BONIVA^®
(ibandronate sodium)
INJECTION

BONIVA (ibandronate sodium) is a nitrogen-containing bisphosphonate that inhibits osteoclast-mediated bone resorption. The chemical name for ibandronate sodium is 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid, monosodium salt, monohydrate with the molecular formula C₉H₂₂NO₇P₂Na•H₂O and a molecular weight of 359.24. Ibandronate sodium is a white- to off-white powder. It is freely soluble in water and practically insoluble in organic solvents. Ibandronate sodium has the following structural formula:

BONIVA Injection is intended for intravenous administration only. BONIVA Injection is available as a sterile, clear, colorless, ready-to-use solution in a prefilled syringe that delivers 3.375 mg of ibandronate monosodium salt monohydrate in 3 mL of solution, equivalent to a dose of 3 mg ibandronate free acid. Inactive ingredients include sodium chloride, glacial acetic acid, sodium acetate and water.

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.

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.

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.

In studies of postmenopausal women, BONIVA 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 BONIVA Injection 3 mg every 3 months and BONIVA 2.5 mg 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 ITT population reached a nadir of 57% (BONIVA Injection) and 62% (BONIVA 2.5 mg tablets) below baseline values by Month 6, and remained stable at Month 12 of treatment.

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 BONIVA 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.

BONIVA Injection is indicated for the treatment of osteoporosis in postmenopausal women.

In postmenopausal women with osteoporosis, BONIVA increases BMD and reduces the incidence of vertebral fractures (see CLINICAL PHARMACOLOGY: Clinical Studies). Osteoporosis may be confirmed by the presence or history of osteoporotic fracture or by a finding of low bone mass (BMD more than 2.0 standard deviations below the premenopausal mean [ie, T-score]).

• Known hypersensitivity to BONIVA Injection or to any of its excipients
• Uncorrected hypocalcemia (see PRECAUTIONS: General)

BONIVA Injection, like other bisphosphonates administered intravenously, may cause a transient decrease in serum calcium values (see PRECAUTIONS).

BONIVA Injection must only be administered intravenously. Care must be taken not to administer BONIVA Injection intra-arterially or paravenously as this could lead to tissue damage.

Do not administer BONIVA Injection by any other route of administration. The safety and efficacy of BONIVA Injection following non-intravenous routes of administration have not been established.

Treatment with intravenous bisphosphonates has been associated with renal toxicity manifested as deterioration in renal function (ie, increased serum creatinine) and in rare cases, acute renal failure. No cases of acute renal failure were observed in controlled clinical trials in which intravenous BONIVA was administered as a 15- to 30-second bolus. The risk of serious renal toxicity with other intravenous bisphosphonates appears to be inversely related to the rate of drug administration.

Patients who receive BONIVA Injection should have serum creatinine measured prior to each dosage administration. Patients with concomitant diseases that have the potential for adverse effects on the kidney or patients who are taking concomitant medications that have the potential for adverse effects on the kidney should be assessed, as clinically appropriate. Treatment should be withheld for renal deterioration.

BONIVA Injection should not be administered to patients with severe renal impairment (ie, patients with serum creatinine >200µmol/L [2.3 mg/dL] or creatinine clearance [measured or estimated]<30 mL/min).

Osteonecrosis, primarily in the jaw, has been reported in patients treated with bisphosphonates. Most cases have been in cancer patients undergoing dental procedures, but some have occurred in patients with postmenopausal osteoporosis or other diagnoses. Known risk factors for osteonecrosis include a diagnosis of cancer, concomitant therapies (eg, chemotherapy, radiotherapy, corticosteroids), and co-morbid disorders (eg, anemia, coagulopathy, infection, pre-existing dental disease). Most reported cases have been in patients treated with bisphosphonates intravenously but some have been in patients treated orally.

For patients who develop osteonecrosis of the jaw (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. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates that are approved for the prevention and treatment of osteoporosis (see ADVERSE REACTIONS). However, such reports have been infrequent. This category of drugs includes BONIVA (ibandronate sodium) Injection. Most of the patients were postmenopausal women. 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. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.

BONIVA Injection must be administered intravenously only by a health care professional. Patients should be instructed to read the Patient Information Leaflet carefully before BONIVA Injection is administered and to re-read it each time the prescription is renewed.

BONIVA Injection should be administered once every 3 months. If the dose is missed, the injection should be administered as soon as it can be rescheduled. Thereafter, injections should be scheduled every 3 months from the date of the last injection. Do not administer BONIVA Injection more frequently than once every 3 months.

Patients must receive supplemental calcium and vitamin D.

See CLINICAL PHARMACOLOGY: Drug Interactions

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

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. It is not known whether BONIVA is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when BONIVA Injection is administered to a nursing woman.

Safety and effectiveness in pediatric patients have not been established.

Of the patients receiving BONIVA Injection 3 mg every 3 months for 1 year (DIVA study), 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.

Treatment with BONIVA 2.5 mg daily oral tablet was studied in over 3900 patients in postmenopausal osteoporosis trials of up to 3 years duration. The overall adverse event profile of BONIVA 2.5 mg once daily tablet in these studies was similar to that of placebo.

Most adverse events were mild or moderate and did not lead to discontinuation. The incidence of serious adverse events was 20% in the placebo group and 23% in the BONIVA 2.5 mg daily oral tablet group. The percentage of patients who withdrew from treatment due to adverse events was approximately 17% in both the BONIVA 2.5 mg daily oral tablet group and the placebo group. Overall, and according to body system, there was no difference between BONIVA daily oral tablet and placebo, with adverse events of the digestive system being the most common reason for withdrawal.

Table 3 uls adverse events from the Treatment and Prevention Studies reported in ≥2% of patients and in more patients treated with BONIVA 2.5 mg daily oral tablet than patients treated with placebo. Adverse events are shown without attribution of causality.

In a 1-year, double-blind, multicenter study comparing BONIVA Injection administered intravenously as 3 mg every 3 months to BONIVA 2.5 mg 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 events was 8.0% in the BONIVA 2.5 mg daily group and 7.5% in the BONIVA Injection 3 mg once every 3 months group. The percentage of patients who withdrew from treatment due to adverse events was approximately 6.7% in the BONIVA 2.5 mg daily group and 8.5% in the BONIVA Injection 3 mg every 3 months group.

Table 4 uls the adverse events reported in >2% of patients without attribution of causality.

No cases of overdose were reported in premarketing studies with BONIVA Injection. Intravenous overdosage may result in hypocalcemia, hypophosphatemia, and hypomagnesemia. Clinically relevant reductions in serum levels of calcium, phosphorus, and magnesium should be corrected by intravenous administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate, respectively.

Dialysis would not be beneficial unless it is administered within 2 hours following the overdose.

The recommended dose of BONIVA Injection for the treatment of postmenopausal osteoporosis is 3 mg every 3 months (see INDICATIONS AND USAGE) administered over a period of 15 to 30 seconds.

No cases of acute renal failure were observed in controlled clinical trials in which intravenous BONIVA was administered as a 15- to 30-second bolus. The risk of serious renal toxicity with other intravenous bisphosphonates appears to be inversely related to the rate of drug administration (see PRECAUTIONS).

BONIVA Injection must be administered by a health care professional.

BONIVA Injection must only be administered intravenously (see WARNINGS). Care must be taken not to administer BONIVA Injection intra-arterially or paravenously as this could lead to tissue damage.

Do not administer BONIVA Injection by any other route of administration. The safety and efficacy of BONIVA Injection following non-intravenous routes of administration have not been established.

Administer BONIVA Injection using the enclosed needle. Prefilled syringes are for single use only. Discard unused portion.

BONIVA Injection must not be mixed with calcium-containing solutions or other intravenously administered drugs.

Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, and not used if particulate matter is visible or product is discolored. Prefilled syringes with particulate matter or discoloration should not be used.

If the dose is missed, BONIVA Injection should be administered as soon as it can be rescheduled. Thereafter, injections should be scheduled every 3 months from the date of the last injection. Do not administer BONIVA Injection (3 mg) more frequently than once every 3 months.

Patients must receive supplemental calcium and vitamin D (see PRECAUTIONS: Information for Patients).

No dose adjustment is necessary (see CLINICAL PHARMACOLOGY: Special Populations).

No dose adjustment is necessary for patients with mild or moderate renal impairment where creatinine clearance is equal to or greater than 30 mL/min.

BONIVA Injection should not be administered to patients with severe renal impairment, ie, patients with serum creatinine >200 µmol/L (2.3 mg/dL) or creatinine clearance (measured or estimated) <30 mL/min (see CLINICAL PHARMACOLOGY: Special Populations).

No dosage adjustment is necessary in the elderly (see PRECAUTIONS: Geriatric Use).

One prefilled syringe of BONIVA Injection (ibandronate sodium), 3 mg/3 mL single-use, clear glass prefilled syringe, in a box with 1 needle and 2 alcohol swabs (NDC 0004-0188-09).

Each syringe is a 5 mL (5 cc) volume syringe supplied with a 23-gauge, 3/4 inch needle with wings, needle-stick protection device, and 3-inch plastic tubing for attachment.

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