brand portia-28 tablet

Cautions

The potential risks of estrogen-progestin contraceptive use have been established in women of reproductive age. The risks should be identical for postpubertal adolescents under 16 years of age and users 16 years of age or older. Estrogen-progestin combination contraceptives including short-term, high-dose postcoital contraceptives are not indicated before menarche.

Exposure to ethinyl estradiol and norelgestromin is higher in women receiving the Ortho-Evra transdermal system than in women receiving an oral contraceptive preparation containing ethinyl estradiol 35 mcg and norgestimate 0.25 mg per tablet. Increased exposure to estrogen may increase the risk for adverse effects.

Exposure to ethinyl estradiol and levonorgestrel is higher in women receiving Lybrel (a fixed-combination continuous-regimen oral contraceptive) than in women receiving a conventional-cycle oral contraceptive containing the same ethinyl estradiol dose and a similar dose of the progestin component; use of Lybrel results in 13 additional weeks of hormone intake per year.

Epidemiologic data are not available to determine whether safety and efficacy associated with the vaginal route of administration of estrogen-progestin contraceptives differ from the oral route. Adverse effects similar to those with oral estrogen-progestin contraceptives generally are expected with vaginal estrogen-progestin contraceptives.

Information on the potential risks of estrogen-progestin contraceptive use (and associated cautions, precautions, and contraindications) is based principally on studies and experience with preparations that contained higher estrogen and/or progestin doses than those in currently available preparations. The relative risks associated with use of currently available lower-dose preparations remains to be determined. For example, while previous experience indicated that the risk of adverse cardiovascular effects associated with oral contraceptives was increased in nonsmoking women older than 40 years of age, this risk may have resulted in part from the high estrogen content of previously available preparations. It currently is not known whether such increased cardiovascular risk also is associated with use of currently available, low-dose preparations, but some experts consider the possible benefits of low-dose (containing no more than 35 mcg of estrogen) oral contraceptives to outweigh the potential risks of pregnancy in healthy nonsmoking women older than 40 years of age who have no other risk factors. 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 risk factors (e.g., hypertension, hyperlipidemias, obesity, diabetes).

Common adverse effects of oral estrogen-progestin contraceptives appear to be mainly caused by the estrogen, are usually most pronounced during the first oral contraceptive cycle, and disappear or diminish after 3 or 4 cycles; there does not appear to be any advantage in changing preparations during this period of time. If minor adverse effects persist after the fourth cycle, a different combination of drugs or a different dosage may be tried. Although conventional-dosage preparations (containing 35 mcg or more of ethinyl estradiol or 50 mcg or more of mestranol) are generally associated with slightly lower pregnancy rates than reduced-dosage preparations, conventional-dosage preparations are generally more frequently associated with adverse effects (e.g., edema, nausea and vomiting, thromboembolic disorders) than reduced-dosage preparations; however, reduced-dosage preparations are more frequently associated with bleeding irregularities, including breakthrough bleeding, spotting, and menstrual irregularities, than conventional-dosage preparations. Because of the increased risk of thromboembolic disorders associated with conventional-dosage preparations, reduced-dosage preparations are recommended for initial use in patients who have not previously received oral contraceptives. Although numerous adverse effects have been reported in women receiving oral contraceptives, many of the reported effects are conditions that could occur spontaneously in women of childbearing age and a causal relationship has, in many instances, been difficult to establish.

It is not known if oral contraceptive combinations containing desogestrel or norgestimate cause fewer androgenic effects (e.g., acne, hirsutism, weight gain) than estrogen-progestin combinations containing conventional progestins (e.g., levonorgestrel, norethindrone). There is some evidence that oral contraceptives containing desogestrel may be associated with an increased risk of nonfatal venous thrombosis. (See Thromboembolic Disorders in Cautions: Cardiovascular Effects.)

Limited data are available concerning the risk of using short-course, high-dose estrogen-progestin combinations for emergency contraception. No serious or long-term complications have been associated with such postcoital regimens in Europe, where experience is extensive. In addition, some evidence indicates that emergency postcoital contraception may not compromise conventional contraception use or sexual behavior (e.g., promiscuity, sexually transmitted disease [STD] risk).

GI Effects

The most frequent adverse effect of oral contraceptives is nausea. In addition, nausea has been reported in women using vaginal or transdermal estrogen-progestin contraceptives.

The principal risk associated with currently recommended high-dose, postcoital estrogen-progestin combination regimens appears to be moderate to severe adverse GI effects including severe vomiting and nausea, which occur in 12-22 and 30-66%, respectively, of women receiving the short-course regimens and may limit compliance with, and effectiveness of, the regimens. In 2 prospective, randomized studies, nausea and vomiting were less common with a high-dose postcoital progestin-only regimen (0.75 mg levonorgestrel every 12 hours for 2 doses) than with a high-dose estrogen-progestin regimen (100 mcg ethinyl estradiol and 0.5 mg levonorgestrel every 12 hours for 2 doses).

Other adverse GI effects include vomiting, abdominal cramps, abdominal pain, bloating, diarrhea, constipation, and inflammatory bowel disease. Gingivitis and dry socket also have been reported. Changes in appetite and changes in weight also may occur.

Dermatologic Effects

The most frequent dermatologic reaction to oral contraceptives is chloasma or melasma. Women who have had melasma during pregnancy appear to be most susceptible. Irregular brown macules may develop slowly on the face within 1 month to 2 years following initiation of oral contraceptive therapy. The macules fade more slowly than in melasma gravidarum and may be permanent.

Acne may improve during oral contraceptive therapy because of decreased sebum production and depression of sebaceous gland activity; however, it may increase in severity during initial therapy and may develop in some women who have not previously had acne.

Other dermatologic reactions include allergic rash, urticaria, erythema multiforme, erythema nodosum, hemorrhagic eruption, pruritus, and angioedema. Hirsutism and alopecia also have occurred. Herpes gestationis and porphyria cutanea have reportedly been adversely affected in women receiving oral contraceptives.

Application site reaction has occurred in women using the transdermal contraceptive system containing ethinyl estradiol and norelgestromin. The manufacturer states that if such skin irritation occurs, the transdermal system may be removed and a new patch applied to a different location until the next new application day.

Cardiovascular Effects

A positive association between the amount of estrogen and progestin in oral contraceptives and the risk of adverse cardiovascular effects has been observed. Adverse effects similar to those with oral combination estrogen-progestin contraceptives generally are expected with vaginal or transdermal estrogen-progestin contraceptives.

Elevated Blood Pressure

Increases in blood pressure may occur in women receiving estrogen-progestin contraceptives. Blood pressure elevations are usually minor, but clinically important hypertension may occur in some women. Some women develop hypertension within 1-3 weeks after initiation of oral contraceptive therapy and become normotensive during the part of the oral contraceptive cycle when they do not receive the drugs. In others, blood pressure increases slowly and may not reach abnormal levels for several months. Elevated blood pressure may gradually decrease or persist after the oral contraceptive is discontinued.

The risk of hypertension increases with increasing duration of oral contraceptive use and is about 2.5-3 times greater in the fifth year of continual use than in the first year. Age also is positively correlated with the risk of hypertension in oral contraceptive users, becoming substantial in women about 35 years of age and older. Women with a history of hypertension, preexisting renal disease, a history of toxemia or elevated blood pressure during pregnancy, a familial tendency toward hypertension or its consequences, or a history of excessive weight gain or fluid retention during the menstrual cycle may be at increased risk of developing elevated blood pressure during estrogen-progestin contraceptive therapy and, therefore, should be monitored closely. Even though elevated blood pressure may remain within the normal range, the clinical implications of elevations should be considered in all patients. All women, but particularly those with other risk factors for cardiovascular disease or stroke, should have blood pressure measurements before an oral contraceptive is prescribed and at regular intervals during therapy.

Thromboembolic Disorders

Oral contraceptive use is associated with an increased risk of thromboembolic and thrombotic disorders. One study has shown an increased relative risk of fatal venous thromboembolism (VTE) and several other studies have shown an increased relative risk of nonfatal VTE in oral contraceptive users. Case-controlled studies estimated that the relative risk for developing fatal or nonfatal thromboembolism (ranging in severity from superficial thrombosis to pulmonary embolism) was 3-11 times greater in oral contraceptive users than in nonusers and 1.5-6 times greater in women predisposed to venous thromboembolic disorders. However, cohort studies suggest that the overall relative risk is somewhat lower, ranging from 3 times greater for new cases to 4.5 times greater for new cases requiring hospitalization in oral contraceptive users when compared with nonusers. A prospective review failed to show increased mortality rates from cardiovascular disorders in oral contraceptive users; however, when a selected subset of this study was analyzed in a retrospective, case-controlled fashion, an increased risk of VTE was associated with oral contraceptive use. Hereditary coagulation disorders, such as factor V Leiden mutation, increase the risk of thromboembolic disease. The risk of thromboembolic disease from oral contraceptive use is not related to the duration of use and disappears when oral contraceptive use is discontinued.

The pharmacokinetic profile for the transdermal contraceptive system containing ethinyl estradiol and norelgestromin (Ortho Evra) differs from the profile for oral contraceptive preparations. Overall exposure to ethinyl estradiol and norelgestromin is higher in women receiving Ortho Evra than in women receiving an oral contraceptive preparation containing ethinyl estradiol 35 mcg and norgestimate 0.25 mg per tablet.(See Pharmacokinetics: Absorption.) Increased exposure to estrogen may increase the risk of certain adverse effects (e.g., VTE). The risk of VTE in women using Ortho Evra relative to the risk in women using an oral contraceptive containing norgestimate or levonorgestrel and ethinyl estradiol 30-35 mcg has been investigated in several epidemiologic, case-controlled studies. In one study that used data from health care claims, current use of Ortho Evra was not associated with an increased risk of nonfatal VTE compared with use of an oral contraceptive (odds ratio [OR] 0.9; 95% confidence interval: 0.5-1.6). In a subsequent analysis that included an additional 17 months of data from this study, current use of Ortho Evra was not associated with an increased risk of nonfatal VTE compared with use of an oral contraceptive (OR 1.1; 95% confidence interval: 0.6-2.1). In another study that used claims data and chart review, current use of Ortho Evra was associated with an increased risk of VTE compared with use of an oral contraceptive (OR 2.4; 95% confidence interval: 1.1-5.5). Findings from another study that used claims data indicated current use of Ortho Evra might be associated with an increased risk of idiopathic VTE compared with use of an oral contraceptive (OR 2; 95% confidence interval: 0.9-4.1).

Because the fixed-combination continuous-regimen oral contraceptive (Lybrel) is administered daily (not cyclically), overall exposure to estrogen and progestin is higher in women receiving this preparation than in women receiving a conventional-cycle oral contraceptive containing the same dose of ethinyl estradiol and a similar dose of the progestin component.

A review conducted by the US Food and Drug Administration (FDA) indicates that the use of oral contraceptive combinations that contain the progestins desogestrel (Desogen, Ortho-Cept) or gestodene (not commercially available in the US) may be associated with an increased risk of nonfatal venous thrombosis compared with oral contraceptives containing conventional progestins (e.g., levonorgestrel, norethindrone). This conclusion was based on interim results of 3 unpublished comparative studies (i.e., by the World Health Organization [WHO], by the Boston Drug Surveillance Program, by the European Transnational study coordinated by McGill University of Canada). Interim results of these unpublished studies indicate that, while the overall risk of nonfatal venous thrombosis is lower than that reported in previous studies, estrogen-progestin combinations containing desogestrel or gestodene appear to be associated with a twofold increased risk of venous thrombosis compared with oral contraceptives containing conventional progestins. Some experts have recommended that estrogen-progestin combinations containing desogestrel or gestodene not be prescribed routinely for prevention of conception in women; however, other clinicians state that further analysis of data is needed for such a recommendation. Although the FDA does not recommend that women currently using oral contraceptives containing desogestrel discontinue such use or switch to another estrogen-progestin combination contraceptive, the FDA states that women using an oral contraceptive containing desogestrel should be advised to discuss such use with their clinician, taking into consideration the relative risks and benefits associated with these oral contraceptives. It should be considered that the contraceptive vaginal ring (NuvaRing) contains etonogestrel, the active metabolite of desogestrel; however, it is not known whether NuvaRing is associated with an increased risk of venous thrombosis.

Another safety review conducted by the FDA indicates that use of combination oral contraceptives containing the progestin drospirenone may be associated with an increased risk of VTE compared with that of oral contraceptives containing levonorgestrel or other progestins. This conclusion was based on results of several epidemiologic studies (i.e., the US postapproval safety study by Ingenix, the European Active Surveillance Study [EURAS], the Long-Term Active Surveillance Study [LASS], 2 Danish cohort studies, the Dutch multiple environmental and genetic assessment of risk factors for venous thrombosis [MEGA] study, the UK General Practice Research Database [GPRD] study, the PharMetrics study, and the FDA-supported study) evaluating the risk of VTE in women using oral contraceptives containing drospirenone. These studies reported that the risk of VTE in such women ranged from no increase to a threefold increase in risk. The FDA's safety review was prompted by results of 2 recent case-control studies that showed a twofold to threefold increased risk of VTE (including deep-vein thrombosis and pulmonary embolism) in patients receiving oral contraceptives containing drospirenone compared with those receiving oral contraceptives containing the progestin levonorgestrel. These 2 studies evaluated cases of idiopathic VTE occurring in women 15-44 years of age who were current users of oral contraceptives containing 30 mcg of estrogen with either drospirenone or levonorgestrel; women with risk factors for VTE were excluded from the studies. The FDA has also reviewed data from a large US retrospective cohort study in more than 800,000 women evaluating thrombotic and thromboembolic risks (including VTE) associated with hormonal contraceptives. Final results from this study suggest an increased risk of VTE (hazard ratio greater than 1) in women using oral contraceptives containing drospirenone compared with women using other hormonal contraceptives.(See Cautions: Precautions and Contraindications.)

Given the conflicting results of the previous epidemiologic studies and the recent findings, the FDA held a joint meeting of the Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee on December 8, 2011, to review the risks and benefits of such therapy and specifically discuss the risk of VTE associated with drospirenone-containing hormonal contraceptives. The studies reviewed by the FDA did not provide consistent data for the comparative risk of thromboembolic events between oral contraceptives that contain drospirenone and those that do not. In addition, the studies did not account for important known and unknown patient characteristics that may influence prescribing patterns and may affect risk of VTE. For these reasons, the FDA states that it is unclear whether the increased risk of thromboembolic events observed in these epidemiologic studies actually resulted from use of drospirenone-containing oral contraceptives. At this time, the FDA has concluded that the risk of VTE may be higher for such oral contraceptives. The FDA will continue to communicate any new safety information as it becomes available.

An increased risk of cerebrovascular disorders, including thrombotic and hemorrhagic stroke, also is associated with oral contraceptive use, although the risk generally is greatest in older (i.e., older than 35 years of age), hypertensive women who also smoke. The use of estrogen-progestin contraceptives also is associated with an increased risk of stroke in women with other underlying risk factors. Hypertension is a risk factor in both users and nonusers of oral contraceptives for both thrombotic and hemorrhagic stroke, while smoking appears to increase the risk for hemorrhagic stroke. Although cigarette smoking alone has been associated with an increased risk of cerebrovascular disorders, concomitant cigarette smoking and oral contraceptive use is associated with a greater risk of these disorders than either alone. The relative risk of thrombotic stroke has been shown to range from 3 for normotensive users of oral contraceptives to 14 for users with hypertension. The relative risk of hemorrhagic stroke is reported to be 1.2 in nonsmoking women who use oral contraceptives, 2.6 in nonusers who do not smoke, 7.6 in users who smoke, 1.8 in normotensive users, and 25.7 in users with severe hypertension. The risk also appears to be greater in older women.

An increased relative risk of myocardial infarction has been associated with oral contraceptive use. In one study, oral contraceptive use was one of several risk factors for coronary artery disease which included cigarette smoking, hypertension, hypercholesterolemia, obesity, diabetes, and preeclamptic toxemia; the risk of myocardial infarction increased as the number of risk factors for coronary artery disease increased. The relative risk of developing fatal myocardial infarction has been estimated as twice as great in oral contraceptive users who do not smoke compared with nonusers who do not smoke, as 5 times greater in oral contraceptive users who smoke compared with users who do not smoke, and about 10-12 times greater in users who smoke compared with nonusers who do not smoke; women who smoke 15 or more cigarettes daily are especially at risk. However, other data suggest that the likelihood of myocardial infarction is not increased in young women who use oral contraceptives and do not smoke or have hypertension or diabetes.

A positive association between thromboembolic disorders and estrogen dosage of oral contraceptives also exists. The progestin content of oral contraceptives also appears to contribute to the risk of thromboembolic disorders. Use of oral contraceptive combinations that contain the progestins desogestrel or gestodene (not commercially available in the US) may be associated with an increased risk of nonfatal venous thrombosis compared with use of oral contraceptives containing conventional progestins (e.g., levonorgestrel, norethindrone). However, desogestrel has minimal androgenic activity and there is some evidence that the risk of myocardial infarction associated with oral contraceptives is lower when the progestin has minimal androgenic activity than when the activity is greater. A relationship between the estrogen and/or progestin dosage of oral contraceptives and the risk of myocardial infarction has not been established. However, a decrease in serum high-density lipoprotein (HDL) concentration has been reported with increasing progestational activity of oral contraceptives and decreased HDL has been associated with an increased risk of ischemic heart disease. (See Effects on Lipids and Lipoproteins, in Cautions: Endocrine and Metabolic Effects.)

The clinician and the woman using estrogen-progestin contraceptives should be alert to the earliest signs and symptoms of thromboembolic and thrombotic disorders (e.g., thrombophlebitis, pulmonary embolism, cerebrovascular insufficiency, coronary occlusion, retinal thrombosis, mesenteric thrombosis). Estrogen-progestin contraceptives should be discontinued immediately when any of these disorders occurs or is suspected. A two- to four-fold increased risk of postsurgery thromboembolic complications has been reported in oral contraceptive users; the risk in women predisposed to venous thromboembolic disorders is twice that in women who have no such predisposition. (See Cautions: Precautions and Contraindications.)

Other Cardiovascular Effects

Oral contraceptives may cause some degree of fluid retention and edema. Oral contraceptives should be used with caution in patients with conditions that might be aggravated by fluid retention. (See Cautions: Precautions and Contraindications.) Premature ventricular and supraventricular complexes and other ECG abnormalities have been reported in women receiving oral contraceptives; however, a causal relationship has not been established.

Endocrine and Metabolic Effects

Endocrine function test results may be altered in patients receiving oral contraceptives. If results of endocrine function tests are abnormal, the tests should be repeated 2 months after the drug has been discontinued.

Effects on Glucose

Decreased glucose tolerance has been observed in a significant percentage of patients receiving oral contraceptives. Fasting blood glucose concentrations are not altered in most patients; however, increased plasma insulin and blood pyruvate concentrations may occur. Although decreased glucose tolerance appears to be directly related to the estrogen of oral contraceptives, estrogen alone does not appear to decrease glucose tolerance and therefore this effect appears to involve both estrogenic and progestinic components. Progestins increase insulin secretion and insulin resistance, and these effects vary among different progestin agents. Prediabetic and diabetic patients should be carefully monitored during estrogen-progestin contraceptive therapy.

Effects on Lipids and Lipoproteins

Increased concentrations of plasma triglyceride, low-density lipoproteins, and total phospholipids may occur during therapy with estrogen-progestin contraceptives. The clinical importance of these alterations in lipid and lipoprotein concentrations has not been established; however, it may be advisable to avoid use of oral contraceptives in women with elevated serum lipids. Generally, the progestin component of oral contraceptives has been shown to decrease high-density lipoprotein cholesterol (HDL-cholesterol), whereas the estrogen component has been shown to increase it; however, some newer progestins (e.g., desogestrel, norgestimate) also may increase HDL-cholesterol. Therefore, it has been suggested that the net effect of estrogen-progestin contraceptives on high-density lipoprotein cholesterol depends on the specific formulation.

Effects on Thyroid

The estrogenic component of estrogen-progestin contraceptives may produce elevations in thyroxine-binding globulin (TBG) resulting in elevated total circulating thyroid hormone, as measured by protein-bound iodine (PBI), thyroxine (T₄) (by column and radioimmunoassay), and butanol extractable iodine. Decreased triiodothyronine (T₃) resin uptake, reflecting elevated TBG, also occurs, while free T₄ concentrations are unaltered. Basal metabolic rate, cholesterol concentrations, iodine-131 uptake, and the free thyroxine index remain unchanged, suggesting that thyroid function is not affected. Abnormal thyroid function test results usually return to pretreatment levels within 2-4 months after estrogen therapy is discontinued.

Other Endocrine and Metabolic Effects

Estrogen-progestin contraceptives also affect other serum proteins. Serum albumin may be increased or decreased and variable effects on immunoglobulins have been reported. Serum cholinesterase, haptoglobulins, and orosomucoid decrease; transferrin, plasminogen, α₂-macroglobulin, and testosterone- and estradiol-binding globulins are increased. Estrogen-progestin contraceptive therapy causes decreased pregnanediol excretion. Ceruloplasmin elevations may give plasma a green color. Cryofibrinogenemia has also been reported. The renin substrate (angiotensinogen) concentration is increased and the aldosterone excretion rate is moderately elevated. Some patients may have hyporesponsive plasma renin activity with normal aldosterone excretion for a few weeks after oral contraceptives are discontinued. Estrogen-progestin contraceptives may cause increased serum magnesium, copper, zinc, and iron concentrations as well as total iron-binding capacity; however, the clinical importance of these increased mineral concentrations has not been determined.

Oral contraceptives may also decrease the response to the metyrapone test. (See Laboratory Test Interferences.)

Because drospirenone has antimineralocorticoid activity, the potential exists for hyperkalemia to occur in high-risk patients (e.g., those with renal or hepatic impairment, adrenal insufficiency) receiving oral contraceptives containing this progestin.

Hepatic Effects

Liver function test results may be altered in patients receiving oral contraceptives and if results of these tests are abnormal, they should be repeated 2 months after the drugs have been discontinued. Increased sulfobromophthalein retention occurs frequently, as a result of interference with the transfer of dye conjugates from liver cells into bile; uptake, conjugation, and storage do not appear to be affected. Less frequently, increased serum aminotransferase and alkaline phosphatase concentrations may occur. Liver function test results usually return to normal within several weeks after oral contraceptives are discontinued; occasionally, however, abnormal test results may persist for longer periods.

Cholestatic jaundice has been reported during oral contraceptive use. Cholestasis is manifested by the development of malaise, anorexia, and pruritus about 2 weeks to 2 months after the start of therapy. Occasionally, arthralgia, fever, and rash may occur. Serum bilirubin concentration may range from 3-10 mg/dL and is mostly conjugated. Women with a history of jaundice during pregnancy have an increased risk of jaundice recurrence while receiving oral contraceptives. If jaundice occurs during oral contraceptive therapy, the drugs should be discontinued. Oral contraceptives may precipitate hepatic forms of porphyria and these drugs probably should not be used by women who have a familial history of hepatic porphyrias, since the occurrence of these conditions appears to be genetically determined. Budd-Chiari syndrome has also occurred in oral contraceptive users. Many patients who develop oral contraceptive- or pregnancy-associated Budd-Chiari syndrome also may have inherited or acquired thrombophilia. Steroid hormones (including oral contraceptives) may be poorly metabolized in patients with hepatic dysfunction; therefore, the drugs should be administered with caution to these individuals.

Liver tumors have been associated with oral contraceptive use. Liver tumors have been benign or malignant and have occurred during short-term and long-term use of oral contraceptives. Most commonly, liver tumors are benign hepatocellular adenomas. Long-term oral contraceptive users have an estimated annual incidence of hepatocellular adenoma of 3-4 per 100,000; risk appears to increase after 4 or more years of use. In several women who developed benign hepatocellular adenomas during oral contraceptive use, these tumors regressed following discontinuance of the drugs. Although benign hepatocellular adenomas are apparently uncommon findings in oral contraceptive users, they may result in death because of their vascularity which predisposes them to rupture and massive hemorrhage. Therefore, the presence of a liver tumor should be considered in women who develop sudden severe abdominal pain or shock. Patients with liver tumors have shown variable clinical features which may make preoperative diagnosis difficult; some of these patients have had right upper quadrant masses, while most have had signs and symptoms of acute intraperitoneal hemorrhage. Routine radiologic and laboratory test evaluations may not be helpful. Liver scans may show a focal defect, and hepatic arteriography may be useful in diagnosing primary liver neoplasm. Hepatocellular carcinoma has also been reported rarely in women receiving oral contraceptives, although a causal relationship to the drugs has not been clearly established. For women using oral contraceptives for 8 or more years, several epidemiologic studies have suggested a relative risk that is up to 7-20 times that of nonusers, although the occurrence of this tumor is rare. It also has not been clearly established whether hepatic adenoma induced by oral contraceptives can differentiate into hepatic carcinoma.

Genitourinary Effects

Breakthrough bleeding and/or spotting (especially within the first 3 months of use), changes in menstrual flow, missed menses (during use), or amenorrhea (after use) may occur in women receiving hormonal contraceptives. Bleeding irregularities are more frequently associated with reduced-dosage preparations than with conventional-dosage preparations. Breakthrough bleeding that occurs early in the cycle generally is caused by a lack of adequate estrogenic stimulation, whereas bleeding after midcycle generally indicates progestin deficiency. Changes in the estrogen and/or progestin dose, ratio, and/or sequence may control or alleviate breakthrough bleeding. In women who develop breakthrough bleeding while receiving a biphasic oral contraceptive, switching to a triphasic oral contraceptive may control or alleviate bleeding since the progestin dose is increased after day 7 with the triphasic regimen. Once the possibility of pregnancy has been ruled out in women with missed menses (absence of withdrawal bleeding) (see Pregnancy, in Cautions: Pregnancy, Fertility, and Lactation), switching to a preparation with higher estrogenic activity or dose or to a triphasic preparation (since it allows endometrial proliferation during the initial 7-day, low-dose progestin period) may be beneficial. However, the risks (e.g., adverse cardiovascular effects) associated with increased estrogen and progestin doses must be considered, and increasing the dose to minimize bleeding irregularities should only be done if necessary.

While use of an extended-cycle oral contraceptive (e.g., LoSeasonique, Seasonale, Seasonique) results in fewer planned menses (4 per year) than conventional-cycle oral contraceptives (13 per year), bleeding irregularities occur more frequently in women using the extended-cycle preparation than in women using the conventional-cycle preparation. Irregular bleeding occurs most often during the first few 91-day cycles. In one study in women who had used oral contraceptives, administration of Seasonale resulted in 7 or more and 20 or more days of intramenstrual bleeding and/or spotting in 65 and 35% of women, respectively, during cycle 1 and in 42 and 15% of women, respectively, during cycle 4. In another study, administration of Seasonique resulted in 7 or more and 20 or more days of intramenstrual bleeding and/or spotting in 64 and 29% of women, respectively, during cycle 1 and in 39 and 11% of women, respectively, during cycle 4. In women receiving a conventional-cycle oral contraceptive, intramenstrual bleeding and/or spotting for 7 or more and 20 or more days occurred in 38 and 6% of women, respectively, during cycles 1-4 and in 39 and 4% of women, respectively, during cycles 10-13.

Use of extended-cycle oral contraceptive preparations is associated with fewer menstrual symptoms than use of conventional-cycle oral contraceptive preparations. Whether adding 10 mcg of estradiol to the final 7 tablets in the cycle (LoSeasonique, Seasonique) will further reduce withdrawal symptoms (e.g., migraine headache) remains to be determined.

While use of a continuous-regimen (noncyclic) estrogen-progestin oral contraceptive (Lybrel) eliminates withdrawal bleeding, irregular bleeding and/or spotting occurs in some women. In one study, administration of Lybrel resulted in 4 or more and 7 or more days of bleeding and/or spotting in 67 and 54% of women, respectively, during the second 28-day dosing period and in 31 and 20% of women, respectively, during the thirteenth 28-day dosing period.

Adequate diagnostic procedures should be performed in patients with undiagnosed persistent or recurrent vaginal bleeding. When pathology has been excluded, time or change to another preparation may resolve the problem. Women with a history of oligomenorrhea or secondary amenorrhea or young women with irregular cycles may tend to remain anovulatory or to become amenorrheic after discontinuance of oral contraceptives; women with these preexisting problems should be advised of this possibility and encouraged to use other contraceptive methods.

Dysmenorrhea also may occur. Post-use anovulation, occasionally accompanied by galactorrhea, and a premenstrual-like syndrome has been reported. Post-use anovulation may be prolonged and may occur in women who had no previous irregularities. Galactorrhea and pituitary tumors (e.g., adenomas) have been associated with amenorrhea in former oral contraceptive users. One study showed a 16-fold increased prevalence of prolactin-secreting pituitary tumors (prolactinomas) among former users of oral contraceptives who had amenorrhea with galactorrhea compared with those without galactorrhea. In another study, the relative risk of prolactinoma was 1.3 when oral contraceptives were used for contraception and 7.7 when the drugs were used for menstrual regulation. In patients with breakthrough bleeding or irregular vaginal bleeding, nonfunctional causes should be considered.

Changes in cervical erosion and secretions and endocervical hyperplasia may occur during oral contraceptive therapy. In addition, preexisting uterine leiomyoma may increase in size in women receiving oral contraceptives. Vaginitis, impaired renal function, and backache and a cystitis-like syndrome have been reported but have not been definitely attributed to the drugs.

An increased incidence of Candida vaginitis has been associated with oral contraceptive therapy. Decreased motility and tonus of the upper urinary tract may occur in some patients leading to overdistention of the ureters, thus promoting bacteriuria and its complications and making treatment of the infection more difficult. Because oral contraceptives change the vaginal pH from acidic to alkaline, it has been suggested that there may be an increased risk of gonorrhea infection upon exposure; however, there is some evidence that progestins may inhibit growth of Neisseria gonorrhoeae in vitro and that oral contraceptives may have some protective effect against gonococcal pelvic inflammatory disease (PID). Although some clinicians have suggested that the risk of PID may be decreased in oral contraceptive users, there is some evidence that the frequency of cervical chlamydial infections may be increased several-fold in women receiving oral contraceptives compared with nonusers or women using barrier contraceptives, possibly secondary to cervical ectopy induced by the drugs; therefore, it should not be assumed that oral contraceptives provide protection against PID (i.e., that caused by Chlamydia trachomatis).

Although it has been suggested (based on very limited data) that use of multiphasic estrogen-progestin oral contraceptives may be associated with an increased risk of functional ovarian cysts, there currently is insufficient evidence to determine whether such increased risk exists. Epidemiologic evidence with monophasic estrogen-progestin oral contraceptives, principally high-dose estrogen preparations, indicates that monophasic contraceptives are associated with a reduced risk of developing functional ovarian risks when compared with nonusers of oral contraceptives. Epidemiologic studies and postmarketing surveillance currently are under way to determine the incidences of ovarian cysts in users of various types of oral contraceptives and in similar women not using the drugs.

Coital problems, device expulsion, and vaginal symptoms (discomfort, vaginitis, leukorrhea, foreign body sensation) have occurred in women using the contraceptive vaginal ring containing ethinyl estradiol and etonogestrel.

Nervous System Effects

Mental depression may occur in women receiving oral contraceptives. In a few cases, mental depression has been severe and has led to suicidal behavior. Mental depression appears to occur most frequently in patients with a history of depression, including premenstrual depression; however, relief of premenstrual tension occurs in some women. Patients with a history of mental depression should be observed carefully and the estrogen-progestin contraceptive discontinued if severe depression recurs during use.

Fatigue, dizziness, nervousness, aggressiveness, anxiety, emotional lability, and irritability have been reported in women receiving estrogen-progestin contraceptives; changes in libido may also occur. Psychotic behavior, chorea, and cerebrovascular disease (with associated mitral valve prolapse) have also been reported; however, a causal relationship has not been established.

Headache, especially migraine headache, may occur during estrogen-progestin contraceptive therapy. Estrogen-progestin contraceptives should be discontinued and the cause evaluated when migraine occurs or is exacerbated, or when a new headache pattern develops which is recurrent, persistent, or severe.

Ocular Effects

Oral contraceptives have been reported to produce harmful ocular effects in myopic women. In women who developed myopia at or near puberty and in whom myopia became stable in adulthood, the drugs have reportedly increased the refractive error 2- to 3-fold, usually after 6 months of use. In women who are myopic and have considerable astigmatism, oral contraceptives may produce marked changes in the astigmatic error, possibly leading to frank keratoconus. In addition, oral contraceptives may produce a rapid advancement of the ocular disorder in patients with a family history of marked myopic astigmatism or keratoconus. Contact lens wearers receiving estrogen-progestin contraceptives may have more difficulties with their contact lenses than do nonusers who wear contact lenses. Contact lens wearers who develop visual disturbances or changes in lens tolerance during estrogen-progestin contraceptive use should be assessed by an ophthalmologist; temporary or permanent cessation of contact lens wear should be considered.

Neuro-ocular lesions such as optic neuritis or retinal thrombosis have been associated with estrogen-progestin contraceptive use. If unexplained, sudden or gradual, partial or complete loss of vision; proptosis or diplopia; papilledema; or retinal vascular lesions occur during therapy with estrogen-progestin contraceptives, the drugs should be discontinued and evaluation for retinal vein thrombosis should be instituted immediately along with other appropriate diagnostic and therapeutic measures. Cataracts have also occurred during oral contraceptive use but have not been directly attributed to the drugs.

Hematologic Effects

Changes in various blood factors and blood components have been observed in patients receiving oral contraceptives; however, further studies are required before the clinical importance of these changes can be established. Increases in fibrinogen and blood coagulation factors II, VII, VIII, IX, X, and XII levels and decreases in antithrombin III activity may occur in women receiving hormonal contraceptives. Blood coagulation factor levels may return to normal one to several weeks after the oral contraceptive is discontinued. Hematocrit may be slightly increased and an increased rate of blood coagulation may occur. The estrogen component of the contraceptive appears to enhance norepinephrine-induced platelet aggregation, whereas the progestin causes increased fibrinolytic activity. Anemia and sickle cell disease have also been reported during oral contraceptive use.

Other Adverse Effects

Breast changes, including tenderness, enlargement, and secretion, may occur during estrogen-progestin contraceptive use.

Oral contraceptive use and estrogen use have appeared to be associated with an increased risk of gallbladder disease, especially in young women. In one study, an increased risk of gallbladder disease occurred after 2 years of use of the drugs and doubled after 4 or 5 years of use. In another study, an increased risk was apparent between 6-12 months of use. However, recent evidence suggests that the risk of gallbladder disease may be minimal in patients using formulations of oral contraceptives containing relatively low dosages of estrogens and/or progestins.

The relationship between oral contraceptive use and systemic lupus erythematosus (SLE) is not well-defined. Positive lupus erythematosus (LE) cell test results and antinuclear antibodies have been associated with oral contraceptive use in some women. Precipitation of SLE and exacerbation of preexisting disease have also been associated with oral contraceptive use in some women, and some clinicians recommend that other methods of contraception be used in women with a history of SLE. Rheumatic symptoms and synovitis have been associated with oral contraceptive use. Although several epidemiologic studies have suggested that oral contraceptive use appears to be associated with a decreased incidence of rheumatoid arthritis compared with nonuse, one epidemiologic study found no such association and the relationship, if any, between oral contraceptive use and rheumatoid arthritis remains to be determined.

Other reported adverse effects of estrogen-progestin contraceptives include Raynaud's phenomenon, auditory disturbances, hemolytic uremic syndrome, colitis, pancreatitis, upper respiratory tract infection, sinusitis, and rhinitis.

Precautions and Contraindications

Use of estrogen-progestin oral contraceptives is associated with an increased risk of several serious conditions including thromboembolism, arterial thrombosis (e.g., stroke, myocardial infarction), liver tumor, gallbladder disease, visual disturbances, fetal abnormalities, and hypertension. The risk of thrombotic events is even higher in women with other risk factors for these events. Cigarette smoking increases the risk of serious adverse cardiovascular effects during oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes daily) and is markedly greater in women older than 35 years of age. Women who are receiving estrogen-progestin contraceptives should be strongly advised not to smoke. Women older than 35 years of age who smoke, and women with ischemic heart disease or a history of this disease, should not use estrogen-progestin contraceptives. Estrogen-progestin contraceptives should be used with caution in women with cardiovascular disease risk factors. Clinicians prescribing estrogen-progestin contraceptives should be aware of the risks associated with such use; the sections in Cautions and the manufacturers' labeling should be consulted for further discussion of these risks and associated precautions. In addition, potential noncontraceptive benefits associated with use of estrogen-progestin contraceptives can be considered. (See Pharmacology: Other Effects.)

Because of dose-related risks of vascular disease from oral contraceptives, the dosage regimen prescribed should contain the least amount of estrogen and progestin that is compatible with a low failure rate and the needs of the patient.

Adverse effects similar to those with oral combination estrogen-progestin contraceptives generally are expected with vaginal or transdermal estrogen-progestin contraceptives.

No data are available concerning the risk of using short-course, high-dose estrogen-progestin combinations for emergency contraception among women with contraindications to routine use of cyclic estrogen-progestin combinations for contraception. Since such postcoital contraceptive regimens do not appear to adversely affect clotting factors, vascular complications (e.g., abnormal blood clotting, stroke, myocardial infarction) are unlikely to occur. No serious or long-term complications have been associated with such postcoital contraceptive regimens in Europe, where experience is extensive. Most experts state that there currently is no real contraindication to postcoital (emergency) contraception with the recommended regimens and that the benefits generally outweigh any theoretical or proven risk.

Patients should be advised that emergency contraceptive regimens are not as effective as most other forms of long-term contraception and should not be used as a woman's routine form of contraception. Patients should be informed that as with all estrogen-progestin contraceptives and other nonbarrier contraceptive methods, emergency contraceptive regimens do not protect against human immunodeficiency virus (HIV) infection or other sexually transmitted diseases.

Women receiving estrogen-progestin contraceptives should be under supervision of a physician who should inform them of the possible risks involved. Women receiving these contraceptives also should be given a copy of the patient labeling for the drugs.

It is good medical practice that all women, including those receiving estrogen-progestin contraceptives, have a medical history and physical examination performed annually. The physical examination may be deferred until after initiation of these contraceptives if requested by the woman and judged appropriate by the clinician. Physical examination should include special attention to blood pressure, breasts, abdomen, and pelvic organs and should include a Papanicolaou test (Pap smear) and relevant laboratory tests.

Women receiving estrogen-progestin contraceptives (including drospirenone-containing oral contraceptives) should be advised to notify their clinician if signs or symptoms of thromboembolic or thrombotic disorders (e.g., thrombophlebitis, pulmonary embolism, cerebrovascular insufficiency, coronary occlusion, retinal thrombosis, mesenteric thrombosis) occur, including sudden severe headache or vomiting, disturbance of vision or speech, sudden partial or complete loss of vision, dizziness or faintness, weakness or numbness in an extremity, sharp or crushing chest pain, unexplained cough, hemoptysis, sudden shortness of breath, calf pain, or heaviness in the chest. Oral contraceptive combinations containing drospirenone should be discontinued if an arterial or venous thrombotic event occurs during therapy. Women currently receiving an oral contraceptive combination containing drospirenone should be informed of the potential risk of thromboembolic events. Patients also should be advised about the current information available regarding the risk of VTE with oral contraceptives containing drospirenone compared with those containing levonorgestrel. Known risk factors for development of VTE include smoking, obesity, family history, and other factors that contraindicate the use of oral contraceptive combinations. Patients should discuss their risk of VTE with their clinician before deciding which contraceptive method to use. The risk of thromboembolic disease associated with oral contraceptive use gradually disappears after such therapy is discontinued. However, the FDA states that patients should not discontinue oral contraceptives containing drospirenone without consulting a clinician.

Although the risk of VTE is higher in women using any oral contraceptives compared with nonusers, the risk remains lower than that associated with pregnancy and the postpartum period. The risk of VTE in women receiving estrogen-progestin oral contraceptives is estimated to be 3-9 per 10,000 woman-years. In comparison, if 10,000 women who are not pregnant and not users of oral contraceptives are followed for one year, 1-5 of these women will develop a VTE. The risk of VTE is highest during the first year of oral contraceptive use. Results from a large, prospective cohort safety study of various estrogen-progestin oral contraceptives suggest that this increased risk is highest during the first 6 months of use compared with that in nonusers. Data from this safety study indicate that the highest risk of VTE occurs after initiation of estrogen-progestin oral contraceptive therapy or resumption of therapy (following a 4-week or longer drug-free interval) with the same or a different oral contraceptive combination. Before initiating use of an estrogen-progestin combination containing drospirenone in a new user or in a woman who is switching from an oral contraceptive not containing drospirenone, clinicians should consider the risks and benefits of drospirenone-containing oral contraceptives, including risk for developing VTE, specific to that woman.

Women receiving estrogen-progestin contraceptives should also be advised to inform their physician if severe abdominal pain or mass (indicating a possible liver tumor), jaundice, severe mental depression, edema, or unusual bleeding occurs. Because severe nausea and vomiting have occurred following postcoital use of high-dose estrogen-progestin combinations as emergency contraception, women taking such therapy should be instructed carefully regarding what to do if vomiting occurs after administering a dose, and concomitant use of an antiemetic should be considered.(See Dosage and Administration: Administration.) Women receiving estrogen-progestin contraceptives should be instructed in self-examination of their breasts and should report nodules or fibrocystic disease in the breast or abnormal breast radiographic or mammographic findings to their physician.

Estrogen-progestin contraceptives should be used with caution, and only with careful monitoring, in patients with conditions that might be aggravated by fluid retention (e.g., asthma, seizure disorders, migraine, or cardiac, renal, or hepatic insufficiency) and in patients being treated for hyperlipidemia, since control of the condition may become difficult. Women with a history of hypertension, hypertension-related diseases, or renal disease should be encouraged to use another method of contraception. Women with hypertension who elect to use estrogen-progestin contraceptives should be monitored closely, and if a clinically important elevation of blood pressure occurs, use of the drugs should be discontinued.

Because a twofold to fourfold increased risk of postsurgery thromboembolic complications has been reported in oral contraceptive users, estrogen-progestin contraceptives should be discontinued whenever feasible, at least 4 weeks before surgery that is associated with an increased risk of thromboembolism or prolonged immobilization; it is also recommended that patients wait 2 weeks after elective surgery associated with an increased risk of thromboembolism or after immobilization before resuming the use of these contraceptives.

Although the absolute rates for developing VTE are increased for users of hormonal contraceptives compared with nonusers, the rates for VTE development are even greater during pregnancy, especially during the postpartum period. Since the immediate postpartum period is associated with an increased risk of thromboembolism, estrogen-progestin contraceptive use should be started no earlier than 4 weeks after delivery in women who elect not to breastfeed their infants or in women who have had a midtrimester pregnancy termination. The risk of thromboembolism decreases while the risk of ovulation increases after the first 3 weeks postpartum.

Oral contraceptives containing the progestin drospirenone should not be used in patients who are predisposed to developing hyperkalemia (e.g., those with renal or hepatic impairment or adrenal insufficiency). If a drospirenone-containing oral contraceptive is used in women receiving daily, long-term therapy with agents that may increase serum potassium concentrations (e.g., angiotensin-converting enzyme (ACE) inhibitors, angiotensin II type 1 (AT₁) receptor antagonists, potassium-sparing diuretics, heparin, aldosterone antagonists [spironolactone], nonsteroidal anti-inflammatory agents [NSAIAs]), the serum potassium concentration should be determined during the first oral contraceptive cycle.

Five out of the 15 pregnancies reported in large clinical trials in women using the transdermal contraceptive system containing ethinyl estradiol and norelgestromin (Ortho Evra) occurred in women with a baseline weight of 90 kg or more; these results suggest that the contraceptive preparation may be less effective in such women than in those with a lower body weight. The clinician and the woman with high body weight should discuss the individual needs of such a patient when choosing an appropriate contraceptive option.

The contraceptive vaginal ring containing ethinyl estradiol and etonogestrel (NuvaRing) may not be suitable for women with conditions that make the vagina susceptible to vaginal irritation or ulceration.

Estrogen-progestin contraceptives are contraindicated in women who are hypersensitive to the drug or any ingredient in the formulation and in those with known or suspected pregnancy, undiagnosed abnormal genital bleeding, diplopia or any ocular lesion arising from ophthalmic vascular disease, classical migraine, active liver disease, or history of cholestatic jaundice with pregnancy or with prior use of oral contraceptives. The drugs also are contraindicated during breast-feeding and in women who have or have had thrombophlebitis or thromboembolic disorders, cerebrovascular or coronary artery disease (including myocardial infarction), severe hypertension, diabetes with vascular involvement, known or suspected carcinoma of the breast, known or suspected estrogen-dependent neoplasia (e.g., carcinoma of the endometrium), or benign or malignant liver tumor that developed during oral contraceptive or other estrogen use. Oral contraceptives containing the progestin drospirenone are contraindicated in women with renal impairment, hepatic tumors (benign or malignant) or hepatic disease, adrenal insufficiency, high risk of arterial or venous thrombotic diseases, undiagnosed abnormal uterine bleeding, history of breast cancer or other estrogen- or progestin-sensitive cancer, and in pregnancy.

Pediatric Precautions

Safety and efficacy of estrogen-progestin contraceptives have been established in women of reproductive age. Safety and efficacy are expected to be identical for postpubertal adolescents under 16 years of age and users 16 years of age or older. The manufacturers of estrogen-progestin contraceptives containing drospirenone state that safety and efficacy are expected to be the same for postpubertal adolescents under 18 years of age and users 18 years of age or older. Estrogen-progestin contraceptives are not indicated before menarche.

Geriatric Precautions

Oral contraceptives have not been evaluated in women 65 years of age and older and are not indicated in this population.

Mutagenicity and Carcinogenicity

Chromosomal abnormalities determined in peripheral lymphocytes have been increased in women receiving oral contraceptives compared with nonusers.

Prolonged continuous administration of natural or synthetic estrogen in certain animal species increases the frequency of certain benign or malignant tumors including those of the breast, cervix, uterus, vagina, ovary, pituitary, and liver. Certain synthetic progestins (none currently contained in oral contraceptives) have increased the frequency of benign and malignant mammary nodules in dogs. Drospirenone has increased the frequency of benign and total (benign plus malignant) adrenal gland pheochromocytomas in rats and the frequency of carcinomas of the harderian gland in mice.

The manufacturers state that there is at present no consistent evidence from human studies of an increased risk of cancer associated with oral contraceptive use; whether this statement also applies to vaginal or transdermal estrogen-progestin contraceptives is not known. Close clinical surveillance of all women using estrogen-progestin contraceptives is, nevertheless, essential. Appropriate diagnostic measures should be undertaken to rule out malignancy in all women with undiagnosed persistent or recurrent abnormal vaginal bleeding. Women with a strong family history of breast cancer or who have breast nodules, fibrocystic disease, or abnormal mammographic findings should be closely monitored if they elect to use estrogen-progestin contraceptives.

Cervical Cancer

There is some evidence from epidemiologic studies that use of oral contraceptives may be associated with an increased risk of cervical carcinoma. In one study, the incidence of biopsy-proven cervical neoplasia (i.e., dysplasia, carcinoma in situ, or invasive carcinoma) was increased in long-term oral contraceptive users compared with women who used an intrauterine contraceptive device (IUD); it was recommended that particular attention to the importance of regular Papanicolaou tests be given in women who have used oral contraceptives for longer than 48 months. Although a causal relationship to the drugs could not be excluded, data from a population-based (Costa Rican women), case-control study suggest that the increased risk of carcinoma in situ associated with oral contraceptive use may have resulted from a detection bias secondary to more frequent use of Papanicolaou tests in oral contraceptive users. These data revealed no evidence of increased risk of invasive cervical cancer in users compared with nonusers. The FDA recommends that all estrogen-progestin contraceptive users be monitored carefully with physical examinations and Papanicolaou tests, at least yearly. (See Cautions: Precautions and Contraindications.)

Endometrial Cancer

Several retrospective case-controlled studies have shown an increased relative risk of endometrial carcinoma in postmenopausal women who received prolonged estrogen replacement therapy for relief of menopausal symptoms. Although an increased risk of adenocarcinoma of the endometrium has been associated with sequential oral contraceptive use (sequential oral contraceptives are no longer available in the US), no association between increased risk of endometrial cancer and use of currently available estrogen-progestin combination preparations or progestin-only preparations has been shown, although individual cases have been reported. The Cancer and Steroid Hormone Study of the US Centers for Disease Control and Prevention (CDC) and the National Institute of Child Health and Human Development (NICHD) showed that women who used estrogen-progestin oral contraceptives had decreased relative risk of epithelial endometrial cancer (i.e., adenocarcinoma, adenoacanthoma, and adenosquamous cancers) compared with nonusers; the protective effect occurred in women who had used combination oral contraceptives for at least 12 months, and it persisted for at least 15 years after discontinuance of oral contraceptives. This decreased risk of endometrial cancer was not evident in women who had used oral contraceptives for less than 12 months.

Ovarian Cancer

Several studies have shown a decreased risk of epithelial ovarian cancer in oral contraceptive users compared with nonusers. The Cancer and Steroid Hormone Study showed that women who used oral contraceptives had a decreased relative risk of epithelial ovarian cancer compared with nonusers; the protective effect occurred in women who had used oral contraceptives for as little as 3-6 months, and it persisted for at least 15 years after discontinuance of oral contraceptive use. The risk of ovarian cancer decreased with increasing duration of oral contraceptive use and did not appear to be affected by the age at the time of first use of oral contraceptives or the oral contraceptive type (i.e., combination or sequential) or specific formulation. Because of inadequate data, the association between use of oral contraceptives and nonepithelial (i.e., germ-cell, sex cord-stromal) ovarian cancers could not be fully assessed.

Breast Cancer

Many studies have shown no increased risk of breast cancer in women receiving oral contraceptives or estrogens. Some studies, however,