Estradiol / norgestimate Side Effects

Not all side effects for estradiol / norgestimate may be reported. You should always consult a doctor or healthcare professional for medical advice. Side effects can be reported to the FDA here.

For the Consumer

Applies to estradiol / norgestimate: tablets

Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Nausea; vomiting; weight change; bleeding between menstrual periods; breast tenderness.

Seek medical attention right away if any of these SEVERE side effects occur while taking estradiol / norgestimate:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); calf/leg pain or swelling; changes in vision; chest pain; difficulty wearing contact lenses; dizziness or fainting; headache or sudden severe headache; lumps in the breast; missed menstrual period; numbness of an arm or leg; one-sided weakness; persistent or recurrent abnormal vaginal bleeding; severe stomach pain; slurred speech; swelling of fingers or ankles; trouble breathing or shortness of breath; yellowing skin or eyes.

For Healthcare Professionals

Applies to estradiol / norgestimate: oral tablet

Gastrointestinal

Gastrointestinal side effects have included abdominal pain (12%), nausea (6%), and flatulence and tooth disorders (5%). Cholestatic jaundice, vomiting, and bloating have occurred. Some studies have demonstrated a 2 to 4 fold increase in gallbladder disease in postmenopausal women taking estrogen therapy.

Oncologic

Oncologic side effects have included reports of increased risk of invasive breast cancer. A large study (n = 16,608 postmenopausal women) of conjugated equine estrogens and medroxyprogesterone was terminated in 2002 due to the increased risk of coronary heart disease, stroke, and pulmonary embolism. Other oncologic side effects of unopposed estrogen therapy have included an increased risk of endometrial carcinoma, and less persuasively, an increased risk of breast cancer. A number of studies have suggested that the risk of endometrial carcinoma is removed (or delayed) by the administration of progestins in combination with estrogen therapy.

The risk of breast cancer due to use of estrogens is controversial. Meta analysis of epidemiological data supports a modest risk increase associated with long-term hormone replacement therapy (HRT).

A study of Swedish women has reported that a 10% increase in the relative risk of breast cancer may occur and that the risk is related to increasing duration of estrogen use had a 70% greater relative risk of breast cancer than controls. That study, however, examined use of a variety of estrogen preparations of which estradiol was the most frequently prescribed. In addition, women who took progestins did not demonstrate a decreased risk of breast cancer and may even have been at higher risk.

The Toronto Breast Cancer Study has reported that women who receive unopposed conjugated estrogens for less than 15 years are not at increased risk of breast cancer. In that study, an increase in the risk of breast cancer for women who used conjugated estrogens for more than 15 years was not ruled out.

The Case-Control Surveillance Study reported "no evidence that the use of unopposed conjugated estrogens increases the risk of breast cancer, even after long duration of use or long latent intervals, but the possibility of a modest increase (less than doubling) could not be excluded."

Follow-up data to the Nurses' Health Study of 1992 concluded, however, that there is an increased risk of breast cancer in women taking estrogen replacement therapy and that the risk is not reduced by concurrent use of progestins. (In that study, greater risk was associated with advanced age and prolonged duration of hormonal therapy.)

A study of middle-aged women in the Puget Sound area concluded that "on the whole, the use of estrogen with progestin HRT [hormone replacement therapy] does not appear to be associated with an increased risk of breast cancer in middle-aged women."

A significant increase in the incidence of breast cancer in beagle dogs in addition to an apparent increase in the incidence of endometrial cancer in rhesus monkeys was noted in early animal carcinogenicity studies.

A prospective cohort study (11 years) of 37,105 women by Gapstur et al evaluated the histology of the breast cancer in women with ever HRT use. Little evidence of association was found between duration of ever HRT use and the incidence of ductal carcinoma in situ or invasive ductal/lobular carcinoma. The duration of ever HRT use was associated with risk of invasive carcinoma with a favorable prognosis [relative risk (RR) = 1.81, 95% confidence interval (CI), 1.07 to 3.07 for HRT use <= and RR = 2.65, CI, 1.32 to 5.23 for HRT use > 5yrs, p = 0.005]. The relative risk of invasive carcinoma with a favorable prognosis for current users (adjusted for age and other risk factors) was 4.42, CI, 2.00 to 9.76 for <= 5yrs and 2.63, CI 1.18 to 5.89 for > 5yrs). Risk of invasive ductal or lobular carcinoma for current users <= 5yrs was RR = 1.38, CI, 1.03 to 1.85.

Cardiovascular

The effects of estrogen therapy in reducing cardiovascular risk have been related to beneficial alterations in lipid profiles in treated women.

Data from the Nurse's Heart Study involving postmenopausal women without coronary heart disease who received combined estrogen-progestin therapy reported a marked decrease in coronary heart disease during a 16 year follow-up. Data from the Heart and Estrogen/progestin Replacement Study (HERS) Research Group involving 2763 postmenopausal women with established coronary disease reported no reduction in the overall rate of coronary heart disease despite a 11% decrease in low density lipoproteins and a 10% increase in high density lipoproteins in patients receiving conjugated estrogen-medroxyprogesterone when compared to the placebo group after an average follow-up of 4.1 years.

Some investigators have suggested that estrogens may increase blood pressure, particularly in patients receiving high doses. Other investigators have suggested that decreases in blood pressure (or no change) occur. In addition, it has been suggested that noncontraceptive use of estrogens in young women (particularly smokers) may substantially increase the risk of nonfatal myocardial infarction. Conflicting data have concluded that no increased risk of myocardial infarction exists.

The majority of cases of thromboembolic disease during hormonal therapy have been attributed to estrogens and not to progestins.

Cardiovascular side effects have included reports of increased risk coronary heart disease, stroke, and pulmonary embolism. A large study (n = 16,608 postmenopausal women) of conjugated equine estrogens and medroxyprogesterone was terminated in 2002 due to the increased risk of coronary heart disease. stroke, and pulmonary embolism. Earlier studies had suggested that unopposed estrogen therapy may decrease the risk of coronary heart disease by as much as 35% and that combination therapy with a progestin may also decrease coronary risk.

Metabolic

Metabolic side effects of estrogens have included increased serum triglyceride levels resulting in pancreatitis in patients with familial lipoprotein metabolic defects. However, metabolic effects in patients treated with estrogens have included generally favorable alterations in plasma lipid profiles. Specifically, increased HDL and decreased cholesterol and LDL levels have occurred.

Metabolic side effects of progestin therapy have included weight changes (increases and decreases), impaired glucose tolerance, and changes in serum cholesterol concentrations.

Hepatic

Hepatic side effects have included cases of focal nodular hyperplasia, liver cell adenomas, hepatic hemangiomas, and rarely, well-differentiated hepatocellular carcinomas.

Hematologic

Hematologic side effects have included hypercoagulability, although the clinical significance of such hypercoagulability in postmenopausal women taking estrogens has not been determined.

Endocrine

Endocrine side effects of estrogens have included increased levels of thyroxin-binding globulin, leading to an increase in total thyroid serum levels and a decrease in resin uptake of T3. Free thyroid hormone levels remain unchanged. Other endocrine effects may include a decrease on fasting plasma glucose.

Endocrine side effects of progestins have included breast tenderness, galactorrhea with or without hyperprolactinemia, prevention of lactation, hirsutism, and Cushing's syndrome.

Genitourinary

Genitourinary side effects have included breast pain (16%) and vaginal bleeding (9%). Dysmenorrhea (8%) and vaginitis (7%) have been reported. Estrogens may increase the size of preexisting uterine leiomyomata.

Several cases of pseudoincontinence (excessive vaginal discharge perceived by patients as urinary incontinence) have been reported in premenopausal women who have undergone hysterectomy-oophorectomy and received postoperative estrogens.

Dermatologic

Dermatologic side effects have included chloasma or melasma which may persist following discontinuation of therapy, reduced scalp hair growth, hirsutism, erythema multiforme, and erythema nodosum.

Musculoskeletal

Musculoskeletal side effects have included arthralgias and myalgias in 9% and 5% of patients, respectively.

Other

Other side effects have included reports that estrogen therapy may increase the risk of "fibrocystic breast disease" by as much as twofold.

Respiratory

Respiratory side effects have included reports of increased risk of pulmonary embolism. A large study (n = 16,608 postmenopausal women) of conjugated equine estrogens and medroxyprogesterone was terminated in 2002 due to the increased risk of coronary heart disease. stroke, and pulmonary embolism. Other respiratory side effects have included infections of the upper respiratory tract in 21% of patients. Pharyngitis (7%), sinusitis (8%), and coughing (5%) have been reported.

Nervous system

Nervous system side effects have included headaches in 23% of patients. Dizziness was reported in 5% of patients.

Psychiatric

Psychiatric side effects have included symptoms of depression in 5% of patients.

Ocular

Ocular side effects of estrogen therapy have included alterations in corneal curvature and contact lens discomfort.

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