RALOXIFENE: 4,185 Adverse Event Reports & Safety Profile

Raloxifene hydrochloride, USP 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, USP has the empirical formula C 28 H 27 NO 4 S•HCl, which corresponds to a molecular weight of 510.05 g/mol. Raloxifene hydrochloride, USP is almost white or pale-yellow powder that is freely soluble in dimethyl sulfoxide, slightly soluble in methanol, very slightly soluble in ethanol and practically insoluble in water, isopropanol and octanol. Raloxifene hydrochloride, USP is supplied in a tablet dosage form for oral administration.

Each Raloxifene Hydrochloride

Tablet USP contains 60 mg of raloxifene hydrochloride, USP which is the molar equivalent of 55.71 mg of free base. Inactive ingredients include colloidal silicon dioxide, crospovidone, hypromellose, lactose anhydrous, lactose monohydrate, magnesium stearate, microcrystalline cellulose, poloxamer, polyethylene glycol 4000, talc, and titanium dioxide. Meets USP dissolution test 3. raloxifene hydrochloride USP chemical structure

AND USAGE Raloxifene hydrochloride tablets are 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: Raloxifene hydrochloride tablets are 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 )

1.1 Treatment and Prevention of Osteoporosis in Postmenopausal Women Raloxifene hydrochloride tablets are indicated for the treatment and prevention of osteoporosis in postmenopausal women <span class="opacity-50 text-xs">[see Clinical Studies ( 14.1 , 14.2 )]</span>.

1.2 Reduction in the Risk of Invasive Breast Cancer in Postmenopausal Women with Osteoporosis Raloxifene hydrochloride tablets are indicated for the reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis <span class="opacity-50 text-xs">[see Clinical Studies ( 14.3 )]</span>.

1.3 Reduction in the Risk of Invasive Breast Cancer in Postmenopausal Women at High Risk of Invasive Breast Cancer Raloxifene hydrochloride tablets are indicated for the reduction in risk of invasive breast cancer in postmenopausal women at high risk of invasive breast cancer <span class="opacity-50 text-xs">[see Clinical Studies ( 14.4 )]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Studies ( 14.4 )]</span>. 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 raloxifene hydrochloride tablets should be based upon an individual assessment of the benefits and risks. Raloxifene hydrochloride tablets does not eliminate the risk of breast cancer. Patients should have breast exams and mammograms before starting raloxifene hydrochloride tablets and should continue regular breast exams and mammograms in keeping with good medical practice after beginning treatment with raloxifene hydrochloride tablets.

Important

Limitations of Use for Breast Cancer Risk Reduction

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

AND ADMINISTRATION 60 mg tablet orally once daily. ( 2.1 )

2.1 Recommended Dosing The recommended dosage is one 60 mg EVISTA (raloxifene hydrochloride tablets) tablet daily, which may be administered any time of day without regard to meals <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . For the indications in risk of invasive breast cancer the optimum duration of treatment is not known <span class="opacity-50 text-xs">[see Clinical Studies ( 14.3 , 14.4 )]</span> .

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

Active or past history of venous thromboembolism, including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis. ( 4.1 ) Pregnancy, women who may become pregnant, and nursing mothers. ( 4.2 , 8.1 , 8.3 )

4.1 Venous Thromboembolism Raloxifene hydrochloride tablets, USP is contraindicated in women with active or past history of venous thromboembolism (VTE), including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span> .

4.2 Pregnancy, Women Who May Become Pregnant, and Nursing Mothers Raloxifene hydrochloride tablets, USP is contraindicated in pregnancy, in women who may become pregnant, and in nursing mothers <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.3 )]</span> . Raloxifene hydrochloride tablets, USP may cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. In rabbit studies, abortion and a low rate of fetal heart anomalies (ventricular septal defects) occurred in rabbits at doses ≥0.1 mg/kg (≥0.04 times the human dose based on surface area, mg/m 2 ), and hydrocephaly was observed in fetuses at doses ≥10 mg/kg (≥4 times the human dose based on surface area, mg/m 2 ). In rat studies, retardation of fetal development and developmental abnormalities (wavy ribs, kidney cavitation) occurred at doses ≥1 mg/kg (≥0.2 times the human dose based on surface area, mg/m 2 ). Treatment of rats at doses of 0.1 to 10 mg/kg (0.02 to 1.6 times the human dose based on surface area, mg/m 2 ) during gestation and lactation produced effects that included delayed and disrupted parturition; decreased neonatal survival and altered physical development; sex - and age- specific reductions in growth and changes in pituitary hormone content; and decreased lymphoid compartment size in offspring.

At

10 mg/kg, raloxifene disrupted parturition, which resulted in maternal and progeny death and morbidity. Effects in adult offspring (4 months of age) included uterine hypoplasia and reduced fertility; however, no ovarian or vaginal pathology was observed.

REACTIONS 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 Cadila Pharmaceuticals Limited at 1-202-355-9785 (Fax 1-202-355-9784), or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to raloxifene hydrochloride tablets in 8,429 patients who were enrolled in placebo-controlled trials, including 6,666 exposed for 1 year and 5,685 for at least 3 years.

Osteoporosis Treatment Clinical

Trial (MORE) — The safety of raloxifene in the treatment of osteoporosis was assessed in a large (7,705 patients) multinational, placebo-controlled trial. Duration of treatment was 36 months, and 5,129 postmenopausal women were exposed to raloxifene hydrochloride (2,557 received 60 mg/day, and 2,572 received 120 mg/day). The incidence of all-cause mortality was similar among groups: 23 (0.9%) placebo, 13 (0.5%) raloxifene hydrochloride tablets-treated (raloxifene HCl 60 mg), and 28 (1.1%) raloxifene HCl 120 mg women died. Therapy was discontinued due to an adverse reaction in 10.9% of raloxifene hydrochloride tablets-treated women and 8.8% of placebo-treated women.

Venous

Thromboembolism : The most serious adverse reaction related to raloxifene hydrochloride tablets was VTE (deep venous thrombosis, pulmonary embolism, and retinal vein thrombosis). During an average of study-drug exposure of 2.6 years, VTE occurred in about 1 out of 100 patients treated with raloxifene hydrochloride tablets. Twenty-six raloxifene hydrochloride tablets-treated women had a VTE compared to 11 placebo-treated women, the hazard ratio was 2.4 (95% confidence interval, 1.2, 4.5), and the highest VTE risk was during the initial months of treatment. Common adverse reactions considered to be related to raloxifene hydrochloride tablets therapy were hot flashes and leg cramps. Hot flashes occurred in about one in 10 patients on raloxifene hydrochloride tablets and were most commonly reported during the first 6 months of treatment and were not different from placebo thereafter. Leg cramps occurred in about one in 14 patients on raloxifene hydrochloride tablets. Placebo-Controlled Osteoporosis Prevention Clinical Trials — The safety of raloxifene has been assessed primarily in 12 Phase 2 and Phase 3 studies with placebo, estrogen, and estrogen-progestin therapy control groups. The duration of treatment ranged from 2 to 30 months, and 2,036 women were exposed to raloxifene HCl (371 patients received 10 to 50 mg/day, 828 received 60 mg/day, and 837 received from 120 to 600 mg/day). Therapy was discontinued due to an adverse reaction in 11.4% of 581 raloxifene hydrochloride tablets-treated women and 12.2% of 584 placebo-treated women. Discontinuation rates due to hot flashes did not differ significantly between raloxifene hydrochloride tablets and placebo groups (1.7% and 2.2%, respectively). Common adverse reactions considered to be drug-related were hot flashes and leg cramps. Hot flashes occurred in about one in four patients on raloxifene hydrochloride tablets versus about one in six on placebo. The first occurrence of hot flashes was most commonly reported during the first 6 months of treatment.

Table

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

Table

1: Adverse Reactions Occurring in Placebo-Controlled Osteoporosis Clinical Trials at a Frequency ≥2.0% and in More Raloxifene Hydrochloride-Treated (60 mg Once Daily) Women than Placebo- Treated Women a a A: Placebo incidence greater than or equal to raloxifene hydrochloride incidence; B: Less than 2% incidence and more frequent with raloxifene hydrochloride. b Includes only patients with an intact uterus: Prevention Trials: raloxifene hydrochloride, n=354 , Placebo, n=364 ; Treatment Trial: raloxifene hydrochloride, n=1,948, Placebo, n=1,999. c Actual terms most frequently referred to endometrial fluid.

Treatment Prevention Raloxifene

Hydrochloride (N=2,557) % Placebo (N=2,576) % Raloxifene Hydrochloride (N=581) % Placebo (N=584) % Body as a Whole Infection A A 15.1

14.6 Flu Syndrome 13.5 11.4 14.6

13.5 Headache 9.2 8.5 A A Leg Cramps 7.0 3.7 5.9

1.9 Chest Pain A A 4.0

3.6 Fever 3.9 3.8 3.1

2.6 Cardiovascular System Hot Flashes 9.7 6.4 24.6

18.3 Migraine A A 2.4

2.1 Syncope 2.3 2.1 B B Varicose Vein 2.2 1.5 A A Digestive System Nausea 8.3 7.8 8.8

8.6 Diarrhea 7.2 6.9 A A Dyspepsia A A 5.9

5.8 Vomiting 4.8 4.3 3.4

3.3 Flatulence A A 3.1

2.4 Gastrointestinal Disorder A A 3.3

2.1 Gastroenteritis B B 2.6

2.1 Metabolic and Nutritional Weight Gain A A 8.8

6.8 Peripheral Edema 5.2 4.4 3.3

1.9 Musculoskeletal System Arthralgia 15.5 14.0 10.7

10.1 Myalgia A A 7.7

6.2 Arthritis A A 4.0

3.6 Tendon Disorder 3.6 3.1 A A Nervous System Depression A A 6.4

6.0 Insomnia A A 5.5

4.3 Vertigo 4.1 3.7 A A Neuralgia 2.4 1.9 B B Hypesthesia 2.1 2.0 B B Respiratory System Sinusitis 7.9 7.5 10.3

6.5 Rhinitis 10.2 10.1 A A Bronchitis 9.5 8.6 A A Pharyngitis 5.3 5.1 7.6

7.2 Cough Increased 9.3 9.2 6.0

5.7 Pneumonia A A 2.6

1.5 Laryngitis B B 2.2

1.4 Skin and Appendages Rash A A 5.5

3.8 Sweating 2.5 2.0 3.1

1.7 Special Senses Conjunctivitis 2.2 1.7 A A Urogenital System Vaginitis A A 4.3

3.6 Urinary Tract Infection A A 4.0

3.9 Cystitis 4.6 4.5 3.3

3.1 Leukorrhea A A 3.3

1.7 Uterine Disorder b, c 3.3 2.3 A A Endometrial Disorder b B B 3.1

1.9 Vaginal Hemorrhage 2.5 2.4 A A Urinary Tract Disorder 2.5 2.1 A A Comparison of raloxifene hydrochloride tablets and Hormone Therapy — Raloxifene hydrochloride tablets were compared with estrogen-progestin therapy in three clinical trials for prevention of osteoporosis.

Table

2 shows adverse reactions occurring more frequently in one treatment group and at an incidence ≥2.0% in any group. Adverse reactions are shown without attribution of causality.

Table

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

Raloxifene

Hydrochloride (N=317) % Hormone Therapy- Continuous Combined b (N=96) % Hormone Therapy- Cyclic c (N=219) % Urogenital Breast Pain 4.4 37.5

29.7 Vaginal Bleeding d 6.2 64.2

88.5 Digestive Flatulence 1.6 12.5

6.4 Cardiovascular Hot Flashes 28.7 3.1

5.9 Body as a Whole Infection 11.0 0

6.8 Abdominal Pain 6.6 10.4

18.7 Chest Pain 2.8 0

0.5 Breast Pain — Across all placebo-controlled trials, raloxifene hydrochloride was indistinguishable from placebo with regard to frequency and severity of breast pain and tenderness. Raloxifene hydrochloride was associated with less breast pain and tenderness than reported by women receiving estrogens with or without added progestin.

Gynecologic

Cancers — Raloxifene hydrochloride-treated and placebo-treated groups had similar incidences of endometrial cancer and ovarian cancer. Placebo-Controlled Trial of Postmenopausal Women at Increased Risk for Major Coronary Events (RUTH) — The safety of raloxifene hydrochloride (60 mg once daily) was assessed in a placebo-controlled multinational trial of 10,101 postmenopausal women (age range 55 to 92) with documented coronary heart disease (CHD) or multiple CHD risk factors. Median study drug exposure was 5.1 years for both treatment groups [ see Clinical Studies ( 14.3 ) ]. Therapy was discontinued due to an adverse reaction in 25% of 5,044 raloxifene hydrochloride-treated women and 24% of 5,057 placebo-treated women. The incidence per year of all-cause mortality was similar between the raloxifene (2.07%) and placebo (2.25%) groups. Adverse reactions reported more frequently in raloxifene hydrochloride-treated women than in placebo-treated women included peripheral edema (14.1% raloxifene versus 11.7% placebo), muscle spasms/leg cramps (12.1% raloxifene versus 8.3% placebo), hot flashes (7.8% raloxifene versus 4.7% placebo), venous thromboembolic events (2.0% raloxifene versus 1.4% placebo), and cholelithiasis (3.3% raloxifene versus 2.6% placebo) [see Clinical Studies ( 14.3 , 14.5 )] . Tamoxifen-Controlled Trial of Postmenopausal Women at Increased Risk for Invasive Breast Cancer (STAR) — The safety of raloxifene hydrochloride tablets 60 mg/day versus tamoxifen 20 mg/day over 5 years was assessed in 19,747 postmenopausal women (age range 35 to 83 years) in a randomized, double-blind trial. As of 31 December 2005, the median follow-up was 4.3 years. The safety profile of raloxifene was similar to that in the placebo-controlled raloxifene trials [see Clinical Studies ( 14.4 )] .

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

AND PRECAUTIONS 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 : Raloxifene hydrochloride tablets 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 )

5.1 Venous Thromboembolism In clinical trials, raloxifene hydrochloride tablets-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 raloxifene hydrochloride 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, raloxifene hydrochloride tablets should be discontinued at least 72 hours prior to and during prolonged immobilization (e.g., post-surgical recovery, prolonged bed rest), and raloxifene hydrochloride tablets therapy should be resumed only after the patient is fully ambulatory. In addition, women taking raloxifene hydrochloride tablets 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 <span class="opacity-50 text-xs">[see Contraindications ( 4.1 ) and Adverse Reactions ( 6.1 )]</span> .

5.2 Death Due to Stroke In a clinical trial of postmenopausal women with documented coronary heart disease or at increased risk for coronary events, an increased risk of death due to stroke was observed after treatment with raloxifene hydrochloride tablets. During an average follow-up of 5.6 years, 59 (1.2%) raloxifene hydrochloride tablets-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 to 2.24; p=0.0499). There was no statistically significant difference between treatment groups in the incidence of stroke (249 in raloxifene hydrochloride tablets [4.9%] versus 224 placebo [4.4%]). Raloxifene hydrochloride tablets 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 <span class="opacity-50 text-xs">[see Clinical Studies ( 14.5 )]</span> .

5.3 Cardiovascular Disease Raloxifene hydrochloride tablets 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 <span class="opacity-50 text-xs">[see Clinical Studies ( 14.5 )]</span> .

5.4 Premenopausal Use There is no indication for premenopausal use of raloxifene hydrochloride tablets. Safety of raloxifene hydrochloride tablets 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 )]</span> .

5.5 Hepatic Impairment Raloxifene hydrochloride tablets should be used with caution in patients with hepatic impairment. Safety and efficacy have not been established in patients with hepatic impairment <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

5.6 Concomitant Estrogen Therapy The safety of concomitant use of raloxifene hydrochloride tablets with systemic estrogens has not been established and its use is not recommended.

5.7 History of Hypertriglyceridemia when Treated with Estrogens Limited clinical data suggest that some women with a history of marked hypertriglyceridemia (&gt;5.6 mmol/L or &gt;500 mg/dL) in response to treatment with oral estrogen or estrogen plus progestin may develop increased levels of triglycerides when treated with raloxifene hydrochloride tablets. Women with this medical history should have serum triglycerides monitored when taking raloxifene hydrochloride tablets.

5.8 Renal Impairment Raloxifene hydrochloride tablets 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

5.9 History of Breast Cancer Raloxifene hydrochloride tablets has not been adequately studied in women with a prior history of breast cancer.

5.10 Use in Men There is no indication for the use of raloxifene hydrochloride tablets in men. Raloxifene hydrochloride tablets has not been adequately studied in men and its use is not recommended.

5.11 Unexplained Uterine Bleeding Any unexplained uterine bleeding should be investigated as clinically indicated. Raloxifene hydrochloride tablets-treated and placebo-treated groups had similar incidences of endometrial proliferation <span class="opacity-50 text-xs">[see Clinical Studies ( 14.1 , 14.2 )]</span> .

5.12 Breast Abnormalities Any unexplained breast abnormality occurring during raloxifene hydrochloride tablets therapy should be investigated. Raloxifene hydrochloride tablets does not eliminate the risk of breast cancer <span class="opacity-50 text-xs">[see Clinical Studies ( 14.4 )]</span> .

INTERACTIONS

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

7.1 Cholestyramine Concomitant administration of cholestyramine with raloxifene hydrochloride is not recommended. Although not specifically studied, it is anticipated that other anion exchange resins would have a similar effect. Raloxifene hydrochloride should not be co-administered with other anion exchange resins <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

7.2 Warfarin If raloxifene hydrochloride is given concomitantly with warfarin or other warfarin derivatives, prothrombin time should be monitored more closely when starting or stopping therapy with raloxifene hydrochloride <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

7.3 Other Highly Protein-Bound Drugs Raloxifene hydrochloride should be used with caution with certain other highly protein-bound drugs such as diazepam, diazoxide, and lidocaine. Although not examined, raloxifene hydrochloride might affect the protein binding of other drugs. Raloxifene is more than 95% bound to plasma proteins <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

7.4 Systemic Estrogens The safety of concomitant use of raloxifene hydrochloride with systemic estrogens has not been established and its use is not recommended.

7.5 Other Concomitant Medications Raloxifene hydrochloride can be concomitantly administered with ampicillin, amoxicillin, antacids, corticosteroids, and digoxin <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . The concomitant use of raloxifene hydrochloride and lipid-lowering agents has not been studied.

Drug Interactions

Cholestyramine — Cholestyramine, an anion exchange resin, causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene after a single dose. Although not specifically studied, it is anticipated that other anion exchange resins would have a similar effect [see Drug Interactions ( 7.1 )] . Warfarin — In vitro , raloxifene did not interact with the binding of warfarin. The concomitant administration of raloxifene hydrochloride and warfarin, a coumarin derivative, has been assessed in a single-dose study. In this study, raloxifene had no effect on the pharmacokinetics of warfarin. However, a 10% decrease in prothrombin time was observed in the single-dose study. In the osteoporosis treatment trial, there were no clinically relevant effects of warfarin co-administration on plasma concentrations of raloxifene [see Drug Interactions ( 7.2 )] .

Other Highly

Protein-Bound Drugs — In the osteoporosis treatment trial, there were no clinically relevant effects of co-administration of other highly protein-bound drugs (e.g., gemfibrozil) on plasma concentrations of raloxifene. In vitro , raloxifene did not interact with the binding of phenytoin, tamoxifen, or warfarin ( see above) [see Drug Interactions ( 7.3 )] . Ampicillin and Amoxicillin — Peak concentrations of raloxifene and the overall extent of absorption are reduced 28% and 14%, respectively, with co-administration of ampicillin. These reductions are consistent with decreased enterohepatic cycling associated with antibiotic reduction of enteric bacteria. However, the systemic exposure and the elimination rate of raloxifene were not affected. In the osteoporosis treatment trial, co-administration of amoxicillin had no discernible differences in plasma raloxifene concentrations [see Drug Interactions ( 7.5 )] . Antacids — Concomitant administration of calcium carbonate or aluminum and magnesium hydroxide-containing antacids does not affect the systemic exposure of raloxifene [see Drug Interactions ( 7.5 )] . Corticosteroids — The chronic administration of raloxifene in postmenopausal women has no effect on the pharmacokinetics of methylprednisolone given as a single oral dose [see Drug Interactions ( 7.5 )] . Digoxin — Raloxifene has no effect on the pharmacokinetics of digoxin [see Drug Interactions ( 7.5 )] . Cyclosporine — Concomitant administration of raloxifene hydrochloride with cyclosporine has not been studied. Lipid-Lowering Agents — Concomitant administration of raloxifene hydrochloride with lipid-lowering agents has not been studied.