Raloxifene Hydrochloride (Page 5 of 9)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis — In a 21-month carcinogenicity study in mice, there was an increased incidence of ovarian tumors in female animals given 9 to 242 mg/kg, which included benign and malignant tumors of granulosa/theca cell origin and benign tumors of epithelial cell origin. Systemic exposure (AUC) of raloxifene in this group was 0.3 to 34 times that in postmenopausal women administered a 60 mg dose. There was also an increased incidence of testicular interstitial cell tumors and prostatic adenomas and adenocarcinomas in male mice given 41 or 210 mg/kg (4.7 or 24 times the AUC in humans) and prostatic leiomyoblastoma in male mice given 210 mg/kg.

In a 2-year carcinogenicity study in rats, an increased incidence in ovarian tumors of granulosa/theca cell origin was observed in female rats given 279 mg/kg (approximately 400 times the AUC in humans). The female rodents in these studies were treated during their reproductive lives when their ovaries were functional and responsive to hormonal stimulation.

Mutagenesis — Raloxifene HCl was not genotoxic in any of the following test systems: the Ames test for bacterial mutagenesis with and without metabolic activation, the unscheduled DNA synthesis assay in rat hepatocytes, the mouse lymphoma assay for mammalian cell mutation, the chromosomal aberration assay in Chinese hamster ovary cells, the in vivo sister chromatid exchange assay in Chinese hamsters, and the in vivo micronucleus test in mice.

Impairment of Fertility — When male and female rats were given daily doses ≥5 mg/kg (≥0.8 times the human dose based on surface area, mg/m2) prior to and during mating, no pregnancies occurred. In male rats, daily doses up to 100 mg/kg (16 times the human dose based on surface area, mg/m2) for at least 2 weeks did not affect sperm production or quality or reproductive performance. In female rats, at doses of 0.1 to 10 mg/kg/day (0.02 to 1.6 times the human dose based on surface area, mg/m2), raloxifene disrupted estrous cycles and inhibited ovulation. These effects of raloxifene were reversible. In another study in rats in which raloxifene was given during the preimplantation period at doses ≥0.1 mg/kg (≥0.02 times the human dose based on surface area, mg/m2), raloxifene delayed and disrupted embryo implantation, resulting in prolonged gestation and reduced litter size. The reproductive and developmental effects observed in animals are consistent with the estrogen receptor activity of raloxifene.

13.2 Animal Toxicology and/or Pharmacology

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 raloxifene as a skeletal antiresorptive agent.

14 CLINICAL STUDIES

14.1 Treatment of Postmenopausal Osteoporosis

Effect on Fracture Incidence

The effects of raloxifene on fracture incidence and BMD in postmenopausal women with osteoporosis were examined at 3 years in a large randomized, placebo-controlled, double-blind, multinational osteoporosis treatment trial (MORE). All vertebral fractures were diagnosed radiographically; some of these fractures also were associated with symptoms (i.e., clinical fractures). The study population consisted of 7705 postmenopausal women with osteoporosis as defined by: a) low BMD (vertebral or hip BMD at least 2.5 standard deviations below the mean value for healthy young women) without baseline vertebral fractures or b) one or more baseline vertebral fractures. Women enrolled in this study had a median age of 67 years (range 31 to 80) and a median time since menopause of 19 years.

Effect on Bone Mineral Density

Raloxifene hydrochloride 60 mg administered once daily, increased spine and hip BMD by 2 to 3%. Raloxifene decreased the incidence of the first vertebral fracture from 4.3% for placebo to 1.9% for raloxifene (relative risk reduction = 55%) and subsequent vertebral fractures from 20.2% for placebo to 14.1% for raloxifene (relative risk reduction = 30%) (see Table 4). All women in the study received calcium (500 mg/day) and vitamin D (400 to 600 IU/day). Raloxifene reduced the incidence of vertebral fractures whether or not patients had a vertebral fracture upon study entry. The decrease in incidence of vertebral fracture was greater than could be accounted for by increase in BMD alone.

Table 4: Effect of Raloxifene on Risk of Vertebral Fractures
a Includes all patients with baseline and at least one follow-up radiograph.

Number of Patients

Absolute Risk Reduction (ARR)

Relative Risk Reduction (95% CI)

Raloxifene Hydrochloride

Placebo

Fractures diagnosed radiographically Patients with no baseline fracture a Number (%) of patients with ≥ 1 new vertebral fracture

n= 140127 (1.9%)

n= 145762 (4.3%)

2.4%

55% (29%, 71%)

Patients with ≥ 1 baseline fracturea Number (%) of patients with ≥ 1 new vertebral fracture

n=858 121 (14.1%)

n=853169 (20.2%)

6.1%

30%(14%, 44%)

Symptomatic vertebral fractures All randomized patients Number (%) of patients with ≥ 1 new clinical (painful) vertebral fracture

n=2557 47 (1.8%)

n=2576 81 (3.1%)

1.3%

41%(17%, 59%)

The mean percentage change in BMD from baseline for raloxifene hydrochloride was statistically significantly greater than for placebo at each skeletal site (see Table 5).

Table 5: Raloxifene Hydrochloride (60 mg Once Daily) Related Increases in BMDa for the Osteoporosis Treatment Study Expressed as Mean Percentage Increase vs. Placebob, c
a Note: all BMD increases were significant (p<0.001).
b Intent-to-treat analysis; last observation carried forward.
c All patients received calcium and vitamin D.
d ND = not done (total body and radius BMD were measured only at 24 months).

Time

Site

12 Months %

24 Months %

36 Months %

Lumbar Spine

2.0

2.6

2.6

Femoral Neck

1.3

1.9

2.1

Ultradistal Radius

NDd

2.2

NDd

Distal Radius

NDd

0.9

NDd

Total Body

NDd

1.1

NDd

Discontinuation from the study was required when excessive bone loss or multiple incident vertebral fractures occurred. Such discontinuation was statistically significantly more frequent in the placebo group (3.7%) than in the raloxifene group (1.1%).

Bone Histology

Bone biopsies for qualitative and quantitative histomorphometry were obtained at baseline and after 2 years of treatment. There were 56 paired biopsies evaluable for all indices. In raloxifene-treated patients, there were statistically significant decreases in bone formation rate per tissue volume, consistent with a reduction in bone turnover. Normal bone quality was maintained; specifically, there was no evidence of osteomalacia, marrow fibrosis, cellular toxicity, or woven bone after 2 years of treatment.

Effect on Endometrium

Endometrial thickness was evaluated annually in a subset of the study population (1781 patients) for 3 years. Placebo-treated women had a 0.27 mm mean decrease from baseline in endometrial thickness over 3 years, whereas the raloxifene-treated women had a 0.06 mm mean increase. Patients in the osteoporosis treatment study were not screened at baseline or excluded for pre-existing endometrial or uterine disease. This study was not specifically designed to detect endometrial polyps. Over the 36 months of the study, clinically or histologically benign endometrial polyps were reported in 17 of 1999 placebo-treated women, 37 of 1948 raloxifene-treated women, and in 31 of 2010 women treated with raloxifene HCl 120 mg/day. There was no difference between raloxifene- and placebo-treated women in the incidences of endometrial carcinoma, vaginal bleeding, or vaginal discharge.

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