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Side Effects & Adverse Reactions
|Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with the extent of smoking (in epidemiologic studies, 15 or more cigarettes per day was associated with a significantly increased risk) 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 risks of several serious conditions including venous and arterial thrombotic and thromboembolic events (such as myocardial infarction, thromboembolism, stroke, and transient ischemic attack), hepatic neoplasia, gallbladder disease, and hypertension, 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 certain inherited or acquired thrombophilias, hypertension, hyperlipidemias, obesity, diabetes, and surgery or trauma with increased risk of thrombosis (see CONTRAINDICATIONS).
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 doses of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower doses 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 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. For further information, the reader is referred to a text on epidemiological methods.
Amethyst is a non-cyclic oral contraceptive that provides a low daily dose of estrogen and progestin; however, Amethyst provide women with more hormonal exposure on a yearly basis (13 additional weeks of hormone intake per year) than conventional cyclic oral contraceptives containing the same strength of synthetic estrogens and similar strength of progestins.
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. 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 infarction in women in their mid-thirties or older with smoking accounting for the majority of excess cases. Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and nonsmokers over the age of 40 (Figure 3) among women who use oral contraceptives.
Figure 3: 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, Lancet, 1:541-546, 1981.
Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age, and obesity. In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism. Oral contraceptives have been shown to increase blood pressure among users (see section 9 in WARNINGS). 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.
An increased risk of venous thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. The risk of venous thrombotic and thromboembolic events is further increased in women with conditions predisposing for venous thrombosis and thromboembolism. 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. 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. The approximate incidence of deep-vein thrombosis and pulmonary embolism in users of low dose (<0.05 mg ethinyl estradiol) combination oral contraceptives is up to 4 per 10,000 woman-years compared to 0.5 to 3 per 10,000 woman-years for non-users. However, the incidence is less than that associated with pregnancy (6 per 10,000 woman-years). The excess risk is highest during the first year a woman ever uses a combined oral contraceptive. Venous thromboembolism may be fatal. The risk of thromboembolic disease due to oral contraceptives is not related to length of use and gradually disappears after pill use is stopped.
A two-to-four fold increase in relative risk of postoperative 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. 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 post-partum 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 breastfeed, or after a midtrimester pregnancy termination.
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, while smoking interacted to increase the risk for hemorrhagic strokes. Transient ischemic attacks have also been associated with oral contraceptive use.
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. The relative risk of hemorrhagic stroke is reported to be 1.2 for nonsmokers 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. The attributable risk is also greater in older women. Oral contraceptives also increase the risk for stroke in women with other underlying risk factors such as certain inherited or acquired thrombophilias. Women with migraine (particularly migraine/headaches with focal neurological symptoms such as aura) who take combination oral contraceptives may be at an increased risk of stroke. (See CONTRAINDICATIONS).
A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease. A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents. 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 nature and absolute amount of progestogen used in the contraceptive. The 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.
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 persisted for at least 9 years for women 40 to 49 years who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups.
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. However, both studies were performed with oral contraceptive formulations containing 0.05 mg or higher of estrogens.
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 3). 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 less than 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. However, current clinical practice involves the use of lower estrogen dose formulations combined with careful restriction of oral contraceptive use to women who do not have the various risk factors listed in this labeling.
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, 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 nonsmoking women (even with the newer low-dose formulations), there are 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 oral contraceptive use by healthy nonsmoking 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.
|Method of control and outcome||AGE|
|15 to 19||20 to 24||25 to 29||30 to 34||35 to 39||40 to 44|
|* Deaths are birth-related|
|**Deaths are method-related|
|Adapted from H.W. Ory, Family Planning Perspectives, 15:57-63, 1983.|
|No fertility-control methods*||7.0||7.4||9.1||14.8||25.7||28.2|
Numerous epidemiological studies have examined the association between the use of oral contraceptives and the incidence of breast and cervical cancer.
The risk of having breast cancer diagnosed may be slightly increased among current and recent users of combination oral contraceptives. However, this excess risk appears to decrease over time after combination oral contraceptive discontinuation and by 10 years after cessation the increased risk disappears. Some studies report an increased risk with duration of use while other studies do not and no consistent relationships have been found with dose or type of steroid. Some studies have reported a small increase in risk for women who first use combination oral contraceptives at a younger age. Most studies show a similar pattern of risk with combination oral contraceptive use regardless of a woman’s reproductive history or her family breast cancer history.
Breast cancers diagnosed in current or previous oral contraceptive users tend to be less clinically advanced than in nonusers.
Women with known or suspected carcinoma of the breast or personal history of breast cancer should not use oral contraceptives because breast cancer is usually a hormonally sensitive tumor.
Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia or invasive cervical cancer in some populations of women. 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 combination oral contraceptive use and breast and cervical cancers, a cause-and-effect relationship has not been established.
Endometrial biopsies performed in a subset of subjects (Study 1; n = 93) ages 18 to 49 years, after 6 to 12 months of use of levonorgestrel and ethinyl estradiol tablets USP, did not reveal any hyperplasias or malignancies. Endometrial malignancy is rare in this age group, so change in the risk is unlikely to be detected with a study of this size.
Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of these 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. Rupture of rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage.
Studies from Britain have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) oral contraceptive user. 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.
There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives that may lead to partial or complete loss of vision. 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.
Extensive epidemiological studies have revealed no increased risk of birth defects in infants born to women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly insofar as cardiac anomalies and limb-reduction defects are concerned, when taken inadvertently during early pregnancy (see CONTRAINDICATIONS section).
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.
The possibility of pregnancy should be considered in any patient who may be experiencing symptoms of pregnancy, especially if she has not adhered to the prescribed schedule. Oral contraceptive use must be discontinued if pregnancy is confirmed.
Combination oral contraceptives may worsen existing gallbladder disease and may accelerate the development of this disease in previously asymptomatic women. Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens. More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal. The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens.
Oral contraceptives have been shown to cause glucose intolerance in a significant percentage of users. Oral contraceptives containing greater than 0.075 mg of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance. Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents. However, in the nondiabetic woman, oral contraceptives appear to have no effect on fasting blood glucose. Because of these demonstrated effects, prediabetic and diabetic women should be carefully observed while taking oral contraceptives.
A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see WARNINGS, 1a. and 1d.; PRECAUTIONS, 3.), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users.
An increase in blood pressure has been reported in women taking oral contraceptives and this increase is more likely in older oral contraceptive users and with continued use. Data from the Royal College of General Practitioners and subsequent randomized trials have shown that the incidence of hypertension increases with increasing quantities of progestogens.
Women with a history of hypertension or hypertension-related diseases, or renal disease should be encouraged to use another method of contraception. If women with hypertension elect to use oral contraceptives, they should be monitored closely and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued (see CONTRAINDICATIONS section). For most women, elevated blood pressure will return to normal after stopping oral contraceptives, and there is no difference in the occurrence of hypertension among ever- and never-users.
The onset or exacerbation of migraine or development of headache with a new pattern that is recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause. (See WARNINGS, 1c. and CONTRAINDICATIONS).
When prescribing Amethyst, the convenience of having no scheduled menstrual bleeding should be weighed against the inconvenience of unscheduled breakthrough bleeding and spotting. In Study 313-NA, 385/2,134 (18%) of women discontinued prematurely due to bleeding that was reported either as an adverse event or where bleeding was given as one of the reasons for discontinuation (see INDICATIONS AND USAGE, Clinical Studies).
Figure 4 shows the percentage of levonorgestrel and ethinyl estradiol tablets USP subjects in study 313-NA by pill pack who experienced unscheduled bleeding or spotting only (Defined as “No sanitary protection required”).
Figure 4: Percentage of Subjects Reporting Bleeding or Spotting Only per Pill Pack
*: The N for each pill pack is the number of subjects with 28 days of data.
Bleeding required sanitary protection; spotting only did not require sanitary protection.
Figure 5 shows the percentage of levonorgestrel and ethinyl estradiol tablets USP subjects with complete bleeding data in Study 313-NA who had 4 or more and 7 or more days of bleeding and/or spotting during each pill pack cycle. During pill pack 2, 67% of subjects experienced 4 or more days of bleeding and/or spotting and 54% of these subjects experienced 7 or more days of bleeding and/or spotting. During the final cycle of use of levonorgestrel and ethinyl estradiol tablets USP (pill pack 13), these percentages were 31% and 20%, respectively.
Figure 5: Percentage of Subjects Reporting Greater than or Equal to 4 or 7 Days of Bleeding and/or Spotting per Pill Pack (Study 313-NA)
*: The N for each pill pack is the number of subjects with 28 days of data.
As in any case of bleeding irregularities, nonhormonal causes should be considered and adequate diagnostic measures may be indicated to rule out pregnancy, infection, malignancy, or other conditions.
Some women may encounter post-pill amenorrhea or oligomenorrhea (possibly with anovulation), especially when such a condition was preexistent.
Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.
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Amethyst™ (levonorgestrel and ethinyl estradiol tablets USP) is indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception.
Oral contraceptives are highly effective for pregnancy prevention. Table 2 lists the typical unintended pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, the IUD, and implants, depend upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.
| % of Women Experiencing an|
within the First Year of Use
| % of Women Continuing Use|
at One Year 3
| Typical Use 1 |
| Perfect Use 2 |
|Levonorgestrel Implants (Norplant®)||0.05||0.05||88|
Emergency Contraceptive Pills: The FDA has concluded that certain combined oral contraceptives containing ethinyl estradiol and norgestrel or levonorgestrel are safe and effective for use as postcoital emergency contraception. Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.9
Lactation Amenorrhea Method: LAM is a highly effective, temporary method of contraception.10
Source: Trussell J. Contraceptive efficacy. In: Hatcher RA, Trussell J, Stewart F, Cates W,
Stewart GK, Kowel D, Guest F. Contraceptive Technology: Seventeenth Revised Edition.
New York NY: Irvington Publishers; 1998.
Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason.
Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason.
Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year.
The percents becoming pregnant in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percent who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether.
Foams, creams, gels, vaginal suppositories, and vaginal film.
Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases.
With spermicidal cream or jelly.
The treatment schedule is one dose within 72 hours after unprotected intercourse, and a second dose 12 hours after the first dose. The FDA has declared the following dosage regimens of oral contraceptives to be safe and effective for emergency contraception: for tablets containing 50 mcg of ethinyl estradiol and 500 mcg of norgestrel 1 dose is 2 tablets; for tablets containing 20 mcg of ethinyl estradiol and 100 mcg of levonorgestrel 1 dose is 5 tablets; for tablets containing 30 mcg of ethinyl estradiol and 150 mcg of levonorgestrel 1 dose is 4 tablets.
However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches 6 months of age.
The efficacy and safety of levonorgestrel and ethinyl estradiol tablets USP were studied in 2 one-year clinical trials of subjects age 18 to 49. There were no exclusions for body mass index (BMI), weight, or bleeding history.
The primary efficacy and safety study (313-NA) was a one-year open-label clinical trial that treated 2,134 subjects in North America. Of these subjects 1,213 (56.8%) discontinued prematurely, including 102 (4.8%) discontinued by the Sponsor for early study closure. The mean weight of subjects in this study was 70.38 kg. The efficacy of levonorgestrel and ethinyl estradiol tablets USP was assessed by the number of pregnancies that occurred after the onset of treatment and within 14 days of the last dose. Among subjects 35 years or less, there were 23 pregnancies (4 of these occurred during the interval 1 to 14 days after the last day of pill use) during 12,572 28-day pill packs of use. The resulting total Pearl Index was 2.38 (95% CI: 1.51, 3.57) and the one-year life table pregnancy rate was 2.39 (95% CI: 1.57, 3.62). Pill pack cycles during which subjects used back-up contraception or were not sexually active were not included in these calculations. Among women 35 years or less who took the pills completely as directed, there were 15 pregnancies (method failures) resulting in a Pearl Index of 1.55 (95% CI: 0.87, 2.56) and the one-year life table pregnancy rate was 1.59 (95% CI: 0.95 to 2.67).
In a second supportive study conducted in Europe (315-EU), 641 subjects were randomized to levonorgestrel and ethinyl estradiol tablets USP (n=323) or the cyclic comparator of 100 mcg levonorgestrel and 20 mcg ethinyl estradiol (n=318). The mean weight of subjects in this study was 63.86 kg. The efficacy analysis among women 35 years or less included 2,756 levonorgestrel and ethinyl estradiol tablets USP pill packs and 2,886 cyclic comparator pill packs. There was one pregnancy in the levonorgestrel and ethinyl estradiol tablets USP group that occurred within 14 days following the last dose. There were three pregnancies in the cyclic comparator group.
Inhibition of Menses (Bleeding Profile)
The bleeding profile for subjects in Study 313-NA also was assessed. Women with a history of unscheduled bleeding and/or spotting were not excluded from the study.
In those subjects who provided complete bleeding data, the percentage of patients who were amenorrheic in a given cycle and remained amenorrheic through cycle 13 (cumulative amenorrhea rate) was determined (Figure 2).
Figure 2: Percentage of Subjects with Cumulative Amenorrhea for Each Pill Pack through Pill Pack 13
The 779 subjects with complete data for 13 pill packs were used in this cumulative analysis.
Subjects were to begin pill pack 1 on the first day of menses.
When prescribing Amethyst, the convenience of having no scheduled menstrual bleeding should be weighed against the inconvenience of unscheduled bleeding and spotting (see WARNINGS, 11).
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Twenty-eight (28) white tablets each containing 90 mcg of levonorgestrel (17α)-(–)13-ethyl-17-hydroxy-18, 19-dinorpregn-4-en-20-yn-3-one, a totally synthetic progestogen, and 20 mcg of ethinyl estradiol, (17α)-19-norpregna-1,3,5(10)-trien-20-yne-3,17-diol. The inactive ingredients present are microcrystalline cellulose, lactose monohydrate, magnesium stearate, croscarmellose sodium, and povidone.