Raloxifeneside effects

Adverse reactions (>2% and more common than with placebo) include: hot flashes, leg cramps, peripheral edema, flu syndrome, arthralgia, sweating. To report SUSPECTED ADVERSE REACTIONS, contact Northstar Rx LLC at 1-800-206-7821 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 in 8429 patients who were enrolled in placebo-controlled trials, including 6666 exposed for 1 year and 5685 for at least 3 years. Osteoporosis Treatment Clinical Trial (MORE) — The safety of raloxifene in the treatment of osteoporosis was assessed in a large (7705 patients) multinational, placebo-controlled trial. Duration of treatment was 36 months, and 5129 postmenopausal women were exposed to raloxifene hydrochloride (2557 received 60 mg/day, and 2572 received 120 mg/day). The incidence of all-cause mortality was similar among groups: 23 (0.9%) placebo, 13 (0.5%) raloxifene hydrochloride-treated (raloxifene hydrochloride 60 mg), and 28 (1.1%) raloxifene hydrochloride 120 mg women died. Therapy was discontinued due to an adverse reaction in 10.9% of raloxifene hydrochloride-treated women and 8.8% of placebo-treated women.

Venous Thromboembolism: The most serious adverse reaction related to raloxifene hydrochloride 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. Twenty-six raloxifene hydrochloride-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 therapy were hot flashes and leg cramps. Hot flashes occurred in about one in 10 patients on raloxifene hydrochloride 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. 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 hydrochloride (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-treated women and 12.2% of 584 placebo-treated women. Discontinuation rates due to hot flashes did not differ significantly between raloxifene hydrochloride 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 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 hydrochloride-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 Hydrochloride-Treated (60 mg Once Daily) Women than Placebo-Treated Women a Treatment Prevention Raloxifene Hydrochloride (N=2557) % Placebo (N=2576) % Raloxifene Hydrochloride (N=581) % Placebo (N=584) % 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=1948, Placebo, n=1999. c Actual terms most frequently referred to endometrial fluid. 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 3.8 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 Comparison of

Raloxifene Hydrochloride and Hormone Therapy — Raloxifene hydrochloride 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 Hydrochloride (60 mg Once Daily) and Continuous Combined or Cyclic Estrogen Plus Progestin (Hormone Therapy) at an Incidence ≥2% in any Treatment Group a Raloxifene Hydrochloride (N=317) % Hormone Therapy- Continuous Combined b (N=96) % Hormone Therapy-Cyclic c (N=219) % 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. 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 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. Therapy was discontinued due to an adverse reaction in 25% of 5044 raloxifene hydrochloride-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 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% raloxifene versus 1.4% placebo), and cholelithiasis (3.3% raloxifene versus 2.6% placebo). Tamoxifen-Controlled Trial of Postmenopausal Women at Increased Risk for Invasive Breast Cancer (STAR) — The safety of raloxifene hydrochloride 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.

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).