Evista Drug Information

Recommended Dosing

The recommended dosage is one 60 mg EVISTA (raloxifene hydrochloride tablets) tablet daily, which may be administered any time of day without regard to meals . For the indications in risk of invasive breast cancer the optimum duration of treatment is not known .

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.

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 8429 patients who were enrolled in placebo-controlled trials, including 6666 exposed for 1 year and 5685 for at least 3 years. Osteoporosis Treatment Clinical Trial (MORE) — 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 hydrochloride (2557 received 60 mg/day, and 2572 received 120 mg/day). The incidence of all-cause mortality was similar among groups: 23 (0.9%) placebo, 13 (0.5%) EVISTA-treated (raloxifene HCl 60 mg), and 28 (1.1%) raloxifene HCl 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 HCl (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 studies were mild and generally did not require discontinuation of therapy. Table 1: Adverse Reactions Occurring in Placebo-Controlled Osteoporosis Clinical Trials at a Frequency ≥2.0% and in More EVISTA-Treated (60 mg Once Daily) Women than Placebo-Treated Women a a A: Placebo incidence greater than or equal to EVISTA incidence; B: Less than 2% incidence and more frequent with EVISTA. b Includes only patients with an intact uterus: Prevention Trials: EVISTA, n=354, Placebo, n=364; Treatment Trial: EVISTA, n=1948, Placebo, n=1999. c Actual terms most frequently referred to endometrial fluid. Treatment Prevention EVISTA (N=2557) % Placebo (N=2576) % EVISTA (N=581) % Placebo (N=584) % Body as a Whole Infection A A 15.1

Flu Syndrome 13.5 11.4 14.6 13.5 Headache 9.2 8.5

A A Leg Cramps 7.0 3.7 5.9

Chest Pain

A A 4.0

Migraine

A A 2.4

Syncope 2.3 2.1 B B Varicose Vein 2.2 1.5

A A Digestive System Nausea 8.3 7.8 8.8

Diarrhea 7.2 6.9

A A Dyspepsia A A 5.9

Vomiting 4.8 4.3 3.4 3.3 Flatulence

A A 3.1

Gastrointestinal Disorder

A A 3.3

Gastroenteritis B B 2.6 2.1 Metabolic and Nutritional Weight Gain

A A 8.8

Myalgia

A A 7.7

Arthritis

A A 4.0

Tendon Disorder 3.6 3.1

A A Nervous System Depression A A 6.4

Insomnia

A A 5.5

Vertigo 4.1 3.7

A A Neuralgia 2.4

B B Hypesthesia 2.1 2.0 B B Respiratory System Sinusitis 7.9 7.5

10.3

Rhinitis 10.2 10.1

A A Bronchitis 9.5

A

A Pharyngitis 5.3 5.1 7.6

Cough Increased 9.3 9.2 6.0 5.7 Pneumonia

A A 2.6

Laryngitis B B 2.2 1.4 Skin and Appendages Rash

A A 5.5

Sweating 2.5 2.0 3.1 1.7 Special Senses Conjunctivitis 2.2 1.7

A A Urogenital System Vaginitis A A 4.3

Urinary Tract Infection

A A 4.0

Cystitis 4.6 4.5 3.3 3.1 Leukorrhea

A A 3.3

Uterine Disorder b, c 3.3 2.3

A A Endometrial Disorder b B B 3.1

Vaginal Hemorrhage 2.5 2.4

A A Urinary Tract Disorder 2.5

A

A 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.

Table 2: Adverse Reactions Reported in the Clinical Trials for Osteoporosis Prevention with EVISTA (60 mg Once Daily) and Continuous Combined or Cyclic Estrogen Plus Progestin (Hormone Therapy) at an Incidence ≥2.0% in any Treatment Group a a These data are from both blinded and open-label studies. b Continuous Combined Hormone Therapy = 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate. c Cyclic Hormone Therapy = 0.625 mg conjugated estrogens for 28 days with concomitant 5 mg medroxyprogesterone acetate or 0.15 mg norgestrel on Days 1 through 14 or 17 through 28. d Includes only patients with an intact uterus: EVISTA, n=290; Hormone Therapy-Continuous Combined, n=67; Hormone Therapy-Cyclic, n=217. EVISTA (N=317) % Hormone Therapy-Continuous Combined b (N=96) % Hormone Therapy-Cyclic c (N=219) % Urogenital Breast Pain 4.4 37.5

Vaginal Bleeding d 6.2 64.2 88.5 Digestive Flatulence 1.6 12.5 6.4 Cardiovascular

Hot Flashes 28.7 3.1

Chest Pain 2.8 0 0.5 Breast Pain — Across all placebo-controlled trials

EVISTA was indistinguishable from placebo with regard to frequency and severity of breast pain and tenderness. EVISTA was associated with less breast pain and tenderness than reported by women receiving estrogens with or without added progestin. Gynecologic Cancers — EVISTA-treated and placebo-treated groups had similar incidences of endometrial cancer and ovarian cancer.

Placebo-Controlled Trial of Postmenopausal Women at Increased Risk for Major Coronary Events (RUTH) — The safety of EVISTA (60 mg once daily) was assessed in a placebo-controlled multinational trial of 10,101 postmenopausal women (age range 55-92) with documented coronary heart disease (CHD) or multiple CHD risk factors. Median study drug exposure was 5.1 years for both treatment groups . Therapy was discontinued due to an adverse reaction in 25% of 5044 EVISTA-treated women and 24% of 5057 placebo-treated women. The incidence per year of all-cause mortality was similar between the raloxifene (2.07%) and placebo (2.25%) groups.

Adverse reactions reported more frequently in EVISTA-treated women than in placebo-treated women included peripheral edema (14.1% raloxifene versus 11.7% placebo), muscle spasms/leg cramps (12.1% raloxifene versus 8.3% placebo), hot flashes (7.8% raloxifene versus 4.7% placebo), venous thromboembolic events (2.0% raloxifene versus 1.4% placebo), and cholelithiasis (3.3% raloxifene versus 2.6% placebo) . Tamoxifen-Controlled Trial of Postmenopausal Women at Increased Risk for Invasive Breast Cancer (STAR) — The safety of EVISTA 60 mg/day versus tamoxifen 20 mg/day over 5 years was assessed in 19,747 postmenopausal women (age range 35-83 years) in a randomized, double-blind trial. As of 31 December 2005, the median follow-up was 4.3 years. The safety profile of raloxifene was similar to that in the placebo-controlled raloxifene trials .

Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported very rarely since market introduction include retinal vein occlusion, stroke, and death associated with venous thromboembolism (VTE).

Cholestyramine

Concomitant administration of cholestyramine with EVISTA is not recommended. Although not specifically studied, it is anticipated that other anion exchange resins would have a similar effect. EVISTA should not be co-administered with other anion exchange resins .

Warfarin

If EVISTA is given concomitantly with warfarin or other warfarin derivatives, prothrombin time should be monitored more closely when starting or stopping therapy with EVISTA .

Other Highly Protein-Bound Drugs

EVISTA should be used with caution with certain other highly protein-bound drugs such as diazepam, diazoxide, and lidocaine. Although not examined, EVISTA might affect the protein binding of other drugs. Raloxifene is more than 95% bound to plasma proteins .

Systemic Estrogens

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

Other

Concomitant Medications EVISTA can be concomitantly administered with ampicillin, amoxicillin, antacids, corticosteroids, and digoxin . The concomitant use of EVISTA and lipid-lowering agents has not been studied.

Pregnancy Risk Summary EVISTA is contraindicated for use in pregnant women, and is not indicated for use in females of reproductive potential. Based on mechanism of action, EVISTA may block the important functions that estrogen has during all stages of pregnancy . Limited data with EVISTA use in pregnant women are insufficient to inform any drug associated risks for births defects or miscarriage. In rabbits and rats dosed during organogenesis or during gestation and lactation, EVISTA produced multiple adverse reproductive and developmental effects, including abortion; fetal anomalies; and delayed or disrupted parturition leading to maternal and neonatal mortality, at doses less than or similar to the maximum recommended human dose (based on human body surface area comparison). Data Animal Data In the developmental and reproductive toxicity studies conducted with EVISTA, numerous adverse effects were observed in multiple animal species.

In rabbits dosed during organogenesis, abortion and a low rate of fetal heart anomalies (ventricular septal defects) occurred at doses ≥0.1 mg/kg (≥0.04 times the human dose based on surface area, mg/m 2 ). In rats dosed during organogenesis, retardation of fetal growth and developmental abnormalities (wavy ribs, kidney cavitation) occurred at doses ≥1 mg/kg (≥0.2 times the human dose based on surface area, mg/m 2 ). Treatment of rats during gestation and lactation with doses of 0.1 to 10 mg/kg (0.02 to 1.6 times the human dose based on surface area, mg/m 2 ) 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, the disruption of parturition resulted in maternal and progeny morbidity and death. Effects in adult offspring (4 months of age) included uterine hypoplasia and reduced fertility; however, no ovarian or vaginal pathology was observed.

Pediatric Use Safety and effectiveness in pediatric patients have not been established.

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 .

Pregnancy

EVISTA is contraindicated for use in pregnancy, as it may cause fetal harm .

In an 8-week study of 63 postmenopausal women, a dose of raloxifene hydrochloride (HCl) 600 mg/day was safely tolerated. In clinical trials, no raloxifene overdose has been reported. In postmarketing spontaneous reports, raloxifene overdose has been reported very rarely (less than 1 out of 10,000 patients treated). The highest overdose has been approximately 1.5 grams.

No fatalities associated with raloxifene overdose have been reported. Adverse reactions were reported in approximately half of the adults who took ≥180 mg raloxifene HCl and included leg cramps and dizziness. Two 18-month-old children each ingested raloxifene HCl 180 mg.

In these two children, symptoms reported included ataxia, dizziness, vomiting, rash, diarrhea, tremor, and flushing, as well as elevation in alkaline phosphatase. There is no specific antidote for raloxifene. No mortality was seen after a single oral dose in rats or mice at 5000 mg/kg (810 times the human dose for rats and 405 times the human dose for mice based on surface area, mg/m 2 ) or in monkeys at 1000 mg/kg (80 times the AUC in humans).