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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 heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.
Gianvi™ (drospirenone and ethinyl estradiol tablets) contains 3 mg of the progestin drospirenone that has antimineralocorticoid activity, including the potential for hyperkalemia in high-risk patients, comparable to a 25 mg dose of spironolactone. Gianvi™ (drospirenone and ethinyl estradiol tablets) should not be used in patients with conditions that predispose to hyperkalemia (i.e., renal insufficiency, hepatic dysfunction and adrenal insufficiency). Women receiving daily, long-term treatment for chronic conditions or diseases with medications that may increase serum potassium should have their serum potassium level checked during the first treatment cycle. Medications that may increase serum potassium include ACE inhibitors, angiotensin – II receptor antagonists, potassium-sparing diuretics, potassium supplementation, heparin, aldosterone antagonists, and NSAIDs.
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), hepatic neoplasia, gallbladder disease, and hypertension. 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 based principally 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, epidemiologic 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. For further information, the reader is referred to a text on epidemiologic methods.
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 infarctions 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 (Table IV) among women who use oral contraceptives.
|(Adapted from P.M. Layde and V. Beral)|
|15 to 24||0||10.5||0||0|
|25 to 34||4.4||14.2||2.7||4.2|
|35 to 44||21.5||63.4||6.4||15.2|
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 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. 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 risk of thromboembolic disease due to oral contraceptives is not related to length of use and disappears after pill use is stopped.
A two- to four-fold increase in the 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. If feasible, oral contraceptives should be discontinued from 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, combined oral contraceptives should be started no earlier than four to six weeks after delivery and at that time only in women who elect not to breast feed.
Several studies have investigated the relative risks of thromboembolism in women using a different drospirenone-containing COC (Yasmin, which contains 0.030 mg of ethinyl estradiol and 3 mg of drospirenone) compared to those in women using COCs containing other progestins. Two prospective cohort studies, both evaluating the risk of venous and arterial thromboembolism and death, were initiated at the time of Yasmin approval.1, 2 The first (EURAS) showed the risk of thromboembolism (particularly venous thromboembolism) and death in Yasmin users to be comparable to that of other oral contraceptive preparations, including those containing levonorgestrel (a so-called second generation COC). The second prospective cohort study (Ingenix) also showed a comparable risk of thromboembolism in Yasmin users compared to users of other COCs, including those containing levonorgestrel. In the second study, COC comparator groups were selected based on their having similar characteristics to those being prescribed Yasmin.
Two additional epidemiological studies, one case-control study (van Hylckama Vlieg et al.3) and one retrospective cohort study (Lidegaard et al.4) suggested that the risk of venous thromboembolism occurring in Yasmin users was higher than that for users of levonorgestrel-containing COCs and lower than that for users of desogestrel/gestodene-containing COCs (so-called third generation COCs). In the case-control study, however, the number of Yasmin cases was very small (1.2% of all cases) making the risk estimates unreliable. The relative risk for Yasmin users in the retrospective cohort study was greater than that for users of other COC products when considering women who used the products for less than one year. However, these one-year estimates may not be reliable because the analysis may include women of varying risk levels. Among women who used the product for 1 to 4 years, the relative risk was similar for users of Yasmin to that for users of other COC products.
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.
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, hyperlipidemias, and obesity. Women with migraine (particularly migraine with aura) who take combination oral contraceptives may be at an increased risk of stroke.
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 that 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 persists for at least 9 years for women aged 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 50 micrograms 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 V). 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 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. 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, women of all ages who take oral contraceptives should take the lowest possible dose formulation that is effective.
|Adapted from H.W. Ory, Family Planning Perspectives, 15:57-63, 1983.|
|Method of Control and Outcome||15 to 19 years||20 to 24 years||25 to 29 years||30 to 34 years||35 to 39 years||40 to 44 years|
|No fertility control methods*||7||7.4||9.1||14.8||25.7||28.2|
|Oral contraceptives non-smoker†||0.3||0.5||0.9||1.9||13.8||31.6|
|Oral contraceptives smoker†||2.2||3.4||6.6||13.5||51.1||117.2|
Numerous epidemiological studies have been performed on the incidence of breast, endometrial, ovarian and cervical cancer in women using oral contraceptives.
Although the risk of having breast cancer diagnosed may be slightly increased among current and recent users of combined oral contraceptives (RR=1.24), this excess risk decreases over time after combination oral contraceptive discontinuation and by 10 years after cessation the increased risk disappears. The risk does not increase with duration of use and no consistent relationships have been found with dose or type of steroid. The patterns of risk are also similar regardless of a woman's reproductive history or her family breast cancer history. The subgroup for whom risk has been found to be significantly elevated is women who first used oral contraceptives before age 20, but because breast cancer is so rare at these young ages, the number of cases attributable to this early oral contraceptive use is extremely small.
Breast cancers diagnosed in current or previous OC users tend to be less clinically advanced than in never users.
Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is a hormonally-sensitive tumor.
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. 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.
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. 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 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.
There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives, which 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 women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb-reduction defects are concerned, 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. (See CONTRAINDICATIONS)
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 dosing 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.
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 75 micrograms 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.), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users.
Women with severe hypertension should not be started on hormonal contraceptives (see CONTRAINDICATIONS).
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 concentrations 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. 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 which is recurrent, persistent or severe requires discontinuation of oral contraceptives and evaluation of the cause.
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 pre-existent.
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FDA Labeling Changes
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Gianvi™ (drospirenone and ethinyl estradiol tablets) 3 mg/0.02 mg is indicated for the prevention of pregnancy in women who elect to use an oral contraceptive.
Oral contraceptives are highly effective. Table II 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 and contraceptive implants and IUDs, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.
Gianvi™ (drospirenone and ethinyl estradiol tablets) is indicated for the treatment of moderate acne vulgaris in women at least 14 years of age, who have no known contraindications to oral contraceptive therapy and have achieved menarche. Gianvi™ (drospirenone and ethinyl estradiol tablets) should be used for the treatment of acne only if the patient desires an oral contraceptive for birth control.
|% of Women Experiencing an Unintended Pregnancy Within the First Year of Use||% of Women Continuing Use at One Year|
|Method (1)||Typical Use (2)||Perfect Use (3)||(4)|
|Copper T 380A||0.8||0.6||78|
|Norplant and Norplant-2||0.05||0.05||88|
|Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.|
|Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception.|
|Source: Trussell J, Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Guest F, Kowal D, Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington Publishers, 1998.|
In the primary contraceptive efficacy study of drospirenone and ethinyl estradiol tablets (3 mg DRSP/0.02 mg EE) of up to 1 year duration, 1,027 subjects were enrolled and completed 11,480 28-day cycles of use. The age range was 17 to 36 years. The racial demographic was: 87.8% Caucasian, 4.6% Hispanic, 4.3% Black, 1.2% Asian, and 2.1% other. Women with a BMI greater than 35 were excluded from the trial. The pregnancy rate (Pearl Index) was 1.41 per 100 woman-years of use based on 12 pregnancies that occurred after the onset of treatment and within 14 days after the last dose of drospirenone and ethinyl estradiol tablets in women 35 years of age or younger during cycles in which no other form of contraception was used.
In two multicenter, double blind, randomized, placebo-controlled studies, 889 subjects, ages 14 to 45 years, with moderate acne received drospirenone and ethinyl estradiol tablets or placebo for six 28 day cycles. The primary efficacy endpoints were the percent change in inflammatory lesions, non-inflammatory lesions, total lesions, and the percentage of subjects with a “clear” or “almost clear” rating on the Investigator’s Static Global Assessment (ISGA) scale on day 15 of cycle 6, as presented in Table III:
|* Evaluated at day 15 of cycle 6, last observation carried forward for the Intent to treat population|
|Study 1||Study 2|
|Drospirenone and Ethinyl Estradiol Tablets N=228||Placebo N=230||Drospirenone and Ethinyl Estradiol Tablets N=218||Placebo N=213|
|ISGA Success Rate||35 (15%)||10 (4%)||46 (21%)||19 (9%)|
Mean Baseline CountMean Absolute (%) Reduction
Mean Baseline CountMean Absolute (%) Reduction
Mean Baseline CountMean Absolute (%) reduction
There is currently no drug history available for this drug.
Gianvi™ (drospirenone and ethinyl estradiol tablets) 3 mg/0.02 mg provides an oral contraceptive regimen consisting of 24 active film-coated tablets each containing 3 mg of drospirenone and 0.02 mg of ethinyl estradiol and 4 inert film-coated tablets. Other ingredients are anhydrous lactose, corn starch, crospovidone, FD&C red no. 40 aluminum lake, FD&C yellow no. 6 aluminum lake, hypromellose, magnesium stearate, polyethylene glycol, polysorbate 80, povidone, pregelatinized starch and titanium dioxide. The inert tablets contain anhydrous lactose, hypromellose, magnesium stearate, and microcrystalline cellulose.
Drospirenone (6R,7R,8R,9S,10R,13S,14S,15S,16S,17S)-1,3’,4’,6,6a,7,8,9,10,11, 12,13,14,15,15a,16-hexadecahydro-10,13-dimethylspiro-[17H-dicyclopropa-[6,7:15,16]cyclopenta[a]phenanthrene-17,2’(5H)-furan]-3,5’(2H)-dione) is a synthetic progestational compound. Ethinyl estradiol (19-nor-17α-pregna 1,3,5(10)-triene-20-yne-3, 17-diol) is a synthetic estrogenic compound. The structural formulas are as follows:
C24H30O3 Molecular Weight: 366.5
C20H24O2 Molecular Weight: 296.4