These Highlights Do Not Include All The Information Needed To Use Evista Safely And Effectively. See Full Prescribing Information For Evista.

Important Limitations of Use for Breast Cancer Risk Reduction

• There are no data available regarding the effect of EVISTA on invasive breast cancer incidence in women with inherited mutations (BRCA1, BRCA2) to be able to make specific recommendations on the effectiveness of EVISTA.
• EVISTA is not indicated for the treatment of invasive breast cancer or reduction of the risk of recurrence.
• EVISTA is not indicated for the reduction in the risk of noninvasive breast cancer.

Medication Guide

EVISTA^® (Ē-VISS-tah)

(raloxifene hydrochloride tablets)

Tablets for Oral Use

Read the Medication Guide that comes with EVISTA before you start taking it and each time you refill your prescription. The information may have changed. This Medication Guide does not take the place of talking with your doctor about your medical condition or treatment. Talk with your doctor about EVISTA when you start taking it and at regular checkups.

What is the most important information I should know about EVISTA?

Serious and life-threatening side effects can occur while taking EVISTA. These include blood clots and dying from stroke:

• Increased risk of blood clots in the legs (deep vein thrombosis) and lungs (pulmonary embolism) have been reported with EVISTA. Women who have or have had blood clots in the legs, lungs, or eyes should not take EVISTA.
• Women who have had a heart attack or are at risk for a heart attack may have an increased risk of dying from stroke when taking EVISTA.

• Before starting EVISTA, tell your doctor if you have had blood clots in your legs, lungs, or eyes, a stroke, mini-stroke (transient ischemic attack), or have an irregular heartbeat.
• Stop taking EVISTA and call your doctor if you have:
  • leg pain or a feeling of warmth in the lower leg (calf).
  • swelling of the legs, hands, or feet.
  • sudden chest pain, shortness of breath, or coughing up blood.
  • sudden change in your vision, such as loss of vision or blurred vision.
• Being still for a long time (such as sitting still during a long car or airplane trip or being in bed after surgery) can increase your risk of blood clots. (See “What should I avoid if I am taking EVISTA?”)

What is EVISTA?

EVISTA is a type of prescription medicine called a Selective Estrogen Receptor Modulator (SERM). EVISTA is for women after menopause, and has more than one use:

• Osteoporosis: EVISTA treats and prevents osteoporosis by helping make your bones stronger and less likely to break.
• Invasive Breast Cancer: If you have osteoporosis or are at high risk for breast cancer, EVISTA can be used to lower your chance of getting invasive breast cancer. EVISTA will not totally get rid of your chance of getting breast cancer. Your doctor can estimate your risk of breast cancer by asking you about risk factors, including:
  • your age (getting older).
  • family history of breast cancer in your mother, sister, or daughter.
  • a history of any breast biopsy, especially an abnormal biopsy.

  You and your doctor should talk about whether the possible benefit of EVISTA in lowering your chance of getting invasive breast cancer is greater than its possible risks.

EVISTA is not for use in premenopausal women (women who have not passed menopause).

Who should not take EVISTA?

Do not take EVISTA if you:

• have or have had blood clots in your legs, lungs, or eyes. Taking EVISTA may increase the risk of getting blood clots.
• are pregnant or could become pregnant. EVISTA could harm your unborn child.
• are nursing a baby. It is not known if EVISTA passes into breast milk or what effect it might have on the baby.

What should I tell my doctor before taking EVISTA?

EVISTA may not be right for you. Before taking EVISTA, tell your doctor about all your medical conditions, including if you:

• have had blood clots in your legs, lungs, or eyes, a stroke, mini-stroke (TIA/transient ischemic attack), or a type of irregular heartbeat (atrial fibrillation).
• have had breast cancer. EVISTA has not been fully studied in women who have a history of breast cancer.
• have liver or kidney problems.
• have taken estrogen in the past and had a high increase of triglycerides (a kind of fat in the blood).
• are pregnant, planning to become pregnant, or breast-feeding (see “Who should not take EVISTA?”).

Tell your doctor about all medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist each time you get a new medicine. Especially tell your doctor if you take*:

• warfarin (Coumadin^®, Jantoven^®)
  
  If you are taking warfarin or other coumarin blood thinners, your doctor may need to do a blood test when you first start or if you need to stop taking EVISTA. Names for this test include “prothrombin time,” “pro-time,” or “INR.” Your doctor may need to adjust the dose of your warfarin or other coumarin blood thinner.
• cholestyramine
• estrogens

EVISTA should not be taken with cholestyramine or estrogens.

How should I take EVISTA?

• Take EVISTA exactly how your doctor tells you to.
• Keep taking EVISTA for as long as your doctor prescribes it for you. It is not known how long you should keep taking EVISTA to lower your chance of getting invasive breast cancers.
• It is important to get your refills on time so you do not run out of the medicine.
• Take one EVISTA tablet each day.
• Take EVISTA at any time of the day, with or without food.
• To help you remember to take EVISTA, it may be best to take it at about the same time each day.
• Calcium and vitamin D may be taken at the same time as EVISTA. It is important to take calcium and vitamin D, as directed by your physician, to prevent or treat osteoporosis.
• If you miss a dose, take it as soon as you remember. However, if it is almost time for your next dose, skip the missed dose and take only your next regularly scheduled dose. Do not take two doses at the same time.

What should I avoid while taking EVISTA?

• Being still for a long time (such as during long trips or being in bed after surgery) can increase the risk of blood clots. EVISTA may add to this risk. If you will need to be still for a long time, talk with your doctor about ways to reduce the risk of blood clots. On long trips, move around periodically. Stop taking EVISTA at least 3 days before a planned surgery or before you plan on being still for a long time. You should start taking EVISTA again when you return to your normal activities.
• Some medicines should not be taken with EVISTA (see “What should I tell my doctor before taking EVISTA?”).

What are the possible side effects of EVISTA?

Serious and life-threatening side effects can occur while taking EVISTA. These include blood clots and dying from stroke:

• Increased risk of blood clots in the legs (deep vein thrombosis) and lungs (pulmonary embolism) have been reported with EVISTA. Women who have or have had blood clots in the legs, lungs, or eyes should not take EVISTA.
• Women who have had a heart attack or are at risk for a heart attack may have an increased risk of dying from stroke when taking EVISTA.

See “What is the most important information I should know about EVISTA?”

The most common side effects of EVISTA are hot flashes, leg cramps, swelling of the feet, ankles, and legs, flu syndrome, joint pain, and sweating. Hot flashes are more common during the first 6 months after starting treatment.

These are not all the side effects of EVISTA. Tell your doctor about any side effect that bothers you or that does not go away. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What else should I know about EVISTA?

• Do not use EVISTA to prevent heart disease, heart attack, or strokes.
• To get the calcium and vitamin D you need, your doctor may advise you to change your diet and/or take supplemental calcium and vitamin D. Your doctor may suggest other ways to help treat or prevent osteoporosis, in addition to taking EVISTA and getting the calcium and vitamin D you need. These may include regular exercise, stopping smoking, and drinking less alcohol.
• Women who have hot flashes can take EVISTA. EVISTA does not treat hot flashes, and it may cause hot flashes in some women. (See “What are the possible side effects of EVISTA?”)
• EVISTA has not been found to cause breast tenderness or enlargement. If you notice any changes in your breasts, call your doctor to find out the cause. Before starting and while taking EVISTA you should have breast exams and mammograms, as directed by your doctor. Because EVISTA does not eliminate the chance of developing breast cancers, you need these examinations to find any breast cancers as early as possible.
• EVISTA should not cause spotting or menstrual-type bleeding. If you have any vaginal bleeding, call your doctor to find out the cause. EVISTA has not been found to increase the risk for cancer of the lining of the uterus.
• Women in clinical trials have taken EVISTA for up to eight years.

How should I store EVISTA?

• Store EVISTA at 68°F to 77°F (20°C-25°C).
• Keep EVISTA and all medicines out of the reach of children.

General Information about the safe and effective use of EVISTA

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use EVISTA for a condition for which it was not prescribed. Do not give your EVISTA to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide is a summary of the most important information about EVISTA. If you would like more information about EVISTA, talk with your doctor. You can ask your doctor or pharmacist for information about EVISTA that is written for health professionals. For more information, call 1-800-545-5979 (toll-free).

What are the ingredients in EVISTA?

Active Ingredient: raloxifene hydrochloride

Inactive Ingredients: anhydrous lactose, carnauba wax, crospovidone, FD&C Blue No. 2 aluminum lake, hypromellose, lactose monohydrate, magnesium stearate, modified pharmaceutical glaze, polyethylene glycol, polysorbate 80, povidone, propylene glycol, and titanium dioxide.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

*The brands listed are trademarks of their respective owners and are not trademarks of Eli Lilly and Company. The makers of these brands are not affiliated with and do not endorse Eli Lilly and Company or its products.

Medication Guide revised August 1, 2014

Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA

Copyright © 1997, 2014, Eli Lilly and Company. All rights reserved.

EVS-0001-MG-20140801

None

PACKAGE LABEL – Evista 60mg 30ct Bottle (0002-4184)

NDC 0002-4184-30

30 Tablets

No. 4165

EVISTA^®

raloxifene HCl tablets 60mg

Rx only

4165

Lilly

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 [see Clinical Pharmacology (12.3)].

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 [<0.01%] 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/m²) or in monkeys at 1000 mg/kg (80 times the AUC in humans).

EVISTA is contraindicated for use in pregnancy, as it may cause fetal harm [see Use in Specific Populations (8.1)].

EVISTA (raloxifene hydrochloride) is an estrogen agonist/antagonist, commonly referred to as a selective estrogen receptor modulator (SERM) that belongs to the benzothiophene class of compounds. The chemical structure is:

The chemical designation is methanone, [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl]-[4-[2-(1-piperidinyl)ethoxy]phenyl]-, hydrochloride. Raloxifene hydrochloride (HCl) has the empirical formula C₂₈H₂₇NO₄S•HCl, which corresponds to a molecular weight of 510.05. Raloxifene HCl is an off-white to pale-yellow solid that is very slightly soluble in water.

EVISTA is supplied in a tablet dosage form for oral administration. Each EVISTA tablet contains 60 mg of raloxifene HCl, which is the molar equivalent of 55.71 mg of free base. Inactive ingredients include anhydrous lactose, carnauba wax, crospovidone, FD&C Blue No. 2 aluminum lake, hypromellose, lactose monohydrate, magnesium stearate, modified pharmaceutical glaze, polyethylene glycol, polysorbate 80, povidone, propylene glycol, and titanium dioxide.

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.

EVISTA 60 mg tablets are white, elliptical, film coated (not scored) and imprinted with 4165 on one side in edible blue ink. They are available as follows:

Safety and effectiveness in pediatric patients have not been established.

Of the total number of patients in placebo-controlled clinical studies of EVISTA, 61% were 65 and over, while 15.5% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Based on clinical trials, there is no need for dose adjustment for geriatric patients [see Clinical Pharmacology (12.3)].

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 [see Clinical Pharmacology (12.3)].

• Active or past history of venous thromboembolism, including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis. (4.1)
• Pregnancy. (4.2, 8.1)

Adverse reactions (>2% and more common than with placebo) include: hot flashes, leg cramps, peripheral edema, flu syndrome, arthralgia, sweating. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-545-5979 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

• Cholestyramine: Use with EVISTA is not recommended. Reduces the absorption and enterohepatic cycling of raloxifene. (7.1, 12.3)
• Warfarin: Monitor prothrombin time when starting or stopping EVISTA. (7.2, 12.3)
• Highly Protein-Bound Drugs: Use with EVISTA with caution. Highly protein-bound drugs include diazepam, diazoxide, and lidocaine. EVISTA is more than 95% bound to plasma proteins. (7.3, 12.3)

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)].

EVISTA should be used with caution in patients with moderate or severe renal impairment [see Warnings and Precautions (5.8) and Clinical Pharmacology (12.3)].

Decreases in estrogen levels after oophorectomy or menopause lead to increases in bone resorption and accelerated bone loss. Bone is initially lost rapidly because the compensatory increase in bone formation is inadequate to offset resorptive losses. In addition to loss of estrogen, this imbalance between resorption and formation may be due to age-related impairment of osteoblasts or their precursors. In some women, these changes will eventually lead to decreased bone mass, osteoporosis, and increased risk for fractures, particularly of the spine, hip, and wrist. Vertebral fractures are the most common type of osteoporotic fracture in postmenopausal women.

In both the osteoporosis treatment and prevention trials, EVISTA therapy resulted in consistent, statistically significant suppression of bone resorption and bone formation, as reflected by changes in serum and urine markers of bone turnover (e.g., bone-specific alkaline phosphatase, osteocalcin, and collagen breakdown products). The suppression of bone turnover markers was evident by 3 months and persisted throughout the 36-month and 24-month observation periods.

In a 31-week, open-label, radiocalcium kinetics study, 33 early postmenopausal women were randomized to treatment with once-daily EVISTA 60 mg, cyclic estrogen/progestin (0.625 mg conjugated estrogens daily with 5 mg medroxyprogesterone acetate daily for the first 2 weeks of each month [hormone therapy]), or no treatment. Treatment with either EVISTA or hormone therapy was associated with reduced bone resorption and a positive shift in calcium balance (-82 mg Ca/day and +60 mg Ca/day, respectively, for EVISTA and -162 mg Ca/day and +91 mg Ca/day, respectively, for hormone therapy).

There were small decreases in serum total calcium, inorganic phosphate, total protein, and albumin, which were generally of lesser magnitude than decreases observed during estrogen or hormone therapy. Platelet count was also decreased slightly and was not different from estrogen therapy.

The disposition of raloxifene has been evaluated in more than 3000 postmenopausal women in selected raloxifene osteoporosis treatment and prevention clinical trials, using a population approach. Pharmacokinetic data also were obtained in conventional pharmacology studies in 292 postmenopausal women. Raloxifene exhibits high within-subject variability (approximately 30% coefficient of variation) of most pharmacokinetic parameters. Table 3 summarizes the pharmacokinetic parameters of raloxifene.

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. Additionally, there is concern regarding inadvertent drug exposure in pregnancy in women of reproductive potential who become pregnant, due to risk of fetal harm [see Use in Specific Populations (8.1)].

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 [see Clinical Pharmacology (12.3)].

For the indications in risk of invasive breast cancer the optimum duration of treatment is not known [see Clinical Studies (14.3, 14.4)].

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)].

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

EVISTA should be used with caution in patients with hepatic impairment [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)].

EVISTA^® is an estrogen agonist/antagonist indicated for:

• Treatment and prevention of osteoporosis in postmenopausal women. (1.1)
• Reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis. (1.2)
• Reduction in risk of invasive breast cancer in postmenopausal women at high risk for invasive breast cancer. (1.3)

Important Limitations: EVISTA is not indicated for the treatment of invasive breast cancer, reduction of the risk of recurrence of breast cancer, or reduction of risk of noninvasive breast cancer. (1.3)

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 (14.5)].

Raloxifene is an estrogen agonist/antagonist, commonly referred to as a selective estrogen receptor modulator (SERM). The biological actions of raloxifene are largely mediated through binding to estrogen receptors. This binding results in activation of estrogenic pathways in some tissues (agonism) and blockade of estrogenic pathways in others (antagonism). The agonistic or antagonistic action of raloxifene depends on the extent of recruitment of coactivators and corepressors to estrogen receptor (ER) target gene promoters.

Raloxifene appears to act as an estrogen agonist in bone. It decreases bone resorption and bone turnover, increases bone mineral density (BMD) and decreases fracture incidence. Preclinical data demonstrate that raloxifene is an estrogen antagonist in uterine and breast tissues. These results are consistent with findings in clinical trials, which suggest that EVISTA lacks estrogen-like effects on the uterus and breast tissue.

Store at controlled room temperature, 20° to 25°C (68° to 77°F) [see USP]. The USP defines controlled room temperature as a temperature maintained thermostatically that encompasses the usual and customary working environment of 20° to 25°C (68° to 77°F); that results in a mean kinetic temperature calculated to be not more than 25°C; and that allows for excursions between 15° and 30°C (59° and 86°F) that are experienced in pharmacies, hospitals, and warehouses.

Any unexplained breast abnormality occurring during EVISTA therapy should be investigated. EVISTA does not eliminate the risk of breast cancer [see Clinical Studies (14.4)].

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 (5.1)].

• Venous Thromboembolism: Increased risk of deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis. Discontinue use 72 hours prior to and during prolonged immobilization. (5.1, 6.1)
• Death Due to Stroke: Increased risk of death due to stroke occurred in a trial in postmenopausal women with documented coronary heart disease or at increased risk for major coronary events. No increased risk of stroke was seen in this trial. Consider risk-benefit balance in women at risk for stroke. (5.2, 14.5)
• Cardiovascular Disease: EVISTA should not be used for the primary or secondary prevention of cardiovascular disease. (5.3, 14.5)
• Premenopausal Women: Use is not recommended. (5.4)
• Hepatic Impairment: Use with caution. (5.5)
• Concomitant Use with Systemic Estrogens: Not recommended. (5.6)
• Hypertriglyceridemia: If previous treatment with estrogen resulted in hypertriglyceridemia, monitor serum triglycerides. (5.7)

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 than with placebo. 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) and Adverse Reactions (6.1)].

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 (14.5)].

EVISTA should be discontinued at least 72 hours prior to and during prolonged immobilization (e.g., post-surgical recovery, prolonged bed rest), and patients should be advised to avoid prolonged restrictions of movement during travel because of the increased risk of venous thromboembolic events [see Warnings and Precautions (5.1)].

EVISTA may increase the incidence of hot flashes and is not effective in reducing hot flashes or flushes associated with estrogen deficiency. In some asymptomatic patients, hot flashes may occur upon beginning EVISTA therapy.

60 mg tablet orally once daily. (2.1)

60 mg, white, elliptical, film-coated tablets (not scored) imprinted with 4165 on one side in edible blue ink.

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

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).

• Pediatric Use: Safety and effectiveness not established. (8.4)

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.

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

See FDA-approved Medication Guide.

Physicians should instruct their patients to read the Medication Guide before starting therapy with EVISTA and to reread it each time the prescription is renewed.

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)].

EVISTA can be concomitantly administered with ampicillin, amoxicillin, antacids, corticosteroids, and digoxin [see Clinical Pharmacology (12.3)].

The concomitant use of EVISTA and lipid-lowering agents has not been studied.

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 [see Clinical Pharmacology (12.3)].

In a randomized, placebo-controlled, double-blind, multinational clinical trial (RUTH) of 10,101 postmenopausal women with documented coronary heart disease or at increased risk for coronary events, no cardiovascular benefit was demonstrated after treatment with EVISTA 60 mg once daily for a median follow-up of 5.6 years. No significant increase or decrease was observed for coronary events (death from coronary causes, nonfatal myocardial infarction, or hospitalization for an acute coronary syndrome). An increased risk of death due to stroke after treatment with EVISTA was observed: 59 (1.2%) EVISTA-treated women died due to a stroke compared to 39 (0.8%) placebo-treated women (2.2 versus 1.5 per 1000 women-years; hazard ratio 1.49; 95% confidence interval, 1.00-2.24; p=0.0499). The incidence of stroke did not differ significantly between treatment groups (249 with EVISTA [4.9%] versus 224 with placebo [4.4%]; hazard ratio 1.10; 95% confidence interval 0.92-1.32; p=0.30; 9.5 versus 8.6 per 1000 women-years) [see Warnings and Precautions (5.2, 5.3)].

The skeletal effects of raloxifene treatment were assessed in ovariectomized rats and monkeys. In rats, raloxifene prevented increased bone resorption and bone loss after ovariectomy. There were positive effects of raloxifene on bone strength, but the effects varied with time. Cynomolgus monkeys were treated with raloxifene or conjugated estrogens for 2 years. In terms of bone cycles, this is equivalent to approximately 6 years in humans. Raloxifene and estrogen suppressed bone turnover and increased BMD in the lumbar spine and in the central cancellous bone of the proximal tibia. In this animal model, there was a positive correlation between vertebral compressive breaking force and BMD of the lumbar spine.

Histologic examination of bone from rats and monkeys treated with raloxifene showed no evidence of woven bone, marrow fibrosis, or mineralization defects.

These results are consistent with data from human studies of radiocalcium kinetics and markers of bone metabolism, and are consistent with the action of EVISTA as a skeletal antiresorptive agent.

The effects of EVISTA on BMD in postmenopausal women were examined in three randomized, placebo-controlled, double-blind osteoporosis prevention trials: (1) a North American trial enrolled 544 women; (2) a European trial, 601 women; and (3) an international trial, 619 women who had undergone hysterectomy. In these trials, all women received calcium supplementation (400 to 600 mg/day). Women enrolled in these trials had a median age of 54 years and a median time since menopause of 5 years (less than 1 year up to 15 years postmenopause). The majority of the women were White (93.5%). Women were included if they had spine BMD between 2.5 standard deviations below and 2 standard deviations above the mean value for healthy young women. The mean T scores (number of standard deviations above or below the mean in healthy young women) for the three trials ranged from -1.01 to -0.74 for spine BMD and included women both with normal and low BMD. EVISTA, 60 mg administered once daily, produced increases in bone mass versus calcium supplementation alone, as reflected by dual-energy x-ray absorptiometric (DXA) measurements of hip, spine, and total body BMD.

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.

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.

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

• Increased risk of deep vein thrombosis and pulmonary embolism have been reported with EVISTA [see Warnings and Precautions (5.1)] . Women with active or past history of venous thromboembolism should not take EVISTA [see Contraindications (4.1)].
• Increased risk of death due to stroke occurred in a trial in postmenopausal women with documented coronary heart disease or at increased risk for major coronary events. Consider risk-benefit balance in women at risk for stroke [see Warnings and Precautions (5.2) and Clinical Studies (14.5)].

For osteoporosis treatment or prevention, patients should be instructed to take supplemental calcium and/or vitamin D if intake is inadequate. Patients at increased risk for vitamin D insufficiency (e.g., over the age of 70 years, nursing home bound, chronically ill, or with gastrointestinal malabsorption syndromes) should be instructed to take additional vitamin D if needed. Weight-bearing exercises should be considered along with the modification of certain behavioral factors, such as cigarette smoking and/or excessive alcohol consumption, if these factors exist.

EVISTA is indicated for the reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis [see Clinical Studies (14.3)].

EVISTA is indicated for the reduction in risk of invasive breast cancer in postmenopausal women at high risk of invasive breast cancer [see Clinical Studies (14.4)].

The effect in the reduction in the incidence of breast cancer was shown in a study of postmenopausal women at high risk for breast cancer with a 5-year planned duration with a median follow-up of 4.3 years [see Clinical Studies (14.4)]. Twenty-seven percent of the participants received drug for 5 years. The long-term effects and the recommended length of treatment are not known.

High risk of breast cancer is defined as at least one breast biopsy showing lobular carcinoma in situ (LCIS) or atypical hyperplasia, one or more first-degree relatives with breast cancer, or a 5-year predicted risk of breast cancer ≥1.66% (based on the modified Gail model). Among the factors included in the modified Gail model are the following: current age, number of first-degree relatives with breast cancer, number of breast biopsies, age at menarche, nulliparity or age of first live birth. Healthcare professionals can obtain a Gail Model Risk Assessment Tool by dialing 1-800-545-5979. Currently, no single clinical finding or test result can quantify risk of breast cancer with certainty.

After an assessment of the risk of developing breast cancer, the decision regarding therapy with EVISTA should be based upon an individual assessment of the benefits and risks.

EVISTA does not eliminate the risk of breast cancer. Patients should have breast exams and mammograms before starting EVISTA and should continue regular breast exams and mammograms in keeping with good medical practice after beginning treatment with EVISTA.

Use of EVISTA is associated with the reduction of the risk of invasive breast cancer in postmenopausal women. EVISTA has not been shown to reduce the risk of noninvasive breast cancer. When considering treatment, physicians need to discuss the potential benefits and risks of EVISTA treatment with the patient.

EVISTA is not indicated for the treatment of invasive breast cancer or reduction of the risk of recurrence.

Patients should have breast exams and mammograms before starting EVISTA and should continue regular breast exams and mammograms in keeping with good medical practice after beginning treatment with EVISTA.

Important Limitations of Use for Breast Cancer Risk Reduction

• There are no data available regarding the effect of EVISTA on invasive breast cancer incidence in women with inherited mutations (BRCA1, BRCA2) to be able to make specific recommendations on the effectiveness of EVISTA.
• EVISTA is not indicated for the treatment of invasive breast cancer or reduction of the risk of recurrence.
• EVISTA is not indicated for the reduction in the risk of noninvasive breast cancer.

Medication Guide

EVISTA^® (Ē-VISS-tah)

(raloxifene hydrochloride tablets)

Tablets for Oral Use

Read the Medication Guide that comes with EVISTA before you start taking it and each time you refill your prescription. The information may have changed. This Medication Guide does not take the place of talking with your doctor about your medical condition or treatment. Talk with your doctor about EVISTA when you start taking it and at regular checkups.

What is the most important information I should know about EVISTA?

Serious and life-threatening side effects can occur while taking EVISTA. These include blood clots and dying from stroke:

• Increased risk of blood clots in the legs (deep vein thrombosis) and lungs (pulmonary embolism) have been reported with EVISTA. Women who have or have had blood clots in the legs, lungs, or eyes should not take EVISTA.
• Women who have had a heart attack or are at risk for a heart attack may have an increased risk of dying from stroke when taking EVISTA.

• Before starting EVISTA, tell your doctor if you have had blood clots in your legs, lungs, or eyes, a stroke, mini-stroke (transient ischemic attack), or have an irregular heartbeat.
• Stop taking EVISTA and call your doctor if you have:
  • leg pain or a feeling of warmth in the lower leg (calf).
  • swelling of the legs, hands, or feet.
  • sudden chest pain, shortness of breath, or coughing up blood.
  • sudden change in your vision, such as loss of vision or blurred vision.
• Being still for a long time (such as sitting still during a long car or airplane trip or being in bed after surgery) can increase your risk of blood clots. (See “What should I avoid if I am taking EVISTA?”)

What is EVISTA?

EVISTA is a type of prescription medicine called a Selective Estrogen Receptor Modulator (SERM). EVISTA is for women after menopause, and has more than one use:

• Osteoporosis: EVISTA treats and prevents osteoporosis by helping make your bones stronger and less likely to break.
• Invasive Breast Cancer: If you have osteoporosis or are at high risk for breast cancer, EVISTA can be used to lower your chance of getting invasive breast cancer. EVISTA will not totally get rid of your chance of getting breast cancer. Your doctor can estimate your risk of breast cancer by asking you about risk factors, including:
  • your age (getting older).
  • family history of breast cancer in your mother, sister, or daughter.
  • a history of any breast biopsy, especially an abnormal biopsy.

  You and your doctor should talk about whether the possible benefit of EVISTA in lowering your chance of getting invasive breast cancer is greater than its possible risks.

EVISTA is not for use in premenopausal women (women who have not passed menopause).

Who should not take EVISTA?

Do not take EVISTA if you:

• have or have had blood clots in your legs, lungs, or eyes. Taking EVISTA may increase the risk of getting blood clots.
• are pregnant or could become pregnant. EVISTA could harm your unborn child.
• are nursing a baby. It is not known if EVISTA passes into breast milk or what effect it might have on the baby.

What should I tell my doctor before taking EVISTA?

EVISTA may not be right for you. Before taking EVISTA, tell your doctor about all your medical conditions, including if you:

• have had blood clots in your legs, lungs, or eyes, a stroke, mini-stroke (TIA/transient ischemic attack), or a type of irregular heartbeat (atrial fibrillation).
• have had breast cancer. EVISTA has not been fully studied in women who have a history of breast cancer.
• have liver or kidney problems.
• have taken estrogen in the past and had a high increase of triglycerides (a kind of fat in the blood).
• are pregnant, planning to become pregnant, or breast-feeding (see “Who should not take EVISTA?”).

Tell your doctor about all medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist each time you get a new medicine. Especially tell your doctor if you take*:

• warfarin (Coumadin^®, Jantoven^®)
  
  If you are taking warfarin or other coumarin blood thinners, your doctor may need to do a blood test when you first start or if you need to stop taking EVISTA. Names for this test include “prothrombin time,” “pro-time,” or “INR.” Your doctor may need to adjust the dose of your warfarin or other coumarin blood thinner.
• cholestyramine
• estrogens

EVISTA should not be taken with cholestyramine or estrogens.

How should I take EVISTA?

• Take EVISTA exactly how your doctor tells you to.
• Keep taking EVISTA for as long as your doctor prescribes it for you. It is not known how long you should keep taking EVISTA to lower your chance of getting invasive breast cancers.
• It is important to get your refills on time so you do not run out of the medicine.
• Take one EVISTA tablet each day.
• Take EVISTA at any time of the day, with or without food.
• To help you remember to take EVISTA, it may be best to take it at about the same time each day.
• Calcium and vitamin D may be taken at the same time as EVISTA. It is important to take calcium and vitamin D, as directed by your physician, to prevent or treat osteoporosis.
• If you miss a dose, take it as soon as you remember. However, if it is almost time for your next dose, skip the missed dose and take only your next regularly scheduled dose. Do not take two doses at the same time.

What should I avoid while taking EVISTA?

• Being still for a long time (such as during long trips or being in bed after surgery) can increase the risk of blood clots. EVISTA may add to this risk. If you will need to be still for a long time, talk with your doctor about ways to reduce the risk of blood clots. On long trips, move around periodically. Stop taking EVISTA at least 3 days before a planned surgery or before you plan on being still for a long time. You should start taking EVISTA again when you return to your normal activities.
• Some medicines should not be taken with EVISTA (see “What should I tell my doctor before taking EVISTA?”).

What are the possible side effects of EVISTA?

Serious and life-threatening side effects can occur while taking EVISTA. These include blood clots and dying from stroke:

• Increased risk of blood clots in the legs (deep vein thrombosis) and lungs (pulmonary embolism) have been reported with EVISTA. Women who have or have had blood clots in the legs, lungs, or eyes should not take EVISTA.
• Women who have had a heart attack or are at risk for a heart attack may have an increased risk of dying from stroke when taking EVISTA.

See “What is the most important information I should know about EVISTA?”

The most common side effects of EVISTA are hot flashes, leg cramps, swelling of the feet, ankles, and legs, flu syndrome, joint pain, and sweating. Hot flashes are more common during the first 6 months after starting treatment.

These are not all the side effects of EVISTA. Tell your doctor about any side effect that bothers you or that does not go away. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What else should I know about EVISTA?

• Do not use EVISTA to prevent heart disease, heart attack, or strokes.
• To get the calcium and vitamin D you need, your doctor may advise you to change your diet and/or take supplemental calcium and vitamin D. Your doctor may suggest other ways to help treat or prevent osteoporosis, in addition to taking EVISTA and getting the calcium and vitamin D you need. These may include regular exercise, stopping smoking, and drinking less alcohol.
• Women who have hot flashes can take EVISTA. EVISTA does not treat hot flashes, and it may cause hot flashes in some women. (See “What are the possible side effects of EVISTA?”)
• EVISTA has not been found to cause breast tenderness or enlargement. If you notice any changes in your breasts, call your doctor to find out the cause. Before starting and while taking EVISTA you should have breast exams and mammograms, as directed by your doctor. Because EVISTA does not eliminate the chance of developing breast cancers, you need these examinations to find any breast cancers as early as possible.
• EVISTA should not cause spotting or menstrual-type bleeding. If you have any vaginal bleeding, call your doctor to find out the cause. EVISTA has not been found to increase the risk for cancer of the lining of the uterus.
• Women in clinical trials have taken EVISTA for up to eight years.

How should I store EVISTA?

• Store EVISTA at 68°F to 77°F (20°C-25°C).
• Keep EVISTA and all medicines out of the reach of children.

General Information about the safe and effective use of EVISTA

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use EVISTA for a condition for which it was not prescribed. Do not give your EVISTA to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide is a summary of the most important information about EVISTA. If you would like more information about EVISTA, talk with your doctor. You can ask your doctor or pharmacist for information about EVISTA that is written for health professionals. For more information, call 1-800-545-5979 (toll-free).

What are the ingredients in EVISTA?

Active Ingredient: raloxifene hydrochloride

Inactive Ingredients: anhydrous lactose, carnauba wax, crospovidone, FD&C Blue No. 2 aluminum lake, hypromellose, lactose monohydrate, magnesium stearate, modified pharmaceutical glaze, polyethylene glycol, polysorbate 80, povidone, propylene glycol, and titanium dioxide.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

*The brands listed are trademarks of their respective owners and are not trademarks of Eli Lilly and Company. The makers of these brands are not affiliated with and do not endorse Eli Lilly and Company or its products.

Medication Guide revised August 1, 2014

Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA

Copyright © 1997, 2014, Eli Lilly and Company. All rights reserved.

EVS-0001-MG-20140801

None

PACKAGE LABEL – Evista 60mg 30ct Bottle (0002-4184)

NDC 0002-4184-30

30 Tablets

No. 4165

EVISTA^®

raloxifene HCl tablets 60mg

Rx only

4165

Lilly

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 [see Clinical Pharmacology (12.3)].

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 [<0.01%] 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/m²) or in monkeys at 1000 mg/kg (80 times the AUC in humans).

EVISTA is contraindicated for use in pregnancy, as it may cause fetal harm [see Use in Specific Populations (8.1)].

EVISTA (raloxifene hydrochloride) is an estrogen agonist/antagonist, commonly referred to as a selective estrogen receptor modulator (SERM) that belongs to the benzothiophene class of compounds. The chemical structure is:

The chemical designation is methanone, [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl]-[4-[2-(1-piperidinyl)ethoxy]phenyl]-, hydrochloride. Raloxifene hydrochloride (HCl) has the empirical formula C₂₈H₂₇NO₄S•HCl, which corresponds to a molecular weight of 510.05. Raloxifene HCl is an off-white to pale-yellow solid that is very slightly soluble in water.

EVISTA is supplied in a tablet dosage form for oral administration. Each EVISTA tablet contains 60 mg of raloxifene HCl, which is the molar equivalent of 55.71 mg of free base. Inactive ingredients include anhydrous lactose, carnauba wax, crospovidone, FD&C Blue No. 2 aluminum lake, hypromellose, lactose monohydrate, magnesium stearate, modified pharmaceutical glaze, polyethylene glycol, polysorbate 80, povidone, propylene glycol, and titanium dioxide.

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.

EVISTA 60 mg tablets are white, elliptical, film coated (not scored) and imprinted with 4165 on one side in edible blue ink. They are available as follows:

Safety and effectiveness in pediatric patients have not been established.

Of the total number of patients in placebo-controlled clinical studies of EVISTA, 61% were 65 and over, while 15.5% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Based on clinical trials, there is no need for dose adjustment for geriatric patients [see Clinical Pharmacology (12.3)].

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 [see Clinical Pharmacology (12.3)].

• Active or past history of venous thromboembolism, including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis. (4.1)
• Pregnancy. (4.2, 8.1)

Adverse reactions (>2% and more common than with placebo) include: hot flashes, leg cramps, peripheral edema, flu syndrome, arthralgia, sweating. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-545-5979 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

• Cholestyramine: Use with EVISTA is not recommended. Reduces the absorption and enterohepatic cycling of raloxifene. (7.1, 12.3)
• Warfarin: Monitor prothrombin time when starting or stopping EVISTA. (7.2, 12.3)
• Highly Protein-Bound Drugs: Use with EVISTA with caution. Highly protein-bound drugs include diazepam, diazoxide, and lidocaine. EVISTA is more than 95% bound to plasma proteins. (7.3, 12.3)

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)].

EVISTA should be used with caution in patients with moderate or severe renal impairment [see Warnings and Precautions (5.8) and Clinical Pharmacology (12.3)].

Decreases in estrogen levels after oophorectomy or menopause lead to increases in bone resorption and accelerated bone loss. Bone is initially lost rapidly because the compensatory increase in bone formation is inadequate to offset resorptive losses. In addition to loss of estrogen, this imbalance between resorption and formation may be due to age-related impairment of osteoblasts or their precursors. In some women, these changes will eventually lead to decreased bone mass, osteoporosis, and increased risk for fractures, particularly of the spine, hip, and wrist. Vertebral fractures are the most common type of osteoporotic fracture in postmenopausal women.

In both the osteoporosis treatment and prevention trials, EVISTA therapy resulted in consistent, statistically significant suppression of bone resorption and bone formation, as reflected by changes in serum and urine markers of bone turnover (e.g., bone-specific alkaline phosphatase, osteocalcin, and collagen breakdown products). The suppression of bone turnover markers was evident by 3 months and persisted throughout the 36-month and 24-month observation periods.

In a 31-week, open-label, radiocalcium kinetics study, 33 early postmenopausal women were randomized to treatment with once-daily EVISTA 60 mg, cyclic estrogen/progestin (0.625 mg conjugated estrogens daily with 5 mg medroxyprogesterone acetate daily for the first 2 weeks of each month [hormone therapy]), or no treatment. Treatment with either EVISTA or hormone therapy was associated with reduced bone resorption and a positive shift in calcium balance (-82 mg Ca/day and +60 mg Ca/day, respectively, for EVISTA and -162 mg Ca/day and +91 mg Ca/day, respectively, for hormone therapy).

There were small decreases in serum total calcium, inorganic phosphate, total protein, and albumin, which were generally of lesser magnitude than decreases observed during estrogen or hormone therapy. Platelet count was also decreased slightly and was not different from estrogen therapy.

The disposition of raloxifene has been evaluated in more than 3000 postmenopausal women in selected raloxifene osteoporosis treatment and prevention clinical trials, using a population approach. Pharmacokinetic data also were obtained in conventional pharmacology studies in 292 postmenopausal women. Raloxifene exhibits high within-subject variability (approximately 30% coefficient of variation) of most pharmacokinetic parameters. Table 3 summarizes the pharmacokinetic parameters of raloxifene.

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. Additionally, there is concern regarding inadvertent drug exposure in pregnancy in women of reproductive potential who become pregnant, due to risk of fetal harm [see Use in Specific Populations (8.1)].

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 [see Clinical Pharmacology (12.3)].

For the indications in risk of invasive breast cancer the optimum duration of treatment is not known [see Clinical Studies (14.3, 14.4)].

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)].

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

EVISTA should be used with caution in patients with hepatic impairment [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)].

EVISTA^® is an estrogen agonist/antagonist indicated for:

• Treatment and prevention of osteoporosis in postmenopausal women. (1.1)
• Reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis. (1.2)
• Reduction in risk of invasive breast cancer in postmenopausal women at high risk for invasive breast cancer. (1.3)

Important Limitations: EVISTA is not indicated for the treatment of invasive breast cancer, reduction of the risk of recurrence of breast cancer, or reduction of risk of noninvasive breast cancer. (1.3)

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 (14.5)].

Raloxifene is an estrogen agonist/antagonist, commonly referred to as a selective estrogen receptor modulator (SERM). The biological actions of raloxifene are largely mediated through binding to estrogen receptors. This binding results in activation of estrogenic pathways in some tissues (agonism) and blockade of estrogenic pathways in others (antagonism). The agonistic or antagonistic action of raloxifene depends on the extent of recruitment of coactivators and corepressors to estrogen receptor (ER) target gene promoters.

Raloxifene appears to act as an estrogen agonist in bone. It decreases bone resorption and bone turnover, increases bone mineral density (BMD) and decreases fracture incidence. Preclinical data demonstrate that raloxifene is an estrogen antagonist in uterine and breast tissues. These results are consistent with findings in clinical trials, which suggest that EVISTA lacks estrogen-like effects on the uterus and breast tissue.

Store at controlled room temperature, 20° to 25°C (68° to 77°F) [see USP]. The USP defines controlled room temperature as a temperature maintained thermostatically that encompasses the usual and customary working environment of 20° to 25°C (68° to 77°F); that results in a mean kinetic temperature calculated to be not more than 25°C; and that allows for excursions between 15° and 30°C (59° and 86°F) that are experienced in pharmacies, hospitals, and warehouses.

Any unexplained breast abnormality occurring during EVISTA therapy should be investigated. EVISTA does not eliminate the risk of breast cancer [see Clinical Studies (14.4)].

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 (5.1)].

• Venous Thromboembolism: Increased risk of deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis. Discontinue use 72 hours prior to and during prolonged immobilization. (5.1, 6.1)
• Death Due to Stroke: Increased risk of death due to stroke occurred in a trial in postmenopausal women with documented coronary heart disease or at increased risk for major coronary events. No increased risk of stroke was seen in this trial. Consider risk-benefit balance in women at risk for stroke. (5.2, 14.5)
• Cardiovascular Disease: EVISTA should not be used for the primary or secondary prevention of cardiovascular disease. (5.3, 14.5)
• Premenopausal Women: Use is not recommended. (5.4)
• Hepatic Impairment: Use with caution. (5.5)
• Concomitant Use with Systemic Estrogens: Not recommended. (5.6)
• Hypertriglyceridemia: If previous treatment with estrogen resulted in hypertriglyceridemia, monitor serum triglycerides. (5.7)

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 than with placebo. 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) and Adverse Reactions (6.1)].

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 (14.5)].

EVISTA should be discontinued at least 72 hours prior to and during prolonged immobilization (e.g., post-surgical recovery, prolonged bed rest), and patients should be advised to avoid prolonged restrictions of movement during travel because of the increased risk of venous thromboembolic events [see Warnings and Precautions (5.1)].

EVISTA may increase the incidence of hot flashes and is not effective in reducing hot flashes or flushes associated with estrogen deficiency. In some asymptomatic patients, hot flashes may occur upon beginning EVISTA therapy.

60 mg tablet orally once daily. (2.1)

60 mg, white, elliptical, film-coated tablets (not scored) imprinted with 4165 on one side in edible blue ink.

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

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).

• Pediatric Use: Safety and effectiveness not established. (8.4)

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.

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

See FDA-approved Medication Guide.

Physicians should instruct their patients to read the Medication Guide before starting therapy with EVISTA and to reread it each time the prescription is renewed.

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)].

EVISTA can be concomitantly administered with ampicillin, amoxicillin, antacids, corticosteroids, and digoxin [see Clinical Pharmacology (12.3)].

The concomitant use of EVISTA and lipid-lowering agents has not been studied.

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 [see Clinical Pharmacology (12.3)].

In a randomized, placebo-controlled, double-blind, multinational clinical trial (RUTH) of 10,101 postmenopausal women with documented coronary heart disease or at increased risk for coronary events, no cardiovascular benefit was demonstrated after treatment with EVISTA 60 mg once daily for a median follow-up of 5.6 years. No significant increase or decrease was observed for coronary events (death from coronary causes, nonfatal myocardial infarction, or hospitalization for an acute coronary syndrome). An increased risk of death due to stroke after treatment with EVISTA was observed: 59 (1.2%) EVISTA-treated women died due to a stroke compared to 39 (0.8%) placebo-treated women (2.2 versus 1.5 per 1000 women-years; hazard ratio 1.49; 95% confidence interval, 1.00-2.24; p=0.0499). The incidence of stroke did not differ significantly between treatment groups (249 with EVISTA [4.9%] versus 224 with placebo [4.4%]; hazard ratio 1.10; 95% confidence interval 0.92-1.32; p=0.30; 9.5 versus 8.6 per 1000 women-years) [see Warnings and Precautions (5.2, 5.3)].

The skeletal effects of raloxifene treatment were assessed in ovariectomized rats and monkeys. In rats, raloxifene prevented increased bone resorption and bone loss after ovariectomy. There were positive effects of raloxifene on bone strength, but the effects varied with time. Cynomolgus monkeys were treated with raloxifene or conjugated estrogens for 2 years. In terms of bone cycles, this is equivalent to approximately 6 years in humans. Raloxifene and estrogen suppressed bone turnover and increased BMD in the lumbar spine and in the central cancellous bone of the proximal tibia. In this animal model, there was a positive correlation between vertebral compressive breaking force and BMD of the lumbar spine.

Histologic examination of bone from rats and monkeys treated with raloxifene showed no evidence of woven bone, marrow fibrosis, or mineralization defects.

These results are consistent with data from human studies of radiocalcium kinetics and markers of bone metabolism, and are consistent with the action of EVISTA as a skeletal antiresorptive agent.

The effects of EVISTA on BMD in postmenopausal women were examined in three randomized, placebo-controlled, double-blind osteoporosis prevention trials: (1) a North American trial enrolled 544 women; (2) a European trial, 601 women; and (3) an international trial, 619 women who had undergone hysterectomy. In these trials, all women received calcium supplementation (400 to 600 mg/day). Women enrolled in these trials had a median age of 54 years and a median time since menopause of 5 years (less than 1 year up to 15 years postmenopause). The majority of the women were White (93.5%). Women were included if they had spine BMD between 2.5 standard deviations below and 2 standard deviations above the mean value for healthy young women. The mean T scores (number of standard deviations above or below the mean in healthy young women) for the three trials ranged from -1.01 to -0.74 for spine BMD and included women both with normal and low BMD. EVISTA, 60 mg administered once daily, produced increases in bone mass versus calcium supplementation alone, as reflected by dual-energy x-ray absorptiometric (DXA) measurements of hip, spine, and total body BMD.

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.

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.

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

• Increased risk of deep vein thrombosis and pulmonary embolism have been reported with EVISTA [see Warnings and Precautions (5.1)] . Women with active or past history of venous thromboembolism should not take EVISTA [see Contraindications (4.1)].
• Increased risk of death due to stroke occurred in a trial in postmenopausal women with documented coronary heart disease or at increased risk for major coronary events. Consider risk-benefit balance in women at risk for stroke [see Warnings and Precautions (5.2) and Clinical Studies (14.5)].

For osteoporosis treatment or prevention, patients should be instructed to take supplemental calcium and/or vitamin D if intake is inadequate. Patients at increased risk for vitamin D insufficiency (e.g., over the age of 70 years, nursing home bound, chronically ill, or with gastrointestinal malabsorption syndromes) should be instructed to take additional vitamin D if needed. Weight-bearing exercises should be considered along with the modification of certain behavioral factors, such as cigarette smoking and/or excessive alcohol consumption, if these factors exist.

EVISTA is indicated for the reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis [see Clinical Studies (14.3)].

EVISTA is indicated for the reduction in risk of invasive breast cancer in postmenopausal women at high risk of invasive breast cancer [see Clinical Studies (14.4)].

The effect in the reduction in the incidence of breast cancer was shown in a study of postmenopausal women at high risk for breast cancer with a 5-year planned duration with a median follow-up of 4.3 years [see Clinical Studies (14.4)]. Twenty-seven percent of the participants received drug for 5 years. The long-term effects and the recommended length of treatment are not known.

High risk of breast cancer is defined as at least one breast biopsy showing lobular carcinoma in situ (LCIS) or atypical hyperplasia, one or more first-degree relatives with breast cancer, or a 5-year predicted risk of breast cancer ≥1.66% (based on the modified Gail model). Among the factors included in the modified Gail model are the following: current age, number of first-degree relatives with breast cancer, number of breast biopsies, age at menarche, nulliparity or age of first live birth. Healthcare professionals can obtain a Gail Model Risk Assessment Tool by dialing 1-800-545-5979. Currently, no single clinical finding or test result can quantify risk of breast cancer with certainty.

After an assessment of the risk of developing breast cancer, the decision regarding therapy with EVISTA should be based upon an individual assessment of the benefits and risks.

EVISTA does not eliminate the risk of breast cancer. Patients should have breast exams and mammograms before starting EVISTA and should continue regular breast exams and mammograms in keeping with good medical practice after beginning treatment with EVISTA.

Use of EVISTA is associated with the reduction of the risk of invasive breast cancer in postmenopausal women. EVISTA has not been shown to reduce the risk of noninvasive breast cancer. When considering treatment, physicians need to discuss the potential benefits and risks of EVISTA treatment with the patient.

EVISTA is not indicated for the treatment of invasive breast cancer or reduction of the risk of recurrence.

Patients should have breast exams and mammograms before starting EVISTA and should continue regular breast exams and mammograms in keeping with good medical practice after beginning treatment with EVISTA.