Raloxifene Hydrochloride (Page 2 of 9)

5 WARNINGS AND PRECAUTIONS

5.1 Venous Thromboembolism

In clinical trials, raloxifene HCl-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 HCl 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 HCl should be discontinued at least 72 hours prior to and during prolonged immobilization (e.g., post-surgical recovery, prolonged bed rest) and raloxifene HCl therapy should be resumed only after the patient is fully ambulatory. In addition, women taking raloxifene HCl 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)] .

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 HCl. During an average follow-up of 5.6 years, 59 (1.2%) raloxifene HCl-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 to 2.24; p=0.0499). There was no statistically significant difference between treatment groups in the incidence of stroke (249 in raloxifene HCl [4.9%] versus 224 placebo [4.4%]). Raloxifene HCl 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)] .

5.3 Cardiovascular Disease

Raloxifene HCl 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)] .

5.4 Premenopausal Use

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

5.5 Hepatic Impairment

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

5.6 Concomitant Estrogen Therapy

The safety of concomitant use of raloxifene HCl 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 (>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 raloxifene HCl. Women with this medical history should have serum triglycerides monitored when taking raloxifene HCl.

5.8 Renal Impairment

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

5.9 History of Breast Cancer

Raloxifene HCl 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 HCl in men. Raloxifene HCl 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 HCl-treated and placebo-treated groups had similar incidences of endometrial proliferation [see Clinical Studies (14.1,14.2)] .

5.12 Breast Abnormalities

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

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

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

The data described below reflect exposure to raloxifene HCl in 8429 patients who were enrolled in placebo-controlled trials, including 6666 exposed for 1 year and 5685 for at least 3 years.

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

Venous Thromboembolism: The most serious adverse reaction related to raloxifene HCl 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 HCl. Twenty-six raloxifene HCl-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 HCl therapy were hot flashes and leg cramps. Hot flashes occurred in about one in 10 patients on raloxifene HCl 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 HCl.

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

Therapy was discontinued due to an adverse reaction in 11.4% of 581 raloxifene HCl-treated women and 12.2% of 584 placebo-treated women. Discontinuation rates due to hot flashes did not differ significantly between raloxifene HCl 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 HCl 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% in either group and in more raloxifene HCl-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% and in More Raloxifene HCl-Treated (60 mg Once Daily) Women than Placebo-Treated Women a
Treatment

Prevention

Raloxifene HCl N=2557 % Placebo N=2576 % Raloxifene HCl 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 3.7 5.9 1.9
Chest Pain A A 4 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 10.7 10.1
Myalgia A A 7.7 6.2
Arthritis A A 4 3.6
Tendon Disorder 3.6 3.1 A A
Nervous System
Depression A A 6.4 6
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 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 5.7
Pneumonia A A 2.6 1.5
Laryngitis B B 2.2 1.4
Skin and Appendages
Rash A A 5.5 3.7
Sweating 2.5 2 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 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
a A: Placebo incidence greater than or equal to raloxifene HCl incidence; B: Less than 2% incidence and more frequent with raloxifene HCl.
b Includes only patients with an intact uterus: Prevention Trials: Raloxifene HCl, n=354, Placebo, n=364; Treatment Trial: Raloxifene HCl, n=1948, Placebo, n=1999.
c Actual terms most frequently referred to endometrial fluid.

Comparison of Raloxifene HCl and Hormone Therapy —Raloxifene HCl was compared with estrogen-progestin therapy in three clinical trials for prevention of osteoporosis. Table 2 shows adverse reactions occurring more frequently in one treatment group and at an incidence ≥2% 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 HCl (60 mg Once Daily) and Continuous Combined or Cyclic Estrogen Plus Progestin (Hormone Therapy) at an Incidence ≥2% in any Treatment Group a
Raloxifene HCl (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 6.8
Abdominal Pain 6.6 10.4 18.7
Chest Pain 2.8 0 0.5
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 HCl, n=290; Hormone Therapy-Continuous Combined, n=67; Hormone Therapy-Cyclic, n=217.

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

Gynecologic Cancers — Raloxifene HCl-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 HCl (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 5044 raloxifene HCl-treated women and 24% of 5057 placebo-treated women. The incidence per year of all-cause mortality was similar between the raloxifene (2.07%) and placebo (2.25%) groups.

Adverse reactions reported more frequently in raloxifene HCl-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% 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 HCl 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)] .

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