Ibandronate Sodium 150 mg Tablet, Film Coated — NDC 60505-2795-0 (Billing 60505-2795-00)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action The action of ibandronate on bone tissue is based on its affinity for hydroxyapatite, which is part of the mineral matrix of bone. Ibandronate inhibits osteoclast activity and reduces bone resorption and turnover. In postmenopausal women, it reduces the elevated rate of bone turnover, leading to, on average, a net gain in bone mass.

12.2Pharmacodynamics Osteoporosis is characterized by decreased bone mass and increased fracture risk, most commonly at the spine, hip, and wrist. The diagnosis can be confirmed by a finding of low bone mass, evidence of fracture on x-ray, a history of osteoporotic fracture, or height loss or kyphosis indicative of vertebral fracture. While osteoporosis occurs in both men and women, it is most common among women following menopause.

In healthy humans, bone formation and resorption are closely linked; old bone is resorbed and replaced by newly formed bone. In postmenopausal osteoporosis, bone resorption exceeds bone formation, leading to bone loss and increased risk of fracture. After menopause, the risk of fractures of the spine and hip increases; approximately 40% of 50-year-old women will experience an osteoporosis-related fracture during their remaining lifetimes.

Ibandronate sodium tablets produced biochemical changes indicative of dose-dependent inhibition of bone resorption, including decreases of biochemical markers of bone collagen degradation (such as deoxypyridinoline, and cross-linked C-telopeptide of Type I collagen) in the daily dose range of 0.25 mg to 5 mg and once-monthly doses from 100 mg to 150 mg in postmenopausal women. Treatment with 2.5 mg daily ibandronate sodium tablets resulted in decreases in biochemical markers of bone turnover, including urinary C-terminal telopeptide of Type I collagen (uCTX) and serum osteocalcin, to levels similar to those in premenopausal women.

Changes in markers of bone formation were observed later than changes in resorption markers, as expected, due to the coupled nature of bone resorption and formation. Treatment with 2.5 mg daily ibandronate sodium tablets decreased levels of uCTX within 1 month of starting treatment and decreased levels of osteocalcin within 3 months. Bone turnover markers reached a nadir of approximately 64% below baseline values by 6 months of treatment and remained stable with continued treatment for up to 3 years.

Following treatment discontinuation, there is a return to pretreatment baseline rates of elevated bone resorption associated with postmenopausal osteoporosis. In a 1-year, study comparing once-monthly vs. once-daily oral dosing regimens, the median decrease from baseline in serum CTX values was -76% for patients treated with the 150 mg once-monthly regimen and -67% for patients treated with the 2.5 mg daily regimen. In a 1-year, prevention study comparing ibandronate sodium tablets 150 mg once-monthly to placebo, the median placebo-subtracted decrease in sCTX was -49.8%.

12.3Pharmacokinetics Absorption The absorption of oral ibandronate occurs in the upper gastrointestinal tract. Plasma concentrations increase in a dose-linear manner up to 50 mg oral intake and increases nonlinearly above this dose. Following oral dosing, the time to maximum observed plasma ibandronate concentrations ranged from 0.5 to 2 hours (median 1 hour) in fasted healthy postmenopausal women.

The mean oral bioavailability of 2.5 mg ibandronate was about 0.6% compared to intravenous dosing. The extent of absorption is impaired by food or beverages (other than plain water). The oral bioavailability of ibandronate is reduced by about 90% when ibandronate sodium tablets are administered concomitantly with a standard breakfast in comparison with bioavailability observed in fasted subjects.

There is no meaningful reduction in bioavailability when ibandronate is taken at least 60 minutes before a meal. However, both bioavailability and the effect on bone mineral density (BMD) are reduced when foo… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action The action of ibandronate on bone tissue is based on its affinity for hydroxyapatite, which is part of the mineral matrix of bone. Ibandronate inhibits osteoclast activity and reduces bone resorption and turnover. In postmenopausal women, it reduces the elevated rate of bone turnover, leading to, on average, a net gain in bone mass.

12.3Pharmacokinetics Absorption The absorption of oral ibandronate occurs in the upper gastrointestinal tract. Plasma concentrations increase in a dose-linear manner up to 50 mg oral intake and increases nonlinearly above this dose. Following oral dosing, the time to maximum observed plasma ibandronate concentrations ranged from 0.5 to 2 hours (median 1 hour) in fasted healthy postmenopausal women.

The mean oral bioavailability of 2.5 mg ibandronate was about 0.6% compared to intravenous dosing. The extent of absorption is impaired by food or beverages (other than plain water). The oral bioavailability of ibandronate is reduced by about 90% when ibandronate sodium tablets are administered concomitantly with a standard breakfast in comparison with bioavailability observed in fasted subjects.

There is no meaningful reduction in bioavailability when ibandronate is taken at least 60 minutes before a meal. However, both bioavailability and the effect on bone mineral density (BMD) are reduced when food or beverages are taken less than 60 minutes following an ibandronate dose. Distribution After absorption, ibandronate either rapidly binds to bone or is excreted into urine.

In humans, the apparent terminal volume of distribution is at least 90 L, and the amount of dose removed from the circulation via the bone is estimated to be 40% to 50% of the circulating dose. In vitro protein binding in human serum was 99.5% to 90.9% over an ibandronate concentration range of 2 to 10 ng/mL in one study and approximately 85.7% over a concentration range of 0.5 to 10 ng/mL in another study. Metabolism Ibandronate does not undergo hepatic metabolism and does not inhibit the hepatic cytochrome P450 system.

Ibandronate is eliminated by renal excretion. Based on a rat study, the ibandronate secretory pathway does not appear to include known acidic or basic transport systems involved in the excretion of other drugs. There is no evidence that ibandronate is metabolized in humans.

Elimination The portion of ibandronate that is not removed from the circulation via bone absorption is eliminated unchanged by the kidney (approximately 50% to 60% of the absorbed dose). Unabsorbed ibandronate is eliminated unchanged in the feces. The plasma elimination of ibandronate is multiphasic.

Its renal clearance and distribution into bone accounts for a rapid and early decline in plasma concentrations, reaching 10% of the C max within 3 or 8 hours after intravenous or oral administration, respectively. This is followed by a slower clearance phase as ibandronate redistributes back into the blood from bone. The observed apparent terminal half-life for ibandronate is generally dependent on the dose studied and on assay sensitivity.

The observed apparent terminal half-life for the 150 mg ibandronate tablet upon oral administration to healthy postmenopausal women ranges from 37 to 157 hours. Total clearance of ibandronate is low, with average values in the range 84 to 160 mL/min. Renal clearance (about 60 mL/min in healthy postmenopausal females) accounts for 50% to 60% of total clearance and is related to creatinine clearance.

The difference between the apparent total and renal clearances likely reflects bone uptake of the drug. Specific Populations Pediatrics The pharmacokinetics of ibandronate has not been studied in patients less than 18 years of age. Geriatric Because ibandronate is not known to be metabolized, the only difference in ibandronate elimination for geriatric patients versus younger patients is expected to relate to progressive age-related changes in renal function.

Gender The bioavailability and pharmacokinetics of ibandronate are similar in both men and women. Race Pharmacokinetic differences due to race have not been studied. Renal Impairment Renal clearance of ibandronate in patients with various degrees of renal impairment is linearly related to creatinine clearance (CLcr).

Following a single dose of 0.5 mg ibandronate by intravenous administration, pa… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Osteoporosis is characterized by decreased bone mass and increased fracture risk, most commonly at the spine, hip, and wrist. The diagnosis can be confirmed by a finding of low bone mass, evidence of fracture on x-ray, a history of osteoporotic fracture, or height loss or kyphosis indicative of vertebral fracture. While osteoporosis occurs in both men and women, it is most common among women following menopause.

In healthy humans, bone formation and resorption are closely linked; old bone is resorbed and replaced by newly formed bone. In postmenopausal osteoporosis, bone resorption exceeds bone formation, leading to bone loss and increased risk of fracture. After menopause, the risk of fractures of the spine and hip increases; approximately 40% of 50-year-old women will experience an osteoporosis-related fracture during their remaining lifetimes.

Ibandronate sodium tablets produced biochemical changes indicative of dose-dependent inhibition of bone resorption, including decreases of biochemical markers of bone collagen degradation (such as deoxypyridinoline, and cross-linked C-telopeptide of Type I collagen) in the daily dose range of 0.25 mg to 5 mg and once-monthly doses from 100 mg to 150 mg in postmenopausal women. Treatment with 2.5 mg daily ibandronate sodium tablets resulted in decreases in biochemical markers of bone turnover, including urinary C-terminal telopeptide of Type I collagen (uCTX) and serum osteocalcin, to levels similar to those in premenopausal women.

Changes in markers of bone formation were observed later than changes in resorption markers, as expected, due to the coupled nature of bone resorption and formation. Treatment with 2.5 mg daily ibandronate sodium tablets decreased levels of uCTX within 1 month of starting treatment and decreased levels of osteocalcin within 3 months. Bone turnover markers reached a nadir of approximately 64% below baseline values by 6 months of treatment and remained stable with continued treatment for up to 3 years.

Following treatment discontinuation, there is a return to pretreatment baseline rates of elevated bone resorption associated with postmenopausal osteoporosis. In a 1-year, study comparing once-monthly vs. once-daily oral dosing regimens, the median decrease from baseline in serum CTX values was -76% for patients treated with the 150 mg once-monthly regimen and -67% for patients treated with the 2.5 mg daily regimen. In a 1-year, prevention study comparing ibandronate sodium tablets 150 mg once-monthly to placebo, the median placebo-subtracted decrease in sCTX was -49.8%.

14 CLINICAL STUDIES

14.1Treatment of Postmenopausal Osteoporosis Daily Dosing The effectiveness and safety of ibandronate sodium 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 lumbar spine BMD 2 to 5 SD below the premenopausal mean (T-score) in at least one vertebra [L1 to L4], and who had 1 to 4 prevalent vertebral fractures. Ibandronate sodium tablets were 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 2 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 Fracture Incidence Ibandronate sodium tablets 2.5 mg daily significantly reduced the incidence of new vertebral (primary efficacy measure) and of new and worsening vertebral fractures. Over the course of the 3-year study, the risk for vertebral fracture was 9.6% in the placebo-treated women and 4.7% in the women treated with ibandronate sodium tablets 2.5 mg (p<0.001) (see Table 3) .

Table 3 Effect of Ibandronate Sodium Tablets on the Incidence of Vertebral Fracture in the 3-Year Osteoporosis Treatment Study* Proportion of Patients with Fracture (%) Placebo n=975 Ibandronate sodium tablets 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 Ibandronate sodium tablets 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 sodium tablets 2.5 mg daily [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 nonvertebral sites: pelvis, femur, wrist, forearm, rib, and hip. Bone Mineral Density (BMD) Ibandronate sodium tablets significantly increased BMD at the lumbar spine and hip relative to treatment with placebo.

In the 3-year osteoporosis treatment study, ibandronate sodium tablets 2.5 mg daily 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 2.5 mg daily ibandronate sodium tablets compared with 1.4% in the placebo group. 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 Daily with Ibandronate Sodium Tablets 2.5 mg 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 sodium tablets 2.5 mg… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, 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 male and female Wistar rats (systemic exposures up to 12 and 7 times, respectively, human exposure at the recommended daily oral dose of 2.5 mg, and cumulative exposures up to 3.5 and 2 times, respectively, human exposure at the recommended once-monthly oral dose of 150 mg, based on AUC comparison). 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 male and female NMRI mice (exposures up to 475 and 70 times, respectively, human exposure at the recommended daily oral dose of 2.5 mg and cumulative exposures up to 135 and 20 times, respectively, human exposure at the recommended once-monthly oral dose of 150 mg, based on AUC comparison). 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 (cumulative monthly exposures in males and females up to 70 and 115 times, respectively, human exposure at the recommended dose of 150 mg, based on AUC comparison).

A dose-related increased incidence of adrenal subcapsular adenoma/carcinoma was observed in female mice, which was statistically significant at 80 mg/kg/day (220 to 400 times human exposure at the recommended daily oral dose of 2.5 mg and 115 times human exposure at the recommended once-monthly oral dose of 150 mg, based on AUC comparison). The relevance of these findings to humans is unknown. 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 were observed at an oral dose of 16 mg/kg/day (45 times human exposure at the recommended daily oral dose of 2.5 mg and 13 times human exposure at the recommended once-monthly oral dose of 150 mg, based on AUC comparison).

13.2Animal 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 tablets administered at therapeutic doses is unlikely to induce osteomalacia. Long-term daily or once-monthly intermittent administration of ibandronate to ovariectomized rats or monkeys was associated with suppression of bone turnover and increases in bone mass. In both rats and monkeys, vertebral BMD, trabecular density, and biomechanical strength were increased dose-dependently at doses up to 15 times the recommended human daily oral dose of 2.5 mg, or cumulative monthly doses up to 8 times (rat) or 6 times (monkey) the recommended human once-monthly oral dose of 150 mg, based on body surface area (mg/m 2 ) or area under the curve (AUC) comparison.

In monkeys, ibandronate maintained the positive correlation between bone mass and strength at the ulna and femoral neck. New bone forme… [Excerpted — this section continues on DailyMed.]