Prescription Drug Information: Ibandronate Sodium (Page 4 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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 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 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 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 every 3 months, based on cumulative dose normalized for body surface area (mg/m2) 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 injection 3 mg 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 2.5 mg 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 injection 3 mg 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 injection 3 mg once every 3 months group and 1.5% in the ibandronate 2.5 mg daily oral tablet group. Consistently higher BMD increases at the femoral neck and trochanter were also observed following ibandronate injection 3 mg once every 3 months compared to ibandronate 2.5 mg 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 2.5 mg Daily Oral Tablet or Ibandronate Injection 3 mg Once Every 3 Months

Figure-1
(click image for full-size original)

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 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 was evaluated at oral doses of 2.5 mg daily and 20 mg 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 2.5 mg 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 2.5 mg daily oral tablet (p<0.001) (see Table 3).

Table 3 Effect of Ibandronate 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 2.5 mg

Daily

n=977

Absolute Risk

Reduction

(%)

95% CI

Relative Risk

Reduction

(%)

95% CI

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)

* The endpoint value is the value at the study’s last time point, 3 years, for all patients who had a fracture identified at that time; otherwise, the last postbaseline value prior to the study’s last time point is used.

** p=0.0003 vs. placebo

*** “Worsening vertebral fracture” defined as a new fracture in a vertebral body with a prevalent fracture


Effect on Nonvertebral Fractures

Ibandronate 2.5 mg daily did not reduce the incidence of nonvertebral fractures (secondary efficacy measure). There was a similar number of nonvertebral osteoporotic fractures at 3 years reported in women treated with ibandronate 2.5 mg daily oral tablet [9.1%, (95% CI: 7.1%, 11.1%)] and placebo [8.2%, (95% CI: 6.3%, 10.2%)]. The two treatment groups were also similar with regard to the number of fractures reported at the individual non-vertebral sites: pelvis, femur, wrist, forearm, rib, and hip.

Effect on BMD

Ibandronate 2.5 mg daily oral tablet significantly increased BMD at the lumbar spine and hip relative to treatment with placebo. In the 3-year osteoporosis treatment study, ibandronate 2.5 mg daily oral tablet produced increases in lumbar spine BMD that were progressive over 3 years of treatment and were statistically significant relative to placebo at 6 months and at all later time points. Lumbar spine BMD increased by 6.4% after 3 years of treatment with ibandronate 2.5 mg daily oral tablet compared with 1.4% in the placebo group (p<0.0001). Table 4 displays the significant increases in BMD seen at the lumbar spine, total hip, femoral neck, and trochanter compared to placebo.

Table 4 Mean Percent Change in BMD from Baseline to Endpoint in Patients Treated with Ibandronate 2.5 mg Daily Oral Tablet or Placebo in the 3-Year Osteoporosis Treatment Study *
*
The endpoint value is the value at the study’s last time point, 3 years, for all patients who had BMD measured at that time; otherwise the last postbaseline value prior to the study’s last time point is used.

Placebo

Ibandronate 2.5 mg

Lumbar Spine

1.4

6.4

(n=693)

(n=712)

Total Hip

-0.7

3.1

(n=638)

(n=654)

Femoral Neck

-0.7

2.6

(n=683)

(n=699)

Trochanter

0.2

5.3

(n=683)

(n=699)

Bone Histology

The effects of ibandronate 2.5 mg daily oral tablet on bone histology were evaluated in iliac crest biopsies from 16 women after 22 months of treatment and 20 women after 34 months of treatment. The histological analysis of bone biopsies showed bone of normal quality and no indication of osteomalacia or a mineralization defect.

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