Boniva Information
Boniva (Ibandronate sodium) Indications And Usage
The safety and effectiveness of Boniva (Ibandronate sodium) for the treatment of osteoporosis are based on clinical data of three years duration. The optimal duration of use has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis.
Boniva (Ibandronate sodium) Dosage And Administration
Boniva (Ibandronate sodium) is not recommended for use in patients with severe renal impairment (creatinine clearance of
No dose adjustment is necessary for patients with mild or moderate renal impairment.
No dose adjustment is necessary for the elderly, or for patients with hepatic impairment.
Boniva (Ibandronate sodium) Dosage Forms And Strengths
Tablets, 2.5 mg and 150 mg
Boniva (Ibandronate sodium) Warnings And Precautions
Boniva (Ibandronate sodium) , 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 . 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.
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 .
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, 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.
Boniva (Ibandronate sodium) Use In Specific Populations
There are no adequate and well-controlled studies in pregnant women. Boniva (Ibandronate sodium) 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 .
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 .
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 .
Boniva (Ibandronate sodium) Overdosage
No specific information is available on the treatment of overdosage of Boniva (Ibandronate sodium) . However, based on knowledge of this class of compounds, oral overdosage may result in hypocalcemia, hypophosphatemia, and upper gastrointestinal adverse events, such as upset stomach, dyspepsia, esophagitis, gastritis, or ulcer. Milk or antacids should be given to bind Boniva (Ibandronate sodium) . Due to the risk of esophageal irritation, vomiting should not be induced, and the patient should remain fully upright. Dialysis would not be beneficial.
Boniva (Ibandronate sodium) Description
Boniva (Ibandronate sodium) is a nitrogen-containing bisphosphonate that inhibits osteoclast-mediated bone resorption. The chemical name for ibandronate sodium is 3-(-methyl--pentyl) amino-1-hydroxypropane-1,1-diphosphonic acid, monosodium salt, monohydrate with the molecular formula CHNOPNa•HO 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 (Ibandronate sodium) is available as a white, oblong, 2.5 mg film-coated tablet for daily oral administration or as a white, oblong, 150 mg film-coated tablet for once-monthly oral administration. One 2.5 mg film-coated tablet contains 2.813 mg ibandronate monosodium monohydrate, equivalent to 2.5 mg free acid. One 150 mg film-coated tablet contains 168.75 mg ibandronate monosodium monohydrate, equivalent to 150 mg free acid. Boniva (Ibandronate sodium) also contains the following inactive ingredients: lactose monohydrate, povidone, microcrystalline cellulose, crospovidone, purified stearic acid, colloidal silicon dioxide, and purified water. The tablet film coating contains hypromellose, titanium dioxide, talc, polyethylene glycol 6000, and purified water.
Boniva (Ibandronate sodium) Clinical Pharmacology
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.
Boniva (Ibandronate sodium) produced biochemical changes indicative of dose-dependent inhibition of bone resorption, including decreases of biochemical markers of bone collagen degradation (such as deoxypyridinoline, and cross-linked C-telopeptide of Type I collagen) in the daily dose range of 0.25 mg to 5 mg and once-monthly doses from 100 mg to 150 mg in postmenopausal women.
Treatment with 2.5 mg daily Boniva (Ibandronate sodium) resulted in decreases in biochemical markers of bone turnover, including urinary C-terminal telopeptide of Type I collagen (uCTX) and serum osteocalcin, to levels similar to those in premenopausal women. Changes in markers of bone formation were observed later than changes in resorption markers, as expected, due to the coupled nature of bone resorption and formation. Treatment with 2.5 mg daily Boniva (Ibandronate sodium) decreased levels of uCTX within 1 month of starting treatment and decreased levels of osteocalcin within 3 months. Bone turnover markers reached a nadir of approximately 64% below baseline values by 6 months of treatment and remained stable with continued treatment for up to 3 years. Following treatment discontinuation, there is a return to pretreatment baseline rates of elevated bone resorption associated with postmenopausal osteoporosis.
In a 1-year, study comparing once-monthly vs. once-daily oral dosing regimens, the median decrease from baseline in serum CTX values was -76% for patients treated with the 150 mg once-monthly regimen and -67% for patients treated with the 2.5 mg daily regimen. In a 1-year, prevention study comparing Boniva (Ibandronate sodium) 150 mg once-monthly to placebo, the median placebo-subtracted decrease in sCTX was -49.8%.
Boniva (Ibandronate sodium) Nonclinical Toxicology
In female rats given oral doses of 1, 4, or 16 mg/kg/day beginning 14 days before mating and continuing through lactation, maternal deaths were observed at the time of delivery in all dose groups (≥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, based on AUC comparison). Perinatal pup loss in dams given 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) was likely related to maternal dystocia. In pregnant rats given oral doses of 6, 20, or 60 mg/kg/day during gestation, calcium supplementation (32 mg/kg/day by subcutaneous injection from gestation day 18 to parturition) did not completely prevent dystocia and periparturient mortality in any of the treated groups (≥16 times human exposure at the recommended daily oral dose of 2.5 mg and ≥4.6 times human exposure at the recommended once-monthly oral dose of 150 mg, based on AUC comparison). 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 with 1, 5, or 20 mg/kg/day 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 ≥5 mg/kg/day (equivalent to human exposure at the recommended daily oral dose of 2.5 mg and ≥4 times human exposure at the recommended once-monthly oral dose of 150 mg, based on 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 oral doses ≥10 mg/kg/day (≥30 times human exposure at the recommended daily oral dose of 2.5 mg and ≥9 times human exposure at the recommended once-monthly oral dose of 150 mg, based on AUC comparison). Impaired pup neuromuscular development (cliff avoidance test) was observed at 16 mg/kg/day when dams were dosed from 14 days before mating through lactation (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).
In pregnant rabbits given oral doses of 1, 4, or 20 mg/kg/day during gestation, dose-related maternal mortality was observed in all treatment groups (≥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, based on body surface area comparison, mg/m). The deaths occurred prior to parturition and were associated with lung edema and hemorrhage. No significant fetal anomalies were observed.
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 (Ibandronate sodium) administered at therapeutic doses is unlikely to induce osteomalacia.
Long-term daily or once-monthly intermittent administration of ibandronate to ovariectomized rats or monkeys was associated with suppression of bone turnover and increases in bone mass. In both rats and monkeys, vertebral BMD, trabecular density, and biomechanical strength were increased dose-dependently at doses up to 15 times the recommended human daily oral dose of 2.5 mg, or cumulative monthly doses up to 8 times (rat) or 6 times (monkey) the recommended human once-monthly oral dose of 150 mg, based on body surface area (mg/m) or AUC comparison. In monkeys, 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 (Ibandronate sodium) How Supplied/storage And Handling
Boniva (Ibandronate sodium) 2.5 mg tablets: supplied as white, oblong, film-coated tablets, engraved with "IT" on one side and "L3" on the other side and packaged in bottles of 30 tablets (NDC 0004-0185-23).
Boniva (Ibandronate sodium) 150 mg tablets: supplied as white, oblong, film-coated tablets, engraved with "BNVA" on one side and "150" on the other side. Packaged in boxes of 3 blister packs containing 1 tablet each (NDC 0004-0186-82).
Boniva (Ibandronate sodium) Patient Counseling Information
See
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 (Ibandronate sodium) . The Medication Guide also includes the dosing instructions in order to maximize absorption and clinical benefit.
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 (Ibandronate sodium) .
Physicians should be alert to signs or symptoms signaling a possible esophageal reaction during therapy, and patients should be instructed to discontinue Boniva (Ibandronate sodium) and seek medical attention if they develop symptoms of esophageal irritation such as new or worsening dysphagia, pain on swallowing, retrosternal pain, or heartburn.
Boniva (Ibandronate sodium)
Boniva (Ibandronate sodium)
