BONIVA- ibandronate sodium tablet, film coated
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use BONIVA Tablets safely and effectively. See full prescribing information for BONIVA Tablets.
BONIVA® (ibandronate sodium) Tablets
Initial U.S. Approval: 2003
INDICATIONS AND USAGE
DOSAGE AND ADMINISTRATION
DOSAGE FORMS AND STRENGTHS
Tablets: 150 mg (3)
WARNINGS AND PRECAUTIONS
The most common adverse reactions (greater than 5%) are back pain, dyspepsia, pain in extremity, diarrhea, headache, and myalgia. (6)
USE IN SPECIFIC POPULATIONS
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
FULL PRESCRIBING INFORMATION: CONTENTS*
BONIVA is indicated for the treatment and prevention of osteoporosis in postmenopausal women. BONIVA increases bone mineral density (BMD) and reduces the incidence of vertebral fractures.
The optimal duration of use has not been determined. The safety and effectiveness of BONIVA for the treatment of osteoporosis are based on clinical data of three years duration. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis. Patients at low-risk for fracture should be considered for drug discontinuation after 3 to 5 years of use. Patients who discontinue therapy should have their risk for fracture re-evaluated periodically.
The dose of BONIVA is one 150 mg tablet taken once monthly on the same date each month.
Instruct Patients to do the following:
Instruct patients to take supplemental calcium and vitamin D if their dietary intake is inadequate. Avoid the use of calcium supplements within 60 minutes of BONIVA administration because co-administration of BONIVA and calcium may interfere with the absorption of ibandronate sodium (see DRUG INTERACTIONS [7.1]).
If the once-monthly dose is missed, instruct patients to do the following:
For subsequent monthly doses for both of the above scenarios, instruct patients to return to their original schedule by taking one BONIVA 150 mg tablet every month on their previous chosen day.
BONIVA 150 mg tablets: white, oblong, engraved with "BNVA" on one side and "150" on the other side.
BONIVA is contraindicated in patients with the following conditions:
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 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 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 [2.2]). In patients who cannot comply with dosing instructions due to mental disability, therapy with BONIVA 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 has been reported in patients taking BONIVA. Treat hypocalcemia and other disturbances of bone and mineral metabolism before starting BONIVA therapy. Instruct patients to take supplemental calcium and vitamin D if their dietary intake is inadequate (see DOSAGE AND ADMINISTRATION [2.3]).
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 of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients taking bisphosphonates, including BONIVA. Known risk factors for osteonecrosis of the jaw include invasive dental procedures (e.g., tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and co-morbid disorders (e.g., periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). The risk of ONJ may increase with duration of exposure to bisphosphonates.
For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk for ONJ. Clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit/risk assessment.
Patients who develop osteonecrosis of the jaw while on bisphosphonate therapy should receive care by an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of bisphosphonate therapy should be considered 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.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Treatment and Prevention of Postmenopausal Osteoporosis
The safety of BONIVA 2.5 mg once daily in the treatment and prevention of postmenopausal osteoporosis was assessed in 3577 patients aged 41 – 82 years. The duration of the trials was 2 to 3 years, with 1134 patients exposed to placebo and 1140 exposed to BONIVA 2.5 mg. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors and H2 antagonists were included in these clinical trials. All patients received 500 mg calcium plus 400 international units vitamin D supplementation daily.
The incidence of all-cause mortality was 1% in the placebo group and 1.2% in the BONIVA 2.5 mg daily group. The incidence of serious adverse reactions was 20% in the placebo group and 23% in the BONIVA 2.5 mg daily group. The percentage of patients who withdrew from treatment due to adverse reactions was approximately 17% in both the BONIVA 2.5 mg daily group and the placebo group. Table 1 lists adverse reactions from the treatment and prevention studies reported in greater than or equal to 2% of patients and more frequently in patients treated daily with BONIVA than patients treated with placebo.
|BONIVA 2.5 mg
|Body as a Whole|
|Pain in Extremity||6||8|
|Upper Respiratory Infection||33||34|
|Urinary Tract Infection||4||6|
Gastrointestinal Adverse Reactions
The incidence of selected gastrointestinal adverse reactions in the placebo and BONIVA 2.5 mg daily groups were: dyspepsia (10% vs. 12%), diarrhea (5% vs. 7%), and abdominal pain (5% vs. 6%).
Musculoskeletal Adverse Reactions
The incidence of selected musculoskeletal adverse reactions in the placebo and BONIVA 2.5 mg daily groups were: back pain (12% vs. 14%), arthralgia (14% vs. 14%) and myalgia (5% vs. 6%).
Ocular Adverse Events
Reports in the medical literature indicate that bisphosphonates may be associated with ocular inflammation such as iritis and scleritis. In some cases, these events did not resolve until the bisphosphonate was discontinued. There were no reports of ocular inflammation in studies with BONIVA 2.5 mg daily.
The safety of BONIVA 150 mg once monthly in the treatment of postmenopausal osteoporosis was assessed in a two year trial which enrolled 1583 patients aged 54 – 81 years, with 395 patients exposed to BONIVA 2.5 mg daily and 396 exposed to BONIVA 150 mg monthly. Patients with active or significant pre-existing gastrointestinal disease were excluded from this trial. Patients with dyspepsia or concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors and H2 antagonists were included in this study. All patients received 500 mg calcium plus 400 international units vitamin D supplementation daily.
After one year, the incidence of all-cause mortality was 0.3% in both the BONIVA 2.5 mg daily group and the BONIVA 150 mg monthly group. The incidence of serious adverse events was 5% in the BONIVA 2.5 mg daily group and 7% in the BONIVA 150 mg monthly group. The percentage of patients who withdrew from treatment due to adverse events was 9% in the BONIVA 2.5 mg daily group and 8% in the BONIVA 150 mg monthly group. Table 2 lists the adverse events reported in greater than or equal to 2% of patients.
|Body System/Adverse Event||BONIVA|
2.5 mg Daily
150 mg Monthly
|Musculoskeletal and Connective Tissue Disorders|
|Pain in Extremity||1.3||4.0|
|Infections and Infestations|
|Urinary Tract Infection||1.8||2.3|
|Upper Respiratory Tract Infection||2.0||2.0|
|Nervous System Disorders|
|General Disorders and Administration Site Conditions|
|Skin and Subcutaneous Tissue Disorders|
Gastrointestinal Adverse Events
The incidence of adverse events in the BONIVA 2.5 mg daily and BONIVA 150 mg monthly groups were: dyspepsia (7% vs. 6%), diarrhea (4% vs. 5%), and abdominal pain (5% vs. 8%).
Musculoskeletal Adverse Events
The incidence of adverse events in the BONIVA 2.5 mg daily and BONIVA 150 mg monthly groups were: back pain (4% vs. 5%), arthralgia (4% vs. 6%) and myalgia (1% vs. 2%).
Acute Phase Reactions
Symptoms consistent with acute phase reactions have been reported with bisphosphonate use. Over the two years of the study, the overall incidence of acute phase reaction symptoms was 3% in the BONIVA 2.5 mg daily group and 9% in the BONIVA 150 mg monthly group. These incidence rates are based on the reporting of any of 33 acute-phase reaction like symptoms within 3 days of the monthly dosing and lasting 7 days or less. Influenza like illness was reported in no patients in the BONIVA 2.5 mg daily group and 2% in the BONIVA 150 mg monthly group.
Ocular Adverse Events
Two patients who received BONIVA 150 mg once-monthly experienced ocular inflammation, one was a case of uveitis and the other scleritis.
One hundred sixty (160) postmenopausal women without osteoporosis participated in a 1-year, double-blind, placebo-controlled study of BONIVA 150 mg once-monthly for prevention of bone loss. Seventy-seven subjects received BONIVA and 83 subjects received placebo. The overall pattern of adverse events was similar to that previously observed.
The following adverse reactions have been identified during postapproval use of BONIVA. 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.
Allergic reactions including anaphylactic reaction/shock with fatalities, angioedema, bronchospasm, asthma exacerbations, rash, Stevens-Johnson syndrome, erythema multiforme, and dermatitis bullous have been reported (see CONTRAINDICATIONS ).
Hypocalcemia has been reported in patients treated with BONIVA (see WARNINGS AND PRECAUTIONS [5.2]).
Bone, joint, or muscle pain (musculoskeletal pain), described as severe or incapacitating, has been reported (see WARNINGS AND PRECAUTIONS [5.3]).
Osteonecrosis of the jaw and other oro-facial sites, including the external auditory canal, have been reported in patients treated with BONIVA (see WARNINGS AND PRECAUTIONS [5.4]).
Atypical Femoral Shaft Fracture
Atypical, low-energy, or low-trauma fractures of the femoral shaft (see WARNINGS AND PRECAUTIONS [5.5]).
Products containing calcium and other multivalent cations (such as aluminum, magnesium, iron) are likely to interfere with absorption of BONIVA. Therefore, instruct patients to take BONIVA 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]).
Because aspirin, NSAIDs, and bisphosphonates are all associated with gastrointestinal irritation, caution should be exercised in the concomitant use of aspirin or NSAIDs with BONIVA.
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]).
BONIVA is not indicated for use in women of reproductive potential. There are no data with BONIVA use in pregnant women to inform any drug-associated risks.
In reproductive toxicity studies in the rat, BONIVA 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, BONIVA 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).
In female rats given ibandronate at oral doses greater than or equal to 3 times human exposure at the recommended 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, 20 mg/kg/day in rabbits.
BONIVA 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.
Of the patients receiving BONIVA 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 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.
No specific information is available on the treatment of overdosage of BONIVA. 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. 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) 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 C9H22NO7P2Na•H2O 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 is available as a white, oblong, 150 mg film-coated tablet for once-monthly oral administration. One 150 mg film-coated tablet contains 168.75 mg ibandronate monosodium monohydrate, equivalent to 150 mg free acid. BONIVA 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.
The action of ibandronate on bone tissue is based on its affinity for hydroxyapatite, which is part of the mineral matrix of bone. Ibandronate inhibits osteoclast activity and reduces bone resorption and turnover. In postmenopausal women, it reduces the elevated rate of bone turnover, leading to, on average, a net gain in bone mass.
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 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 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 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 150 mg once-monthly to placebo, the median placebo-subtracted decrease in sCTX was -49.8%.
The absorption of oral ibandronate occurs in the upper gastrointestinal tract. Plasma concentrations increase in a dose-linear manner up to 50 mg oral intake and increases nonlinearly above this dose.
Following oral dosing, the time to maximum observed plasma ibandronate concentrations ranged from 0.5 to 2 hours (median 1 hour) in fasted healthy postmenopausal women. The mean oral bioavailability of 2.5 mg ibandronate was about 0.6% compared to intravenous dosing. The extent of absorption is impaired by food or beverages (other than plain water). The oral bioavailability of ibandronate is reduced by about 90% when BONIVA is administered concomitantly with a standard breakfast in comparison with bioavailability observed in fasted subjects. There is no meaningful reduction in bioavailability when ibandronate is taken at least 60 minutes before a meal. However, both bioavailability and the effect on bone mineral density (BMD) are reduced when food or beverages are taken less than 60 minutes following an ibandronate dose.
After absorption, ibandronate either rapidly binds to bone or is excreted into urine. In humans, the apparent terminal volume of distribution is at least 90 L, and the amount of dose removed from the circulation via the bone is estimated to be 40% to 50% of the circulating dose. In vitro protein binding in human serum was 99.5% to 90.9% over an ibandronate concentration range of 2 to 10 ng/mL in one study and approximately 85.7% over a concentration range of 0.5 to 10 ng/mL in another study.
Ibandronate does not undergo hepatic metabolism and does not inhibit the hepatic cytochrome P450 system. Ibandronate is eliminated by renal excretion. Based on a rat study, the ibandronate secretory pathway does not appear to include known acidic or basic transport systems involved in the excretion of other drugs. There is no evidence that ibandronate is metabolized in humans.
The portion of ibandronate that is not removed from the circulation via bone absorption is eliminated unchanged by the kidney (approximately 50% to 60% of the absorbed dose). Unabsorbed ibandronate is eliminated unchanged in the feces.
The plasma elimination of ibandronate is multiphasic. Its renal clearance and distribution into bone accounts for a rapid and early decline in plasma concentrations, reaching 10% of the Cmax within 3 or 8 hours after intravenous or oral administration, respectively. This is followed by a slower clearance phase as ibandronate redistributes back into the blood from bone. The observed apparent terminal half-life for ibandronate is generally dependent on the dose studied and on assay sensitivity. The observed apparent terminal half-life for the 150 mg ibandronate tablet upon oral administration to healthy postmenopausal women ranges from 37 to 157 hours.
Total clearance of ibandronate is low, with average values in the range 84 to 160 mL/min. Renal clearance (about 60 mL/min in healthy postmenopausal females) accounts for 50% to 60% of total clearance and is related to creatinine clearance. The difference between the apparent total and renal clearances likely reflects bone uptake of the drug.
The pharmacokinetics of ibandronate has not been studied in patients less than 18 years of age.
Because ibandronate is not known to be metabolized, the only difference in ibandronate elimination for geriatric patients versus younger patients is expected to relate to progressive age-related changes in renal function.
Renal clearance of ibandronate in patients with various degrees of renal impairment is linearly related to creatinine clearance (CLcr).
Following a single dose of 0.5 mg ibandronate by intravenous administration, patients with CLcr 40 to 70 mL/min had 55% higher exposure (AUC∞) than the exposure observed in subjects with CLcr greater than 90 mL/min. Patients with CLcr less than 30 mL/min had more than a two-fold increase in exposure compared to the exposure for healthy subjects (see DOSAGE AND ADMINISTRATION [2.4]).
Drug Interaction Studies
Products containing calcium and other multivalent cations (such as aluminum, magnesium, iron), including milk, food, and antacids are likely to interfere with absorption of ibandronate, which is consistent with findings in animal studies.
A pharmacokinetic interaction study in healthy volunteers demonstrated that 75 mg ranitidine (25 mg injected intravenously 90 and 15 minutes before and 30 minutes after ibandronate administration) increased the oral bioavailability of 10 mg ibandronate by about 20%. This degree of increase is not considered to be clinically relevant.
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).
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 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/m2) or area under the curve (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.
The effectiveness and safety of BONIVA were demonstrated in a randomized, double-blind, placebo-controlled, multinational study (Treatment Study) of 2946 women aged 55 to 80 years, who were on average 21 years postmenopause, who had lumbar spine BMD 2 to 5 SD below the premenopausal mean (T-score) in at least one vertebra [L1-L4], and who had 1 to 4 prevalent vertebral fractures. BONIVA was evaluated at oral doses of 2.5 mg daily and 20 mg intermittently. The main outcome measure was the occurrence of new radiographically diagnosed vertebral fractures after 3 years of treatment. The diagnosis of an incident vertebral fracture was based on both qualitative diagnosis by the radiologist and quantitative morphometric criterion. The morphometric criterion required the dual occurrence of 2 events: a relative height ratio or relative height reduction in a vertebral body of at least 20%, together with at least a 4 mm absolute decrease in height. All women received 400 international units vitamin D and 500 mg calcium supplementation per day.
Effect on Fracture Incidence
BONIVA 2.5 mg daily significantly reduced the incidence of new vertebral (primary efficacy measure) and of new and worsening vertebral fractures. Over the course of the 3-year study, the risk for vertebral fracture was 9.6% in the placebo-treated women and 4.7% in the women treated with BONIVA 2.5 mg (p<0.001) (see Table 3).
|Proportion of Patients with Fracture (%)|
|BONIVA 2.5 mg Daily|
|Absolute Risk Reduction|
|Relative Risk Reduction (%)
|New Vertebral Fracture||9.6||4.7||4.9||52 †|
|0-3 Year||(2.3, 7.4)||(29, 68)|
|New and Worsening Vertebral Fracture||10.4||5.1||5.3||52|
|0-3 Year||(2.6, 7.9)||(30, 67)|
|Clinical (Symptomatic) Vertebral Fracture||5.3||2.8||2.5||49|
|0-3 Year||(0.6, 4.5)||(14, 69)|
BONIVA 2.5 mg daily did not reduce the incidence of nonvertebral fractures (secondary efficacy measure). There was a similar number of nonvertebral osteoporotic fractures at 3 years reported in women treated with BONIVA 2.5 mg daily [9.1%, (95% CI: 7.1%, 11.1%)] and placebo [8.2%, (95% CI: 6.3%, 10.2%)]. The two treatment groups were also similar with regard to the number of fractures reported at the individual nonvertebral sites: pelvis, femur, wrist, forearm, rib, and hip.
Bone Mineral Density (BMD)
BONIVA significantly increased BMD at the lumbar spine and hip relative to treatment with placebo. In the 3-year osteoporosis treatment study, BONIVA 2.5 mg daily produced increases in lumbar spine BMD that were progressive over 3 years of treatment and were statistically significant relative to placebo at 6 months and at all later time points. Lumbar spine BMD increased by 6.4% after 3 years of treatment with 2.5 mg daily BONIVA compared with 1.4% in the placebo group. Table 4 displays the significant increases in BMD seen at the lumbar spine, total hip, femoral neck, and trochanter compared to placebo.
|Placebo||BONIVA 2.5 mg Daily|
The effects of BONIVA 2.5 mg daily on bone histology were evaluated in iliac crest biopsies from 16 women after 22 months of treatment and 20 women after 34 months of treatment.
The histological analysis of bone biopsies showed bone of normal quality and no indication of osteomalacia or a mineralization defect.
The effectiveness and safety of BONIVA once-monthly were demonstrated in a randomized, double-blind, multinational, noninferiority trial in 1602 women aged 54 to 81 years, who were on average 18 years postmenopause, and had L2-L4 lumbar spine BMD T-score below -2.5 SD at baseline. The main outcome measure was the comparison of the percentage change from baseline in lumbar spine BMD after 1 year of treatment with once-monthly ibandronate (100 mg, 150 mg) to daily ibandronate (2.5 mg). All patients received 400 international units vitamin D and 500 mg calcium supplementation per day.
BONIVA 150 mg once-monthly (n=327) was shown to be noninferior to BONIVA 2.5 mg daily (n=318) in lumbar spine BMD in a 1-year, double-blind, multicenter study of women with postmenopausal osteoporosis. In the primary efficacy analysis (per-protocol population), the mean increases from baseline in lumbar spine BMD at 1 year were 3.86% (95% CI: 3.40%, 4.32%) in the 2.5 mg daily group and 4.85% (95% CI: 4.41%, 5.29%) in the 150 mg once-monthly group; the mean difference between 2.5 mg daily and 150 mg once-monthly was 0.99% (95% CI: 0.38%, 1.60%), which was statistically significant (p=0.002). The results of the intent-to-treat analysis were consistent with the primary efficacy analysis. The 150 mg once-monthly group also had consistently higher BMD increases at the other skeletal sites compared to the 2.5 mg daily group.
The safety and effectiveness of BONIVA 2.5 mg daily for the prevention of postmenopausal osteoporosis were demonstrated in a randomized, double-blind, placebo-controlled 2-year study (Prevention Study) of 653 postmenopausal women without osteoporosis at baseline. Women were aged 41 to 82 years, were on average 8.5 years postmenopause, and had lumbar spine BMD T-scores greater than -2.5. Women were stratified according to time since menopause (1 to 3 years, greater than 3 years) and baseline lumbar spine BMD (T-score: greater than -1, -1 to -2.5). The study compared daily BONIVA at three dose levels (0.5 mg, 1.0 mg, 2.5 mg) with placebo. All women received 500 mg of supplemental calcium per day.
The primary efficacy measure was the change in BMD of lumbar spine after 2 years of treatment. BONIVA 2.5 mg daily resulted in a mean increase in lumbar spine BMD of 3.1% compared with placebo following 2 years of treatment. Increases in BMD were seen at 6 months and at all later time points. Irrespective of the time since menopause or the degree of pre-existing bone loss, treatment with BONIVA resulted in a higher BMD response at the lumbar spine compared with placebo across all four baseline strata [time since menopause (1 to 3 years, greater than 3 years) and baseline lumbar spine BMD (T-score: greater than -1, -1 to -2.5)].
Compared with placebo, treatment with BONIVA 2.5 mg daily increased BMD of the total hip by 1.8%, the femoral neck by 2.0%, and the trochanter by 2.1%.
The safety and effectiveness of BONIVA 150 mg once-monthly for the prevention of postmenopausal osteoporosis were demonstrated in a randomized, double-blind, placebo-controlled 1-year study (Monthly Prevention Study) of 160 postmenopausal women with low bone mass at baseline (T-score of -1 to -2.5). Women, aged 46 to 60 years, were on average 5.4 years postmenopause. All women received 400 international units of vitamin D and 500 mg calcium supplementation daily.
The primary efficacy measure was the relative change in BMD at the lumbar spine after 1 year of treatment. BONIVA 150 mg once-monthly resulted in a mean increase in lumbar spine BMD of 4.12% (95% confidence interval 2.96 – 5.28) compared with placebo following 1 year of treatment (p<0.0001), based on a 3.73% and -0.39% mean change in BMD from baseline in the 150 mg once-monthly BONIVA and placebo treatment groups, respectively. BMD at other skeletal sites was also increased relative to baseline values.
BONIVA 150 mg tablets: supplied as white, oblong, film-coated tablets, engraved with "BNVA" on one side and "150" on the other side. Packaged as a three-month supply in:
A box with 1 blister pack containing 3 tablets (NDC 0004-0186-83).
Instruct patients to read the Medication Guide carefully before taking BONIVA 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.
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 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.
Read the Medication Guide that comes with BONIVA before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or your treatment. Talk to your doctor if you have any questions about BONIVA.
BONIVA may cause serious side effects including:
Call your doctor right away if you have any of these side effects.
What is BONIVA?
BONIVA is a prescription medicine used to treat or prevent osteoporosis in women after menopause. BONIVA helps increase bone mass and helps reduce the chance of having a spinal fracture (break).
It is not known how long BONIVA works for the treatment and prevention of osteoporosis. You should see your doctor regularly to determine if BONIVA is still right for you.
It is not known if BONIVA is safe and effective in children.
Who should not take BONIVA?
Do not take BONIVA if you:
What should I tell my doctor before taking BONIVA?
Before you start BONIVA, be sure to talk to your doctor if you:
Tell your doctor and dentist about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Certain medicines may affect how BONIVA works.
Especially tell your doctor if you take:
Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist each time you get a new medicine.
After swallowing BONIVA tablet, wait at least 60 minutes:
Do not lie down for at least 60 minutes after you take BONIVA and do not eat your first food of the day for at least 60 minutes after you take BONIVA.
If you miss a dose of BONIVA, do not take it later in the day. Call your doctor for instructions.
If you take too much BONIVA, call your doctor. Do not try to vomit. Do not lie down.
What are the possible side effects of BONIVA?
BONIVA may cause serious side effects.
The most common side effects of BONIVA are:
You may get allergic reactions, such as hives, breathing difficulties, swelling of your face, lips, tongue or throat, or feeling faint.
Tell your doctor if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of BONIVA. For more information, ask your doctor or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Genentech at 1-888-835-2555.
How do I store BONIVA?
Keep BONIVA and all medicines out of the reach of children.
General information about the safe and effective use of BONIVA.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use BONIVA for a condition for which it was not prescribed. Do not give BONIVA to other people, even if they have the same symptoms you have. It may harm them.
This Medication Guide summarizes the most important information about BONIVA. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about BONIVA that is written for health professionals.
What are the ingredients in BONIVA?
Active ingredient: ibandronate sodium
Inactive ingredients: lactose monohydrate, povidone, microcrystalline cellulose, crospovidone, purified stearic acid, colloidal silicon dioxide, and purified water. Tablet film coating contains: hypromellose, titanium dioxide, talc, polyethylene glycol 6000 and purified water.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
BONIVA is a registered trademark of Roche Therapeutics Inc.
Genentech USA, Inc.
A Member of the Roche Group
1 DNA Way
South San Francisco, CA 94080-4990
Revised: December 2016
© 2016 Genentech, Inc. All rights reserved.
Representative sample of labeling (see the HOW SUPPLIED section for complete listing):
Three 150 mg Tablets =
(ibandronate sodium) Tablets
One tablet contains 168.75 mg ibandronate monosodium monohydrate, equivalent to 150 mg free acid.
PHARMACIST: Dispense intact with the enclosed Medication Guide to each patient
USUAL DOSAGE: One tablet once a month.
(ibandronate sodium) Tablets
One tablet contains 168.75 mg ibandronate monosodium monohydrate,
equivalent to 150 mg free acid.
PHARMACIST: Dispense the enclosed Medication Guide to each patient.
USUAL DOSAGE: See package insert.
3 Packs–One Tablet Per Pack
ibandronate sodium tablet, film coated
|Labeler - Genentech, Inc. (080129000)|
|Roche Diagnostics GmbH||315028860||ANALYSIS(0004-0186) , API MANUFACTURE(0004-0186)|
|F. Hoffmann-La Roche Ltd||485244961||LABEL(0004-0186) , PACK(0004-0186) , ANALYSIS(0004-0186)|
|F. Hoffmann-La Roche AG||482242971||ANALYSIS(0004-0186) , API MANUFACTURE(0004-0186) , LABEL(0004-0186) , MANUFACTURE(0004-0186) , PACK(0004-0186)|