IBANDRONATE SODIUM (Page 4 of 8)

7 DRUG INTERACTIONS

7.1 Melphalan/Prednisolone

Intravenous ibandronate (6 mg) did not interact with intravenous melphalan (10 mg/m 2 ) or oral prednisolone (60 mg/m 2 ). [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 have not been performed.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Ibandronate Sodium is not indicated for use in women of reproductive potential. There are no data with ibandronate sodium use in pregnant women to inform any drug-associated risks.

In reproductive toxicity studies in the rat, ibandronate sodium caused obstruction of labor, with maternal periparturient mortality, pup loss and reduced pup weight at greater than or equal to 2 times human exposure at the recommended human intravenous dose of 3 mg. Abnormal pup odontogeny was observed at greater than or equal to 18 times human exposure. In rats dosed during pregnancy, kidney developmental toxicity occurred in offspring at greater than or equal to 47 times human exposure. Also, fetal weight and pup growth were reduced at greater than or equal to 5 times human exposure. In reproductive studies in the rabbit, ibandronate sodium caused maternal mortality, reduced maternal body weight gain, decreased litter size due to increased resorption rate, and decreased fetal weight at 19 times the recommended human dose ( see Data ).

Data

Animal Data

In pregnant rats given intravenous doses producing 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 producing 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 producing 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 ibandronate every 3 months and were based on cumulative area under the curve (AUC) comparison. Exposure multiples for the rabbit study were calculated for the recommended human intravenous dose of 3 mg ibandronate 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.

8.2 Lactation

Risk Summary

Ibandronate Sodium is not indicated for use in women of reproductive potential. There is no information on the presence of ibandronate in human milk, the effects of ibandronate on the breastfed infant, or the effects of ibandronate on milk production. Ibandronate is present in rat milk ( see Data ). The clinical relevance of this data is unclear.

Data

Animal Data

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 in pediatric patients have not been established.

8.5 Geriatric Use

Of the patients receiving ibandronate sodium injection 3 mg (ibandronate) 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) ] .

10 OVERDOSAGE

No cases of overdose were reported in premarketing studies with ibandronate sodium injection. Overdosage with intravenous bisphosphonates 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.

11 DESCRIPTION

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 C 9 H 22 NO 7 P 2 Na•H 2 O 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:

c988dc8-e4af-400a-b47d-debbe71e9ba2
(click image for full-size original)

Ibandronate Sodium Injection is intended for intravenous administration only. Ibandronate Sodium 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 glacial acetic acid (1.53 mg), sodium acetate (0.612 mg), sodium chloride (25.8 mg), and water for injection (quantity sufficient to 3 mL). Glacial acetic acid and sodium acetate are used to adjust pH.

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