Ethinylestradiol

In women at risk for breast cancer due to family history or susceptibility genes (BRCA1, BRCA2), the use of combination hormonal contraceptives has not been shown to modify the risk for breast cancer. However, breast cancer is a hormonal sensitive tumor and the prognosis for women with a current or recent history of breast cancer may be worse with combination hormonal contraceptive use (Curtis 2016b). Use is contraindicated in women with (or history of) breast cancer.

The use of combination hormonal contraceptives has been associated with a slight increased risk of cervical cancer; however, studies are not consistent and may be related to additional risk factors (Gierisch 2013). Theoretically, use may affect prognosis of existing disease. Women awaiting treatment for cervical cancer may use combination hormonal contraceptives (Curtis 2016b).

Combination hormonal contraceptives, as well as sun exposure and pregnancy, are triggers for chloasma. Women with a susceptibility to chloasma or additional risk factors should avoid exposure to sun or ultraviolet radiation during therapy (Handel, 2014).

Risk of cholestasis may be increased with previous cholestasis of pregnancy or cholestasis with prior oral contraceptive use. Use is contraindicated with use with cholestatic jaundice or jaundice of pregnancy.

Combination hormonal contraceptives may adversely affect lipid levels, including serum triglycerides. Women with hypertriglyceridemia or a family history of hypertriglyceridemia may be at increased risk of pancreatitis when using combination hormonal contraceptives. Consider alternative contraception for women with uncontrolled dyslipidemia.

Discontinue if unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions occur and immediately evaluate for retinal vein thrombosis.

Discontinue use of combination hormonal contraceptives if an arterial or venous thrombotic event occurs. Oral contraceptives may increase the risk of venous thromboembolism (risk is greatest during first year of use and less than the risk associated with pregnancy); some studies suggest this risk may be higher in preparations with third- or fourth-generation progestins and/or high dose ethinyl estradiol. Women with inherited thrombophilias (eg, protein C or S deficiency, factor V Leiden mutation, prothrombin mutation, antithrombin deficiency) may have increased risk of venous thromboembolism. Age >35 years, hypertension, obesity, and tobacco use also increase the risk of thrombotic events in women taking combination hormonal contraceptives (ASRM 2017; Curtis 2016b; DeSancho 2010; van Vlijmen 2011). Combination hormonal contraceptives may also increase the risk of arterial thrombosis (eg, MI, stroke) and should not be used in women with a history of stroke or ischemic heart disease (Curtis 2016b). Use of combination hormonal contraceptives is contraindicated in women with a high risk of arterial or venous thrombotic disease.

Breakthrough or intracyclic bleeding and spotting may occur, especially during the first 3 months of therapy. In addition, occasional missed periods may occur. Presentation of irregular, unresolving vaginal bleeding warrants further evaluation to rule out malignancy or pregnancy. Amenorrhea or oligomenorrhea may occur after discontinuing combination hormonal contraceptives, especially when such a condition was preexistent. Disease-related concerns:

Use with caution in patients with risk factors for cardiovascular disease ( eg, hypertension, low HDL, high LDL, high triglycerides, older age, diabetes, women who smoke); use of combination hormonal contraceptives may increase the risk of cardiovascular disease (Curtis 2016b). Use is contraindicated in women at high risk of arterial or venous thrombotic diseases.

Use with caution in patients with a history of depression; discontinue if serious depression recurs.

May impair glucose tolerance; use caution in women with diabetes or prediabetes. In general, use of combination oral contraceptives has limited effects on daily insulin needs and no long term effects on diabetes control in women with nonvascular disease. However, use in women with concomitant nephropathy, neuropathy, retinopathy, other vascular disease, or diabetes >20 years' duration should be evaluated for contraceptive use based on the severity of the condition (Curtis 2016b). Use is contraindicated in women with diabetes mellitus and vascular disease.

Use with caution in patients with diseases which may be exacerbated by fluid retention.

The risk of endometrial or ovarian cancer is decreased in women using combination hormonal contraceptives (Curtis 2016b; Walker 2015). Oral contraceptives may be used to reduce the risk of ovarian cancer including those women with BRCA1 and BRCA2 mutations (Walker 2015). Women awaiting treatment for endometrial or ovarian cancer may use combination hormonal contraceptives (Curtis 2016b).

Combination hormonal contraceptives may cause a small increased risk of gallbladder disease or may worsen existing gallbladder disease (Curtis 2016b).

Use of combination hormonal contraceptives is associated with hepatic adenomas (rare); rupture may cause fatal intra-abdominal hemorrhage. Long-term use may be associated with an increased risk of hepatocellular carcinoma (rare). Use is contraindicated in women with preexisting hepatic tumors.

Combination hormonal contraceptives may be poorly metabolized in women with hepatic impairment. Discontinue if jaundice develops during therapy or if liver function becomes abnormal. Use is contraindicated in women with hepatic disease. Use of combination hormonal contraceptives may be considered in women with mild (compensated) cirrhosis but should not be used in women with severe (decompensated) cirrhosis (Curtis 2016b).

Initiation of combination hormonal contraceptives is not recommended in women with acute viral hepatitis or during a flare. Continuation of use in women with chronic hepatitis has not been shown to increase the rate or severity of cirrhotic fibrosis or hepatocellular carcinoma. Continuation of use in women who are carriers has not been shown to trigger liver failure or severe hepatic dysfunction (Curtis 2016b).

Estrogens may induce or exacerbate symptoms in women with hereditary angioedema (Geng, 2013; Zuraw, 2013).

The risk of hypertension may be increased with age, dose, and duration of use. Combination hormonal contraceptives should not be used in women with hypertension and vascular disease, or persistent blood pressure values ≥160 mm Hg systolic or ≥100 mm Hg diastolic. The risks of use may not outweigh the benefits of treatment in women with less severe hypertension (140 to 159 mm Hg systolic or 90 to 99 mm Hg diastolic) or those with hypertension that is adequately controlled (Curtis 2016a). Other risk factors for cardiovascular disease (eg, older age, smoking, diabetes) should be considered when prescribing contraceptives (Curtis 2016b).

Evaluate new, recurrent, severe, or persistent headaches. Use of combination hormonal contraceptives may be considered in women who have migraines without aura (including menstrual migraines) (Curtis 2016b). Use in women with headaches with focal neurological symptoms, or migraine headaches with or without aura if >35 years is contraindicated.

Although data is limited, serious medical complications have been reported in women with complicated organ transplants (eg, graft failure, rejection, cardiac allograft vasculopathy); use of combination hormonal contraceptives is not recommended in women with complicated organ transplants (Curtis 2016b).

Women with systemic lupus erythematosus (SLE) are at an increased risk for heart disease, stroke, and VTE. Combination hormonal contraceptives should not be used in women with SLE who have positive (or unknown) antiphospholipid antibodies, due to an increased risk of arterial and venous thrombosis (Curtis 2016b). Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Estrogens may increase thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels. Women on thyroid replacement therapy may require higher doses of thyroid hormone while receiving estrogens. Special populations:

Available evidence suggests efficacy of combination hormonal contraceptives may be decreased in women with a BMI ≥30 kg/m2; however, reductions in effectiveness are considered minimal and information is conflicting. The risk of VTE may be increased in obese women using combination hormonal contraceptives. In general, the benefits of combination hormonal contraceptives may outweigh the risks in obese women who otherwise are eligible for this method (Curtis 2016b).

Not for use prior to menarche.

Use is not indicated in postmenopausal women.

Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptives 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. Women who use oral contraceptives should be strongly advised not to smoke.

Whenever possible, should be discontinued at least 4 weeks prior to and for 2 weeks following elective surgery associated with an increased risk of thromboembolism or during periods of prolonged immobilization. Other warnings/precautions:

When initiating a combination oral contraceptive, consider initiating with a monthly bleeding monophasic formulation containing ethinyl estradiol 30 to 35 mcg plus a progestin, and adjusting based on adverse events and patient preference (Ott 2014).

Combination hormonal contraceptives do not protect against HIV infection or other sexually transmitted diseases (Curtis 2016a; Curtis 2016b).

The use of estrogens and/or progestins may change the results of some laboratory tests (eg, coagulation factors, lipids, glucose tolerance, binding proteins).