IMPORTANT SAFETY INFORMATION (Combined for Pfizer’s Menopause Hormone Therapies)

WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST CANCER and PROBABLE DEMENTIA

Endometrial Cancer

There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Duavee has been shown to reduce the risk of endometrial hyperplasia. Women taking Duavee should not take progestins, additional estrogens, or additional estrogen agonist/antagonists. 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 genital bleeding.

Cardiovascular Disorders and Probable Dementia

Estrogen-alone therapy and estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia.

The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (CE) 0.625 mg-alone, relative to placebo. The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary embolism (PE), stroke, and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral CE 0.625 mg combined with medroxyprogesterone acetate (MPA) 2.5 mg, relative to placebo.

The WHI Memory Study (WHIMS) reported an increased risk of developing probable dementia in postmenopausal women aged 65 years and older during 5.2 years of treatment with daily CE 0.625 mg-alone and during 4 years of treatment with daily CE 0.625 mg combined with MPA 2.5 mg, relative to placebo. It is unknown whether these findings apply to younger postmenopausal women.

Breast Cancer

The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer.

In the absence of comparable data, these risks should be assumed to be similar for other doses of CE or CE and MPA and other dosage forms of estrogens or combinations and dosage forms of estrogens and progestins.

Estrogens with or without progestins should be prescribed at the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman.

CONTRAINDICATIONS

Duavee, Premarin Tablets, Estring, Premarin Vaginal Cream, and Prempro should not be used in women with any of the following conditions: undiagnosed abnormal uterine or genital bleeding; known, suspected, or a history of breast cancer; known or suspected estrogen-dependent neoplasia; active or history of DVT or PE; active or history of arterial thromboembolic disease (e.g., stroke, MI); known anaphylactic reaction, angioedema, or hypersensitivity to Duavee, Premarin Tablets, Estring, Premarin Vaginal Cream, Prempro, or any of their ingredients; hepatic impairment or disease; protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders; and pregnancy.

WARNINGS AND PRECAUTIONS

Cardiovascular Disorders
An increased risk of PE, DVT, stroke and MI has been reported with estrogen plus progestin therapy. An increased risk of stroke and DVT has been reported with estrogen-alone therapy. Estrogen agonist/antagonists, including bazedoxifene, a component of Duavee, are also known to increase the risk of venous thromboembolism. Should any of these events occur or be suspected, Duavee, Premarin Tablets, Estring, Premarin Vaginal Cream, and Prempro should be discontinued immediately.

Malignant Neoplasms
In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily CE 0.625 mg-alone was not associated with an increased risk of invasive breast cancer (relative risk [RR] 0.80).

Consistent with the WHI trials, 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. One large meta-analysis of prospective cohort studies reported increased risks that were dependent upon duration of use and could last up to >10 years after discontinuation of estrogen plus progestin therapy and estrogen‑alone therapy. Extension of the WHI trials also demonstrated increased breast cancer risk associated with estrogen plus progestin therapy. Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to the risk with 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.

The use of estrogen alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms, requiring further evaluation. The effect of treatment with Duavee on the risk of breast cancer is unknown.

The WHI estrogen plus progestin substudy reported a statistically nonsignificant increased risk of ovarian cancer. 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 exact duration of hormone therapy use associated with an increased risk of ovarian cancer, however, is unknown. The effect of treatment with Duavee on the risk of ovarian cancer is unknown.

Other Warnings and Precautions
Estrogens increase the risk of gallbladder disease. Discontinue estrogen if hypercalcemia, sudden partial or complete loss of vision, sudden onset of proptosis, diplopia, or migraine occurs; or if examination reveals papilledema or retinal vascular lesions. Estrogen therapy may elevate blood pressure or may cause fluid retention. Estrogen therapy may exacerbate pre-existing hypertriglyceridemia. Discontinue Duavee, Premarin Tablets, Estring, Premarin Vaginal Cream, and Prempro if pancreatitis or cholestatic jaundice occurs. Monitor thyroid function in women on thyroid replacement therapy because estrogens may be associated with increased thyroid-binding globulin (TBG) levels. Estrogen therapy may cause hypocalcemia in patients with hypoparathyroidism. For women known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.

Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.

Renal Impairment
Duavee is not recommended for use in patients with renal impairment.

Lactation
Estrogen administration to lactating women has been shown to decrease the quantity and quality of breast milk. The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for Premarin Tablets, Premarin Vaginal Cream, or Prempro and any potential adverse effects on the breast-fed child from these medications or from the underlying maternal condition. Estring should not be used during lactation. Duavee is not indicated for use in females of reproductive potential.

ADVERSE REACTIONS

The most common adverse reactions in:

• Duavee (≥5%): muscle spasms, nausea, diarrhea, dyspepsia, abdominal pain upper, oropharyngeal pain, dizziness, and neck pain
• Premarin Tablets (≥5%): abdominal pain, asthenia, pain, back pain, headache, flatulence, nausea, depression, insomnia, breast pain, endometrial hyperplasia, leucorrhea, vaginal hemorrhage, and vaginitis
• Estring (≥3%): back pain, arthritis, arthralgia, headache, insomnia, abdominal pain, nausea, upper respiratory tract infection, sinusitis, leukorrhea, vaginitis, vaginal discomfort/pain, vaginal hemorrhage, asymptomatic genital bacterial growth, genital moniliasis, flu-like symptoms
• Premarin Vaginal Cream (≥2%): headache, pelvic pain, vasodilation, breast pain, leucorrhea, metrorrhagia, vaginitis, vulvovaginal disorder
• Prempro (>5%): abdominal pain, asthenia, back pain, headache, flatulence, nausea, depression, pruritus, breast pain, dysmenorrhea, and leukorrhea

These are not all reported adverse reactions of Duavee, Premarin Tablets, Estring, Premarin Vaginal Cream, and Prempro.

Duavee (conjugated estrogens/bazedoxifene) is a combination of conjugated estrogens with an estrogen agonist/antagonist indicated for treatment of the following conditions in women with a uterus:

• Treatment of moderate to severe vasomotor symptoms associated with menopause
• Prevention of postmenopausal osteoporosis

Limitations of Use:

• Duavee should be used for the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary
• When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medications should be carefully considered

Premarin Tablets (conjugated estrogens tablets, USP) are indicated for:

• Treatment of moderate to severe vasomotor symptoms due to menopause 
• Treatment of moderate to severe vulvar and vaginal atrophy due to menopause
• Prevention of postmenopausal osteoporosis

Limitations of Use:

• When prescribing solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause, topical vaginal products should be considered.
• When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered.

Estring (estradiol vaginal system) is indicated for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause.
 

Premarin Vaginal Cream (conjugated estrogens) is indicated for the treatment of atrophic vaginitis and kraurosis vulvae and for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause.

Prempro (conjugated estrogens/
medroxyprogesterone acetate tablets) is an estrogen plus progestin indicated in a woman with a uterus for:

• Treatment of moderate to severe vasomotor symptoms due to menopause
• Prevention of postmenopausal osteoporosis

Limitations of Use:

• Use of estrogen-alone, or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary.
• When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medications should be carefully considered.

Please see full Prescribing Information, including BOXED WARNING and Patient Information, for each medication. (Links to the PI for Duavee, Premarin Tablets, Estring, Premarin Vaginal Cream, Prempro)