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Duavee

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Duavee

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Drugs Containing Progestins, Estrogens or Estrogen Agonist/Antagonists

DUAVEE contains conjugated estrogens and bazedoxifene, an estrogen agonist/antagonist. Women taking DUAVEE should not take progestins, additional estrogens or additional estrogen agonist/antagonists.

Cardiovascular Disorders

Estrogen agonist/antagonists (including bazedoxifene, a component of DUAVEE) and estrogens individually are known to increase the risk of VTE.

An increased risk of stroke and DVT has been reported with estrogen-alone therapy. Should any of these occur or be suspected, DUAVEE should be discontinued immediately.

Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or VTE (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.

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 daily conjugated estrogens (CE) (0.625 mg)- alone compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in year 1 and persisted [see Clinical Studies].

Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving conjugated estrogens (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years).

Should a stroke occur or be suspected, DUAVEE should be discontinued immediately [see CONTRAINDICATIONS].

Coronary Heart Disease

In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as nonfatal myocardial infarction, silent myocardial infarction, or CHD death) was reported in women receiving estrogen-alone compared to placebo [see Clinical Studies].

Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women with less than 10 years since menopause (8 versus 16 per 10,000 women-years).

Venous Thromboembolism (VTE)

In the WHI estrogen-alone substudy, the risk of VTE [DVT and pulmonary embolism (PE)] was increased for women receiving daily conjugated estrogens (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first 2 years [see Clinical Studies].

If feasible, DUAVEE should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. Because immobilization increases the risk for venous thromboembolic events independent of therapy, DUAVEE should be discontinued prior to and during prolonged immobilization (e.g., post-surgical recovery, prolonged bed rest) and DUAVEE therapy should be resumed only after the patient is fully ambulatory. In addition, women taking DUAVEE should be advised to move about periodically during travel involving prolonged immobilization.

Malignant Neoplasms

Endometrial Cancer

An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in women with a uterus. 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 of treatment. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.

DUAVEE contains an estrogen agonist/antagonist. This component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component. Endometrial hyperplasia may be a precursor to endometrial cancer. Women taking DUAVEE should not take additional estrogens as this may increase the risk of endometrial hyperplasia.

Clinical surveillance of all women taking DUAVEE 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 genital bleeding.

Breast Cancer

The most important randomized clinical study providing information about breast cancer in estrogen-alone users is the WHI substudy of daily conjugated estrogens (0.625 mg)-alone. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily conjugated estrogen (0.625 mg)-alone was not associated with an increased risk of invasive breast cancer (relative risk [RR] 0.80).

The use of estrogen-alone 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.

All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.

Ovarian Cancer

In some epidemiological studies, the use of estrogen-only products, in particular for 5 or more years, has been associated with an increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies, and some report no association. The effect of treatment with DUAVEE on the risk of ovarian cancer is unknown.

Probable Dementia

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 CE (0.625 mg)-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 CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years [see Use in Specific Populations and Clinical Studies].

Gallbladder Disease

A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.

Visual Abnormalities

Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, DUAVEE should be permanently discontinued.

Elevated Blood Pressure

In a small number of case reports in women receiving estrogens, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical study, a generalized effect of estrogens on blood pressure was not seen.

Hypertriglyceridemia

In women with pre-existing hypertriglyceridemia, treatment with estrogens may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of DUAVEE if pancreatitis occurs.

Hepatic Impairment and Past History of Cholestatic Jaundice

DUAVEE has not been studied in women with impaired liver function or past history of cholestatic jaundice.

Estrogens may be poorly metabolized in women with impaired liver function.

On average, women with hepatic impairment treated with bazedoxifene alone showed a 4.3-fold increase in overall exposures compared with controls [see Use In Specific Populations and CLINICAL PHARMACOLOGY].

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, DUAVEE should be discontinued. Use of DUAVEE in patients with hepatic impairment is contraindicated [see CONTRAINDICATIONS].

Hypothyroidism

Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.

Fluid Retention

Estrogens may cause some degree of fluid retention. Because of this, patients who have conditions that might be influenced by this factor, such as cardiac dysfunction or renal impairment, warrant careful observation when estrogens are prescribed. Use of DUAVEE in patients with renal impairment is not recommended [see Use in Specific Populations].

Hypocalcemia

Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogeninduced hypocalcemia may occur.

Hereditary Angioedema

Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.

Exacerbation of Other Conditions

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

Premenopausal Women

There is no indication for premenopausal use of DUAVEE. The efficacy and safety of DUAVEE in premenopausal women have not been established, and its use is not recommended.

Laboratory Tests

Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of moderate to severe vasomotor symptoms.

Drug-Laboratory Test Interactions

Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.

Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay), or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone.

Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).

Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentrations, increased triglyceride levels.

Impaired glucose tolerance.

Patient Counseling Information

See FDA-approved patient labeling (PATIENT INFORMATION).

Instructions for Patients
  • Keep DUAVEE in the original container to protect from moisture. Do not place DUAVEE in pill boxes or pill organizers.
  • If more than one blister package is dispensed to the patient, instruct them to open one foil pouch at a time.
  • Instruct patient to record the date the blister package is opened in the space provided on the blister package label. Do not use if the blister package has been open more than 60 days.
  • Instruct patient to remove only one tablet from the blister package at the time of use.
Venous Thromboembolic Events

Advise patients to immediately report to their physician any signs or symptoms related to venous thrombosis and thromboembolic events [see WARNINGS AND PRECAUTIONS].

Abnormal Vaginal Bleeding

Inform postmenopausal women of the importance of reporting abnormal vaginal bleeding to their healthcare provider as soon as possible [see WARNINGS AND PRECAUTIONS].

Possible Serious Adverse Reactions with Estrogen Therapy

Inform postmenopausal women of possible serious adverse reactions of estrogen therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see WARNINGS AND PRECAUTIONS].

Possible Less Serious Adverse Reactions with DUAVEE

Inform postmenopausal women of possible less serious but common adverse reactions of DUAVEE therapy such as muscle spasms, nausea, diarrhea, dyspepsia, upper abdominal pain, throat pain, dizziness and neck pain.

Calcium and Vitamin D Intake

Advise patients to add supplemental calcium and/or vitamin D to the diet if daily intake is inadequate.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies with conjugated estrogens/bazedoxifene have not been conducted.

Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.

In 6-month oral gavage carcinogenicity studies of bazedoxifene in transgenic Tg.RasH2 mice, there was a drug-related increased incidence of benign, ovarian granulosa-cell tumors in female mice given 150 or 500 mg/kg/day. In a two-year dietary carcinogenicity study of bazedoxifene in rats (administered at 0.003%, 0.01%, 0.03%, or 0.1%) a drug-related marked increased incidence of benign, ovarian granulosa-cell tumors was observed in female rats at concentrations of 0.03% and 0.1%. Systemic exposure (AUC) of bazedoxifene in these groups was 3 and 8 times that observed in postmenopausal women administered 20 mg/day. In male rats, drug-related renal tumors (adenomas and carcinomas), in the presence of renal toxicity, were observed at all doses tested, which corresponded to exposure ratios of 0.06 to 5 times the clinical AUC at a dose of 20 mg.

Mutagenesis

Mutagenicity studies with conjugated estrogens/bazedoxifene have not been conducted.

Bazedoxifene was not genotoxic or mutagenic in a battery of tests, including in vitro bacterial reverse mutation assay, in vitro mammalian cell forward mutation assay at the thymidine kinase (TK+/-) locus in L5178Y mouse lymphoma cells, in vitro chromosome aberration assay in Chinese hamster ovary (CHO) cells, and in vivo mouse micronucleus assay.

Impairment of Fertility

Impairment of fertility studies with conjugated estrogens/bazedoxifene have not been conducted.

Female rats were administered daily dosages of 0.3 to 30 mg/kg bazedoxifene (0.03 to 10 times human AUC at the 20 mg dose) prior to and during mating with untreated males. Estrous cycles and fertility were adversely affected in all bazedoxifene-treated female groups.

Use In Specific Populations

Pregnancy

Pregnancy Category X [see CONTRAINDICATIONS]

DUAVEE must not be used in women who are or may become pregnant.

No studies were performed on animals to evaluate the effects on reproduction with conjugated estrogens/bazedoxifene.

Administration of bazedoxifene to rats at maternally toxic dosages ≥ 1 mg/kg/day ( ≥ 0.3 times the human area under the curve (AUC) at the 20 mg dose) resulted in reduced numbers of live fetuses and/or reductions in fetal body weights. No fetal developmental anomalies were observed. In studies conducted with pregnant rabbits treated with bazedoxifene, abortion and an increased incidence of heart (ventricular septal defect) and skeletal system (ossification delays, misshapen or misaligned bones, primarily of the spine and skull) anomalies in the fetuses were present at maternally toxic dosages of ≥ 0.5 mg/kg/day (2 times the human AUC at the 20 mg dose).

Nursing Mothers

DUAVEE should not be used by lactating women [see CONTRAINDICATIONS]. It is not known whether this drug is excreted in human milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving conjugated estrogens. Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk.

Pediatric Use

DUAVEE is not indicated for use in children [see INDICATIONS AND USAGE].

Geriatric Use

DUAVEE is not recommended for use in women greater than 75 years of age [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

Of the total number of women in phase 3 clinical studies who received DUAVEE, 4.60% (n=224) were 65 years and over. DUAVEE was not studied in women aged 75 and over. No overall differences in safety or effectiveness were observed between women 65-74 years of age and younger women, and other reported clinical experience has not identified differences in responses between the elderly and younger women, but greater sensitivity of some older women cannot be ruled out.

An increased risk of probable dementia in women over 65 years of age was reported in the Women's Health Initiative Memory ancillary studies of the Women's Health Initiative using daily conjugated estrogens (0.625 mg) [see Clinical Studies].

Renal Impairment

DUAVEE is not recommended for use in patients with renal impairment [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

The pharmacokinetics, safety, and efficacy of DUAVEE have not been evaluated in women with renal impairment.

Hepatic Impairment

DUAVEE is contraindicated in patients with hepatic impairment [see CONTRAINDICATIONS and CLINICAL PHARMACOLOGY].

The pharmacokinetics, safety, and efficacy of DUAVEE have not been evaluated in women with hepatic impairment. In a pharmacokinetics study of bazedoxifene 20 mg alone, the Cmax and AUC of bazedoxifene increased 67% and 143%, respectively, in women with mild hepatic impairment (Child Pugh Class A), compared to healthy women. The Cmax and AUC of bazedoxifene increased 32% and 109%, respectively, in women with moderate hepatic impairment (Child Pugh Class B). The Cmax and AUC of bazedoxifene increased 20% and 268%, respectively, in women with severe hepatic impairment (Child Pugh Class C).

No pharmacokinetic studies with conjugated estrogens were conducted in women with hepatic impairment.

Use in Women with Body Mass Index (BMI) > 27 kg/m²

A 17% reduction in bazedoxifene exposure was predicted in women with BMI > 27 kg/m² (N=144) compared to those with BMI ≤ 27 kg/m² (N=93) after administration of DUAVEE, based on a population pharmacokinetic model using data from four Phase 1 studies. A reduction in bazedoxifene exposure may be associated with an increased risk of endometrial hyperplasia. Regardless of BMI, 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.

Last reviewed on RxList: 11/7/2013
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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