WARNINGS
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.
PRECAUTIONS
General
Mineral Metabolism
Hypocalcemia, hypovitaminosis D, and other disturbances of bone and mineral metabolism must be effectively treated before starting BONIVA Injection therapy. Adequate intake of calcium and vitamin D is important in all patients. Patients must receive supplemental calcium and vitamin D.
Renal Impairment
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).
Jaw Osteonecrosis
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.
Musculoskeletal Pain
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.
Information for Patients
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.
Drug Interactions
See CLINICAL PHARMACOLOGY: Drug Interactions
Drug/Laboratory Test Interactions
Bisphosphonates are known to interfere with the use of bone-imaging agents. Specific studies with ibandronate have not been performed.
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 at the recommended intravenous dose of 3 mg every 3 months, based on cumulative 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 NMRI mice (exposures in males and females up to 96 and 14 times, respectively, human exposure at the recommended intravenous dose of 3 mg every 3 months, based on cumulative 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. 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 at the recommended intravenous dose of 3 mg every 3 months, based on cumulative 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, and increased preimplantation loss were observed at an intravenous dose of 1.2 mg/kg/day (117 times human exposure at the recommended intravenous dose of 3 mg every 3 months, based on cumulative AUC comparison). In male rats treated for 28 days prior to mating, a decrease in sperm production and altered sperm morphology were observed at intravenous doses ≥0.3 mg/kg/day (≥40 times human exposure at the recommended intravenous dose of 3 mg every 3 months, based on cumulative AUC comparison).
Pregnancy
Pregnancy Category C
In pregnant rats given intravenous doses of 0.05, 0.15, or 0.5 mg/kg/day 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 (≥2 times human exposure at the recommended intravenous dose of 3 mg every 3 months, based on cumulative AUC comparison). Reduced body weight at birth was observed at 0.15 and 0.5 mg/kg/day (≥4 times human exposure at the recommended intravenous dose of 3 mg every 3 months, based on cumulative AUC comparison). Pups exhibited abnormal odontogeny that decreased food consumption and body weight gain at 0.15 and 0.5 mg/kg/day (≥18 times human exposure at the recommended intravenous dose of 3 mg every 3 months, based on cumulative AUC comparison). 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 of 1 mg/kg/day (≥47 times human exposure at the recommended intravenous dose of 3 mg every 3 months, based on cumulative AUC comparison). 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 ≥0.1 mg/kg/day (≥5 times human exposure at the recommended intravenous dose of 3 mg every 3 months, based on cumulative AUC comparison).
In pregnant rabbits given intravenous doses of 0.03, 0.07 or 0.2 mg/kg/day 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 0.2 mg/kg/day (19 times the recommended human intravenous dose of 3 mg every 3 months, based on cumulative body surface area comparison, mg/m2).
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 (eg, 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.
There are no adequate and well-controlled studies in pregnant women. BONIVA Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.
Nursing Mothers
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.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
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.
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