. 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.

Therefore, 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 the lowest possible dose formulation that is effective.

TABLE III: ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NON-STERILE WOMEN, BY FERTILITY CONTROL METHOD ACCORDING TO AGE

Method of control and outcome	15 to 19	20 to 24	25 to 29	30 to 34	35 to 39	40 to 44
No fertility control methodsa	7	7.4	9.1	14.8	25.7	28.2
Oral contraceptives non-smokerb	0.3	0.5	0.9	1.9	13.8	31.6
Oral contraceptives smokerb	2.2	3.4	6.6	13.5	51.1	117.2
IUDb	0.8	0.8	1	1	1.4	1.4
Condoma	1.1	1.6	0.7	0.2	0.3	0.4
Diaphragm/spermicidea	1.9	1.2	1.2	1.3	2.2	2.8
Periodic abstinencea	2.5	1.6	1.6	1.7	2.9	3.6
Adapted from H.W. Ory, ref. #35.

^a) Deaths are birth related

^b) Deaths are method related

3. Malignant Neoplasms

Breast Cancer

VIORELE^® 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 Adverse Reactions, Postmarketing Experience).

Cervical Cancer

Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intra-epithelial neoplasia in some populations of women (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.