Ostex

Ostex

ibandronic acid

Manufacturer:

Nang Kuang Pharmaceutical

Distributor:

Symgens

Marketer:

Symgens
Full Prescribing Info
Contents
Ibandronate sodium.
Description
Ibandronate sodium is a nitrogen-containing bisphosphonate that inhibits osteoclast-mediated bone resorption. The chemical name for Ibandronate sodium is 3-(NmethylN-pentyl)amino-1-hydroxypropane-1, 1-diphosphonic acid, monosodium salt, with the molecular formula C9H22NO7P3Na and a molecular weight of 341. Ibandronate sodium is a white-to off-white powder. It is freely soluble in water and practically insoluble in organic solvents.
Ostex is intended for IV administration only. Ostex is available as a sterile, clear, colorless, ready-to-use solution in a pre-filled syringe that delivers 3.375 mg of Ibandronate sodium salt in 3 mL of solution, equivalent to a dose of Ibandronate free acid 3 mg.
Excipients/Inactive Ingredients: Sodium chloride, glacial acetic acid, sodium acetate and water.
Action
Pharmacology: Mechanism of Action: The action of lbandronate 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.
Pharmacodynamics: 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.
In studies of postmenopausal women, Ibandronate sodium injection at doses of 0.5 mg to 3 mg produced biochemical changes indicative of inhibition of bone resorption, including decreases of biochemical markers of bone collagen degradation [cross-linked C-telopeptide of Type I collagen (CTX)]. Changes in markers of bone formation (osteocalcin) were observed later than changes in resorption markers, as expected, due to the coupled nature of bone resorption and formation.
Year 1 results from an efficacy and safety study comparing Ibandronate sodium injection 3 mg every 3 months and Ibandronate sodium 2.5 mg daily oral tablet demonstrated that both dosing regimens significantly suppressed serum CTX levels at Months 3, 6 and 12. The median pre-dose or trough serum CTX levels in the ITT population reached a nadir of 57% (Ibandronate sodium Injection) and 62% (Ibandronate sodium 2.5 mg tablets) below baseline values by Month 6, and remained stable at Month 12 of treatment.
Clinical Studies: Daily Oral Tablets: The effectiveness and safety of Ibandronate sodium daily oral tablets were demonstrated in a randomized, double-blind, placebo-controlled, multinational study (Treatment Study) of 2946 women aged 55-80 years, who were on average 21 years postmenopause, who had lumbar spine bone mineral density (BMD) 2-5 SD below the premenopausal mean (T-score) in at least 1 vertebra (Ll-L4), and who had 1-4 prevalent vertebral fractures. lbandronate sodium 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 IV vitamin D and calcium 500 mg supplementation per day.
Quarterly IV Injection: The effectiveness and safety of Ibandronate sodium injection 3 mg once every 3 months were demonstrated in a randomized, double-blind, multinational, noninferiority study (DIVA Study) in 1358 women with postmenopausal osteoporosis (L2-L4 lumbar spine BMD, T-score below -2.5 SD at baseline). The control group received lbandronate sodium 2.5 mg daily oral tablets. The primary efficacy parameter was the relative change from baseline to 1 year of treatment in lumbar spine BMD, which was compared between the IV injection and the daily oral treatment groups. All patients received vitamin D 400 IU and calcium 500 mg supplementation per day.
Effect on Vertebral Fracture: Ibandronate sodium 2.5 mg daily oral tablet significantly reduced the incidence of new vertebral and of new and worsening vertebral fractures (Daily Oral Tablet-Treatment Study). 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 lbandronate sodium 2.5 mg daily oral tablet (p<0.001) (see Table 1). In an unapproved regimen, intermittent oral administration of lbandronate sodium 20 mg, involving a 9- to 10-week drug-free interval, produced a statistically significant reduction (50%) in the incidence of new vertebral fractures, similar to that seen with the daily oral 2.5 mg regimen. (See Table 1.)

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Effect on Nonvertebral Fractures: There was a similar number of nonvertebral osteoporotic fractures at 3 years reported in women treated with lbandronate sodium 2.5 mg daily oral tablet [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 non-vertebral sites: pelvis, femur, wrist, forearm, rib, and hip (Daily Oral Tablet-Treatment Study).
Effect on Bone Mineral Density (BMD): Daily Oral Tablet-Treatment Study: Ibandronate sodium 2.5 mg daily oral tablet significantly increased BMD at the lumbar spine and hip relative to treatment with placebo. In the 3-year osteoporosis treatment study, lbandronate sodium 2.5 mg daily oral tablet 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 Ibandronate sodium 2.5 mg daily oral tablet compared with 1.4% in the placebo group. Table 2 displays the significant increases in BMD seen at the lumbar spine, total hip, femoral neck, and trochanter compared to placebo. (See Table 2.)

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Quarterly IV Injection DIVA Study: In the ITT efficacy analysis, the least-squares mean increase at 1 year in lumbar spine BMD in patients (n=429) treated with Ibandronate sodium injection 3 mg once every 3 months (4.5%) was statistically superior to that in patients (n=434) treated with daily oral tablets (3.5%). The mean difference between groups was 1.05% (95% CI: 0.53%, 1.57%; p<0.001; see Figure). The mean increases from baseline in total hip BMD at 1 year were 2.1% in the Ibandronate sodium injection 3 mg once every 3 months group and 1.5% in the Ibandronate sodium 2.5 mg daily oral tablet group. Consistently higher BMD increases at the femoral neck and trochanter were also observed following Ibandronate sodium injection 3 mg once every 3 months compared to Ibandronate sodium 2.5 mg daily oral tablet. (See Figure.)

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Bone Histology: The effects of Ibandronate sodium 2.5 mg daily oral tablet 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 histological analysis of bone biopsies after 22 months of treatment with IV Ibandronate 3 mg every 3 months (n=30) or 23 months of treatment with IV Ibandronate 2 mg every 2 months (n=27) in women with postmenopausal osteoporosis showed bone of normal quality and no indication of a mineralization defect.
Animal Pharmacology: 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 (SC), 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 Ibandronate sodium injection administered at a therapeutic dose is unlikely to induce osteomalacia.
Long-term daily or intermittent administration of Ibandronate to ovariectomized rats or monkeys was associated with suppression of bone turnover and increases in bone mass. Vertebral BMD, trabecular density, and biomechanical strength were increased dose-dependently in rats and monkeys, at doses up to 8 to 4 times the human IV dose of 3 mg every 3 months, based on cumulative dose normalized for body surface area (mg/m2) and AUC comparison, respectively. 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.
Pharmacokinetics: Distribution: Area under the serum Ibandronate concentrations versus time curve increases in a dose proportional manner after administration of 2 mg to 6 mg by IV injection.
After administration, 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 into the bone is estimated to be 40% to 50% of the circulating dose.
In vitro protein binding in human serum was approximately 86% over an Ibandronate concentration range of 20 to 2000 ng/mL (approximate range of maximum serum Ibandronate concentrations upon IV bolus administration) in 1 study.
Metabolism: There is no evidence that Ibandronate is metabolized in humans. Ibandronate does not inhibit human P450 1A2, 2A6, 2C9, 2Cl9, 2D6, 2El, and 3A4 isozymes in vitro.
Elimination: 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 administered IV dose).
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 Cmax within 3 or 8 hrs after IV 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 IV 2 and 4 mg Ibandronate alter 2 hrs of infusion ranges from 4.6 to 15.3 hrs and 5 to 25.5 hrs, respectively.
Following intravenous administration, 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 women) 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.
Special Populations: Children: The pharmacokinetics of Ibandronate has not been studied in patients <18 years.
Gender: The pharmacokinetics of lbandronate is similar in both men and women.
Elderly: 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).
Race: Pharmacokinetic differences due to race have not been studied.
Renal Impairment: Renal clearance of Ibandronate in patients with various degrees of renal impairment is linearly related to creatinine clearance (CrCl).
Following a single dose of Ibandronate 0.5 mg by IV administration, patients with CrCl 40-70 mL/min had 55% higher exposure (AUC) than the exposure observed in subjects with CrCl >90 mL/min. Patients with CrCl <30 mL/min had more than a 2-fold increase in exposure compared to the exposure for healthy subjects (see Renal Impairment under Dosage & Administration).
Hepatic Impairment: No studies have been performed to assess the pharmacokinetics of Ibandronate in patients with hepatic impairment since lbandronate is not metabolized in the human liver.
Drug Interactions: 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.
Melphalan/Prednisolone: A pharmacokinetic interaction study in multiple myeloma patients demonstrated that IV melphalan (10 mg/m2) and oral prednisolone (60 mg/m2) did not interact with Ibandronate 6 mg upon IV co-administration. Ibandronate did not interact with melphalan or prednisolone.
Tamoxifen: A pharmacokinetic interaction study in healthy postmenopausal women demonstrated that there was no interaction between oral tamoxifen 30 mg and IV Ibandronate 2 mg.
Indications/Uses
Ostex is indicated for the treatment of osteoporosis in postmenopausal women.
In postmenopausal women with osteoporosis, Ibandronate sodium increases BMD and reduces the incidence of vertebral fractures (see Pharmacology: Clinical Studies under Actions). Osteoporosis may be confirmed by the presence or histmy of osteoporotic fracture or by a finding of low bone mass [BMD more than 2.0 standard deviations below the premenopausal mean (ie, T-score)].
The safety and effectiveness of Ibandronate sodium for the treatment of osteoporosis are based on clinical data of 1 year 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.
Dosage/Direction for Use
Ostex must be administered by a health care professional.
Adults: The recommended dose of Ostex for the treatment of postmenopausal osteoporosis is 3 mg every 3 months (see Indications) administered over a period of 15-30 sec.
No cases of acute renal failure were observed in controlled clinical trials in which IV Ibandronate Sodium was administered as a 15- to 30-sec bolus. The risk of serious renal toxicity with other IV bisphosphonates appears to be inversely related to the rate of drug administration (see Precautions).
Ostex must only be administered IV (see Precautions). Care must be taken not to administer Ostex intra-arterially or paravenously as this could lead to tissue damage.
Do not administer Ostex by any other route of administration. The safety and efficacy of Ostex following non-IV routes of administration have not been established.
Administer Ostex using the enclosed needle. Pre-filled syringes are for single use only. Discard unused portion.
Ostex must not be mixed with calcium-containing solutions or other IV administered drugs. Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, and not used if particulate matter is visible or product is discolored. Pre-filled syringes with particulate marter or discoloration should not be used. If the dose is missed, Ostex should be administered as soon as it can be rescheduled. Thereafter, injections should be scheduled every 3 months from the date of the last injection. Do not administer Ostex more frequently than once every 3 months. Patients must receive supplemental calcium and vitamin D (see Information for Patients under Precautions).
Hepatic Impairment: No dose adjustment is necessary (see Pharmacology: Pharmacokinetics: Special Populations under Actions).
Renal Impairment: No dose adjustment is necessary for patients with mild or moderate renal impairment where creatinine clearance is ≥30 mL/min.
Ostex should not be administered to patients with severe renal impairment, ie, patients with serum creatinine >200 ftmol/L (2.3 mg/dL) or creatnine clearance (measured or estimated) <30 mL/min (see Pharmacology: Pharmacokinetics: Special Populations).
Elderly: No dosage adjustment is necessary in the elderly (see Precautions).
Administration: One pre-filled syringe of Ostex is single-use, clear glass pre-filled syringe, in a box with needle.
Each syringe is a 5 mL (5 cc) volume syringe supplied with a 25-gauge, 3/4 inch needle with wings, needle-stick protection device, a 17.78 mm plastic tubing for attachment, and a Luer cap with needle. Remove Luer cap with needle and attach syringe to the Luer adapter before IV administration.
Overdosage
No cases of overdose were reported in pre-marketing studies with Ibandronate Sodium injection. Intravenous overdosage may result in hypocalcemia, hypophosphatemia, and hypomagnesemia. Clinically relevant reductions in serum levels of calcium, phosphorus, and magnesium should be corrected by IV administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate, respectively.
Dialysis would not be beneficial unless it is administered within 2 hrs following the overdose.
Contraindications
Known hypersensitivity to Ibandronate sodium or to any of the excipients of Ostex. Uncorrected hypocalcemia (see Precautions).
Warnings
Ostex, like other bisphosphonates administered IV, may cause a transient decrease in serum calcium values (see Precautions).
Ostex must only be administered IV. Care must be taken not to administer Ostex intra-arterially or paravenously as this could lead to tissue damage.
Do not administer Ostex by any other route of administration. The safety and efficacy of Ostex following non-IV routes of administration have not been established.
Special Precautions
General: Mineral Metabolism: Hypocalcemia, hypovitaminosis D, and other disturbances of bone and mineral metabolism must be effectively treated before starting Ostex. Adequate intake of calcium and vitamin D is important in all patients. Patients must receive supplemental calcium and vitamin D.
Jaw Osteonecrosis: Osteonecrosis, primarily in the jaw, has been reported in patients treated with bisphosphonates. Most cases have been in cancer patients undergoing dental procedures, but some have occurred in patients with postmenopausal osteoporosis or other diagnoses. Known risk factors for osteonecrosis include a diagnosis of cancer, concomitant therapies (eg, chemotherapy, radiotherapy, corticosteroids), and co-morbid disorders (eg, anemia, coagulopathy, infection, preexisting dental disease). Most reported cases have been in patients treated with bisphosphonates IV but some have been in patients treated orally.
For patients who develop osteonecrosis of the jaw (ONJ) while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.
Musculoskeletal Pain: In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or musclepain has been reported in patients taking bisphosphonates that are approved for the prevention and treatment of osteoporosis (see Adverse Reactions). However, such reports have been infrequent. This category of drugs includes Ibandronate sodium injection. Most of the patients were postmenopausal women. The time to onset of symptoms varied from one day to several months after starting the drug. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.
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 (eg, 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 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.
Information for Patients: Ostex must be administered IV only by a health care professional. Patients should be instructed to read the Patient Information Leaflet carefully before taking Ibandronate sodium injection, and to re-read it each time the prescription is renewed because it contains important information the patient should know about Ibandronate sodium injection.
Ostex should be administered once every 3 months. If the dose is missed, the injection should be administered as soon as it can be rescheduled. Thereafter, injections should be scheduled every 3 months from the date of the last injection. Do not administer Ostex more frequently than once every 3 months.
Patients must receive supplemental calcium and vitamin D.
Renal Impairment: Treatment with IV bisphosphonates has been associated with renal toxicity manifested as deterioration in renal function (ie, increased serum creatinine) and in rare cases, acute renal failure. No cases of acute renal failure were observed in controlled clinical trials in which IV Ibandronate sodium was administered as a 15- to 30-sec bolus. The risk of serious renal toxicity with other intravenous bisphosphonates appears to be inversely related to the rate of drug administration.
Patients who receive Ostex should have serum creatinine measured prior to each dosage administration. Patients with concomitant diseases that have the potential for adverse effects on the kidney or patients who are taking concomitant medications that have the potential for adverse effects on the kidney should be assessed, as clinically appropriate. Treatment should be withheld for renal deterioration.
Ostex should not be administered to patients with severe renal impairment [ie, patients with serum creatinine >200 11 micromol/L (2.3 mg/dL)] or creatinine clearance (measured or estimated) <30 mL/min).
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: In a 104-week carcinogenicity study, doses of 3, 7, or 15 mg/kg/day were administered by oral gavage to Wistar rats (systemic exposures in males and females up to 3 and 1 times, respectively,
human exposure at the recommended IV dose of 3 mg every 3 months, based on cumulative AUC comparison). There were no significant drug-related tumor findings in male or female rats. In a 78-week carcinogenicity study, doses of 5, 20, or 40 mg/kg/day were administered by oral gavage to NMRl mice (exposures in males and females up to 96 and 14 times, respectively, human exposure at the recommended IV dose of 3 mg every 3 months, based on cumulative AUC comparison). There were no significant drug-related tumor findings in male or female mice. In a 90-week carcinogenicity study, doses of 5, 20, or 80 mg/kg/day were administered in the drinking water to NMRl mice. A dose-related increased incidence of adrenal subcapsular adenoma/carcinoma was observed in female mice, which was statistically significant at 80 mg/kg/day (32 to 51 times of human exposure at the recommended IV dose of 3 mg every 3 months, based on cumulative AUC comparison). The relevance of these findings to humans is unknown.
Mutagenesis: There was no evidence for a mutagenic or clastogenic potential of lbandronate 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. lbandronate was not genotoxic in the in vivo mouse micronucleus tests for chromosomal damage.
Impairment of Fertility: In female rats treated from 14 days prior to mating through gestation, decreases in fertility, corpora lutea and implantation sites, and increased preimplantation loss were observed at an IV dose of 1.2 mg/kg/day (117 times human exposure at the recommended IV dose of 3 mg every 3 months, based on cumulative AUC comparison). In male rats treated for 28 days prior to mating, a decrease in sperm production and altered sperm morphology were observed at IV doses ≥0.3 mg/kg/day (≥40 times human exposure at the recommended IV dose of 3 mg every 3 months, based on cumulative AUC comparison).
Use in Children: Safety and effectiveness in pediatric patients have not been established.
Use in Elderly: Of the patients receiving Ibandronate sodium injection every 3 months for I year (DIY A study), 51% were over 65 years. 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.
Use In Pregnancy & Lactation
Use in Pregnancy: Pregnancy Category C: In pregnant rats given IV doses of 0.05, 0.15, or 0.5 mg/kg/day from Day 17 post-coitum until Day 20 post-partum, lbandronate treatment resulted in dystocia, matemal mortality, and early postnatal pup loss in all dose groups (≥2 times human exposure at the recommended IV dose of 3 mg every 3 months, based on cumulative AUC comparison). Reduced body weight at birth was observed at 0.15 and 0.5 mg/kg/day (≥4 times human exposure at the recommended IV dose of 3 mg every 3 months, based on cumulative AUC comparison). Pups exhibited abnormal odontogeny that decreased food consumption and body weight gain at 0.15 and 0.5 mg/kg/clay (≥18 times human exposure at the recommended IV close of 3 mg every 3 months, based on cumulative AUC comparison). Periparturient mortality has also been observed with other bisphosphonates and appears to be a class effect related to inhibition of skeletal calcium mobilization resulting in hypocalcemia and dystocia.
Exposure of pregnant rats during the period of organogenesis resulted in an increased fetal incidence of RPU (renal pelvis ureter) syndrome at an IV dose of 1 mg/kg/day (≥47 times human exposure at the recommended IV dose of 3 mg every 3 months, based on cumulative AUC comparison). In this spontaneous delivery study, dystocia was counteracted by perinatal calcium supplementation. In rat studies with IV dosing during gestation, fetal weight and pup growth were reduced at doses ≥0.1 mg/kg/day (≥5 times human exposure at the recommended IV dose of 3 mg every 3 months, based on cumulative AUC comparison).
In pregnant rabbits given IV doses of 0.03, 0.07 or 0.2 mg/kg/day during the period of organogenesis, maternal mortality, reduced maternal body weight gain, decreased litter size due to increased resorption rate, and decreased fetal weight were observed at 0.2 mg/kg/day (19 times the recommended human IV dose of 3 mg every 3 months, based on cumulative body surface area comparison, mg/m2).
Bisphosphonates are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into matemal bone. Therefore, there is a theoretical risk of fetal hmm (eg, skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (IV versus oral) on this risk has not been established.
There are no adequate and well-controlled studies in pregnant women. Ibandronate sodium injection should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.
Use in Lactation: In lactating rats treated with IV doses of 0.08 mg/kg, Ibandronate was present in breast milk at concentrations of 8.1 to 0.4 ng/mL from 2 to 24 hrs after dose administration. Concentrations in milk averaged 1.5 times plasma concentrations. It is not known whether Ibandronate sodium is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Ibandronate sodium injection is administered to a nursing woman.
Adverse Reactions
Daily Oral Tablet: Treatment with Ibandronate sodium 2.5 mg daily oral tablet was studied in over 3900 patients in postmenopausal osteoporosis trials of up to 3 years duration. The overall adverse event profile of Ibandronate sodium 2.5 mg once daily tablet in these studies was similar to that of placebo.
Most adverse events were mild or moderate and did not lead to discontinuation. The incidence of serious adverse events was 20% in the placebo group and 23% in the Ibandronate sodium 2.5 mg daily oral tablet group. The percentage of patients who withdrew from treatment due to adverse events was approximately 17% in both the Ibandronate sodium 2.5 mg daily oral tablet group and the placebo group. Overall, and according to body system, there was no difference between Ibandronate sodium daily oral tablet and placebo, with adverse events of the digestive system being the most common reason for withdrawal.
Table 3 lists adverse events from the Treatment and Prevention Studies reported in ≥2% of patients and in more patients treated with Ibandronate sodium 2.5 mg daily oral tablet than patients treated with placebo. Adverse events are shown without attribution of causality. (See Table 3.)

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Quarterly IV Injection-DIVA Study: In a 1-year, double-blind, multicenter study comparing lbandronate sodium injection administered IV as 3 mg every 3 months to lbandronate sodium 2.5 mg daily oral tablet in women with postmenopausal osteoporosis, the overall safety and tolerability profiles of the two dosing regimens were similar. The incidence of serious adverse events was 8.0% in the lbandronate sodium 2.5 mg daily group and 7.5% in the lbandronate sodium injection 3 mg once every 3 months group. The percentage of patients who withdrew from treatment due to adverse events was approximately 6.7% in the Ibandronate sodium 2.5 mg daily group and 8.5% in the lbandronate sodium injection 3 mg every 3 months group.
Table 4 lists the adverse events reported in >2% of patients without attribution of causality. (See Table 4.)

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Acute Phase Reaction-like Events:
Symptoms consistent with acute phase reaction (APR) have been reported with IV bisphosphonate use. The overall incidence of patients with APR-like events was higher in the IV treatment group (4% in the Ibandronate sodium 2.5 mg daily oral tablet group vs. 10% in the Ibandronate sodium injection 3 mg once every 3 months group). These incidence rates are based on reporting of any of 33 potential APR-like symptoms within 3 days of an IV dose and for a duration of 7 days or less. In most cases, no specific treatment was required and the symptoms subsided within 24 to 48 hrs.
Injection Site Reactions: Local reactions at the injection site, such as redness or swelling, were observed infrequently, but at a higher incidence in patients treated with Ibandronate sodium injection 3 mg every 3 months (<2%; 8/469) than in patients treated with placebo injections (<1%;1/465). In most cases, the reaction was of mild to moderate severity.
Ocular Adverse Events: Bisphosphonates may be associated with ocular inflammation such as uveitis and scleritis. In some cases, these events did not resolve until the bisphosphonate was discontinued.
Laboratory Test Findings: There were no clinically significant changes from baseline values or shifts in any laboratory variable with oral Ibandronate. As expected with bisphosphonate treatment, a decrease in total alkaline phosphatase levels was seen with 2.5 mg daily oral Ibandronate sodium compared to placebo. There was no difference compared with placebo for laboratory abnormalities indicative of hepatic or renal dysfunction, hypocalcemia, or hypophosphatemia. There also was no evidence that Ostex every 3 months induced clincally significant laboratory abnormalities indicative of hepatic or renal dysfunction compared to Ibandronate sodium 2.5 mg daily oral tablet.
Drug Interactions
See Pharmacology: Pharmacokinetics: Drug Interactions under Actions.
Drug/Laboratory Test Interactions: Bisphosphonates are known to interfere with the use of bone-imaging agents. Specific studies with Ibandronate have not been performed.
Storage
Store below 30°C (86°F).
ATC Classification
M05BA06 - ibandronic acid ; Belongs to the class of bisphosphonates. Used in the treatment of bone diseases.
Presentation/Packing
Soln for inj (pre-filled) 3 mg/3 mL  x 1's.
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