Oral Contraceptives, Combinations

Thromboembolism and thrombus formation are serious adverse reactions related to CHC therapy and may include deep venous thrombosis, pulmonary embolism, retinal thrombosis, myocardial infarction or stroke. Should any of these events occur or be suspected, the CHC should be discontinued immediately. The risk for thromboembolism due to CHCs is approximately 4 to 10 per 10,000 woman-years, which is still lower than the risk during pregnancy or the immediate postpartum period. Heart attack and ischemic stroke are rare in people without co-existing risk factors. Persons with high risk for thromboembolism, such as presence of thrombophilia, systemic lupus erythematosus (SLE), diabetes mellitus with vascular complications or more than a 20-year history of diabetes mellitus, certain types of cardiovascular disease, or history of migraine with aura are generally not suitable candidates for CHCs. Risk factors such as tobacco smoking, increasing age (more than 35 years), hypertension, obesity, and prolonged immobilization influence the risk for thromboembolism. People who smoke have significantly increased risk, especially if over the age of 35 years or if they are heavy smokers (more than 15 cigarettes per day). There is a positive association between dosage of estrogen and risk for thromboembolism, as estrogens increase the production of clotting factors. Oral CHCs containing ethinyl estradiol 50 mcg/day or more are associated with a higher risk compared to those containing 35 mcg/day or less. The risk may vary based on progestin component in combination oral contraceptives, but the data are not clear and require further consideration. Some evidence suggests that the risk of venous thromboembolism is higher with newer progestins (e.g., desogestrel, drospirenone, and dienogest) in CHCs versus the usual risk for older progestins in CHC products, and other evidence does not. Many of the retrospective observational studies available vary in their ability to control for preexisting confounding risk factors and prescribing bias. For example, prospective observational studies have not found an increased risk for products containing drospirenone relative to products containing levonorgestrel.[48201] [40220] [40221] [40229] [45774] [45775] [49691] [51081] [51082] [51083] [51084] [62902] [62903]

Because certain reproductive cancers can be hormonally responsive, do not use combined hormonal contraceptives (CHCs) in patients with a history of such cancers, including cancers of the breast, reproductive organs, or genitals.[48201]

Breast

The link between CHC use and breast cancer has been controversial. There is substantial evidence that CHCs do not significantly increase the incidence of breast cancer. Some past studies have suggested that CHCs might increase the incidence of breast cancer; more recent studies have not confirmed such findings. Data suggest a small increased risk of breast cancer, if any, and no increased risk in breast cancer death. From one large study published in 2017, the risk of breast cancer was higher among women who currently or recently used contemporary hormonal contraceptives than among women who had never used hormonal contraceptives, and this risk increased with longer duration of use; however, absolute increases in risk were small. The absolute risk of breast cancer associated with any hormonal contraceptive use was 13 per 100,000 women-years, which corresponds to 1 extra case of breast cancer for every 7,690 CHC users in 1 year.[62904] The same study data suggest that an increased risk of breast cancer usually disappears rapidly after an interruption in the use of CHCs.[62904] There continues to be controversy regarding the risk of CHC use by individuals with a family history of breast cancer (e.g., BRCA mutations). Instruct CHC users to perform a monthly self-breast examination and report any breast changes, lumps or breast discharge to their health care professional.[48201] [51085] [62647] [62904]

Cervical

In general, the data suggest an increased risk of cervical cancer among CHC users. Some studies suggest that CHC use has been associated with an increase in the risk of cervical cancer or intraepithelial neoplasia; however, such findings may be due to differences in sexual behavior, the presence of the human papillomavirus (HPV) and other factors. HPV is thought to be the cause of more than 90% of all cervical cancers, although, hormonal factors may influence risk. The relative risk of invasive cervical cancer of 1.37 after 4 years of use; relative risk increased to 1.6 after 8 years of use. Because a potential for cervical dysplasia may exist, regularly evaluate CHC users via cervical cytology screening as recommended per standards of care.[48201] [62647] [51085]

Endometrial and Ovarian

In general, the data suggest a decreased risk of endometrial and ovarian cancer among CHC users, except for hereditary forms of ovarian cancer (e.g., women who carry BRCA1 or BRCA2 gene alterations).[48201] [62647] [51085]

Hepatoma

Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (more than 8 years) CHC users. However, these cancers are rare in the United States, and the attributable risk (the excess incidence) of liver cancers in CHC users approaches less than 1 per million users.[62647] [51085]

Combined hormonal contraceptive (CHC) therapy has been reported to cause elevations in blood pressure and the incidence increases with duration of use, patient age and, possibly, progestin concentration. If the blood pressure rises significantly during use, the CHC should generally be discontinued. People with pre-existing hypertension or hyperlipidemias should be monitored and managed appropriately during CHC use.[48201]

Mental depression and mood changes have been reported infrequently with combined hormonal contraceptive (CHC) use. If significant depression occurs, discontinue the CHC.[48201]

Gallbladder disease, biliary obstruction, cholestatic jaundice, cholelithiasis, and cholecystitis have been reported with CHC use. Hepatitis, elevated hepatic enzymes, peliosis hepatis, enlargement of hepatic hemangiomas, and pancreatitis are rare adverse reactions. Cases of bowel ischemia have been reported during combined estrogen and progesterone use; mesenteric vein thrombosis due to hypercoagulability is the proposed mechanism. Discontinue the CHC and evaluate the patient if jaundice, cholestasis, or severe abdominal pain occur.

Headaches/migraines may be hormonally mediated; thus, CHC use may result in the development of headaches/migraines, alter the frequency, duration, or severity of existing headache patterns, or decrease the occurrence of migraines. A headache or migraine with focal symptoms or vision changes during CHC use should be evaluated immediately, since such symptoms can be related to cerebrovascular events or retinal thrombosis.[48201][30858]

Melasma and photosensitivity, as well as various infrequent dermatological reactions, such as maculopapular rash, urticaria, erythema, alopecia or hirsutism, have been reported with CHC use. Aggravation of acne may occur, but in some patients acne may improve.

[48201][70662][70685][70687][51098][51097]

Estrogens and progestins are partially metabolized by CYP3A4; therefore, coadministration with CYP3A4 inhibitors or inducers may result in increased or decreased plasma concentrations of estrogens/progestins, respectively. Concomitant therapy with CYP3A4 inducers increases the risk of contraceptive failure, and these drug interactions may require adjustments to the patient's contraceptive choices and regimens. People with epilepsy taking anticonvulsants may be at higher risk for folate deficiency when taking combined hormonal contraception.[48201][70622]

People with hepatitis C infection who are being treated with ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, are also contraindicated to receive oral combined hormonal contraceptives (CHCs). During clinical trials with the hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in people using ethinyl estradiol-containing medications. Discontinue CHCs prior to starting hepatitis C therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir; CHCs can be restarted approximately 2 weeks following completion of treatment with these regimens.[58664][60002][61023]

People living with HIV may require careful review of their antiretroviral regimens for interactions with hormonal contraceptives. CHCs should not be administered with amprenavir or fosamprenavir. CHCs may decrease the serum concentrations of certain antiretroviral medications which could result in the loss of virologic response and possible viral resistance.[29012] Other antiretroviral medications may increase or decrease the metabolism of estrogens or progestins found in CHCs.[48201][46638]

The use of estrogens, including CHCs, is not recommended during aromatase inhibitor treatment (e.g., aminoglutethimide, anastrozole, exemestane, letrozole, testolactone, vorozole) due to opposing pharmacologic actions. The indications for use of the aromatase inhibitors generally preclude the use of estrogen-containing hormonal contraception.

Subtherapeutic response to metyrapone is seen when given with estrogens; thus, it is recommended to avoid concomitant administration.[33528]

Anticoagulant effects of warfarin are usually reduced with coadministration of estrogen therapy. If concurrent therapy is given, warfarin dose adjustments should be based on either the prothrombin time or INR value. CHCs containing 50 mcg/day or more of ethinyl estradiol are associated with the greatest risk of thromboembolic complications and should be avoided in most people. In general, CHCs are contraindicated in patients with active or recent thromboembolic disease or with prominent risk factors for thromboembolism.[28549]

Guidelines state that the contraceptive effectiveness of CHCs is not affected by coadministration of most broad-spectrum antibiotics based on intermediate level evidence.[48201][48204] It has been reported that antibiotics, such as penicillins, sulfonamides, tetracyclines, clindamycin, neomycin and nitrofurantoin, may affect the gut flora, resulting in lower estrogen reabsorption and reduced efficacy of oral CHCs; however, some studies have found no no differences in ovulation suppression or breakthrough bleeding when antibiotics are coprescribed with CHCs. Some drug interaction studies and case reports suffer from issues such as recall bias, small sample size, and study design flaws. An additional method of contraception during antibiotic use may be advisable with use of selected agents.[28509][70622]

Generally, antiestrogenic selective estrogen receptor modulators (SERMS) such as tamoxifen and raloxifene are pharmacological opposites of estrogens, and the indication for use of the SERM precludes the use of estogen-containing hormonal contraception.[63589][29603]

Drospirenone is a spironolactone derivative with antimineralocorticoid effects and may increase serum potassium levels. Thus concurrent administration of drospirenone and potassium containing products (e.g., potassium iodide, potassium salts, dietary salt substitutes), other potassium containing medications (e.g., antibiotics), potassium-sparing diuretics, angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin II receptor antagonists or eplerenone may increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitor serum potassium levels if these drugs are use concurrently with drospirenone-containing contraceptives, particularly during the first month of therapy.[50684]

CHCs are associated with thromboembolic disease such as deep venous thrombosis (DVT) and pulmonary embolism (PE). Combined hormonal contraceptives (CHCs) are contraindicated in people with a current or past history of stroke, cerebrovascular disease, coronary artery disease, coronary thrombosis, myocardial infarction (MI), thrombophlebitis, thromboembolism or thromboembolic disease, or valvular heart disease with complications. CHCs are also generally contraindicated in thrombogenic valvular or thrombogenic rhythm diseases of the heart (e.g., subacute bacterial endocarditis with valvular disease or atrial fibrillation), or known inherited or acquired hypercoagulopathies (e.g., protein S deficiency, protein C deficiency, Factor V Leiden, prothrombin G20210A mutation, antithrombin deficiency, antiphospholipid antibodies). Because tobacco smoking increases the risk of thromboembolism, DVT, myocardial infarction, stroke and other thromboembolic disease, CHC recipients are strongly advised not to smoke. Risk is especially high for heavy smokers (15 or more cigarettes per day) over 35 years of age; therefore, CHCs are considered contraindicated in tobacco smokers more than 35 years of age. Due to an association of estrogen dosage with thromboembolic risk, CHCs containing 50-mcg/day ethinyl estradiol should not be used unless medically indicated. In addition, certain progestins may increase thromboembolic risk. The overall risk of venous thromboembolism in oral CHC users has been estimated to be 3 to 9 per 10,000 women-years (and 3 to 12 per 10,000 women-years for non-oral CHC users). Preliminary data from a large, prospective cohort safety study suggests that the risk is greatest during the first 6 months after initially starting CHC therapy or after restarting (following a break of 4 weeks or more) with the same or different CHC product. The risk of arterial thromboses, such as stroke and MI, is especially increased in those with other risk factors, such as pre-existing high blood pressure, kidney disease, hypercholesterolemia, hyperlipidemia, diabetes with vascular disease, or if morbidly overweight. After a CHC is discontinued, the risk of thromboembolic disease due to CHCs gradually disappears. Also, to minimize the risk of VTE, CHCs should be stopped at least 4 weeks before any elective surgery that may be associated with an increased risk of thromboembolism; patients should not restart the contraceptive until ambulatory. Also, discontinue CHC use during any period of prolonged immobilization.[30858][48201][70662]

In general, CHC use is contraindicated in people with headaches, such as migraine, that include focal neurological symptoms, such as aura. The risk for cerebral thromboembolic events may be increased. Those with new onset or exacerbation of migraines, visual disturbances or focal neurologic symptoms, or who develop headache with a new pattern which is recurrent, persistent or severe should be evaluated to identify the cause. In some cases, such symptoms may be warning signs for stroke or other serious events.[48201]

CHCs are associated with elevations in blood pressure; as such, they are generally contraindicated in patients with uncontrolled hypertension and should be used with caution in patients with controlled hypertension or chronic kidney disease. Oral products containing 50 mcg/day of ethinyl estradiol or equivalent should not be used unless medically necessary. Blood pressure should be monitored for all CHC recipients; any significant increase in blood pressure may require discontinuation of the CHC.[48201]

CHCs are contraindicated in patients with known, suspected or personal history of breast cancer, endometrial cancer, cervical cancer, ovarian cancer, uterine cancer, vaginal cancer, other estrogen-responsive tumors, and undiagnosed, abnormal vaginal bleeding. Use with caution in patients with uterine leiomyomata (fibroids). Pelvic and breast examinations and cervical cytology screening should be performed as per standards of care for the individual's age and risk factors during CHC use.[48201]

CHCs are contraindicated for use in people with acute or chronic hepatic disease with abnormal liver function and in those with history of cholestatic jaundice of pregnancy or jaundice with prior hormonal contraceptive use. Discontinue the CHC if jaundice or cholestasis develops during CHC use. Acute or chronic disturbances of liver function may necessitate CHC discontinuation until markers of liver function return to normal and CHC causation has been excluded. Liver conditions for which estrogen-containing contraception is inappropriate include Budd-Chiari syndrome, decompensated cirrhosis (cirrhosis with complications, such as ascites or confusion), a liver transplant that is not working well, or hepatic adenomas or cancerous liver tumors. Patients with hepatitis C infection who are being treated with ombitasvir/paritaprevir/ritonavir regimens, with or without dasabuvir, are also contraindicated to receive CHCs, due to a risk for elevated hepatic enzymes and hepatotoxicity. CHCs can be restarted approximately 2 weeks following completion these hepatitis C treatment regimens. Use CHCs is also contraindicated in patients with hepatic adenomas or hepatocellular cancer. Benign hepatic adenomas are associated with CHC use, although the incidence of benign tumors is rare in the United States and the attributable risk (the excess incidence) of liver cancers in CHC users approaches less than 1 per million users. Studies suggest an increased risk of developing gallbladder disease among CHC users and use of CHCs may also worsen existing gallbladder disease.[48201][70437]

Discontinue combined hormonal contraceptives (CHCs) if pregnancy is detected as there is no reason to continue a CHC during pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to CHCs before conception or during early pregnancy. The administration of CHCs to induce withdrawal bleeding should not be used as a test for pregnancy. CHCs should not be used during pregnancy to treat threatened or habitual abortion. For any patient who has missed 2 consecutive periods, pregnancy should be ruled out before continuing CHC use. If the patient has not adhered to the prescribed schedule, consider the possibility of pregnancy at the first missed period; CHC use should be discontinued until pregnancy is ruled out.[30858][48201]

Manufacturers recommend avoidance of combined hormonal contraceptives (CHCs) during breast-feeding until an individual has completely weaned their child. Small amounts of hormonal contraceptive steroids (estrogens and progestins) have been identified in human milk and a few reports of effects on the infant exist, including jaundice and breast enlargement.[30858] The U.S. Medical Eligibility Criteria state that postpartum women who are breast-feeding should not use CHCs during the first 3 weeks after obstetric delivery because of the increased risk for venous thromboembolism, and generally should not use CHCs through the fourth week postpartum because of concerns about potential effects of estrogen on breastfeeding performance. Postpartum individuals with other risk factors for venous thromboembolism generally should not use CHCs until 4 to 6 weeks after delivery. CHCs may be used after 6 weeks postpartum without restriction as thromboembolism risk returns to baseline; if the individual is breast-feeding, general monitoring of the breastfed infant for appetite changes, breast changes, and proper weight gain/growth should occur.[48201] One study found that low-dose CHCs (e.g., 10 mcg per day EE) may not adversely affect lactation.[48200] However, a systematic review concluded that the available evidence, even from randomized controlled trials, is limited and of low quality; proper trials are needed.[48202] The World Health Organization (WHO) has published contraceptive criteria recommendations that are more restrictive than U.S. recommendations; the WHO criteria state CHCs should not be used in an individual who is breast-feeding before 42 days postpartum and that the disadvantages of using CHCs generally outweigh the advantages between 6 weeks and 6 months postpartum.[48204] Alternate contraceptive agents to consider for the breast-feeding individual include non-hormonal contraceptive methods (e.g., copper IUD, barrier methods) and progestin-only contraceptives (e.g., medroxyprogesterone contraceptive injections, norgestrel oral contraceptive, levonorgestrel IUDs).[48201]

Drospirenone has antimineralocorticoid activity, which may increase serum potassium levels or impair adrenal function; thus, drospirenone-containing CHCs are contraindicated in patients with renal impairment, renal failure, renal disease or adrenal insufficiency. Monitor serum potassium levels in patients at risk for elevations, particularly during the first month of therapy with a drospirenone-containing hormonal contraceptive. Drospirenone may cause hyponatremia in high-risk patients.[42068][40219][41929] No dosage adjustments for other CHCs are needed in patients with renal impairment; however, depending on the cause and degree of the renal impairment/chronic kidney disease (CKD), other contraceptive methods may be preferred over CHCs. If the person with CKD is a candidate for CHC use, monitor for blood pressure increase, changes in proteinuria, and thromboembolism risk during CHC initiation and periodically thereafter.[48201][70659]