Estrogens (Conjugated / Equine) and Medroxyprogesterone

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache.
• Upset stomach or throwing up.
• Cramps.
• Bloating.
• Enlarged breasts.
• Tender breasts.
• Hair loss.
• Vaginal bleeding or spotting.
• This medicine may cause dark patches of skin on your face. Avoid sun, sunlamps, and tanning beds. Use sunscreen and wear clothing and eyewear that protects you from the sun.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Administration with food decreases nausea, administer with food. Ensure adequate calcium and vitamin D intake when used for the prevention of osteoporosis.

Also see individual agents.

>10%:

Central nervous system: Headache (15% to 19%)

Gastrointestinal: Abdominal pain (7% to 17%)

Genitourinary: Mastalgia (13% to 36%), dysmenorrhea (3% to 13%)

1% to 10%:

Cardiovascular: Edema (≤4%), peripheral edema (2% to 3%), hypertension (2%), vasodilatation (≤2%), chest pain (1%), palpitations (≤1%)

Central nervous system: Depression (7% to 8%), pain (5%), emotional lability (3%), dizziness (2% to 3%), migraine (2% to 3%), nervousness (1% to 3%), anxiety (2%), hypertonia (1% to 2%), insomnia (1% to 2%)

Dermatologic: Pruritus (2% to 6%), skin rash (2%), acne vulgaris (≤2%), alopecia (≤2%), skin discoloration (1% to 2%), diaphoresis (≤1%), xeroderma (≤1%)

Endocrine & metabolic: Weight gain (3%), decreased glucose tolerance (≤1%), hypermenorrhea (≤1%)

Gastrointestinal: Nausea (6% to 8%), flatulence (4% to 8%), diarrhea (≤6%), constipation (2%), increased appetite (≤2%), eructation (≤1%)

Genitourinary: Leukorrhea (3% to 8%), breast hypertrophy (2% to 5%), pelvic pain (2% to 5%), vaginal hemorrhage (≤5%), vaginitis (2% to 4%), breakthrough bleeding (1% to 4%), uterine spasm (1% to 4%), vulvovaginal candidiasis (1% to 4%), cervical changes (1% to 3%), abnormal Pap smear (≤2%), breast engorgement (≤1%), urinary incontinence (≤1%)

Hematologic & oncologic: Malignant neoplasm of breast (≤1%)

Infection: Candidiasis (≤2%), infection (≤1%)

Neuromuscular & skeletal: Weakness (3% to 6%), back pain (2% to 7%), leg cramps (2% to 4%)

Respiratory: Pharyngitis (>5%), sinusitis (>5%), flu-like symptoms (≤1%)

<1% (Limited to important or life-threatening): Abnormal uterine bleeding, amenorrhea, anaphylactoid reaction, anaphylaxis, angioedema, cerebrovascular accident, cholestatic jaundice, contact lens intolerance, deep vein thrombosis, dementia, endometrial carcinoma, endometrial hyperplasia, erythema multiforme, erythema nodosum, exacerbation of asthma, exacerbation of epilepsy, exacerbation of tics, fibrocystic breast changes, galactorrhea, gallbladder disease, hirsutism, hypersensitivity reaction, ischemic colitis, malignant neoplasm of ovary, meningioma (benign; possible growth), myocardial infarction, pancreatitis, pulmonary embolism, retinal thrombosis, superficial venous thrombosis, thrombophlebitis, upper respiratory tract infection, uterine fibroids (increase in size), vulvovaginal candidiasis

Concerns related to adverse effects:

• Anaphylaxis: Anaphylaxis requiring emergency medical management has been reported and may develop at any time during therapy. Angioedema involving the face, feet, hands, larynx, and tongue has also been reported.

• Breast cancer: [US Boxed Warning]: Based on data from the Women’s Health Initiative (WHI) studies, an increased risk of invasive breast cancer was observed in postmenopausal women using conjugated estrogens (CE) in combination with medroxyprogesterone acetate (MPA). This risk may be associated with duration of use and declines once combined therapy is discontinued (Chlebowski, 2009). The risk of invasive breast cancer was decreased in postmenopausal women with a hysterectomy using CE only, regardless of weight. However, the risk was not significantly decreased in women at high risk for breast cancer (family history of breast cancer, personal history of benign breast disease) (Anderson, 2012). An increase in abnormal mammogram findings has also been reported with estrogen alone or in combination with progestin therapy. Estrogen use may also lead to severe hypercalcemia in patients with breast cancer and bone metastases; discontinue estrogen if hypercalcemia occurs. Use is contraindicated in patients with known or suspected breast cancer.

• Dementia: [US Boxed Warning]: Estrogens with or without progestin should not be used to prevent dementia. In the Women’s Health Initiative Memory Study (WHIMS), an increased incidence of dementia was observed in women ≥65 years of age taking CE alone or in combination with MPA.

• Endometrial cancer: [US Boxed Warning]: The use of unopposed estrogen in women with a uterus is associated with an increased risk of endometrial cancer. The addition of a progestin to estrogen therapy may decrease the risk of endometrial hyperplasia, a precursor to endometrial cancer. Adequate diagnostic measures, including endometrial sampling if indicated, should be performed to rule out malignancy in postmenopausal women with undiagnosed abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens at equivalent estrogen doses. The risk of endometrial cancer appears to be dose and duration dependent; risk appears to be greatest with use ≥5 years and may persist following discontinuation of therapy.

• Endometriosis: Estrogens may exacerbate endometriosis. Malignant transformation of residual endometrial implants has been reported posthysterectomy with unopposed estrogen therapy. Consider adding a progestin in women with residual endometriosis posthysterectomy.

• Inherited thrombophilia: Women with inherited thrombophilias (eg, protein C or S deficiency) may have increased risk of venous thromboembolism (DeSancho, 2010; van Vlijmen, 2011). Use is contraindicated in women with protein C, protein S, antithrombin deficiency, or other known thrombophilic disorders.

• Lipid effects: Estrogen compounds are generally associated with lipid effects such as increased HDL-cholesterol and decreased LDL-cholesterol. Triglycerides may also be increased in women with preexisting hypertriglyceridemia; discontinue if pancreatitis occurs.

• Ovarian cancer: Postmenopausal estrogens with or without progestins may increase the risk of ovarian cancer; however, the absolute risk to an individual woman is small. Although results from various studies are not consistent, risk does not appear to be significantly associated with the duration, route, or dose of therapy. In one study, the risk decreased after 2 years following discontinuation of therapy (Mørch, 2009). Although the risk of ovarian cancer is rare, women who are at an increased risk (eg, family history) should be counseled about the association (NAMS, 2012).

• Retinal vascular thrombosis: Estrogens may cause retinal vascular thrombosis; discontinue if migraine, loss of vision, proptosis, diplopia, or other visual disturbances occur; discontinue permanently if papilledema or retinal vascular lesions are observed on examination.

Disease-related concerns:

• Asthma: Use caution in patients with asthma; may exacerbate disease.

• Carbohydrate intolerance: May have adverse effects on glucose tolerance; use caution in women with diabetes.

• Cardiovascular disease: [US Boxed Warning]: Estrogens with or without progestin should not be used to prevent cardiovascular disease. Using data from the Women’s Health Initiative (WHI) studies, an increased risk of deep vein thrombosis (DVT) and stroke has been reported with CE and an increased risk of DVT, stroke, pulmonary emboli (PE) and myocardial infarction (MI) has been reported with CE with MPA in postmenopausal women 50 to 79 years of age. Additional risk factors include diabetes mellitus, hypercholesterolemia, hypertension, SLE, obesity, tobacco use, and/or history of venous thromboembolism (VTE). Risk factors should be managed appropriately; discontinue use immediately if adverse cardiovascular events occur or are suspected. Use is contraindicated in women with active DVT or PE (or a history of these conditions) or in women with active or recent arterial thromboembolic disease (stroke and MI), or a history of these conditions.

• Diseases exacerbated by fluid retention: Use with caution in patients with diseases which may be exacerbated by fluid retention, including cardiac or renal dysfunction.

• Epilepsy: Use caution with epilepsy; may exacerbate disease.

• Gallbladder disease: Use of postmenopausal estrogen may be associated with an increased risk of gallbladder disease requiring surgery.

• Hepatic dysfunction: Estrogens are poorly metabolized in patients with hepatic dysfunction. Use caution with a history of cholestatic jaundice associated with prior estrogen use or pregnancy. Discontinue if jaundice develops or if acute or chronic hepatic disturbances occur. Use is contraindicated with hepatic impairment or disease.

• Hepatic hemangiomas: Use with caution in patients with hepatic hemangiomas; may exacerbate disease.

• Hereditary angioedema: Exogenous estrogens may exacerbate angioedema symptoms in women with hereditary angioedema.

• Hypoparathyroidism: Use caution with hypoparathyroidism; estrogen-induced hypocalcemia may occur.

• Migraine: Use caution with migraine; may exacerbate disease.

• Porphyria: Use with caution in patients with porphyria; may exacerbate disease.

• SLE: Use with caution in patients with SLE; may exacerbate disease.

Concurrent drug therapy issues:

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

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

Special populations:

• Elderly: Although hormone therapy is recommended to be initiated in healthy symptomatic women within 10 years of menopause or <60 years of age who do not have contraindications for use, symptoms may continue in women >60 years of age. The continuation of hormone therapy in women >65 years of age should consider the risks and benefits for the individual woman and should not be discontinued only because of the woman’s age (NAMS 2015).

• Surgical patients: Whenever possible, should be discontinued at least 4 to 6 weeks prior to elective surgery associated with an increased risk of thromboembolism or during periods of prolonged immobilization.

Other warnings/precautions:

• Laboratory changes: The use of estrogens and/or progestins may change the results of some laboratory tests (eg, coagulation factors, lipids, glucose tolerance, binding proteins). The dose, route, and the specific estrogen/progestin influences these changes. In addition, personal risk factors (eg, cardiovascular disease, smoking, diabetes, age) also contribute to adverse events; use of specific products may be contraindicated in women with certain risk factors.

• Osteoporosis use: For use only in women at significant risk of osteoporosis and for who other nonestrogen medications are not considered appropriate.

• Risks vs benefits: [US Boxed Warning]: Estrogens with or without progestin should be used for the shortest duration possible at the lowest effective dose consistent with treatment goals and risks for the individual woman. Hormone therapy for menopausal symptoms is generally initiated in healthy symptomatic women within 10 years of menopause or <60 years of age who do not have contraindications for use (Stuenkel 2015). Patients should be reevaluated as clinically appropriate to determine if treatment is still necessary. Available data related to treatment risks are from Women’s Health Initiative (WHI) studies, which evaluated oral CE 0.625 mg with or without MPA 2.5 mg relative to placebo in postmenopausal women. Other combinations and dosage forms of estrogens and progestins were not studied. Outcomes reported from clinical trials using CE with or without MPA should be assumed to be similar for other doses and other dosage forms of estrogens and progestins until comparable data becomes available. Women who are early in menopause, who are in good cardiovascular health, and who are at low risk for adverse cardiovascular events can be considered candidates for estrogen with or without progestin therapy for the relief of menopausal symptoms (ACOG 565 2013). Women at high risk of cardiovascular disease or intermediate to high risk of breast cancer should use nonhormonal therapy to treat vasomotor symptoms of menopause (Stuenkel 2015). Use of a transdermal product should be considered over an oral agent in women requiring systemic therapy who have moderate risk factors for coronary heart disease (ACOG 556 2013; Schenck-Gustafsson 2011; Stuenkel 2015). Nonoral routes of therapy are recommended for women at increased risk for venous thromboembolism (Stuenkel 2015; Tremollieres 2011)

• Vulvar and vaginal atrophy use: Moderate to severe symptoms of vulvar and vaginal atrophy include vaginal dryness, dyspareunia, and atrophic vaginitis. [The combined conditions of vulvovaginal atrophy and urinary tract dysfunction is also referred to as genitourinary syndrome of menopause (GSM) (Portman 2014; Stuenkel 2015)]. When used solely for the treatment of vulvar and vaginal atrophy, topical vaginal products should be considered. Use caution applying topical products to severely atrophic vaginal mucosa. Use of a progestin is normally not required when low-dose estrogen is applied locally and only for this purpose (NAMS 2012; NAMS 2013; Stuenkel 2015).

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience cramps, bloating, enlarged breasts, hair loss, or dark patches on face. Have patient report immediately to prescriber signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), angina, shortness of breath, edema, coughing up blood, severe headache, severe nausea, vomiting, severe dizziness, passing out, bulging eyes, contact lens discomfort, vision changes, eye pain, severe eye irritation, lump in breast, breast soreness or pain, nipple discharge, vaginal bleeding, vaginitis, depression, or memory impairment (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.