1.1 Treatment of Postmenopausal Osteoporosis

Ibandronate sodium injection is indicated for the treatment of osteoporosis in postmenopausal women. In postmenopausal women with osteoporosis, ibandronate sodium injection increases bone mineral density (BMD) and reduces the incidence of vertebral fractures [see Clinical Studies (14)].

1.2 Important Limitations of Use

The safety and effectiveness of ibandronate sodium injection for the treatment of osteoporosis are based on clinical data of one year duration. The optimal duration of use has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis. Patients at low-risk for fracture should be considered for drug discontinuation after 3 to 5 years of use. Patients who discontinue therapy should have their risk for fracture re-evaluated periodically.

2.1 Important Administration Instructions

Ibandronate sodium injection must be administered intravenously only by a health care professional. Care must be taken not to administer intra-arterially or paravenously as this could lead to tissue damage [see Warnings and Precautions (5.4)].

• Appropriate medical support and monitoring measures should be readily available when ibandronate sodium injection is administered. If anaphylactic or other severe hypersensitivity/allergic reactions occur, immediately discontinue the injection and initiate appropriate treatment [see Warnings and Precautions (5.2)].
• Visually inspect the liquid in the vial for particulate matter and discoloration before administration.  Do not use vials with particulate matter or discoloration.
• Discard any unused portion.
• Do not mix with calcium-containing solutions or other intravenously administered drugs.
• Vials are for single use only.

2.2 Dosage Information

The recommended dose of ibandronate sodium injection for the treatment of postmenopausal osteoporosis is 3 mg every 3 months administered intravenously over a period of 15 to 30 seconds. Do not administer more frequently than once every 3 months.

2.3 Laboratory Testing and Oral Examination Prior to Administration

Prior to administration of each dose obtain a serum creatinine [see Warnings and Precautions (5.3)]. Given that bisphosphonates have been associated with osteonecrosis of the jaw (ONJ), perform a routine oral examination prior to administration of ibandronate sodium injection.

2.4 Calcium and Vitamin D Supplementation

Instruct patients to take supplemental calcium and vitamin D if their dietary intake is inadequate.  [see Warnings and Precautions (5.1)].

2.5 Dosing After Missed Dose

If the dose is missed, administer as soon as it can be re-scheduled. Thereafter, ibandronate sodium injection should be scheduled every 3 months from the date of the last injection.

2.6 Dosage Modifications in Patients with Renal Impairment

Do not administer to patients with severe renal impairment (creatinine clearance less than 30 mL/minute) [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)]. No dose adjustment is necessary for patients with mild or moderate renal impairment (creatinine clearance greater than or equal to 30 mL/min) [see Clinical Pharmacology (12.3)].

5.1 Hypocalcemia and Mineral Metabolism

Ibandronate sodium injection may cause a decrease in serum calcium values. Treat hypocalcemia, hypovitaminosis D, and other disturbances of bone and mineral metabolism before starting ibandronate sodium injection therapy.
Adequate intake of calcium and vitamin D is important in all patients. It is recommended that patients receive supplemental calcium and vitamin D if dietary intake is inadequate.

5.2 Anaphylactic Reaction

Cases of anaphylaxis, including fatal events, have been reported in patients treated with ibandronate sodium injection.
Appropriate medical support and monitoring measures should be readily available when ibandronate sodium injection is administered. If anaphylactic or other severe hypersensitivity/allergic reactions occur, immediately discontinue the injection and initiate appropriate treatment.

5.3 Renal Impairment

Treatment with intravenous bisphosphonates has been associated with renal toxicity manifested as deterioration in renal function and acute renal failure. Although no cases of acute renal failure were observed in controlled clinical trials in which intravenous ibandronate sodium was administered as a 15- to 30-second bolus, acute renal failure has been reported postmarketing. Do not administer ibandronate sodium injection to patients with severe renal impairment (creatinine clearance less than 30 mL/min).
Obtain serum creatinine prior to each ibandronate sodium injection. After ibandronate sodium injection, assess renal function, as clinically appropriate, in patients with concomitant diseases or taking medications that have the potential for adverse effects on the kidney. Ibandronate sodium injection should be withheld in patients with renal deterioration.

5.4 Tissue Damage Related to Inappropriate Drug Administration

Ibandronate sodium injection must only be administered intravenously. Care must be taken not to administer ibandronate sodium injection intra-arterially or paravenously as this could lead to tissue damage.
Do not administer ibandronate sodium injection by any other route of administration. The safety and efficacy of ibandronate sodium injection following non-intravenous routes of administration have not been established.

5.5 Osteonecrosis of the Jaw

Osteonecrosis of the jaw (ONJ) has been reported in patients treated with bisphosphonates, including ibandronate sodium injection. Most cases have been in cancer patients treated with intravenous bisphosphonates undergoing dental procedures. Some cases have occurred in patients with postmenopausal osteoporosis treated with either oral or intravenous bisphosphonates. A routine oral examination should be performed by the prescriber prior to initiation of bisphosphonate treatment. Consider a dental examination with appropriate preventive dentistry prior to treatment with bisphosphonates in patients with a history of concomitant risk factors (e.g., cancer, chemotherapy, angiogenesis inhibitors, radiotherapy, corticosteroids, poor oral hygiene, pre-existing dental disease or infection, anemia, coagulopathy). Concomitant administration of drugs associated with ONJ may increase the risk of developing ONJ. The risk of ONJ may increase with duration of exposure to bisphosphonates.
While on treatment, patients with concomitant risk factors should avoid invasive dental procedures if possible. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. The clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment [see Adverse Reactions (6.1)].

5.6 Musculoskeletal Pain

Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking ibandronate sodium injection and other bisphosphonates [see Adverse Reactions (6.2)]. The time to onset of symptoms varied from one day to several months after starting the drug. Most patients had relief of symptoms after stopping the bisphosphonate. A subset of patients had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. Discontinue ibandronate sodium injection if severe symptoms develop.

5.7 Atypical Subtrochanteric and Diaphyseal Femoral Fractures

Atypical, low-energy, or low-trauma fractures of the femoral shaft have been reported in bisphosphonate-treated patients. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with bisphosphonates. 

Atypical femur fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g., prednisone) at the time of fracture. 

Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patients presenting with an atypical fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of bisphosphonate therapy should be considered, pending a risk/benefit assessment, on an individual basis.

6.1 Clinical Trials Experience

Because clinical trials 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.

Quarterly Intravenous Injection –
In a 1-year, double-blind, multicenter study comparing ibandronate sodium injection administered intravenously as 3 mg every 3 months to ibandronate sodium tablets 2.5 mg (ibandronate) daily oral tablet in women with postmenopausal osteoporosis, the overall safety and tolerability profiles of the two dosing regimens were similar. The incidence of serious adverse reactions was 8% in the ibandronate sodium tablets 2.5 mg (ibandronate) daily group and 7.5% in the ibandronate sodium injection 3 mg once every 3 months group. The percentage of patients who withdrew from treatment due to adverse reactions was approximately 6.7% in the ibandronate sodium tablets 2.5 mg (ibandronate) daily group and 8.5% in the ibandronate sodium injection 3 mg every 3 months group. Table 1 lists the adverse reactions reported in greater than 2% of patients.

Acute Phase Reaction-like Events
Symptoms consistent with acute phase reaction (APR) have been reported with intravenous bisphosphonate use. The overall incidence of patients with APR-like events was higher in the intravenous treatment group (4% in the ibandronate sodium tablets 2.5 mg (ibandronate) daily oral tablet group vs. 10% in the ibandronate sodium injection 3 mg once every 3 months group). These incidence rates are based upon reporting of any of 33 potential APR-like symptoms within 3 days of an intravenous dose and lasting 7 days or less. In most cases, no specific treatment was required and the symptoms subsided within 24 to 48 hours.
Injection Site Reactions
Local reactions at the injection site, such as redness or swelling, were observed at a higher incidence in patients treated with ibandronate sodium injection 3 mg every 3 months (1.7%; 8/469) than in patients treated with placebo injections (0.2%; 1/465). In most cases, the reaction was of mild to moderate severity.

Daily Oral Tablet -
The safety of ibandronate sodium tablets 2.5 mg (ibandronate) once daily in the treatment and prevention of postmenopausal osteoporosis was assessed in 3,577 patients aged 41 to 82 years. The duration of the trials was 2 to 3 years, with 1,134 patients exposed to placebo and 1,140 exposed to ibandronate sodium tablets 2.5 mg (ibandronate). Patients with preexisting gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors and H2 antagonists were included in these clinical trials. All patients received 500 mg calcium plus 400 international units vitamin D supplementation daily.

The incidence of all-cause mortality was 1% in the placebo group and 1.2% in the ibandronate sodium tablets 2.5 mg (ibandronate) daily group. The incidence of serious adverse reactions was 20% in the placebo group and 23% in the ibandronate sodium tablets 2.5 mg (ibandronate) daily oral tablet group. The percentage of patients who withdrew from treatment due to adverse reactions was approximately 17% in both the placebo group and the ibandronate sodium tablets 2.5 mg (ibandronate) daily oral tablet group. Table 2 lists adverse reactions from the Treatment and Prevention Studies reported in greater than or equal to 2% of patients and in more patients treated with ibandronate sodium tablets 2.5 mg (ibandronate) daily oral tablet than patients treated with placebo.

Gastrointestinal Adverse Reactions

The incidence of selected gastrointestinal adverse reactions in the placebo and ibandronate sodium tablets 2.5 mg (ibandronate) daily groups were: dyspepsia (10% vs. 12%), diarrhea (5% vs. 7%), and abdominal pain (5% vs. 6%). 

Musculoskeletal Adverse Reactions
The incidence of selected musculoskeletal adverse reactions in the placebo and ibandronate sodium tablets 2.5 mg (ibandronate) daily groups were: back pain (12% vs. 14%), arthralgia (14% vs. 14%) and myalgia (5% vs. 6%).

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ibandronate sodium injection. 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. 

Hypersensitivity: Allergic reactions including anaphylaxis with fatalities, angioedema, asthma exacerbation, bronchospasm, rash, Stevens-Johnson syndrome, erythema multiforme, and dermatitis bullous [see Contraindications (4), Warnings and Precautions (5.2)]. 

Hypocalcemia: Hypocalcemia [see Warnings and Precautions (5.1)]. 

Renal Toxicity: Acute renal failure [see Warnings and Precautions (5.3)]. 

Osteonecrosis of the Jaw: Osteonecrosis of the jaw [see Warnings and Precautions (5.5)]. 

Musculoskeletal Pain: Bone, joint, or muscle pain (musculoskeletal pain), described as severe or incapacitating [see Warnings and Precautions (5.6)]. 

Atypical Femoral Shaft Fracture: Atypical, low-energy, or low-trauma fractures of the femoral shaft [see Warnings and Precautions (5.7)]. 
Eye Inflammation: Iritis and uveitis. In some cases with other bisphosphonates, these events did not resolve until the bisphosphonate was discontinued. 

7.1 Melphalan/Prednisolone

Intravenous ibandronate (6 mg) did not interact with intravenous melphalan (10 mg/m2) or oral prednisolone (60 mg/m2). [See Clinical Pharmacology (12.3)]

7.2 Tamoxifen

There was no interaction between oral 30 mg tamoxifen and intravenous 2 mg ibandronate. [See Clinical Pharmacology (12.3)]

7.3 Bone Imaging Agents

Bisphosphonates are known to interfere with the use of bone-imaging agents. Specific studies with ibandronate sodium injection have not been performed.

8.1 Pregnancy

Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. Ibandronate sodium injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Bisphosphonates are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been established.

In pregnant rats given intravenous doses  greater than or equal to 2 times human exposure from Day 17 post-­coitum until Day 20 post-partum, ibandronate treatment resulted in dystocia, maternal mortality, and early postnatal pup loss in all dose groups. Reduced body weight at birth was observed at greater than or equal to 4 times the human exposure. Pups exhibited abnormal odontogeny that decreased food consumption and body weight gain at greater than or equal to 18 times human exposure. Periparturient mortality has also been observed with other bisphosphonates and appears to be a class effect related to inhibition of skeletal calcium mobilization resulting in hypocalcemia and dystocia.

Exposure of pregnant rats during the period of organogenesis resulted in an increased fetal incidence of RPU (renal pelvis ureter) syndrome at an intravenous dose greater than or equal to 47 times human exposure. In this spontaneous delivery study, dystocia was counteracted by perinatal calcium supplementation. In rat studies with intravenous dosing during gestation, fetal weight and pup growth were reduced at doses greater than or equal to 5 times human exposure. 

In pregnant rabbits given intravenous doses during the period of organogenesis, maternal mortality, reduced maternal body weight gain, decreased litter size due to increased resorption rate, and decreased fetal weight were observed at 19 times the recommended human intravenous dose. 

Exposure multiples for the rat studies were calculated using human exposure at the recommended intravenous dose of 3 mg every 3 months and were based on cumulative area under the time-concentration (AUC) comparison. Exposure multiples for the rabbit study were calculated for the recommended human intravenous dose of 3 mg every 3 months and were based on cumulative dose/[body surface area] comparison. Doses in pregnant animals were 0.05, 0.1, 0.15, 0.3, 0.5 or 1 mg/kg/day in rats, and 0.03, 0.07, or 0.2 mg/kg/day in rabbits.

8.3 Nursing Mothers

It is not known whether ibandronate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ibandronate sodium injection is administered to a nursing woman. In lactating rats treated with intravenous doses of 0.08 mg/kg, ibandronate was present in breast milk at concentrations of 8.1 to 0.4 ng/mL from 2 to 24 hours after dose administration. Concentrations in milk averaged 1.5 times plasma concentrations.

8.4 Pediatric Use

Safety and effectiveness of ibandronate sodium injection in pediatric patients have not been established.

8.5 Geriatric Use

Of the patients receiving ibandronate sodium injection 3 mg every 3 months for 1 year, 51% were over 65 years of age. No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity in some older individuals cannot be ruled out.

8.6 Renal Impairment

Ibandronate sodium injection should not be administered to patients with severe renal impairment (creatinine clearance less than 30 mL/min) [see Warnings and Precautions (5.3)].

12.1 Mechanism of Action

The action of ibandronate on bone 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.

12.2 Pharmacodynamics

In studies of postmenopausal women, ibandronate sodium injection at doses of 0.5 mg to 3 mg produced biochemical changes indicative of inhibition of bone resorption, including decreases of biochemical markers of bone collagen degradation (cross-linked C-telopeptide of Type I collagen [CTX]). Changes in markers of bone formation (osteocalcin) were observed later than changes in resorption markers, as expected, due to the coupled nature of bone resorption and formation.

Year 1 results from an efficacy and safety study comparing ibandronate sodium injection 3 mg every 3 months and ibandronate sodium tablets 2.5 mg (ibandronate) daily oral tablet demonstrated that both dosing regimens significantly suppressed serum CTX levels at Months 3, 6, and 12. The median pre-dose or trough serum CTX levels in the intent-to-treat population reached a nadir of 57% (ibandronate sodium injection) and 62% (ibandronate sodium tablets 2.5 mg (ibandronate)) below baseline values by Month 6, and remained stable at Month 12 of treatment.

12.3 Pharmacokinetics

Distribution

Area under the serum ibandronate concentrations versus time curve increases in a dose proportional manner after administration of 2 mg to 6 mg by intravenous injection. 

After administration, 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 into the bone is estimated to be 40% to 50% of the circulating dose. In one study, in vitro protein binding in human serum was approximately 86% over an ibandronate concentration range of 20 to 2,000 ng/mL (approximate range of maximum serum ibandronate concentrations upon intravenous bolus administration). 

Metabolism

There is no evidence that ibandronate is metabolized in humans. Ibandronate does not inhibit human P450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 isozymes in vitro. 

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.  

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 administered intravenous dose).  

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 Cmax 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 intravenous 2 and 4 mg ibandronate after 2 hours of infusion ranges from 4.6 to 15.3 hours and 5 to 25.5 hours, respectively.   

Following intravenous administration, 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 women) 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.

Pharmacokinetics in Specific Populations

Pediatrics

The pharmacokinetics of ibandronate have not been studied in patients less than 18 years of age.

Gender

The pharmacokinetics of ibandronate are similar in both men and women.

Geriatric

Since 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 [see Use in Specific Populations (8.5)]. 

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, patients with creatinine clearance 40 to 70 mL/min had 55% higher exposure (AUC∞) than the exposure observed in patients with creatinine clearance higher than 90 mL/min. Patients with severe renal impairment (creatinine clearance below 30 mL/min) had more than a two-fold increase in exposure compared to the exposure for patients with creatinine clearance equal to or higher than 80 mL/min [see Dosage and Administration (2.6) and Use in Specific Populations (8.6)].  

Hepatic Impairment

No studies have been performed to assess the pharmacokinetics of ibandronate in patients with hepatic impairment since ibandronate is not metabolized in the human liver.   

Drug Interaction

Melphalan/Prednisolone

A pharmacokinetic interaction study in multiple myeloma patients demonstrated that intravenous melphalan (10 mg/m2) and oral prednisolone (60 mg/m2) did not interact with 6 mg ibandronate upon intravenous coadministration.  Ibandronate did not interact with melphalan or prednisolone.  

Tamoxifen

A pharmacokinetic interaction study in healthy postmenopausal women demonstrated that there was no interaction between oral 30 mg tamoxifen and intravenous 2 mg ibandronate.

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 1,000 times the lowest antiresorptive dose of 0.005 mg/kg/day in this model, and 5,000 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 every 3 months, based on cumulative dose normalized for body surface area (mg/m2) and 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.

14.1 Treatment of Postmenopausal Osteoporosis

Quarterly Intravenous Injection

The effectiveness and safety of ibandronate sodium injection 3 mg once every 3 months were demonstrated in a randomized, double-blind, multinational, noninferiority study in 1,358 women with postmenopausal osteoporosis (L2 to L4 lumbar spine BMD, T-score below -2.5 SD at baseline). The control group received ibandronate sodium tablets 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 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 once every 3 months group and 1.5% in the ibandronate sodium tablets 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 once every 3 months compared to ibandronate sodium tablets 2.5 mg (ibandronate) daily oral tablet.

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 tablets 2.5 mg (ibandronate) daily oral tablets were demonstrated in a randomized, double-blind, placebo-controlled, multinational study (Treatment Study) of 2,946 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 to L4], and who had one to four prevalent vertebral fractures. Ibandronate sodium 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 sodium tablets 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 tablets 2.5 mg (ibandronate) daily oral tablet (p<0.001) (see Table 3).

Effect on Nonvertebral Fractures

Ibandronate sodium tablets 2.5 mg (ibandronate) 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 (ibandronate) 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 sodium tablets 2.5 mg (ibandronate) 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 sodium tablets 2.5 mg (ibandronate) 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 sodium tablets 2.5 mg (ibandronate) 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.

Bone Histology

The effects of ibandronate sodium tablets 2.5 mg (ibandronate) 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.

16.1 How Supplied

Ibandronate sodium injection is available as follows:

NDC 62756-218-40    1 mg/mL, 3 mL single-dose vial, carton of 1

16.2 Storage and Handling

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature].