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The committee voted 12-9 against continued marketing of the drug, citing"...
Upper Gastrointestinal Adverse Reactions
BONIVA, like other bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when BONIVA (ibandronate sodium) is given to patients with active upper gastrointestinal problems (such as known Barrett's esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis or ulcers).
Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates. In some cases, these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue BONIVA (ibandronate sodium) and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.
The risk of severe esophageal adverse experiences appears to be greater in patients who lie down after taking oral bisphosphonates and/or who fail to swallow it with the recommended full glass (6-8 oz) of water, and/or who continue to take oral bisphosphonates after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient (see DOSAGE AND ADMINISTRATION). In patients who cannot comply with dosing instructions due to mental disability, therapy with BONIVA (ibandronate sodium) should be used under appropriate supervision.
There have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications, although no increased risk was observed in controlled clinical trials.
Hypocalcemia and Mineral Metabolism
Treat hypocalcemia and other disturbances of bone and mineral metabolism before starting BONIVA (ibandronate sodium) therapy. Adequate intake of calcium and vitamin D is important in all patients to prevent hypocalcemia (see DOSAGE AND ADMINISTRATION). Hypocalcemia following dosing has been reported postmarketing.
Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking BONIVA and other bisphosphonates (see ADVERSE REACTIONS). 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. Consider discontinuing use if severe symptoms develop.
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 (e.g., chemotherapy, radiotherapy, corticosteroids), and co-morbid disorders (e.g., 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 (see ADVERSE REACTIONS).
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.
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.
Severe Renal Impairment
BONIVA (ibandronate sodium) is not recommended for use in patients with severe renal impairment (creatinine clearance of < 30 mL/min).
Patient Counseling Information
See Fda-Approved Medication Guide
Patients should be instructed to read the Medication Guide carefully before taking BONIVA (ibandronate sodium) and to re-read it each time the prescription is renewed because it contains important information the patient should know about BONIVA. The Medication Guide also includes the dosing instructions in order to maximize absorption and clinical benefit.
- BONIVA (ibandronate sodium) should be taken at least 60 minutes before the first food or drink (other than water) of the day and before taking any oral medication or supplementation including calcium, antacids or vitamins (see DRUG INTERACTIONS).
- To facilitate delivery to the stomach, and thus reduce the potential for esophageal irritation, BONIVA (ibandronate sodium) tablets should be swallowed whole with a full glass of plain water (6 to 8 oz) while the patient is standing or sitting in an upright position. Patients should not lie down for 60 minutes after taking BONIVA.
- Patients should not eat, drink anything except for water, or take other medications for 60 minutes after taking BONIVA.
- Plain water is the only drink that should be taken with BONIVA. Note that some mineral waters may have a higher concentration of calcium and therefore should not be used.
- Patients should not chew or suck the tablet because of a potential for oropharyngeal ulceration.
- The BONIVA (ibandronate sodium) 2.5 mg tablet should be taken at the same time each day.
- If a once-daily dose is missed, the patient should be instructed to skip that dose and return to their normal schedule the next day.
- The patient must not take two 2.5 mg tablets within the same day.
- The BONIVA (ibandronate sodium) 150 mg tablet should be taken on the same date each month (i.e., the patient's BONIVA (ibandronate sodium) day).
- The patient must not take two 150 mg tablets within the same week.
- If the once-monthly dose is missed, and the patient's next scheduled BONIVA day is more than 7 days away, the patient should be instructed to take one BONIVA (ibandronate sodium) 150 mg tablet in the morning following the date that it is remembered (see DOSAGE AND ADMINISTRATION). The patient should then return to taking one BONIVA (ibandronate sodium) 150 mg tablet every month in the morning of their chosen day, according to their original schedule.
- If the once-monthly dose is missed, and the patient's next scheduled BONIVA day is only 1 to 7 days away, the patient must wait until the subsequent month's scheduled BONIVA (ibandronate sodium) day to take their tablet. The patient should then return to taking one BONIVA (ibandronate sodium) 150 mg tablet every month in the morning of their chosen day, according to their original schedule.
Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate. Intake of supplemental calcium and vitamin D should be delayed for at least 60 minutes following oral administration of BONIVA (ibandronate sodium) in order to maximize absorption of BONIVA.
Physicians should be alert to signs or symptoms signaling a possible esophageal reaction during therapy, and patients should be instructed to discontinue BONIVA and seek medical attention if they develop symptoms of esophageal irritation such as new or worsening dysphagia, pain on swallowing, retrosternal pain, or heartburn.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 104-week carcinogenicity study, doses of 3, 7, or 15 mg/kg/day were administered by oral gavage to male and female Wistar rats (systemic exposures up to 12 and 7 times, respectively, human exposure at the recommended daily oral dose of 2.5 mg, and cumulative exposures up to 3.5 and 2 times, respectively, human exposure at the recommended once-monthly oral dose of 150 mg, based on 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 male and female NMRI mice (exposures up to 475 and 70 times, respectively, human exposure at the recommended daily oral dose of 2.5 mg and cumulative exposures up to 135 and 20 times, respectively, human exposure at the recommended once-monthly oral dose of 150 mg, based on 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 (cumulative monthly exposures in males and females up to 70 and 115 times, respectively, human exposure at the recommended dose of 150 mg, based on AUC comparison). A dose-related increased incidence of adrenal subcapsular adenoma/carcinoma was observed in female mice, which was statistically significant at 80 mg/kg/day (220 to 400 times human exposure at the recommended daily oral dose of 2.5 mg and 115 times human exposure at the recommended once-monthly oral dose of 150 mg, based on AUC comparison). The relevance of these findings to humans is unknown.
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 were observed at an oral dose of 16 mg/kg/day (45 times human exposure at the recommended daily oral dose of 2.5 mg and 13 times human exposure at the recommended once-monthly oral dose of 150 mg, based on AUC comparison).
Use In Specific Populations
Pregnancy: Category C
There are no adequate and well-controlled studies in pregnant women. BONIVA should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and 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 female rats given ibandronate orally at doses ≥ 3 times human exposure at the recommended daily oral dose of 2.5 mg or ≥ 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 45 times human exposure at the recommended daily dose and 13 times 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 ≥ 16 times the recommended daily dose and ≥ 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 and ≥ 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 (see Nonclinical Toxicology).
Exposure of pregnant rats during the period of organogenesis resulted in an increased fetal incidence of RPU (renal pelvis ureter) syndrome at oral doses 30 times the human exposure at the recommended daily oral dose of 2.5 mg and ≥ 9 times 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 (see Nonclinical Toxicology).
In pregnant rabbits treated orally with ibandronate during gestation at doses ≥ 8 times the recommended human daily oral dose of 2.5 mg and ≥ 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 (see Nonclinical Toxicology).
It is not known whether BONIVA (ibandronate sodium) is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when BONIVA (ibandronate sodium) is administered to a nursing woman. In lactating rats treated with intravenous doses, ibandronate was present in breast milk from 2 to 24 hours after dose administration. Concentrations in milk averaged 1.5 times plasma concentrations.
Safety and effectiveness in pediatric patients have not been established.
Of the patients receiving BONIVA (ibandronate sodium) 2.5 mg daily in postmenopausal osteoporosis studies, 52% were over 65 years of age, and 10% were over 75 years of age. Of the patients receiving BONIVA (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.
BONIVA (ibandronate sodium) is not recommended for use in patients with severe renal impairment (creatinine clearance < 30 mL/min).
Last reviewed on RxList: 3/10/2011
This monograph has been modified to include the generic and brand name in many instances.
Additional Boniva Information
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