EVISTA (raloxifene hydrochloride) is indicated for the treatment and prevention of osteoporosis in postmenopausal women.

For either osteoporosis treatment or prevention, supplemental calcium and/or vitamin D should be added to the diet if daily intake is inadequate.

Postmenopausal osteoporosis may be diagnosed by history or radiographic documentation of osteoporotic fracture, bone mineral densitometry, or physical signs of vertebral crush fractures (e.g., height loss, dorsal kyphosis). Women with diagnosed postmenopausal osteoporosis should be considered for pharmacologic therapy, in conjunction with education and appropriate lifestyle modifications.

No single clinical finding or test result can quantify risk of postmenopausal osteoporosis with certainty. However, clinical assessment can help to identify women at increased risk. Widely accepted risk factors include Caucasian or Asian descent, slender body build, early estrogen deficiency, smoking, alcohol consumption, low calcium diet, sedentary lifestyle, personal history of any fracture after age 40 and family history of osteoporosis. Evidence of increased bone turnover from serum and urine markers and low bone mass (e.g. at least 1 standard deviation below the mean for healthy, young adult women) as determined by densitometric techniques are also predictive. The greater the number of clinical risk factors, the greater the probability of developing postmenopausal osteoporosis. These risk factors may be considered in the decision to use EVISTA for prevention of postmenopausal osteoporosis.

Safety and efficacy in older and younger postmenopausal women in the osteoporosis treatment trial appeared to be comparable (see Warnings and Precautions).

The safety and efficacy of EVISTA have not been studied in pediatric populations. EVISTA should not be used in pediatric patients (see Warnings and Precautions).

EVISTA is contraindicated in women of childbearing potential. EVISTA therapy during pregnancy may be associated with an increased risk of congenital defects in the fetus.

EVISTA is contraindicated in women with active or past history of venous thromboembolic events, including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis.

EVISTA is contraindicated in women known to be hypersensitive to raloxifene or other ingredients of the tablets. For a complete listing, see Dosage Forms, Composition and Packaging.

The risk-benefit balance should be considered in women at risk of thromboembolic disease for any reason. 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 clinical trials, EVISTA-treated women had an increased risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism). The risk of VTE is reported infrequently, occurring in 1.44, 3.32 and 3.63 events per 1000 person-years for placebo, raloxifene 60 mg/day and raloxifene 120 mg/day, respectively. Other venous thromboembolic events could also 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 is similar to that associated with use of hormone replacement therapy.

The risk-benefit balance of EVISTA in postmenopausal women with a history of stroke or other significant stroke risk factors, such as transient ischemic attack or atrial fibrillation, should be considered when prescribing EVISTA. The Raloxifene Use for The Heart (RUTH) trial investigated the effects of EVISTA in postmenopausal women (average age=67 years) with known heart disease or at high risk for a coronary event. The RUTH trial demonstrated an increase in mortality due to stroke for EVISTA compared to placebo. The incidence of stroke mortality was 1.5 per 1000 women per year for placebo versus 2.2 per 1000 women per year for EVISTA (p=0.0499). The incidence of stroke, myocardial infarction, hospitalized acute coronary syndrome, cardiovascular mortality, or overall mortality (all causes combined) was comparable for EVISTA and placebo. It can therefore be concluded that EVISTA has no effect on clinical cardiovascular outcomes, in spite of the observed changes in lipid profile measurements.

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 (see Contraindications).

Raloxifene was studied as a single dose in patients with Child-Pugh Class A cirrhosis with total serum bilirubin ranging from 0.6 to 2.0 mg/dL (10.3 to 34.2 mmol/L). Plasma raloxifene concentrations were approximately 2.5 times higher than in controls and correlated with total bilirubin concentrations. Safety and efficacy have not been established in patients with moderate or severe hepatic insufficiency.

Safety information regarding the concurrent use of EVISTA and systemic hormone therapy (estrogen with or without progestin) is limited and therefore concomitant use of EVISTA with systemic estrogens is not recommended.

EVISTA lowers serum total and LDL cholesterol by 6% to 11%, but does not affect serum concentrations of total HDL cholesterol or triglycerides. HDL-2 cholesterol subfraction is increased by EVISTA. These effects should be taken into account in therapeutic decisions for patients who may require therapy for hyperlipidemia. Concurrent use of EVISTA and lipid lowering agents has not been studied.

Unexplained uterine bleeding should be investigated as clinically indicated.

Any unexplained breast abnormality occurring during EVISTA therapy should be investigated.

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

Any change in cognition and affect during EVISTA therapy should be investigated as clinically indicated.

Patients with a history of estrogen-induced hypertriglyceridemia can experience an increase in triglyceride levels during treatment with EVISTA. Therefore, triglyceride levels should be followed in such patients and the risk-benefit balance of EVISTA treatment in such cases should be reassessed.

For safe and effective use of EVISTA, the physician should inform patients about the following:

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 because of the increased risk of venous thromboembolic events.

EVISTA is not effective in reducing vasodilatation (hot flashes or flushes) associated with estrogen deficiency. In some patients, vasodilatation may occur upon beginning EVISTA therapy.

Patients should be instructed to take supplemental calcium and/or vitamin D, if daily dietary intake is inadequate. Weight-bearing exercise should be considered along with the modification of certain behavioral factors, such as cigarette smoking, and/or alcohol consumption, if these factors exist.

There is no indication for use of EVISTA in men.

EVISTA should not be used in pediatric patients.

In the osteoporosis treatment trial of 7705 postmenopausal women, 4621 women were considered geriatric (greater than 65 years old). Of these, 845 women were greater than 75 years old. Safety and efficacy in older and younger postmenopausal women in the osteoporosis treatment trial appeared to be comparable.

EVISTA should not be used in women who are or may become pregnant (see Contraindications).

EVISTA has no recognized use during labour or delivery.

EVISTA should not be used by lactating women (see Contraindications). It is not known whether raloxifene is excreted in human milk.

The safety of raloxifene has been established in Phase 2 and Phase 3 placebo-controlled, estrogen-controlled, and HRT-controlled studies. Twelve studies comprised the primary safety database for the prevention indication, and the safety of raloxifene in the treatment of osteoporosis was assessed in a large, multinational, placebo-controlled trial. In the osteoporosis prevention trials, the duration of treatment ranged from 2 to 30 months and 2036 women were exposed to raloxifene. In the osteoporosis treatment trial, 5129 women were exposed to raloxifene (2557 received 60 mg/day and 2572 received 120 mg/day) for 36 months. The osteoporosis treatment trial was extended by 12 months to a 4^th year during which patients were permitted the concomitant use of bisphosphonates, fluorides and calcitonins.

The most commonly observed treatment-emergent adverse events associated with the use of EVISTA in double-blind, placebo-controlled, osteoporosis treatment and prevention clinical trials were vasodilatation and leg cramps.

Vasodilatation events (hot flashes or flushes) were common in placebo-treated women, and the frequency was modestly increased in EVISTA-treated women. The first occurrence of this event was most commonly reported during the first 6 months of treatment and infrequently was reported de novo after that time.

Venous thromboembolism (VTE) is an uncommon but serious adverse event associated with raloxifene therapy. In clinical trials, EVISTA-treated women had an increased risk of VTE (deep vein thrombosis and pulmonary embolism). The risk of VTE is reported infrequently, occurring in 1.44, 3.32 and 3.63 events per 1000 person-years for placebo, raloxifene 60 mg/day and raloxifene 120 mg/day, respectively. Other venous thromboembolic events could also 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 is similar to that associated with use of hormone replacement therapy (see Warnings and Precautions).

The Raloxifene Use for The Heart (RUTH) trial investigated the effects of EVISTA in postmenopausal women (average age=67 years) with known heart disease or at high risk for a coronary event. The RUTH trial demonstrated an increase in mortality due to stroke for EVISTA compared to placebo. The incidence of stroke mortality was 1.5 per 1000 women per year for placebo versus 2.2 per 1000 women per year for EVISTA (p=0.0499). The incidence of stroke, myocardial infarction, hospitalized acute coronary syndrome, cardiovascular mortality, or overall mortality (all causes combined) was comparable for EVISTA and placebo (see Warnings and Precautions).

The majority of adverse events occurring during clinical trials were mild and did not require discontinuation of therapy. Discontinuation of therapy due to any clinical adverse experience occurred in 10.9% of 2557 EVISTA-treated women and 8.8% of 2576 placebo-treated women in the osteoporosis treatment trial, and in 11.4% of 581 EVISTA-treated women and 12.2% of 584 placebo-treated women in the osteoporosis prevention trials.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Table 1 lists adverse events occurring in either the osteoporosis treatment (up to 3 years) or prevention placebo-controlled clinical trials with EVISTA at a frequency ≥1.0% in EVISTAtreated women and at a significantly greater incidence than in placebo-treated women.

Table 1: EVISTA

Adverse Events Occurring in Placebo-Controlled Osteoporosis Clinical Trials (up to 36 Months) at a Frequency ≥1.0% in EVISTA-treated (60 mg once daily) Women and at a Significantly Greater Incidence Than in Placebo-treated Women

Adverse Event	Treatment		Prevention
	EVISTA (N=2557) %	Placebo (N=2576) %	EVISTA (N=581) %	Placebo (N=584) %
Body as a Whole
Flu Syndrome	13.5a	11.4	14.6	13.5
Leg Cramps	7.0a	3.7	5.9a	1.9
Cardiovascular
Vasodilatation	9.7a	6.4	24.6	18.3
Metabolic and Nutritional
Diabetes Mellitus	1.2a	0.5	A	A

^a. Significantly (p<0.05) different from placebo.

Diabetes mellitus was reported more frequently as an adverse event among EVISTA-treated patients (1.2%) compared with placebo-treated patients (0.5%) in the osteoporosis treatment trial. However, there were no differences between the raloxifene and placebo groups in either fasting glucose or hemoglobin A_1c (objective measures of glycemic control) in the osteoporosis treatment trial.

A significant dose trend was observed for peripheral edema in the treatment and prevention studies. However, there was not a statistically significant difference observed between the recommended dose, raloxifene 60 mg/day, and placebo. Cumulative frequency of the event at this dose was 5.2% for EVISTA-treated patients versus 4.4% for placebo treated patients in the treatment study, and 3.3% for EVISTA-treated patients versus 1.9% for placebotreated patients in the prevention studies.

The osteoporosis treatment trial was extended by 12 months to a 4^th year during which patients were permitted the concomitant use of bisphosphonates, fluorides and calcitonins. The incidence trend of treatment-emergent adverse events occurring at a frequency ≥1.0% in EVISTA-treated women, and at a significantly greater incidence than in placebo-treated women after year 4 of the osteoporosis treatment trial, were generally similar to the 1 to 3 year results presented in Table 1.

At 48 months in the osteoporosis treatment trial, vasodilatation was reported in 10.6% of patients on EVISTA versus 7.1% of placebo patients (p<0.001), and leg cramps were reported in 9.2% of patients on EVISTA versus 6.0% of placebo patients (p<0.001).

At 48 months in the same osteoporosis treatment trial, flu syndrome (16.2% of EVISTA treated patients versus 14.0% of placebo patients), uterine disorder (endometrial cavity fluid in 12.7% of EVISTA treated patients versus 9.6% of placebo patients), diabetes mellitus (1.5% of EVISTA treated patients versus 0.7% of placebo patients), and peripheral edema (7.1% of EVISTA treated patients versus 6.1% of placebo patients) were also treatment-emergent adverse events which occurred more frequently with patients receiving EVISTA compared to placebo (p<0.05).

EVISTA (N=317) was compared with continuous combined (N=96) hormone replacement therapy (HRT) or cyclic estrogen plus progestin HRT in 3 clinical trials for prevention of osteoporosis.

The incidence of breast pain (4.4% for EVISTA-treated patients, 37.5% for continuous combined HRT-treated patients, and 29.7% for cyclic estrogen plus progestin HRT-treated patients), vaginal bleeding (6.2% for EVISTA-treated patients, 64.2% for continuous combined HRT-treated patients and 88.5% for cyclic estrogen plus progestin HRT-treated patients), and abdominal pain (6.6% for EVISTA-treated patients, 10.4% for continuous combined HRTtreated patients, and 18.7% for cyclic estrogen plus progestin HRT-treated patients) were significantly lower in EVISTA-treated patients versus patients treated with either form of HRT (p<0.05).

Conversely, the incidence of vasodilatation (28.7% for EVISTA-treated patients, 3.1% for continuous combined HRT-treated patients, and 5.9% for cyclic estrogen plus progestin HRTtreated patients) was significantly greater in EVISTA-treated patients versus patients treated with either form of HRT (p<0.05).

The following changes in analyte concentrations are commonly observed during EVISTA therapy: increased serum HDL-2 cholesterol subfraction and apolipoprotein A1; and reduced serum total cholesterol, LDL cholesterol, fibrinogen, apolipoprotein B, and lipoprotein (a). EVISTA modestly increases hormone-binding globulin concentrations, including sex steroid binding globulin, thyroxine binding globulin, and corticosteroid binding globulin with corresponding increases in measured total hormone concentrations. There is no evidence that these changes in hormone binding globulin concentrations affect concentrations of the corresponding free hormones.

Cholestyramine, an anion exchange resin, significantly reduces the absorption and enterohepatic cycling of raloxifene and should not be coadministered with raloxifene. Although not specifically studied, it is anticipated that other anion exchange resins would have a similar effect.

Coadministration of raloxifene and warfarin does not alter the pharmacokinetics of either compound. However, modest decreases in prothrombin time have been observed in singledose studies. If raloxifene is given concurrently with warfarin or other coumarin derivatives, prothrombin time should be monitored.

Peak concentrations of raloxifene are reduced with coadministration of ampicillin. The reduction in peak concentrations is consistent with reduced enterohepatic cycling associated with antibiotic reduction of enteric bacteria. Since the overall extent of absorption and the elimination rate of raloxifene are not affected, raloxifene can be concurrently administered with ampicillin. In the osteoporosis treatment trial, co-administered oral antimicrobial agents (including amoxicillin, cephalexin, ciprofloxacin, macrolide antibiotics, sulfamethoxazole/trimethoprim and tetracycline) had no effect on plasma raloxifene concentrations.

The chronic administration of raloxifene in postmenopausal women has no effect on the pharmacokinetics of methylprednisolone given as a single oral dose.

Raloxifene has no effect on the pharmacokinetics of digoxin. In the osteoporosis treatment trial, coadministered digoxin had no effect on plasma raloxifene concentration.

Concurrent administration of calcium carbonate or aluminum and magnesium hydroxide-containing antacids does not affect the systemic exposure of raloxifene. In the osteoporosis treatment trial, coadministered gastrointestinal medications (including bisacodyl, cisapride, docusate, H₂-antagonists, laxatives, loperamide, omeprazole and psyllium) had no effect on plasma raloxifene concentration.

Raloxifene is more than 95% bound to plasma proteins. The influence of co-administered highly protein-bound drugs (including diazepam, gemfibrozil, ibuprofen, naproxen and warfarin) on raloxifene plasma concentrations was evaluated in the osteoporosis treatment trial. No clinically significant effects of these agents on raloxifene plasma concentrations were identified. In vitro, raloxifene did not affect the binding of phenytoin, tamoxifen or warfarin.

Raloxifene undergoes extensive first-pass metabolism to glucuronide conjugates. The influence of co-administered highly glucuronidated drugs (including acetaminophen, ketoprofen, morphine and oxazepam) on raloxifene plasma concentrations was evaluated in the osteoporosis treatment trial. No clinically significant effects of these agents on raloxifene plasma concentrations were identified.

The influence of concomitant medications on raloxifene plasma concentrations was evaluated in the osteoporosis treatment clinical trial. The 152 most commonly co-administered medications were grouped by pharmacological class based on their therapeutic use. Frequently co-administered drugs included: ACE inhibitors and angiotensin antagonists, alpha agonists and antagonists, anticholinergics, antidepressants, antimicrobials, antipsychotics, benzodiazepines, beta blockers and agonists, bisphosphonates, calcium channel blockers, diuretics, estrogen preparations, glucocorticoids, guaifenesin, H₁-antagonists, H₂-antagonists and proton pump inhibitors, hypoglycemics, hypolipidemics, iron preparations, muscle relaxants, nitrates, non-benzodiazepine hypnotics, non-steroidal anti-inflammatory drugs (NSAIDs), opioid analgesics, theophylline and thyroid hormone. No clinically relevant effects of the co-administration of any of these agents on raloxifene plasma concentrations were observed.