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1  INDICATIONS AND USAGE

1.1  Treatment and Prevention of Osteoporosis in Postmenopausal Women

Evista is indicated for the treatment and prevention of osteoporosis in postmenopausal women [see Clinical Studies (14.1, 14.2)].

2  DOSAGE AND ADMINISTRATION

2.1  Osteoporosis in Postmenopausal Women Indication

The recommended dosage is one 60 mg Evista tablet daily, which may be administered any time of day without regard to meals [see Clinical Pharmacology (12.3)].

2.2  Recommendations for Calcium and Vitamin D Supplementation

For either osteoporosis treatment or prevention, supplemental calcium and/or vitamin D should be added to the diet if daily intake is inadequate. Postmenopausal women require an average of 1500 mg/day of elemental calcium. Total daily intake of calcium above 1500 mg has not demonstrated additional bone benefits while daily intake above 2000 mg has been associated with increased risk of adverse effects, including hypercalcemia and kidney stones. The recommended intake of vitamin D is 400-800 IU daily. Patients at increased risk for vitamin D insufficiency (e.g., over the age of 70 years, nursing home bound, or chronically ill) may need additional vitamin D supplements. Patients with gastrointestinal malabsorption syndromes may require higher doses of vitamin D supplementation and measurement of 25-hydroxyvitamin D should be considered.

3  DOSAGE FORMS AND STRENGTHS

60 mg, white, elliptical, film-coated tablets (not scored). They are imprinted on one side with LILLY and the tablet code 4165 in edible blue ink.

4  CONTRAINDICATIONS

4.1  Venous Thromboembolism

Evista is contraindicated in women with active or past history of venous thromboembolism (VTE), including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis [see Warnings and Precautions (5.2)].

4.2  Pregnancy, Women Who May Become Pregnant, and Nursing Mothers

Evista is contraindicated in pregnancy, in women who may become pregnant, and in nursing mothers. Evista 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 the fetus.

In rabbit studies, abortion and a low rate of fetal heart anomalies (ventricular septal defects) occurred in rabbits at doses ≥0.1 mg/kg (≥0.04 times the human dose based on surface area, mg/m2), and hydrocephaly was observed in fetuses at doses ≥10 mg/kg (≥4 times the human dose based on surface area, mg/m2). In rat studies, retardation of fetal development and developmental abnormalities (wavy ribs, kidney cavitation) occurred at doses ≥1 mg/kg (≥0.2 times the human dose based on surface area, mg/m2). Treatment of rats at doses of 0.1 to 10 mg/kg (0.02 to 1.6 times the human dose based on surface area, mg/m2) during gestation and lactation produced effects that included delayed and disrupted parturition; decreased neonatal survival and altered physical development; sex- and age-specific reductions in growth and changes in pituitary hormone content; and decreased lymphoid compartment size in offspring. At 10 mg/kg, raloxifene disrupted parturition, which resulted in maternal and progeny death and morbidity. Effects in adult offspring (4 months of age) included uterine hypoplasia and reduced fertility; however, no ovarian or vaginal pathology was observed.

5  WARNINGS AND PRECAUTIONS

5.1  Cardiovascular Disease

 Evista should not be used for the primary or secondary prevention of cardiovascular disease. In a clinical trial of postmenopausal women with documented coronary heart disease or at increased risk for coronary events, no cardiovascular benefit was demonstrated after treatment with raloxifene for 5 years [see Clinical Studies (14.4)].

5.2  Venous Thromboembolism

In clinical trials, Evista-treated women had an increased risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism). Other venous thromboembolic events also could occur. A less serious event, superficial thrombophlebitis, also has been reported more frequently with Evista. The greatest risk for deep vein thrombosis and pulmonary embolism occurs during the first 4 months of treatment, and the magnitude of risk appears to be similar to the reported risk associated with use of hormone therapy. Because immobilization increases the risk for venous thromboembolic events independent of therapy, Evista should be discontinued at least 72 hours prior to and during prolonged immobilization (e.g., post-surgical recovery, prolonged bed rest), and Evista therapy should be resumed only after the patient is fully ambulatory. In addition, women taking Evista should be advised to move about periodically during prolonged travel. The risk-benefit balance should be considered in women at risk of thromboembolic disease for other reasons, such as congestive heart failure, superficial thrombophlebitis, and active malignancy [see Contraindications (4.1), Adverse Reactions (6.1)].

5.3  Death Due to Stroke

 In a clinical trial of postmenopausal women with documented coronary heart disease or at increased risk for coronary events, an increased risk of death due to stroke was observed after treatment with Evista. During an average follow-up of 5.6 years, 59 (1.2%) Evista-treated women died due to a stroke compared to 39 (0.8%) placebo-treated women (22 versus 15 per 10,000 women-years; hazard ratio 1.49; 95% confidence interval, 1.00-2.24; p=0.0499). There was no statistically significant difference between treatment groups in the incidence of stroke (249 in Evista [4.9%] versus 224 placebo [4.4%]). Evista had no significant effect on all-cause mortality. The risk-benefit balance should be considered in women at risk for stroke, such as prior stroke or transient ischemic attack (TIA), atrial fibrillation, hypertension, or cigarette smoking [see Clinical Studies (14.4)].

5.4  Premenopausal Use

There is no indication for premenopausal use of Evista. Safety of Evista in premenopausal women has not been established and its use is not recommended.

5.5  Renal Impairment

 Evista should be used with caution in patients with moderate or severe renal impairment. Safety and efficacy have not been established in patients with moderate or severe renal impairment [see Clinical Pharmacology (12.3)].

5.6  Hepatic Impairment

Evista should be used with caution in patients with hepatic impairment. Safety and efficacy have not been established in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

5.7  Concomitant Estrogen Therapy

The safety of concomitant use of Evista with systemic estrogens has not been established and its use is not recommended.

5.8  History of Hypertriglyceridemia when Treated with Estrogens

Limited clinical data suggest that some women with a history of marked hypertriglyceridemia (>5.6 mmol/L or >500 mg/dL) in response to treatment with oral estrogen or estrogen plus progestin may develop increased levels of triglycerides when treated with Evista. Women with this medical history should have serum triglycerides monitored when taking Evista.

5.9  History of Breast Cancer

Evista has not been adequately studied in women with a prior history of breast cancer.

5.10  Use in Men

There is no indication for the use of Evista in men. Evista has not been adequately studied in men and its use is not recommended.

5.11  Unexplained Uterine Bleeding

Any unexplained uterine bleeding should be investigated as clinically indicated. Evista-treated and placebo-treated groups had similar incidences of endometrial proliferation [see Clinical Studies (14.1, 14.2)].

5.12  Breast Abnormalities

Any unexplained breast abnormality occurring during Evista therapy should be investigated. Evista does not eliminate the risk of breast cancer [see Clinical Studies (14.3)].

6  ADVERSE REACTIONS

6.1  Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to Evista in 3385 patients, including 2250 exposed for 1 year and 1972 for at least 3 years.

Osteoporosis Treatment Clinical Trial — The safety of raloxifene in the treatment of osteoporosis was assessed in a large (7705 patients) multinational, placebo-controlled trial. Duration of treatment was 36 months, and 5129 postmenopausal women were exposed to raloxifene (2557 received 60 mg/day, and 2572 received 120 mg/day). The incidence of all-cause mortality was similar between groups: 23 (0.9%) placebo, 13 (0.5%) Evista-treated (raloxifene 60 mg), and 28 (1.1%) raloxifene 120 mg women died. Therapy was discontinued due to an adverse reaction in 10.9% of Evista-treated women and 8.8% of placebo-treated women.

Venous Thromboembolism: The most serious adverse reaction related to Evista was VTE (deep venous thrombosis, pulmonary embolism, and retinal vein thrombosis). During an average of study-drug exposure of 2.6 years, VTE occurred in about 1 out of 100 patients treated with Evista. Twenty-six Evista-treated women had a VTE compared to 11 placebo-treated women, the hazard ratio was 2.4 (95% confidence interval, 1.2, 4.5), and the highest VTE risk was during the initial months of treatment.

Common adverse reactions considered to be related to Evista therapy were hot flashes and leg cramps. Hot flashes occurred in about one in 10 patients on Evista and were most commonly reported during the first 6 months of treatment and were not different from placebo thereafter. Leg cramps occurred in about one in 14 patients on Evista.

Placebo-Controlled Osteoporosis Prevention Clinical Trials — The safety of raloxifene has been assessed primarily in 12 Phase 2 and Phase 3 studies with placebo, estrogen, and estrogen-progestin therapy control groups. The duration of treatment ranged from 2 to 30 months, and 2036 women were exposed to raloxifene (371 patients received 10 to 50 mg/day, 828 received 60 mg/day, and 837 received from 120 to 600 mg/day).

Therapy was discontinued due to an adverse reaction in 11.4% of 581 Evista-treated women and 12.2% of 584 placebo-treated women. Discontinuation rates due to hot flashes did not differ significantly between Evista and placebo groups (1.7% and 2.2%, respectively).

Common adverse reactions considered to be drug-related were hot flashes and leg cramps. Hot flashes occurred in about one in four patients on Evista versus about one in six on placebo. The first occurrence of hot flashes was most commonly reported during the first 6 months of treatment.

Table 1 lists adverse reactions occurring in either the osteoporosis treatment or in five prevention placebo-controlled clinical trials at a frequency≥2.0% in either group and in more Evista-treated women than in placebo-treated women. Adverse reactions are shown without attribution of causality. The majority of adverse reactions occurring during the study were mild and generally did not require discontinuation of therapy.

Comparison of Evista and Hormone Therapy — Evista was compared with estrogen-progestin therapy in three clinical trials for prevention of osteoporosis. Table 2 shows adverse reactions occurring more frequently in one treatment group and at an incidence ≥2.0% in any group. Adverse reactions are shown without attribution of causality.