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Breakthrough bleeding and spotting are sometimes encountered, especially during the first 3 months of oral contraceptive use such as ethinyl estradiol; norethindrone acetate. When breakthrough bleeding occurs cyclically after the first 3 months, the time the menstrual irregularity occurs in the cycle can indicate which component (i.e., estrogen or progestin) requires readjustment. In the event of breakthrough vaginal bleeding, consider nonhormonal causes and take adequate diagnostic measures to rule out malignancy or pregnancy. If pathology has been excluded, time or a change to another formulation may solve the problem. Change in menstrual flow (menstrual irregularity, 5%) and amenorrhea have also been reported and are believed to be drug-related. Amenorrhea and oligomenorrhea have been reported in patients taking ethinyl estradiol; norethindrone acetate; in patients using it for contraception, amenorrhea occurred in 32% to 49% of patients with the incidence increasing with duration of use. For patients taking it for HRT, amenorrhea occurred in up to 90% of patients after 1 year of treatment. With continuous administration of the combined HRT regimen, amenorrhea usually occurs within 2—3 months of treatment. Amenorrhea is desirable in many women and not considered to be an adverse effect. In the event of amenorrhea, rule out pregnancy. Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was pre-existent. Other adverse effects may include dysmenorrhea (4%), menorrhagia (5%), metrorrhagia (5%), and pelvic pain (2—6%).[43360]

Breast tenderness or mastalgia (2—9%), breast enlargement, and breast discharge or secretion have been reported in patients receiving oral contraceptives such as ethinyl estradiol; norethindrone acetate and are believed to be drug-related. Galactorrhea and lactation suppression may also occur.[43360]

Vaginitis (2—6%) and vaginal candidiasis (2—6%) have been reported in patients receiving ethinyl estradiol; norethindrone acetate, regardless of indication. Symptoms of these include vaginal discharge (leukorrhea) and/or vaginal irritation. Urinary tract infection (2—6.2%) has also been reported. Other adverse events reported when used for hormone replacement therapy (HRT) include changes in cervical erosion, or enlargement of uterine leiomyomatas (fibroids).[43360]

Oral contraceptives may cause edema (fluid retention) and, thus, weight gain. An increased risk of hypertension has been associated with the use of combined oral contraceptives (COCs) such as ethinyl estradiol; norethindrone acetate. An increase in blood pressure is more likely in older oral contraceptive users and with continued use. The incidence of hypertension increases with increasing concentrations of progestogens. Close monitoring of blood pressures is recommended for patients at risk for hypertension; discontinue ethinyl estradiol; norethindrone acetate if significant elevation of blood pressure occurs. Blood pressures usually return to normal after discontinuation of therapy, and no difference in the occurrence of hypertension exists among ever- and never-users.[48201] An increase in fluid retention and increased blood pressure may also occur with estrogen-progestin hormone replacement therapy. Discontinue HRT if significant increases in blood pressure occur.[43360]

HORMONE REPLACEMENT THERAPY (HRT): An increased risk of  venous thromboembolism (VTE), including pulmonary embolism (PE), deep venous thrombosis (DVT), and myocardial infarction (MI) has been reported with estrogen plus progestin hormone replacement therapy (HRT). Should any of these events occur or be suspected, discontinue HRT immediately.[43360] In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving estrogen plus progestin HRT compared to women receiving placebo (35 vs. 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 vs. 13 per 10,000 women-years) and PE (18 vs. 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted.[17825] [27272] Estrogens with or without progestins should not be used for the prevention of cardiac disease or cardiovascular disease (e.g., coronary artery disease). In the Women's Health Initiative (WHI) estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as non-fatal MI, silent MI, or CHD death ) was reported in women receiving estrogen-alone compared to placebo. Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE-alone vs. placebo) in women with less than 10 years since menopause (8 vs. 16 per 10,000 women-years). In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events (such as myocardial infarction) reported in women receiving daily estrogen plus progestin compared to women receiving placebo (41 vs. 34 per 10,000 women-years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5.[27272] [17808] Studies have also shown no cardiovascular benefit to the use of estrogens or estrogen-progestin therapy for secondary prevention in women with documented cardiac disease or CHD.[25473] [27270] [43360] ORAL CONTRACEPTIVES: Combined oral contraceptives (COCs, such as ethinyl estradiol; norethindrone acetate) are associated with an increased risk of thromboembolic and thrombotic disease. The risk for the development of VTE, such as deep venous thrombosis and/or pulmonary embolism is approximately 3 to 6 times greater in OC users than in nonusers. In several studies, the risk was reported to be substantially higher in smokers compared with nonsmokers, and especially if the woman smoker was over 35 years of age. The relative risk of venous thromboembolism (VTE) in women who have predisposing conditions is twice that of women without such medical conditions. The risk of VTE due to COC use gradually disappears after the combined hormonal contraceptive is discontinued. VTE risk is highest in the first year of use and when a combination oral contraceptive is started or re-started after a break in use of 4 weeks or more. Estrogens decrease levels of antithrombin-III and increase the production of blood clotting factors VII, VIII, IX and X; risks increase with ethinyl estradiol doses more than 50 mcg/day. Serious thromboembolic events, such as myocardial infarction or cerebrovascular accidents, are reported rarely in users of COCs who do not smoke.[48201]

HORMONE REPLACEMENT THERAPY (HRT): In the WHI estrogen plus progestin substudy, a statistically significant increased risk of thromboembolic stroke was reported in women 50 to 79 years of age receiving daily estrogen plus progestin HRT compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women- years). The increase in risk was demonstrated after the first year and persisted. Should a stroke occur or be suspected, estrogen plus progestin HRT should be discontinued immediately.[43360] ORAL CONTRACEPTIVES: An increase in both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes) has been shown in users of combined oral contraceptives (COCs) such as ethinyl estradiol; norethindrone acetate. In general, the risk is greatest among older, hypertensive women over the age of 35 years who also smoke. Hypertension was found to be a risk factor for both users and non-users for both types of strokes while smoking interacted to increase the risk for hemorrhagic strokes. In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension. The relative risk of hemorrhagic stroke (intracranial bleeding) is reported to be 1.2 for non-smokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users, and 25.7 for users with severe hypertension. The attributable risk also is greater in women in their mid-thirties or older and among smokers.[50744] Although the risk of stroke in users of COCs appears to be related to estrogen amount (i.e., increased risk has been demonstrated with products containing 50 mcg or more but not for products containing l35 mcg or less of ethinyl estradiol), further studies are needed to clarify the relationship of type of progestin to risk of stroke in users of OCs.[48201]

Clinical case reports of retinal thrombosis associated with estrogen hormone replacement therapy (HRT) and oral contraceptive use exist. Optic neuritis, which may lead to partial or complete loss of vision has been reported in users of oral contraceptives, however the association has been neither confirmed nor refuted. Likewise, cataracts have been reported during oral contraceptive use without evidence of causality.[44124] Exogenous estrogen use can cause a conical cornea to develop from steepening or increased curvature of the cornea, caused by thinning of the stroma. Patients with contact lenses may develop intolerance to their lenses. Any change in vision or visual acuity should be examined by an ophthalmologist. In the event of unexplained visual impairment, onset of proptosis or diplopia, papilledema, or retinal vascular lesions, discontinue ethinyl estradiol; norethindrone acetate. Immediately take appropriate diagnostic and therapeutic measures.[43360] 

Depression (2—5.8%) has been reported in patients receiving oral contraceptives such as ethinyl estradiol; norethindrone acetate and is believed to be drug-related. During clinical studies, anxiety (2%), depression (2—5.8%), mood swings/emotional lability (2—6%), and nervousness (1.6—5.4%) were reported in patients receiving ethinyl estradiol; norethindrone acetate, regardless of indication.[43360] Fatigue, asthenia, and irritability have also been reported. In addition, libido increase or libido decrease may occur; specifically, in women receiving ethinyl estradiol; norethindrone acetate for HRT, positive changes in libido may occur as a result of improvements in vulvar and vaginal atrophy. Carefully observe women with a history of depression. Discontinue ethinyl estradiol; norethindrone acetate if depression recurs to a serious degree. Also, stop ethinyl estradiol; norethindrone acetate in patients who become significantly depressed to try to determine whether the depression is drug related.

During oral contraceptive studies, headache (2—7%) was reported in patients receiving ethinyl estradiol; norethindrone acetate; in hormone replacement studies, the incidence of headache was higher (15.2—18.2%).[43360] Migraine has been reported in patients receiving oral contraceptives such as ethinyl estradiol; norethindrone acetate and is believed to be drug-related. A number of changes can occur when a woman initiates oral contraceptive therapy and include 1) migraines can appear for the first time, 2) a change in frequency, severity and duration of migraine headaches may be seen, or 3) an improvement or decrease in the occurrence of migraine headaches. When initiating ethinyl estradiol; norethindrone acetate therapy, observe an individual's migraine pattern.The onset or exacerbation of migraine or development of headache with a new pattern that is recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause.

Ethinyl estradiol; norethindrone acetate can cause a variety of dermatological reactions such as maculopapular rash, rash (unspecified), and pruritus. Anaphylactoid reactions including urticaria, angioedema, and severe reactions with respiratory and circulatory symptoms have also been reported in patients receiving oral contraceptives.[43360] Melasma, in the form of tan or brown patches, may develop on the forehead, cheeks, temples, and upper lip. These patches may persist after the drug is discontinued. Photosensitivity can be experienced with oral contraceptive use and protective clothing and sunscreens should be employed when exposed to sunlight or UV light.[57603] An association of oral contraceptives with acne vulgaris, hirsutism, alopecia, erythema multiforme, or erythema nodosum has been neither confirmed nor refuted. Although oral contraceptives can be used to treat acne vulgaris, in some cases they may induce or aggravate an existing acne vulgaris (2—6%). Oral contraceptives have not been shown to increase the incidence of skin cancer of any type, including melanoma.

Some women taking estrogens or oral contraceptives notice tenderness, swelling, or minor bleeding of their gums, which may lead to gingivitis. Proper attention to oral care and regular dental visits during ethinyl estradiol; norethindrone acetate therapy are recommended.

Exogenous estrogen use has been associated with gastrointestinal adverse reactions. Events occurring during oral contraceptive or hormone replacement therapy (HRT) trials, or during post marketing surveillance of either, include: nausea, vomiting, abdominal pain (HRT trials: 5.3% to 6.8%), abdominal cramps, bloating, cholestatic jaundice, and gallbladder disease including cholecystitis, cholelithiasis, and cholestasis.[43360] [57612] Cholestatic jaundice of pregnancy or jaundice with prior oral contraceptive use are contraindications for ethinyl estradiol; norethindrone acetate use. Discontinue ethinyl estradiol; norethindrone acetate if jaundice develops, as steroid hormones may be poorly metabolized in patients with impaired liver function.[57612] The increased risk of gallbladder disease associated with oral contraceptive use may be minimal, especially with the use of oral contraceptive formulations that contain lower hormonal doses of estrogens and progestogens. Other GI events including colitis, elevated hepatic enzymes, hepatitis, hyperlipidemia, and anorexia with weight loss may also occur with oral contraceptive use. Rare but serious gastrointestinal events which may occur with oral contraceptive use include peliosis hepatis, Budd-Chiari syndrome, or hepatic vein obstruction. Peliosis hepatis, a very rare consequence of taking estrogens and combined oral contraceptives, is characterized by the presence of blood-filled spaces.[51257] In rare cases, oral contraceptives can cause benign but dangerous liver tumors. Indirect calculations have estimated the attributable risk of hepatoma to be in the range of 3.3 cases per 100,000 for users, a risk that increases after 4 or more years of use. These benign liver tumors can rupture and cause fatal internal bleeding.[57612] In patients with familial defects of lipoprotein metabolism receiving estrogen-containing preparations, significant elevations of plasma triglycerides (hypertriglyceridemia) leading to pancreatitis have been reported. In hormone therapy studies, digestive system adverse events were reported in (9.6% to 13.1%) of patients. Post marketing reports have included cases of enlargement of hepatic hemangiomas and pancreatitis.[43360] Numerous cases of bowel ischemia have been reported during combined estrogen and progesterone use; mesenteric vein thrombus due to hypercoagulability is the proposed mechanism.[57614]

Hormone replacement therapy (HRT), both estrogen/progestin combination therapy and estrogen alone therapy, fails to prevent mild impaired cognition (memory loss) and is positively associated with the risk of developing dementia in women 65 years and older; do not use HRT to prevent or treat dementia or preserve cognition (memory).[43360] When data from the 2 populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95% CI 1.19 to 2.60, p = 0.005). Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women.[27451] [32126] [50638] In the Women’s Health Initiative Memory Study (WHIMS) estrogen plus progestin ancillary study, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily estrogen plus progestin or placebo. After an average follow-up of 4 years, 40 women in the estrogen plus progestin group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for estrogen plus progestin vs. placebo was 2.05 (95% CI, 1.21 to 3.48). The absolute risk of probable dementia for estrogen plus progestin vs. placebo was 45 vs. 22 cases per 10,000 women-years.[27451] In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily estrogen-alone or placebo. After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for estrogen-alone vs. placebo was 1.49 (95% CI, 0.83 to 2.66). The absolute risk of probable dementia for estrogen-alone versus placebo was 37 vs. 25 cases per 10,000 women-years.[32126]

In women with a history of cardiovascular disease, the use of estrogen and progestin combination therapy (e.g., ethinyl estradiol; norethindrone acetate) increases the risk of developing urinary incontinence. Patients in the HERS study who did not have urinary incontinence prior to the studies initiation were observed to determine if hormone replacement therapy was helpful in preventing urinary incontinence. The study found that women who received estrogen/progestin therapy were almost twice as likely as patients receiving placebo to develop urge incontinence and 3 times as likely to develop stress incontinence after 1 year of treatment. At 4 years, the effect of hormone replacement therapy became even more pronounced, increasing the risk to 3.23 for urge incontinence and to 4.81 for stress incontinence. The applicability of these findings to women who use estrogen alone is unclear.[27457]

Myalgia (7.8% to 8.6%), arthralgia (2.9% to 5.8%), back pain (4.7% to 5.3%), and musculoskeletal pain have been noted with combined oral contraceptives (COCs) such as ethinyl estradiol; norethindrone acetate. Systemic lupus erythematosus (lupus-like symptoms) has been reported in COC users.[57612] Arthralgias, leg muscle cramps, and myalgia have been reported with ethinyl estradiol; norethindrone acetate for hormonal replacement therapy (HRT) in postmarketing use.[43360]

Cystitis has been noted with combined oral contraceptives such as ethinyl estradiol; norethindrone acetate.[57612]

Rhinitis (12.7% to 15.1%) and sinusitis (2% to 9.4%) have been noted with ethinyl estradiol; norethindrone acetate combination oral contraceptives and hormone replacement therapy; however, incidence rates are similar to those reported with placebo.[57612] [43360]

Aggravation of porphyria has been noted with estrogens; including hormone replacement and oral contraceptives products such as ethinyl estradiol; norethindrone acetate.[43360] [57612]

The issue of hormonal influences on the development of cancers has been widely researched for many decades. The risks of various cancers for combined oral contraceptive (COC) use in premenopausal women differ from the risks associated with hormone replacement therapy (HRT) in postmenopausal women. HORMONE REPLACEMENT THERAPY POSTMENOPAUSE: Numerous epidemiologic studies have examined the effects of estrogen and estrogen-progestin hormone replacement therapy (HRT) on the development of new primary malignancy (e.g., breast cancer, endometrial cancer, ovarian cancer) in postmenopausal women. The Women's Health Initiative (WHI) estrogen plus progestin study reported increased risks of invasive breast cancer in patients taking combined estrogen-progestin HRT vs. placebo. The potential risk of breast cancer may increase with longer duration of use. Due to breast cancer and other cancer risks, combined HRT should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.[43360] [27272] [32125] [27273] [50638] There is an association of unopposed estrogen therapy and endometrial cancer in women with an intact uterus. Adding a progestin to estrogen therapy has been shown to reduce, but not eliminate, the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal vaginal bleeding. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Among combined estrogen/progestin HRT users, roughly 10% will have some endometrial thickening. Postmarketing reports of endometrial hyperplasia have been reported in women receiving combined estrogen/progestin HRT; however, the incidence of endometrial hyperplasia is estimated to be 1% or less in these patients.[43360] [50638] [23505] [27272] Women who used HRT for menopausal symptoms also had an increased risk for ovarian cancer, but data are still uncertain if risk is associated with a specific duration of use. The contraindications and precautions sections for the ethinyl estradiol-norethindrone acetate HRT product labels more fully discuss the data and what is known about HRT use with respect to risks for various cancers.[43360] [27272] [32125] [27273] [50638] ORAL CONTRACEPTIVES: Most studies have been performed with combined oral contraceptives (COCs), and the risks related to combined hormonal contraceptives, regardless of route of administration, are thought to be similar. In general, the data suggest an increased risk of cervical cancer among combined oral contraceptive (COC) users, with a decreased risk for endometrial and ovarian cancers. Epidemiology studies have not found a consistent association between use of COCs and breast cancer risk. Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer. However, some studies report a small increase in the risk of breast cancer among current or recent users (less than 6 months since last use) and current users with longer duration of COC use.[57612] [62904] Several large, well-designed observational studies have provided data regarding the risk of breast cancer with combined oral contraceptive (COC) use.[27233] [24750] [27234] Breast cancers diagnosed in current or previous COC users tend to be less advanced clinically than in never-users. The risk of breast cancer is only slightly increased in current and recent COC users (i.e., within 10 years); however, 10 years after COC cessation, the risk of breast cancer appears to be similar to that in those patients that have never used COCs.[62647] 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 durations 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 COC users in 1 year.[62904] Moreover, the same study data suggest that any increased risk of breast cancer usually disappears rapidly after an interruption in the use of COCs.[62904] There continues to be controversy regarding the risk of COC use in women with a family history of breast cancer (e.g., BRCA mutations). However, evidence does not suggest that the increased risk for breast cancer among women with either a family history of breast cancer or breast cancer susceptibility genes is modified by the use of COCs.[48201] Patients should be instructed to perform monthly self-breast examination and report any breast changes, lumps, or discharge to their health care professional. If breast cancer is suspected in a woman who is taking hormonal contraceptives, the contraceptive should be discontinued.[57612] Some studies suggest that COC 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, 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 patients taking COCs via cervical cytology screening as recommended per standards of care.[62647] A meta-analysis of 10 studies indicated significant trends for a reduced risk for endometrial and ovarian cancer with increased duration of COC use. Risk of endometrial or ovarian cancers may be reduced by up to 60% with 4 or more years of use.[25198] Data suggest COCs do not protect against hereditary forms of ovarian cancer (e.g., women who carry BRCA1 or BRCA2 gene alterations).[25199] Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (more than 8 years) COC users. However, these cancers are rare in the United States, and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than 1 per million users.[62647] [57612]

Norethindrone acetate; ethinyl estradiol combined hormonal oral contraceptive (COC) products do not protect against human immunodeficiency virus (HIV) infection or other sexually transmitted disease. Patients with known HIV infection or acquired immunodeficiency syndrome (AIDS) should be aware that COC use will not prevent the transmission of HIV or other diseases to their partner(s).[57612]

Combined hormonal oral contraceptives (COCs) and estrogen-containing hormonal replacement therapy (HRT) products are contraindicated in patients with a current or past history of stroke, cerebrovascular disease, coronary artery disease, coronary thrombosis, myocardial infarction, thrombophlebitis, thromboembolism or thromboembolic disease, or valvular heart disease with complications. Hormonal COCs and estrogen-containing HRT have been associated with thromboembolism such as deep venous thrombosis (DVT) and pulmonary embolism (PE). COCs and estrogen-containing HRT are also generally contraindicated in women who have 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).[43360] [57612] [48201] COMBINED ORAL HORMONAL CONTRACEPTIVES: COCs have been associated with thromboembolism such as deep venous thrombosis (DVT). Should a thromboembolic event occur or be suspected, the COC should be discontinued immediately.[57612] Because tobacco smoking increases the risk of thromboembolism, DVT, myocardial infarction, stroke and other thromboembolic disease, patients receiving COCs are strongly advised not to smoke. Risk is especially high for female smokers more than 35 years of age or those who smoke 15 or more cigarettes per day. Therefore, COCs are generally considered contraindicated in women over the age of 35 years who are tobacco smokers. A positive relationship between estrogen dosage and thromboembolic disease has been demonstrated, and oral products containing 50-mcg ethinyl estradiol should not be used unless medically indicated. In addition, certain progestins may increase thromboembolic risk. The overall risk of venous thromboembolism in women using COCs has been estimated to be 3 to 9 per 10,000 woman-years. Preliminary data from a large, prospective cohort safety study suggests that the risk is greatest during the first 6 months after initially starting COC therapy or restarting (following a break from therapy 4 weeks or more) with the same or different combination product. The risk of arterial thromboses, such as stroke and myocardial infarction, is especially increased in women with other risk factors for these events. Pre-existing high blood pressure, kidney disease, hypercholesterolemia, diabetes with vascular disease, and patients who are morbidly obese may also increase risk. After a COC is discontinued, the risk of thromboembolic disease due to COCs gradually disappears. Because of their association with elevations in blood pressure, COCs should be used cautiously in patients with mild to moderate hypertension or kidney disease; use is contraindicated in patients with uncontrolled or severe hypertension or hypertension with vascular disease. An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use. The incidence of hypertension increases with increasing concentration of progestin. Blood pressure should be monitored closely in individuals with high blood pressure; discontinue the COC if blood pressure rises significantly. COCs may also cause fluid retention, and patients predisposed to complications from edema, such as those with cardiac disease or renal disease, should be closely monitored.[57612] [48201] HORMONE REPLACEMENT THERAPY (HRT): An increased risk of thromboembolism, such as pulmonary embolism (PE), DVT, as well as cardiovascular events, such as stroke and myocardial infarction (MI) has been reported with estrogen plus progestin hormone replacement therapy (HRT) in postmenopausal women. Should any of these events occur or be suspected, discontinue HRT immediately.[43360] Estrogens with or without progestins should not be used for the prevention of cardiac disease or cardiovascular disease (e.g., coronary artery disease). Patients with certain risk factors for arterial vascular disease (e.g., hypertension, diabetes, tobacco smoking, hypercholesterolemia, and morbidly obese) and/or venous thromboembolism (VTE) [e.g., personal history or family history of VTE, obese or systemic lupus (SLE)] should be monitored and managed appropriately during HRT use.[43360] In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving estrogen plus progestin HRT compared to women receiving placebo (35 vs. 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 vs. 13 per 10,000 women-years) and PE (18 vs. 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted.[17825] [27272]  In the Women's Health Initiative (WHI) estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as non-fatal MI, silent MI, or CHD death) was reported in women receiving estrogen-alone compared to placebo. Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE-alone vs. placebo) in women with less than 10 years since menopause (8 vs. 16 per 10,000 women-years). In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily estrogen plus progestin compared to women receiving placebo (41 vs. 34 per 10,000 women-years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5.[27272] [17808] Studies have also shown no cardiovascular benefit to the use of estrogens or estrogen-progestin therapy for secondary prevention in women with documented cardiac disease or CHD.[25473] [27270] Estrogens also increase the risk for stroke. In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving estrogen-alone compared to women in the same age group receiving placebo (45 vs. 33 per 10,000 women-years). The increase in risk was demonstrated in the first year and persisted. Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving estrogen-alone versus those receiving placebo (18 vs. 21 per 10,000 women-years). In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving estrogen plus progestin HRT compared to women in the same age group receiving placebo (33 vs. 25 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted. Women older than 65 years of age were at increased risk for non-fatal stroke.[38488] [27272] Patients with hypertension should be monitored closely for increases in blood pressure if HRT is administered. In a few case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogen HRT therapy. In a large, randomized, placebo controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen. Estrogen-based HRT may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as a cardiac disease, warrant careful observation when estrogens are prescribed.[43360]

Surgery can increase the risk for thromboembolism from combined hormonal contraceptives(COCs) and estrogen-based hormone replacement therapy (HRT). If feasible, discontinue norethindrone acetate; ethinyl estradiol products at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism, and during and following any prolonged immobilization. The decision on when to resume COCs or HRT after such procedures or conditions would be based on the perceived additional thromboembolic risk; resume only after the patient is fully ambulatory. In addition, advise treated patients to move about periodically during travel involving prolonged immobilization.[57612] [43360]

Because of the increased potential for embolic risk, combined oral contraceptives (COCs) containing ethinyl estradiol; norethindrone acetate are contraindicated in women who currently have diabetes mellitus and are over 35 years of age, diabetes mellitus with hypertension or with vascular disease or end-organ damage, or diabetes mellitus of greater than 20 years duration.[43360] Patients with diabetes mellitus should be observed for changes in glucose tolerance when initiating or discontinuing estrogen therapy with COC or as hormone replacement therapy (HRT), since estrogen therapy may exacerbate diabetes. Altered glucose tolerance secondary to decreased insulin sensitivity has been reported.[43360] [57612]

Women who are being treated for dyslipidemia should be followed closely if they elect to use combined hormonal oral contraceptives (COCs) or hormone replacement therapy (HRT). Some progestogens may elevate LDL levels and may render the control of hyperlipidemia more difficult. Females with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs. Consider discontinuation of treatment if pancreatitis occurs.[43360] [57612]

Ethinyl estradiol; norethindrone acetate combined hormonal oral contraceptive (COC) products are contraindicated in patients with migraine or other headache that is accompanied by focal neurological symptoms, such as aura, or women over age 35 with any migraine headaches. COCs may cause an exacerbation of migraine or a change in headache patterns and should be used with caution in women with migraine. Patients who complain of migraine with focal neurologic visual changes should be medically evaluated, and in some patients, such changes may indicate cerebrovascular events.[57612] Similarly to COC products, estrogen-based hormone replacement therapy (HRT) may cause an exacerbation of migraine, and should be used with caution in women with these conditions.[43360]

Do not use norethindrone acetate; ethinyl estradiol products in patients with a known hypersensitivity to any of the specific product ingredients; ethinyl estradiol is contraindicated in patients with known anaphylactic reactions or history of angioedema to the drug. Cases of both anaphylactic reactions and angioedema have been reported in patients taking estrogens. Events have developed in minutes and have required emergency medical treatment. Exogenous estrogens may also induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema, which can be hormonally sensitive.[57612] [43360]

Given the increased prevalence of hypercoagulable states in patients with systemic lupus erythematosus (SLE) (in particular antiphospholipid antibodies and lupus anticoagulant) and the risk factors for thromboembolism, consider risks vs. benefit of COC or estrogen-based HRT use in these patients. Avoid COC or estrogen-based HRT use in SLE patients with a history of venous or arterial thrombosis or the presence of a hypercoagulable state. If COCs are initiated in SLE patients without hypercoagulable states, choose a low-dose estrogen contraceptive (e.g., ethinyl estradiol 35 mcg per day or less); consider use of a progestin-only contraceptive. Combined hormonal oral contraceptive (COC) or estrogen-based hormone replacement therapy (HRT) use has also been reported to induce, unmask, or exacerbate SLE; more data are needed.[31435] [48201] [43360]

Discontinue norethindrone acetate; ethinyl estradiol products if pregnancy is detected; there is no reason to continue combined oral hormonal contraceptives (COCs) during pregnancy. Estrogen-based hormone replacement therapy (HRT) should not be used 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 COCs before conception or during early pregnancy. For any patient who has missed two consecutive periods, pregnancy should be ruled out. If the patient has not adhered to the prescribed COC schedule, consider the possibility of pregnancy at the first missed period. Discontinue COC use if pregnancy is confirmed.[43360] [57612]

Estrogen-based hormone replacement therapy (HRT) should not be used during lactation.[43360] Manufacturers recommend avoidance of combined hormonal oral contraceptives (COCs) if possible until a mother has completely weaned her child.[57612] Small amounts of oral contraceptive steroids (estrogens and progestins) have been identified in the milk of nursing mothers and a few reports of effects on the infant exist, including jaundice and breast enlargement. Experts often recommend avoidance of estrogen-containing hormonal contraceptives, in the first 21 days postpartum due to maternal post-partum risks for thromboembolism following obstetric delivery, and the potential for COCs to interfere with the establishment of lactation. It is generally accepted that estrogen-containing combined hormonal contraceptives may be used after this period in healthy women without other risk factors; general monitoring of the infant for effects such as appetite changes, breast changes and proper weight gain and growth should occur.[48201] Estrogens, including ethinyl estradiol (EE), have been reported to interfere with milk production and duration of lactation in some women, particularly at doses of 30 mcg per day or more.[48204] One study found that lower dose oral combined contraceptives (e.g., 10 mcg per day EE) may not affect lactation.[48200] However, a systematic review concluded that the available evidence, even from randomized controlled trials, is limited and of poor quality; proper trials are needed.[48202] Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. Alternate contraceptive agents for consideration for use during breast-feeding include non-hormonal contraceptive methods and also progestin-only contraceptives (e.g., medroxyprogesterone injection).[48201]

LIVER/GI SYSTEM ISSUES with COMBINED HORMONAL ORAL CONTRACEPTIVES: Combined oral contraceptives (COCs) are contraindicated in patients with hepatic disease. Because of the association with cholestasis and hepatic neoplasms, estrogens are contraindicated in the presence of hepatocellular cancer, hepatic adenoma, other liver tumors (benign or malignant), or markedly impaired liver function (e.g., uncompensated cirrhosis). Do not use COCs in patients with a history of cholestatic jaundice/pruritus of pregnancy or jaundice from prior hormonal contraceptives; these conditions can recur with subsequent COC use. Discontinue use of the COC if jaundice develops during combined oral contraceptive use. Steroid hormones may be poorly metabolized in patients with liver impairment. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded. Patients with hepatitis C who are being treated with ombitasvir/paritaprevir/ritonavir, with or without dasabuvir are also contraindicated to receive COCs. 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 women using ethinyl estradiol-containing medications. Discontinue COCs before starting hepatitis C therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir; a COC can be restarted approximately 2 weeks following completion of treatment with the hepatitis C combination drug regimen. Hepatic adenomas are associated with COC use. An estimate of the attributable risk is 3.3 cases/100,000 COC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage. Studies have shown an increased risk of developing hepatocellular carcinoma in long term (more than 8 years) COC users. However, the attributable risk of liver cancers in COC users is less than 1 case per million users. Use COCs with caution in patients with pre-existing gallbladder disease; however, recent studies have shown that the relative risk of developing gallbladder disease among COC users appears minimal due to the use of products that contain lower doses of hormones.[57612] [48201] LIVER/GI SYSTEM ISSUES with ESTROGEN-BASED HRT POSTMENOPAUSE: Ethinyl estradiol; norethindrone acetate HRT products are contraindicated in the presence of hepatocellular cancer, hepatic adenoma, or in severe hepatic disease of any type. Estrogens and progestins may be poorly metabolized in women with impaired liver function. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised, and in the case of recurrence, estrogens should be discontinued. Estrogens should also be used cautiously in patients with acute intermittent, or variegate hepatic porphyria, which can be exacerbated. Estrogens have been reported during trials to increase the risk of gallbladder disease (e.g., cholestasis, cholelithiasis and cholecystitis) by roughly 2- to 4-fold in postmenopausal women; use with caution in patients with a history of gallbladder disease.[25473] [43360]

Mood disorders, like depression, may be aggravated in women taking combined oral hormonal contraceptives (COCs). Data regarding the association of COCs with onset of depression or exacerbation of existing depression are limited. If significant depression occurs, norethindrone acetate; ethinyl estradiol products should be discontinued.[57612] Mood disorders, like depression, may be aggravated in women taking estrogen-based hormone replacement therapy (HRT); if significant depression occurs, the HRT should be discontinued.[43360]

Norethindrone acetate; ethinyl estradiol products, including combined hormonal oral contraceptives (COCs) and hormone replacement therapy (HRT), are contraindicated in patients with a history of, or known or suspected breast cancer, as breast cancer is a hormonally-sensitive tumor. COMBINED HORMONAL CONTRACEPTION: Epidemiology studies have not found a consistent association between use of COCs and breast cancer risk. Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer. However, some studies report a small increase in the risk of breast cancer among current or recent users (less than 6 months since last use) and current users with longer duration of COC use. Several large, well-designed observational studies have provided data regarding the risk of breast cancer with combined oral contraceptive (COC) use.[27233] [24750] [62647] 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 durations 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 COC users in 1 year.[62904] Moreover, the same study data suggest that any increased risk of breast cancer usually disappears rapidly after an interruption in the use of COCs.[62904] There continues to be controversy regarding the risk of COC use in women with a family history of breast cancer (e.g., BRCA mutations). However, evidence does not suggest that the increased risk for breast cancer among women with either a family history of breast cancer or breast cancer susceptibility genes is modified by the use of COCs.[48201] All women taking COCs should receive clinical breast examinations and perform monthly self-examinations as recommended by their health care professional based on patient age, known risk factors, and current standards of care. If breast cancer is suspected in a woman who is taking hormonal contraceptives, the contraceptive should be discontinued.[48201] ESTROGEN-BASED HORMONE REPLACEMENT THERAPY (HRT): Studies suggest that the use of estrogen-progestin HRT in postmenopausal women increases the risk for invasive breast cancer (new primary malignancy). The use of estrogen-alone and estrogen plus progestin HRT has been reported to result in an increase in abnormal mammograms, requiring further evaluation. All women taking estrogen with or without a progestin as HRT should receive an annual clinical breast examination, perform monthly self-examinations, and have regular mammograms as recommended by their health care professional based on patient age, risk factors, and prior mammogram results.[43360] Since the 1970s, numerous epidemiological studies have examined the association of estrogens or combined HRT and breast cancer.[23505] The most important randomized clinical trial providing information about breast cancer in patients taking combined estrogen-progestin HRT regimens is the WHI substudy of estogen-progestin therapy.[27530] [27272] After a mean follow-up of 5.6 years, the WHI estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily estogen-progestin vs. placebo. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for estrogen/progestin compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs. 25 cases per 10,000 women-years for estrogen/progestin compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs. 36 cases per 10,000 women-years for estrogen/progestin compared with placebo. In the same WHI substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the combined HRT group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the 2 groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the 2 groups.[27530] Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with combined HRT as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration. While estrogen therapy may be used rarely for the palliative treatment of advanced breast cancer in men and women, estrogen HRT use may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of HRT should be stopped and appropriate measures taken to reduce the serum calcium level.[43360]

Estrogen-based hormone regimens are contraindicated in the presence of cervical cancer or other estrogen-responsive tumors.[57612] [43360] COMBINED HORMONAL ORAL CONTRACEPTIVES (COCs): Most cervical cancers are related to the presence of the human papillomavirus (HPV), but hormonal factors influence risk. In women taking COCs, studies have found an increased risk of cervical cancer compared with never-users. The risk appears to increase with duration of use and appears to decline when COCs are discontinued. Clinical surveillance of all women using COCs is important; all women receiving COC treatment should have a pelvic examination and other diagnostic or screening tests, such as cervical cytology, as clinically indicated or as generally recommended based on age, risk factors, and other individual needs.[48201] [57612] ESTROGEN-BASED HORMONE REPLACEMENT THERAPY: An increased risk for cervical dysplasia or cancer has NOT been noted with the use of estrogen-progestin hormone replacement therapy (HRT) postmenopause.[50638] Because estrogens influence the growth of endometrial tissues, use estradiol or other estrogens cautiously in women with endometriosis or uterine leiomyomata (uterine fibroids). A few cases of malignant transformation of residual endometrial growths have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometriosis post-hysterectomy, consider the addition of a progestin to estrogen therapy, such as the use of estradiol; norethindrone products, to reduce the risk of endometrial tissue growth. Clinical surveillance of all women using estrogen-alone or estrogen plus progestin HRT is important; all women receiving estrogen treatment should have a pelvic examination and other diagnostic or screening tests, such as cervical cytology, as clinically indicated or as generally recommended based on age, risk factors, and other individual needs.[43360]

Norethindrone acetate; ethinyl estradiol combined oral contraceptive (COC) and hormonal replacement therapy (HRT) products are contraindicated in women with estrogen-dependent neoplasms, including ovarian cancer. ORAL CONTRACEPTIVES: Many studies have documented a protective effect of COCs against ovarian cancer, with the protective effects increasing with duration of use; the protective effects appear to persist for 15 years or more after stopping COC use.[25198] [48201] [57612] [62647] HORMONE REPLACEMENT THERAPY (HRT): The use of HRT increases ovarian cancer risk in peri- and postmenopausal women. What is known about the risk of ovarian cancer due to HRT is derived from data available for estrogen-alone and estrogen plus progestin products. The Women's Health Initiative (WHI) estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for estrogen plus progestin versus placebo was 1.58 (95% CI 0.77 to 3.24). The absolute risk for estrogen plus progestin versus placebo was 4 versus 3 cases per 10,000 women-years.[17829] A meta-analysis of 17 prospective and 35 retrospective epidemiology studies found that women who used hormonal therapy for menopausal symptoms had an increased risk for ovarian cancer. The primary analysis, using case-control comparisons, included 12,110 cancer cases from the 17 prospective studies. The relative risk associated with current use of hormonal therapy was 1.41 (95% confidence interval [CI] 1.32 to 1.5); there was no difference in the risk estimates by duration of the exposure (less than 5 years [median of 3 years] vs. greater than 5 years [median of 10 years] of use before the cancer diagnosis). The relative risk associated with combined current and recent use (discontinued use within 5 years before cancer diagnosis) was 1.37 (95% CI 1.27 to 1.48), and the elevated risk was significant for both estrogen-alone and estrogen plus progestin products. The exact duration of hormone therapy use associated with an increased risk of ovarian cancer, however, is unknown.[43360]

Combined oral contraceptives (COCs) and hormone replacement therapy (HRT) are contraindicated in the presence of vaginal cancer, cervical cancer, uterine cancer, or other estrogen-responsive tumors. Clinical surveillance of all women using COCs or HRT is important; all women receiving COC or HRT treatment should have a pelvic examination and other diagnostic or screening tests, such as cervical cytology, as clinically indicated or as generally recommended based on age, risk factors, and other individual needs.[43360] [48201][57612] Because estrogens influence the growth of endometrial tissues, use estradiol or other estrogens for HRT cautiously in women with endometriosis or uterine leiomyomata (uterine fibroids). A few cases of malignant transformation of residual endometrial growths have been reported in women treated post-hysterectomy with estrogen-alone HRT therapy. For women known to have residual endometriosis post-hysterectomy, consider the addition of a progestin to estrogen HRT, such as the use of norethindrone acetate; ethinyl estradiol products, to reduce the risk of endometrial tissue growth.[43360]

Norethindrone acetate; ethinyl estradiol products are contraindicated in patients with known estrogen-dependent malignancies, such as endometrial cancer.[43360] [57612] HORMONE REPLACEMENT THERAPY (HRT): There is an association of unopposed estrogen therapy and endometrial cancer in women with an intact uterus. Adding a progestin to estrogen therapy has been shown to reduce, but not eliminate, the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal vaginal bleeding. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15-to 24-fold for 5 to 10 years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. With concurrent progestin use, such as choosing a combination HRT product, the incidence of endometrial hyperplasia due to estrogen therapy is estimated to be 1% or less.[43360] [23505] [27272] HORMONAL CONTRACEPTIVES: Hormonal contraceptives are contraindicated in women with undiagnosed vaginal bleeding; evaluate such patients before use and determine if a contraindication exists.[48201] [57612] Unlike HRT, the use of combined oral contraceptives (COCs) appears to have a protective effect on the endometrium. In women using COCs, a meta-analysis of 10 studies indicates a significant trend in decreasing endometrial carcinoma risk with increasing duration of COC use. The beneficial effects of COCs in this regard may persist for 15 years or more after COC use ceases.[25198] [48201] [62647]

The estrogen component of combined oral hormonal contraceptives or HRT may raise the serum concentrations of thyroid-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin. Doses of thyroid hormone replacement for hypothyroidism may need to be increased, as indicated by clinical and laboratory monitoring for the individual. Cortisol replacement therapy (e.g., corticosteroid therapy) may also need adjusted for some patients.[43360] [57612]

Chloasma may occur with combined oral hormonal contraceptive (COC) use, especially in women with a history of chloasma gravidarum (melasma). Advise females who tend to develop chloasma to avoid exposure to the sun or ultraviolet (UV) exposure while taking norethindrone acetate; ethinyl estradiol for birth control.[57612]

Preexisting morbid obesity is one factor that may increase cardiovascular or thromboembolic risks associated with combination hormonal contraceptive use. Consider the presence of obesity and other underlying risk factors that may increase the risk of cardiovascular disease or thromboembolism, particularly for women over 35 years of age.[57612] Obesity may also increase thromboembolic risks due to HRT in postmenopausal women.[43360] Limited literature suggests that the effectiveness of some hormonal contraceptive formulations might decrease with increasing body mass index (BMI). However, the evidence is conflicting; there are also data to suggest that the efficacy of most combined hormonal contraceptive products (with a few known exceptions) does not seem to be compromised in women who are overweight.[48201] [66895]

Estrogen replacement therapy, such as the use of norethindrone acetate; ethinyl estradiol as HRT for menopause or osteoporosis, should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.[43360]

The safety and efficacy of norethindrone acetate; ethinyl estradiol hormone replacement therapy (HRT) have not been established in pediatric patients.[43360] The safety and efficacy of hormonal contraceptive products have only been established in females of reproductive age. Safety and efficacy of hormonal birth control is expected to be the same for postpubertal children under the age of 16 and for users 16 years of age and older. Use of hormonal contraceptive products in female children before menarche is not indicated.[57612]

Hormone replacement therapy (HRT) with norethindrone acetate; ethinyl estradiol should not be used for the prevention of dementia. HRT, both estrogen-progestin combination therapy and estrogen alone therapy, has been found to fail to prevent mild cognitive impairment (memory loss) and to increase the risk of dementia in women 65 years and older.[43360] Administration of HRT should generally be avoided in women 65 years of age and older, and HRT should not be used to prevent or treat dementia or preserve cognition (memory). Overall risk vs. benefit should be considered along with the goals of use of HRT for the individual patient when considering whether to continue HRT in a geriatric woman over 65 years of age.[27451] [32126] [50638] According to the Beers Criteria, oral, topical patch, or other systemic forms of estrogens (with or without progestins), are considered potentially inappropriate medications (PIMs) for use in geriatric patients and should be avoided due to evidence of carcinogenic potential (i.e., breast and endometrium) and lack of cardiovascular or cognitive protective effects in older women. Additionally, the Beers expert panel recommends avoiding oral or transdermal estrogen in elderly women with any type of urinary incontinence due to lack of efficacy. The Beers expert panel considers use of vaginal estrogens acceptable for the management of dyspareunia, recurrent lower urinary tract infections, and other vaginal/vulvar symptoms.[63923]