Ibandronate Sodium (Page 3 of 7)

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of ibandronate sodium. 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 anaphylactic reaction/shock; with fatalities, angioedema, bronchospasm, asthma exacerbations,rash, Stevens-Johnson syndrome, erythema muliforme, and dermatitis bullous have been reported (see Contraindications [4])

Hypocalcemia

Hypocalcemia has been reported in patients treated with ibandronate sodium (see Warningsand Precautions [5.2]).

Musculoskeletal Pain

Bone, joint, or muscle pain (musculoskeletal pain), described as severe or incapacitating, has been reported (see Warningsand Precautions [5.3]).

Jaw Osteonecrosis

Osteonecrosis of the jaw and other oro-facial sites, including the external auditory canal, have been reported in patients treated with ibandronate sodium (see Warningsand Precautions [5.4]).

Atypical Femoral Shaft Fracture

Atypical, low-energy, or low-trauma fractures of the femoral shaft (see Warnings and Precautions [5.5]).

7 DRUG INTERACTIONS

7.1 Calcium Supplements/Antacids

Products containing calcium and other multivalent cations (such as aluminum, magnesium, iron) are likely to interfere with absorption of ibandronate sodium. Therefore, instruct patients to take ibandronate sodium at least 60 minutes before any oral medications, including medications containing multivalent cations (such as antacids, supplements or vitamins). Also, patients should wait at least 60 minutes after dosing before taking any other oral medications (see Dosage and Administration [ 2.3]).

7.2 Aspirin/Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Because aspirin, NSAIDs, and bisphosphonates are all associated with gastrointestinal irritation, caution should be exercised in the concomitant use of aspirin or NSAIDs with ibandronate sodium.

7.3 H2 Blockers

In healthy volunteers, co-administration with ranitidine resulted in a 20% increased bioavailability of ibandronate, which was not considered to be clinically relevant (see Clinical Pharmacology [12.3]).

7.4 Drug/Laboratory Test Interactions

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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

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

In reproductive toxicity studies in the rat, ibandronate caused post-implantation loss and obstruction of labor with maternal and fetal periparturient mortality at greater than or equal to 3 times human exposure at the recommended 2.5 mg daily oral dose, or at greater than or equal to 1 times human exposure at the recommended 150 mg once-monthly oral dose. In pregnant rats, kidney developmental toxicity occurred in offspring at greater than or equal to 30 times the daily 2.5 mg human dose or at greater than or equal to 9 times the once-monthly 150 mg human dose. In rat reproductive studies, impaired pup neuromuscular development was observed at 45 times the daily 2.5 mg dose and 13 times the once-monthly 150 mg dose. In reproductive studies in the rabbit, ibandronate caused maternal mortality at greater than or equal to 8 times the daily 2.5 mg dose and greater than or equal to 4 times the once-monthly 150 mg dose (see Data).

Data

Animal Data

In female rats given ibandronate at oral doses greater than or equal to 3 times human exposure at therecommended daily oral dose of 2.5 mg or greater than or equal to 1 times human exposure at the recommended once-monthly oral dose of 150 mg beginning 14 days before mating and continuing through lactation, maternal deaths were observed at the time of delivery in all dose groups. Perinatal pup loss in dams given doses producing 45 times human exposure at the recommended daily dose and 13 times human exposure at the recommended once-monthly dose was likely related to maternal dystocia. Calcium supplementation did not completely prevent dystocia and periparturient mortality in any of the treated groups at greater than or equal to 16 times the recommended daily dose and greater than or equal to 4.6 times the recommended once-monthly dose. A low incidence of postimplantation loss was observed in rats treated from 14 days before mating throughout lactation or during gestation, only at doses causing maternal dystocia and periparturient mortality. In pregnant rats dosed orally from gestation day 17 through lactation day 21 (following closure of the hard palate through weaning), maternal toxicity, including dystocia and mortality, fetal perinatal and postnatal mortality, were observed at doses equivalent to human exposure at the recommended daily dose and greater than or equal to 4 times the recommended once-monthly dose. 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 oral doses producing 30 times human exposure at the recommended daily oral dose of 2.5 mg and greater than or equal to 9 times human exposure at the recommended once-monthly oral dose of 150 mg. Impaired pup neuromuscular development (cliff avoidance test) was observed at 45 times human exposure at the daily dose and 13 times the once-monthly dose.

In pregnant rabbits treated orally with ibandronate during gestation at doses greater than or equal to 8 times the recommended human daily oral dose of 2.5 mg and greater than or equal to 4 times the recommended human once-monthly oral dose of 150 mg, dose-related maternal mortality was observed in all treatment groups. The deaths occurred prior to parturition and were associated with lung edema and hemorrhage. No significant fetal anomalies were observed.

Exposure multiples for the rat studies were calculated for the recommended daily oral dose of 2.5 mg or once monthly dose of 150 mg based on area under the curve (AUC) comparison. Exposure multiples for the rabbit study were calculated for the recommended human daily oral dose of 2.5 mg or once-monthly dose of 150 mg based on dose/body surface area comparison. Doses used in pregnant animals were 1, 4, 5, 6, 16, 10, 20, 30, 60 or 100 mg/kg/day in rats, and 1, 4 or 20 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 these data is unclear.

Data

Animal Data

In lactating rats treated with intravenous doses of 0.08 mg/kg, ibandronate was present in breast milk from 2 to 24 hours after dose administration. Concentrations in milk averaged 1.5 times plasma concentrations.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Of the patients receiving ibandronate 2.5 mg daily in postmenopausal osteoporosis studies, 52% were over65 years of age, and 10% were over 75 years of age. Of the patients receiving ibandronate sodium 150 mg once-monthly in the postmenopausal osteoporosis 1-year study, 52% were over 65 years of age, and 9% were over 75 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 is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/min).

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