IBANDRONATE SODIUM (Page 6 of 8)

Carcinogenesis

In a 104-week carcinogenicity study, doses of 3, 7, or 15 mg/kg/day were administered by oral gavage to Wistar rats (systemic exposures in males and females up to 3 and 1 times, respectively, human exposure). There were no significant drug-related tumor findings in male or female rats. In a 78-week carcinogenicity study, doses of 5, 20, or 40 mg/kg/day were administered by oral gavage to NMRI mice (exposures in males and females up to 96 and 14 times, respectively, human exposure). There were no significant drug-related tumor findings in male or female mice. In a 90-week carcinogenicity study, doses of 5, 20, or 80 mg/kg/day were administered in the drinking water to NMRI mice. A dose-related increased incidence of adrenal subcapsular adenoma/carcinoma was observed in female mice, which was statistically significant at 80 mg/kg/day (32 to 51 times human exposure). The relevance of these findings to humans is unknown.

Exposure multiples comparing human and rodent doses were calculated using human exposure at the recommended intravenous dose of 3 mg ibandronate every 3 months, based on cumulative AUC comparison.

Mutagenesis

There was no evidence for a mutagenic or clastogenic potential of ibandronate in the following assays: in vitro bacterial mutagenesis assay in Salmonella typhimurium and Escherichia coli (Ames test), mammalian cell mutagenesis assay in Chinese hamster V79 cells, and chromosomal aberration test in human peripheral lymphocytes, each with and without metabolic activation. Ibandronate was not genotoxic in the in vivo mouse micronucleus tests for chromosomal damage.

Impairment of Fertility

In female rats treated from 14 days prior to mating through gestation, decreases in fertility, corpora lutea and implantation sites, and increased preimplantation loss were observed at an intravenous dose of 1.2 mg/kg/day (117 times human exposure). In male rats treated for 28 days prior to mating, a decrease in sperm production and altered sperm morphology were observed at intravenous doses greater than or equal to 0.3 mg/kg/day (greater than or equal to 40 times human exposure).

Exposure multiples comparing human and rat doses were calculated using human exposure at the recommended intravenous dose of 3 mg ibandronate every 3 months, based on cumulative AUC comparison.

13.2 Animal Pharmacology

Animal studies have shown that ibandronate is an inhibitor of osteoclast-mediated bone resorption. In the Schenk assay in growing rats, ibandronate inhibited bone resorption and increased bone volume, based on histologic examination of the tibial metaphyses. There was no evidence of impaired mineralization at the highest dose of 5 mg/kg/day (subcutaneously), which is 1000 times the lowest antiresorptive dose of 0.005 mg/kg/day in this model, and 5000 times the optimal antiresorptive dose of 0.001 mg/kg/day in the aged ovariectomized rat. This indicates that ibandronate sodium injection administered at a therapeutic dose is unlikely to induce osteomalacia.

Long-term daily or intermittent administration of ibandronate to ovariectomized rats or monkeys was associated with suppression of bone turnover and increases in bone mass. Vertebral BMD, trabecular density, and biomechanical strength were increased dose-dependently in rats and monkeys, at doses up to 8 to 4 times the human intravenous dose of 3 mg ibandronate every 3 months, based on cumulative dose normalized for body surface area (mg/m ² ) and area under the curve (AUC) comparison, respectively. Ibandronate maintained the positive correlation between bone mass and strength at the ulna and femoral neck. New bone formed in the presence of ibandronate had normal histologic structure and did not show mineralization defects.

14 CLINICAL STUDIES

14.1 Treatment of Postmenopausal Osteoporosis

Quarterly Intravenous Injection

The effectiveness and safety of ibandronate sodium injection 3 mg (ibandronate) once every 3 months were demonstrated in a randomized, double-blind, multinational, noninferiority study in 1358 women with postmenopausal osteoporosis (L2-L4 lumbar spine BMD, T-score below -2.5 SD at baseline). The control group received ibandronate sodium 2.5 mg (ibandronate) daily oral tablets. The primary efficacy parameter was the relative change from baseline to 1 year of treatment in lumbar spine BMD, which was compared between the intravenous injection and the daily oral treatment groups. All patients received 400 international units vitamin D and 500 mg calcium supplementation per day.

Effect on BMD

In the intent-to-treat (ITT) efficacy analysis, the least-squares mean increase at 1 year in lumbar spine BMD in patients (n=429) treated with ibandronate sodium injection 3 mg (ibandronate) once every 3 months (4.5%) was statistically superior to that in patients (n=434) treated with daily oral tablets (3.5%). The mean difference between groups was 1.1% (95% confidence interval: 0.5%, 1.6%; p<0.001; see Figure 1 ). The mean increase from baseline in total hip BMD at 1 year was 2.1% in the ibandronate sodium injection 3 mg (ibandronate) once every 3 months group and 1.5% in the ibandronate sodium 2.5 mg (ibandronate) daily oral tablet group. Consistently higher BMD increases at the femoral neck and trochanter were also observed following ibandronate sodium injection 3 mg (ibandronate) once every 3 months compared to ibandronate sodium 2.5 mg (ibandronate) daily oral tablet.

Figure 1 Mean Percent Change (95% Confidence Interval) from Baseline in Lumbar Spine BMD at One Year in Patients Treated with Ibandronate Sodium 2.5 mg (ibandronate) Daily Oral Tablet or Ibandronate Sodium injection 3 mg (ibandronate) Once Every 3 Months

Bone Histology

The histological analysis of bone biopsies after 22 months of treatment with 3 mg intravenous ibandronate every 3 months (n=30) or 23 months of treatment with 2 mg intravenous ibandronate every 2 months (n=27) in women with postmenopausal osteoporosis showed bone of normal quality and no indication of a mineralization defect.

Daily Oral Tablets

The effectiveness and safety of ibandronate sodium daily oral tablets were demonstrated in a randomized, double-blind, placebo-controlled, multinational study (Treatment Study) of 2946 women aged 55 to 80 years, who were on average 21 years postmenopause, who had a lumbar spine BMD 2 to 5 SD below the premenopausal mean (T-score) in at least one vertebra [L1-L4], and who had one to four prevalent vertebral fractures. Ibandronate Sodium was evaluated at oral doses of 2.5 mg ibandronate daily and 20 mg ibandronate intermittently. The main outcome measure was the occurrence of new radiographically diagnosed, vertebral fractures after 3 years of treatment. The diagnosis of an incident vertebral fracture was based on both qualitative diagnosis by the radiologist and quantitative morphometric criterion. The morphometric criterion required the dual occurrence of two events: a relative height ratio or relative height reduction in a vertebral body of at least 20%, together with at least a 4 mm absolute decrease in height. All women received 400 international units vitamin D and 500 mg calcium supplementation per day.

Effect on Vertebral Fracture

Ibandronate Sodium 2.5 mg (ibandronate) daily oral tablet significantly reduced the incidence of new vertebral fractures compared to placebo. Over the course of the 3-year study, the risk for new vertebral fracture was 9.6% in the placebo-treated women and 4.7% in the women treated with Ibandronate Sodium 2.5 mg (ibandronate) daily oral tablet (p<0.001) (see Table 3 ).

Table 3 Effect of Ibandronate Sodium Daily Oral Tablet on the Incidence of Vertebral Fracture in the 3-Year Osteoporosis Treatment Study

	Proportion of Patients with Fracture (%)
	Placebo n=975	Ibandronate Sodium 2.5 mg (ibandronate) Daily n=977	Absolute Risk Reduction (%) 95% CI	Relative Risk Reduction (%) 95% CI
* p=0.0003 vs. placebo † “Worsening vertebral fracture” defined as a new fracture in a vertebral body with a prevalent fracture
New Vertebral Fracture	9.6	4.7	4.9	52 *
0-3 Year			(2.3, 7.4)	(29, 68)
New and Worsening Vertebral Fracture †	10.4	5.1	5.3	52
0-3 Year			(2.6, 7.9)	(30, 67)
Clinical (Symptomatic) Vertebral Fracture	5.3	2.8	2.5	49
0-3 Year			(0.6, 4.5)	(14, 69)