Ibandronate Sodium Tablets
TABLE OF CONTENTS
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.H20 and a molecular weight of 359.24. Ibandronate sodium has the following structural formula:
Ibandronate sodium is a white- to off-white powder. It is freely soluble in water and practically insoluble in organic solvents.
Ibandronate 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. Ibandronate 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.
|2. INDICATIONS AND USAGE|
2.1 Treatment and Prevention of Postmenopausal Osteoporosis
Ibandronate is indicated for the treatment and prevention of osteoporosis in postmenopausal women. Ibandronate increases bone mineral density (BMD) and reduces the incidence of vertebral fractures.
2.2 Important Limitations of Use
The optimal duration of use has not been determined. The safety and effectiveness of ibandronate 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.
|3. DOSAGE AND ADMINISTRATION|
The dose of ibandronate is one 150 mg tablet taken once monthly on the same date each month.
3.2 Important Administration Instructions
Instruct patients to do the following:
• Take ibandronate at least 60 minutes before the first food or drink (other than water) of the day or before taking any oral medication or supplementation, including calcium, antacids, or vitamins to maximize absorption and clinical benefit, (see DRUG INTERACTIONS). Avoid the use of water with supplements including mineral water because they may have a higher concentration of calcium.
• Swallow ibandronate tablets whole with a full glass of plain water (6 to 8 oz) while standing or sitting in an upright position to reduce the potential for esophageal irritation. Avoid lying down for 60 minutes after taking ibandronate (see WARNINGS AND PRECAUTIONS). Do not chew or suck the tablet because of a potential for oropharyngeal ulceration.
• Do not eat, drink anything except plain water, or take other medications for at least 60 minutes after taking ibandronate.
3.3 Recommendations for Calcium and Vitamin D Supplementation
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 BONVIA administration because co-administration of ibandronate and calcium may interfere with the absorption of ibandronate sodium (see DRUG INTERACTIONS).
3.4 Administration Instructions for Missed Once-Monthly Doses
If the once-monthly dose is missed, instruct patients to do the following:
• If the next scheduled ibandronate day is more than 7 days away, take one ibandronate 150 mg tablet in the morning following the date that it is remembered.
• If the next scheduled ibandronate day is only 1 to 7 days away, wait until the subsequent month’s scheduled ibandronate day to take their tablet.
For subsequent monthly doses for both of the above scenarios, instruct patients to return to their original schedule by taking one ibandronate 150 mg tablet every month on their previous chosen day.
Ibandronate is contraindicated in patients with the following conditions:
• Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia (see Upper Gastrointestinal Adverse Reactions)
• Inability to stand or sit upright for at least 60 minutes (see Dosing Instructions, Upper Gastrointestinal Adverse Reactions)
• Hypocalcemia (see WARNINGS AND PRECAUTIONS)
• Known hypersensitivity to ibandronate or to any of its excipients (see ADVERSE REACTIONS}
|5. MECHANISM OF ACTION|
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.
|6. USE IN SPECIFIC POPULATIONS|
Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. This drug should be used during pregnancy only if the potential benefit justifies the potential risk to the 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 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 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 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 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 30 times the human exposure at the recommended daily oral dose of 2.5 mg and greater than or equal to 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 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.
6.2 Nursing Mothers
It is not known whether ibandronate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ibandronate 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.
6.3 Pediatric Use
Safety and effectiveness in the pediatric population have not been established.
6.4 Geriatric Use
Of the patients receiving ibandronate 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 ibandronate 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.
6.5 Renal Impairment
Ibandronate is not recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/min).
|7. WARNINGS AND PRECAUTIONS|
7.1 Upper Gastrointestinal Adverse Reactions
Ibandronate, 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 ibandronate 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 ibandronate 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 ibandronate 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.
7.2 Hypocalcemia and Mineral Metabolism
Treat hypocalcemia and other disturbances of bone and mineral metabolism before starting ibandronate 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.
7.3 Musculoskeletal Pain
Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking ibandronate 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.
7.4 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 (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.
7.5 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.
7.6 Severe Renal Impairment
Ibandronate is not recommended for use in patients with severe renal impairment (creatinine clearance of < 30 mL/min).
|8. ADVERSE REACTIONS|
8.1 Clinical Trials Experience
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 ibandronate 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 ibandronate 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 IU vitamin D supplementation daily.
The incidence of all-cause mortality was 1% in the placebo group and 1.2% in the ibandronate 2.5 mg daily group. The incidence of serious adverse events was 20% in the placebo group and 23% in the ibandronate 2.5 mg daily group. The percentage of patients who withdrew from treatment due to adverse events was approximately 17% in both the ibandronate 2.5 mg daily group and the placebo group. Table 1 lists adverse events from the treatment and prevention studies reported in ≥2% of patients and more frequently in patients treated daily with ibandronate than patients treated with placebo.
Table 1. Adverse Events Occurring at a Frequency ≥2% and More Frequently in Patients Treated with Ibandronate than in Patients Treated with Placebo Daily in the Osteoporosis Treatment and Prevention Studies
Gastrointestinal Adverse Events
The incidence of adverse events in the placebo and ibandronate 2.5 mg daily groups were: dyspepsia (10% vs. 12%), diarrhea (5% vs. 7%), and abdominal pain (5% vs. 6%).
Musculoskeletal Adverse Events
The incidence of adverse events in the placebo and ibandronate 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 ibandronate 2.5 mg daily.
The safety of ibandronate 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 ibandronate 2.5 mg daily and 396 exposed to ibandronate 150 mg monthly. Patients with active or significant pre-existing gastrointestinal disease were excluded from this trial. Patients with dyspepsia or concomitant use of nonsteroidal anti-inflammatory drugs, proton pump inhibitors and H2 antagonists were included in this study. All patients received 500 mg calcium plus 400 IU vitamin D supplementation daily.
After one year, the incidence of all-cause mortality was 0.3% in both the ibandronate 2.5 mg daily group and the ibandronate 150 mg monthly group. The incidence of serious adverse events was 5% in the ibandronate 2.5 mg daily group and 7% in the ibandronate 150 mg monthly group. The percentage of patients who withdrew from treatment due to adverse events was 9% in the ibandronate 2.5 mg daily group and 8% in the ibandronate 150 mg monthly group. Table 2 lists the adverse events reported in ≥2% of patients.
Table 2. Adverse Events with an Incidence of at Least 2% in Patients Treated with Ibandronate 2.5 mg Daily or 150 mg Once-Monthly for Treatment of Postmenopausal Osteoporosis
a Combination of abdominal pain and abdominal pain upper
b Combination of influenza-like illness and acute phase reaction
c Combination of rash pruritic, rash macular, rash papular, rash generalized, rash erythematous, dermatitis, dermatitis allergic, dermatitis medicamentosa, erythema and exanthem
Gastrointestinal Adverse Events
The incidence of adverse events in the ibandronate 2.5 mg daily and ibandronate 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 ibandronate 2.5 mg daily and ibandronate 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 ibandronate 2.5 mg daily group and 9% in the ibandronate 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 ibandronate 2.5 mg daily group and 2% in the ibandronate 150 mg monthly group.
Ocular Adverse Events
Two patients who received ibandronate 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 ibandronate 150 mg once-monthly for prevention of bone loss. Seventy-seven subjects received ibandronate and 83 subjects received placebo. The overall pattern of adverse events was similar to that previously observed.
8.2 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of ibandronate. 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 anaphylaxis, angioedema, bronchospasm and rash have been reported (see CONTRAINDICATIONS).
Hypocalcemia has been reported in patients treated with ibandronate (see WARNINGS AND PRECAUTIONS).
Bone, joint, or muscle pain (musculoskeletal pain), described as severe or incapacitating, has been reported (see WARNINGS AND PRECAUTIONS).
Osteonecrosis of the jaw has been reported in patients treated with ibandronate (see WARNINGS AND PRECAUTIONS}.
No specific information is available on the treatment of overdosage with ibandronate. 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 ibandronate. Due to the risk of esophageal irritation, vomiting should not be induced, and the patient should remain fully upright. Dialysis would not be beneficial.
|10. DRUG INTERACTIONS|
Products containing calcium and other multivalent cations (such as aluminum, magnesium, iron) are likely to interfere with absorption of ibandronate. Ibandronate should be taken at least 60 minutes before any oral medications containing multivalent cations (including antacids, supplements or vitamins).
H2 Blockers and Proton Pump Inhibitors (PPIs)
Of over 3500 patients enrolled in the ibandronate osteoporosis Treatment and Prevention Studies, 15% used anti-peptic agents (primarily H2 blockers and PPIs). Among these patients, the incidence of upper gastrointestinal adverse experiences in the patients treated with ibandronate was similar to that in placebo-treated patients.
Aspirin/Nonsteroidal Antiinflammatory Drugs (NSAIDs)
In the large, placebo-controlled osteoporosis Treatment Study, aspirin and nonsteroidal antiinflammatory drugs were taken by 62% of the 2946 patients. Among aspirin or NSAID users, the incidence of upper gastrointestinal adverse events in patients treated with ibandronate 2.5 mg daily (28.9%) was similar to that in placebo-treated patients (30.7%). However, since aspirin, NSAIDs, and bisphosphonates are all associated with gastrointestinal irritation, caution should be exercised in the concomitant use of aspirin or NSAIDs with ibandronate.
Drug/Laboratory Test Interactions
Bisphosphonates are known to interfere with the use of bone-imaging agents. Specific studies with ibandronate have not been performed.
The absorption of ibandronate occurs in the upper gastrointestinal tract. After a 2.5 mg oral dose, 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 ibandronate is administered 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.
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 range of observed apparent half-lives is broad and dependent on the dose studied and on assay sensitivity, but the apparent terminal half-life is generally in the range of 10 to 60 hours. However, early plasma levels fall quickly, reaching 10% of peak values within 3 and 8 hours after intravenous or oral administration, respectively.
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 <18 years of age.
The bioavailability and pharmacokinetics of ibandronate are similar in both men and women.
Since 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 (see Special Populations: Renal Impairment).
Pharmacokinetic differences due to race have not been studied.
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 >90 mL/min. Patients with CLcr <30 mL/min had more than a two-fold increase in exposure compared to the exposure for healthy subjects (see DOSAGE AND ADMINISTRATION: Patients with Renal Impairment).
No studies have been performed to assess the pharmacokinetics of ibandronate in patients with hepatic impairment since ibandronate is not metabolized in the human liver.
|12. HOW SUPPLIED/STORAGE AND HANDLING|
1) How Available:
a) Brand name: BONIVA, by Roche Laboratories Inc.
b) Generic drugs: Ibandronate sodium, by various manufacturers.
2) How Supplied:
Ibandronate sodium tablets (by Dr. Reddy’s Laboratories Limited), 150 mg are white, film coated and capsule shaped tablets printed with R575 on one side and plain on other side. They are supplied in carton of 3 packs containing 1 tablet each.
Carton of 3 packs (NDC 55111-575-03), each pack containing 1 tablet (NDC 55111-575-11)
3) Storage: Store at 25°C (77°F); excursions permitted between 15° and 30°C (59° and 86°F).