Duavive

/ Pfizer

Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause: The recommended dosage is one  tablet daily.
Prevention of Postmenopausal Osteoporosis: The recommended dosage is one tablet daily.
General Dosing Information:  once daily, without regard to meals. Tablets should be swallowed whole.
Recommendations for Calcium and Vitamin D Supplementation: Women taking this drug for prevention of postmenopausal osteoporosis should add supplemental calcium and/or vitamin D to their diet if daily intake is inadequate.
Administration Instructions for Missed Doses: If a dose is missed, instruct patients to take it as soon as remembered unless it is almost time for the next scheduled dose. They should not take two doses at the same time.
Use in Patients with Renal Impairment: The pharmacokinetics of this drug have not been evaluated in patients with renal impairment. Use in patients with renal impairment is not recommended.
Use in the Elderly: The drug  has not been studied in women over 75 years of age. Use in women over 75 years of age is not recommended.

Treatment of the following conditions in women with a uterus: Treatment of moderate to severe vasomotor symptoms associated with menopause. Prevention of postmenopausal osteoporosis.

Undiagnosed abnormal uterine bleeding; Known, suspected, or past history of breast cancer; Known or suspected estrogen-dependent neoplasia; Active deep venous thrombosis, pulmonary embolism, or history of these conditions; Active arterial thromboembolic disease (for example, stroke, myocardial infarction) or history of these conditions; Hypersensitivity (for example, anaphylaxis, angioedema) to estrogens, bazedoxifene, or any ingredients; Known hepatic impairment or disease; Known protein C, protein S, or antithrombin deficiency or other known thrombophilic disorders; Pregnancy, women who may become pregnant, and nursing mothers. this formulation may cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Drugs Containing Progestins, Estrogens or Estrogen Agonist/Antagonists:
This medicinal product contains conjugated estrogens and bazedoxifene, an estrogen agonist/antagonist. Women taking this drug should not take progestins, additional estrogens or additional estrogen agonist/antagonists.
Cardiovascular Disorders:
Estrogen agonist/antagonists 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, this drug 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. The increase in risk was demonstrated in year 1 and persisted.
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.
Should a stroke occur or be suspected, this drug should be discontinued immediately.
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.
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.
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, although only the increased risk of DVT reached statistical significance. The increase in VTE risk was demonstrated during the first 2 years.
If feasible, this medicinal product 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, this drug should be discontinued prior to and during prolonged immobilization (e.g., post-surgical recovery, prolonged bed rest) and therapy should be resumed only after the patient is fully ambulatory. In addition, women taking this drug 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.
This medicinal product 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 this drug should not take additional estrogens as this may increase the risk of endometrial hyperplasia.
Clinical surveillance of all women taking this drug 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 WHI substudy of daily conjugated estrogens (0.625 mg)-alone provided information about breast cancer in estrogen-alone users. 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 this drug 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: 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 risks associated with current use of hormonal therapy was 1.41 (95% confidence interval [CI] 1.32 to 1.50); 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 1.27-1.48), 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.
The effect of treatment with this drug 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.
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, this drug 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 this drug if pancreatitis occurs.
Hepatic Impairment and Past History of Cholestatic Jaundice:
This medicinal product 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.
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, this medicinal product should be discontinued. Use in patients with hepatic impairment is contraindicated.
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 in patients with renal impairment is not recommended.
Hypocalcemia:
Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced 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. The efficacy and safety of this medicinal product in premenopausal women have not been established, and its use is not recommended. Additionally, there is concern regarding inadvertent drug exposure in pregnancy in women of reproductive potential who become pregnant, due to risk of fetal harm.
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. See prescribing information for more details about drug-laboratory test interactions.
Important information regarding some of the ingredients of the medicine:
This medicinal product  contains lactose, sucrose, glucose (in polydextrose and maltitol liquid) and sorbitol (in polydextrose). Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
See prescribing information for full details.

The most commonly observed adverse reactions (incidence ≥ 5%) more frequently reported in women treated with DUAVIVE than placebo are:
Gastrointestinal disorders: Nausea, Diarrhea, Dyspepsia, Abdominal pain upper.
Musculoskeletal and connective tissue disorders: Muscle spasms, Neck pain.
Nervous system disorders: Dizziness.
Respiratory, thoracic, and mediastinal disorders: Oropharyngeal pain.
See prescribing information for full details.

Cytochrome P450 (CYP): In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Concomitant administration of itraconazole, a strong CYP3A4 inhibitor, with this drug, resulted in increases in bazedoxifene exposure (40%) and, to a lesser extent, conjugated estrogens exposure (9% for baseline-adjusted total estrone, 5% for total equilin), compared to this formulation  alone . Inducers of CYP3A4, such as St. John’s Wort (Hypericum perforatum) preparations, phenobarbital, carbamazepine, and rifampin, may reduce plasma concentrations of some estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile.
Bazedoxifene does not induce or inhibit the activities of major CYP isoenzymes. In vitro data suggest that bazedoxifene is unlikely to interact with co-administered drugs via CYP-mediated metabolism.
Uridine Diphosphate Glucuronosyltransferase (UGT): Bazedoxifene undergoes metabolism by UGT enzymes in the intestinal tract and liver. The metabolism of bazedoxifene may be increased by concomitant use of substances known to induce UGTs, such as rifampin, phenobarbital, carbamazepine, and phenytoin. A reduction in bazedoxifene exposure may be associated with an increase risk of endometrial hyperplasia. 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.
Atorvastatin: Concomitant administration of bazedoxifene (40 mg daily) and atorvastatin (20 mg, single-dose) to healthy postmenopausal women did not affect the pharmacokinetics of bazedoxifene, atorvastatin or its active metabolites.

Pregnancy: contraindicated for use in pregnant women and is not indicated for use in females of reproductive potential.
Lactation: There are no data on the presence of bazedoxifene in  human breast milk.
See prescribing information for full details.

In case of overdosage, there is no specific antidote, and the treatment should be symptomatic. Symptoms of overdosage of estrogen-containing products in adults and children may include nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue; withdrawal bleeding may occur.

Storage: Do not store above 25ºC.
Lactose: contains lactose.