CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Treatment of Postmenopausal Osteoporosis. Quarterly Intravenous InjectionThe effectiveness and safety of ibandronate sodium injection mg (ibandronate) once every months were demonstrated in randomized, double-blind, multinational, noninferiority study in 1358 women with postmenopausal osteoporosis (L2-L4 lumbar spine BMD, T-score below -2.5 SD at baseline). The control group received ibandronate sodium 2.5 mg (ibandronate) daily oral tablets. The primary efficacy parameter was the relative change from baseline to year of treatment in lumbar spine BMD, which was compared between the intravenous injection and the daily oral treatment groups. All patients received 400 international units vitamin and 500 mg calcium supplementation per day.. Effect on BMDIn the intent-to-treat (ITT) efficacy analysis, the least-squares mean increase at year in lumbar spine BMD in patients (n=429) treated with ibandronate sodium injection mg (ibandronate) once every 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 1.1% (95% confidence interval: 0.5%, 1.6%; p<0.001; see Figure ). The mean increase from baseline in total hip BMD at year was 2.1% in the ibandronate sodium injection mg (ibandronate) once every months group and 1.5% in the ibandronate sodium 2.5 mg (ibandronate) daily oral tablet group. Consistently higher BMD increases at the femoral neck and trochanter were also observed following ibandronate sodium injection mg (ibandronate) once every months compared to ibandronate sodium 2.5 mg (ibandronate) daily oral tablet.Figure Mean Percent Change (95% Confidence Interval) from Baseline in Lumbar Spine BMD at One Year in Patients Treated with Ibandronate Sodium 2.5 mg (ibandronate) Daily Oral Tablet or Ibandronate Sodium injection mg (ibandronate) Once Every Months. 40c108c-9923-4c53-8ed3-11b9c18168be. Bone HistologyThe histological analysis of bone biopsies after 22 months of treatment with mg intravenous ibandronate every months (n=30) or 23 months of treatment with mg intravenous ibandronate every months (n=27) in women with postmenopausal osteoporosis showed bone of normal quality and no indication of mineralization defect.. Daily Oral TabletsThe effectiveness and safety of ibandronate sodium daily oral tablets were demonstrated in 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 to SD below the premenopausal mean (T-score) in at least one vertebra [L1-L4], and who had one to four prevalent vertebral fractures. Ibandronate Sodium was evaluated at oral doses of 2.5 mg ibandronate daily and 20 mg ibandronate intermittently. The main outcome measure was the occurrence of new radiographically diagnosed, vertebral fractures after 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 two events: relative height ratio or relative height reduction in vertebral body of at least 20%, together with at least 4 mm absolute decrease in height. All women received 400 international units vitamin and 500 mg calcium supplementation per day.. Effect on Vertebral FractureIbandronate Sodium 2.5 mg (ibandronate) daily oral tablet significantly reduced the incidence of new vertebral fractures compared to placebo. Over the course of the 3-year study, the risk for new vertebral fracture was 9.6% in the placebo-treated women and 4.7% in the women treated with Ibandronate Sodium 2.5 mg (ibandronate) daily oral tablet (p<0.001) (see Table ).Table Effect of Ibandronate Sodium Daily Oral Tablet on the Incidence of Vertebral Fracture in the 3-Year Osteoporosis Treatment Study Proportion of Patients with Fracture (%)Placebon=975Ibandronate Sodium 2.5 mg (ibandronate) Dailyn=977Absolute Risk Reduction(%)95% CIRelative Risk Reduction (%)95% CINew Vertebral Fracture9.64.74.952 p=0.0003 vs. placebo0-3 Year (2.3, 7.4)(29, 68)New and Worsening Vertebral Fracture Worsening vertebral fracture defined as new fracture in vertebral body with prevalent fracture10.45.15.3520-3 Year (2.6, 7.9)(30, 67)Clinical (Symptomatic) Vertebral Fracture5.32.82.5490-3 Year (0.6, 4.5)(14, 69). Effect on Nonvertebral FracturesIbandronate Sodium 2.5 mg (ibandronate) daily did not reduce the incidence of nonvertebral fractures (secondary efficacy measure). There was similar number of nonvertebral osteoporotic fractures at years reported in women treated with ibandronate sodium 2.5 mg (ibandronate) 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.. Effect on BMDIbandronate Sodium 2.5 mg (ibandronate) daily oral tablet significantly increased BMD at the lumbar spine and hip relative to treatment with placebo. In the 3-year osteoporosis treatment study, ibandronate sodium 2.5 mg (ibandronate) daily oral tablet produced increases in lumbar spine BMD that were progressive over years of treatment and were statistically significant relative to placebo at months and at all later time points. Lumbar spine BMD increased by 6.4% after years of treatment with ibandronate sodium 2.5 mg (ibandronate) daily oral tablet compared with 1.4% in the placebo group (p<0.0001). Table displays the significant increases in BMD seen at the lumbar spine, total hip, femoral neck, and trochanter compared to placebo.Table Mean Percent Change in BMD from Baseline to Endpoint in Patients Treated with Ibandronate Sodium 2.5 mg (ibandronate) Daily Oral Tablet or Placebo in the 3-Year Osteoporosis Treatment Study PlaceboIbandronate Sodium 2.5 mg (ibandronate)Lumbar Spine1.4(n=693)6.4(n=712)Total Hip-0.7(n=638)3.1(n=654)Femoral Neck-0.7(n=683)2.6(n=699)Trochanter0.2(n=683)5.3(n=699). Bone HistologyThe effects of ibandronate sodium 2.5 mg (ibandronate) 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 mineralization defect.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Adverse reactions that appear in other sections of the labeling include:Hypocalcemia and Mineral Metabolism see Warnings and Precautions (5.1) ]Anaphylactic Reaction see Warnings and Precautions (5.2) ]Renal Impairment see Warnings and Precautions (5.3) ]Tissue Damage Related to Inappropriate Drug Administration see Warnings and Precautions (5.4) ]Osteonecrosis of the Jaw see Warnings and Precautions (5.5) ]Musculoskeletal Pain see Warnings and Precautions (5.6) ]Atypical Subtrochanteric and Diaphyseal Femoral Fractures see Warnings and Precautions (5.7) ]. Hypocalcemia and Mineral Metabolism see Warnings and Precautions (5.1) ]. Anaphylactic Reaction see Warnings and Precautions (5.2) ]. Renal Impairment see Warnings and Precautions (5.3) ]. Tissue Damage Related to Inappropriate Drug Administration see Warnings and Precautions (5.4) ]. Osteonecrosis of the Jaw see Warnings and Precautions (5.5) ]. Musculoskeletal Pain see Warnings and Precautions (5.6) ]. Atypical Subtrochanteric and Diaphyseal Femoral Fractures see Warnings and Precautions (5.7) ]. The most frequently reported adverse reactions (>5%) are arthralgia, back pain, and abdominal pain. 6.1 )To report SUSPECTED ADVERSE REACTIONS, contact TAGI Pharma, Inc. at 1-855-225-8244 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Quarterly Intravenous Injection -In 1-year, double-blind, multicenter study comparing ibandronate sodium injection administered intravenously as mg (ibandronate) every months to ibandronate sodium 2.5 mg (ibandronate) 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 reactions was 8.0% in the ibandronate sodium 2.5 mg (ibandronate) daily group and 7.5% in the ibandronate sodium injection mg (ibandronate) once every months group. The percentage of patients who withdrew from treatment due to adverse reactions was approximately 6.7% in the ibandronate sodium 2.5 mg (ibandronate) daily group and 8.5% in the ibandronate sodium injection mg (ibandronate) every months group. Table lists the adverse reactions reported in greater than 2% of patients.Table Adverse Reactions With an Incidence of at Least 2% in Patients Treated with Ibandronate Sodium Injection (3 mg ibandronate once every months) or Ibandronate Sodium Daily Oral Tablet (2.5 mg ibandronate)Body System/Adverse ReactionIbandronate Sodium2.5 mg (ibandronate)Daily (Oral)%(n=465)Ibandronate Sodium3 mg (ibandronate)every months (Intravenous)%(n=469)Infections and Infestations Influenza85Nasopharyngitis63Cystitis32Gastroenteritis32Urinary Tract Infection33Bronchitis32Upper Respiratory Tract Infection31Gastrointestinal Disorders Abdominal Pain Combination of abdominal pain and abdominal pain upper65Dyspepsia44Nausea42Constipation43Diarrhea23Gastritis22Musculoskeletal and Connective Tissue Disorders Arthralgia910Back Pain87Localized Osteoarthritis22Pain in Extremity23Myalgia13Nervous System Disorders Dizziness32Headache34Psychiatric Disorders Insomnia31Depression21General Disorders and Administration Site Conditions Influenza-like Illness Combination of influenza-like illness and acute phase reaction15Fatigue13Skin and Subcutaneous Tissue Disorders Rash Combination of rash, rash pruritic, rash macular, dermatitis, dermatitis allergic, exanthema, erythema, rash papular, rash generalized, dermatitis medicamentosa, rash erythematous32. Acute Phase Reaction-like EventsSymptoms consistent with acute phase reaction (APR) have been reported with intravenous bisphosphonate use. The overall incidence of patients with APR-like events was higher in the intravenous treatment group (4% in the ibandronate sodium 2.5 mg (ibandronate) daily oral tablet group vs. 10% in the ibandronate sodium injection mg (ibandronate) once every months group). These incidence rates are based upon reporting of any of 33 potential APR-like symptoms within days of an intravenous dose and lasting days or less. In most cases, no specific treatment was required and the symptoms subsided within 24 to 48 hours.. Injection Site ReactionsLocal reactions at the injection site, such as redness or swelling, were observed at higher incidence in patients treated with ibandronate sodium injection mg (ibandronate) every months (1.7%; 8/469) than in patients treated with placebo injections (0.2%; 1/465). In most cases, the reaction was of mild to moderate severity.. Daily Oral Tablet -The safety of ibandronate sodium 2.5 mg (ibandronate) 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 to years, with 1134 patients exposed to placebo and 1140 exposed to ibandronate sodium 2.5 mg (ibandronate). 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 supplementation daily.The incidence of all-cause mortality was 1% in the placebo group and 1.2% in the ibandronate sodium 2.5 mg (ibandronate) daily group. The incidence of serious adverse reactions was 20% in the placebo group and 23% in the ibandronate sodium 2.5 mg (ibandronate) daily oral tablet group. The percentage of patients who withdrew from treatment due to adverse reactions was approximately 17% in both the placebo group and the ibandronate sodium 2.5 mg (ibandronate) daily oral tablet group. Table lists adverse reactions from the Treatment and Prevention Studies reported in greater than or equal to 2% of patients and in more patients treated with ibandronate sodium 2.5 mg (ibandronate) daily oral tablet than patients treated with placebo.Table Adverse Reactions Occurring at an Incidence greater than or equal to 2% and in More Patients Treated with Ibandronate Sodium 2.5 mg (ibandronate) Daily Oral Tablet than in Patients Treated with Placebo in the Osteoporosis Treatment and Prevention StudiesBody SystemPlacebo%(n=1134)Ibandronate Sodium2.5 mg (ibandronate) daily%(n=1140)Body as Whole Back Pain1214Pain in Extremity68Asthenia24Allergic Reaction23Digestive System Dyspepsia1012Diarrhea57Tooth Disorder24Vomiting23Gastritis22Musculoskeletal System Myalgia56Joint Disorder34Arthritis33Nervous System Headache67Dizziness34Vertigo33Respiratory System Upper Respiratory Infection3334Bronchitis710Pneumonia46Pharyngitis23Urogenital System Urinary Tract Infection46. Gastrointestinal Adverse ReactionsThe incidence of selected gastrointestinal adverse reactions in the placebo and ibandronate sodium 2.5 mg (ibandronate) daily groups were: dyspepsia (10% vs. 12%), diarrhea (5% vs. 7%), and abdominal pain (5% vs. 6%).. Musculoskeletal Adverse ReactionsThe incidence of selected musculoskeletal adverse reactions in the placebo and ibandronate sodium 2.5 mg (ibandronate) daily groups were: back pain (12% vs. 14%), arthralgia (14% vs. 14%) and myalgia (5% vs. 6%).. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of ibandronate sodium injection. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Hypersensitivity Allergic reactions including anaphylaxis with fatalities, angioedema, asthma exacerbation, bronchospasm, rash, Stevens-Johnson syndrome, erythema multiforme, and dermatitis bullous [seeContraindications (4),Warnings and Precautions (5.2)] .Hypocalcemia Hypocalcemia [seeWarnings and Precautions (5.1)].Renal Toxicity Acute renal failure [seeWarnings and Precautions (5.3)].Osteonecrosis of the Jaw Osteonecrosis of the jaw and other oro-facial sites, including the external auditory canal [seeWarnings and Precautions (5.5)] .Musculoskeletal Pain Bone, joint, or muscle pain (musculoskeletal pain), described as severe or incapacitating [seeWarnings and Precautions (5.6)] .Atypical Femoral Shaft Fracture Atypical, low-energy, or low-trauma fractures of the femoral shaft [seeWarnings and Precautions (5.7) ].Eye Inflammation Iritis and uveitis. In some cases with other bisphosphonates, these events did not resolve until the bisphosphonate was discontinued.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisIn 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 and times, respectively, human exposure). There were no significant drug-related tumor findings in male or female rats. In 78-week carcinogenicity study, doses of 5, 20, or 40 mg/kg/day were administered by oral gavage to NMRI mice (exposures in males and females up to 96 and 14 times, respectively, human exposure). There were no significant drug-related tumor findings in male or female mice. In 90-week carcinogenicity study, doses of 5, 20, or 80 mg/kg/day were administered in the drinking water to NMRI mice. 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 human exposure). The relevance of these findings to humans is unknown.Exposure multiples comparing human and rodent doses were calculated using human exposure at the recommended intravenous dose of mg ibandronate every months, based on cumulative AUC comparison.. MutagenesisThere was no evidence for mutagenic or clastogenic potential of ibandronate in the following assays: in vitro bacterial mutagenesis assay inSalmonella typhimuriumandEscherichia 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 FertilityIn 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 intravenous dose of 1.2 mg/kg/day (117 times human exposure). In male rats treated for 28 days prior to mating, decrease in sperm production and altered sperm morphology were observed at intravenous doses greater than or equal to 0.3 mg/kg/day (greater than or equal to 40 times human exposure).Exposure multiples comparing human and rat doses were calculated using human exposure at the recommended intravenous dose of mg ibandronate every months, based on cumulative AUC comparison.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The action of ibandronate on bone 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, net gain in bone mass.. 12.2 Pharmacodynamics. In studies of postmenopausal women, ibandronate sodium injection at doses of 0.5 mg to 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 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 results from an efficacy and safety study comparing ibandronate sodium injection mg (ibandronate) every months and ibandronate sodium 2.5 mg (ibandronate) 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 intent-to-treat population reached nadir of 57% (ibandronate sodium injection) and 62% (ibandronate sodium 2.5 mg (ibandronate) tablets) below baseline values by Month 6, and remained stable at Month 12 of treatment.. 12.3 Pharmacokinetics. DistributionArea under the serum ibandronate concentrations versus time curve increases in dose proportional manner after administration of mg to mg ibandronate by intravenous 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 one study, 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 intravenous bolus administration).. MetabolismThere is no evidence that ibandronate is metabolized in humans. Ibandronate does not inhibit human P450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 isozymes in vitro.Ibandronate does not undergo hepatic metabolism and does not inhibit the hepatic cytochrome P450 system. Ibandronate is eliminated by renal excretion. Based on rat study, the ibandronate secretory pathway does not appear to include known acidic or basic transport systems involved in the excretion of other drugs.. EliminationThe 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 intravenous dose).The plasma elimination of ibandronate is multiphasic. Its renal clearance and distribution into bone accounts for rapid and early decline in plasma concentrations, reaching 10% of Cmax within or hours after intravenous or oral administration, respectively. This is followed by 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 intravenous and mg ibandronate after hours of infusion ranges from 4.6 to 15.3 hours and to 25.5 hours, 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.. Pharmacokinetics in Specific Populations. PediatricsThe pharmacokinetics of ibandronate have not been studied in patients less than 18 years of age.. GenderThe pharmacokinetics of ibandronate are similar in both men and women.. GeriatricSince 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 seeUse in Specific Populations (8.5)] .. RacePharmacokinetic differences due to race have not been studied.. Renal ImpairmentRenal clearance of ibandronate in patients with various degrees of renal impairment is linearly related to creatinine clearance (CLcr).Following single dose of 0.5 mg ibandronate by intravenous administration, patients with creatinine clearance 40 to 70 mL/min had 55% higher exposure (AUC ) than the exposure observed in patients with creatinine clearance higher than 90 mL/min. Patients with severe renal impairment (creatinine clearance below 30 mL/min) had more than two-fold increase in exposure compared to the exposure for patients with creatinine clearance equal to or higher than 80 mL/min [seeDosage and Administration (2.6)andUse in Specific Populations (8.6)] .. Hepatic ImpairmentNo studies have been performed to assess the pharmacokinetics of ibandronate in patients with hepatic impairment since ibandronate is not metabolized in the human liver.. Drug Interaction. Melphalan/PrednisoloneA pharmacokinetic interaction study in multiple myeloma patients demonstrated that intravenous melphalan (10 mg/m2) and oral prednisolone (60 mg/m2) did not interact with mg ibandronate upon intravenous coadministration. Ibandronate did not interact with melphalan or prednisolone.. TamoxifenA pharmacokinetic interaction study in healthy postmenopausal women demonstrated that there was no interaction between oral 30 mg tamoxifen and intravenous mg ibandronate.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. mg every months administered intravenously over period of 15 to 30 seconds 2.2 )Dosing Instructions:Only administer intravenously by health care professional. 2.1 )Do not mix with calcium-containing solutions or other intravenously administered drugs. 2.1 )Do not administer more frequently than once every months. 2.2 )Instruct patients to take supplemental calcium and vitamin if dietary intake is inadequate. mg every months administered intravenously over period of 15 to 30 seconds 2.2 ). Dosing Instructions:Only administer intravenously by health care professional. 2.1 )Do not mix with calcium-containing solutions or other intravenously administered drugs. 2.1 )Do not administer more frequently than once every months. 2.2 ). Only administer intravenously by health care professional. 2.1 ). Do not mix with calcium-containing solutions or other intravenously administered drugs. 2.1 ). Do not administer more frequently than once every months. 2.2 ). Instruct patients to take supplemental calcium and vitamin if dietary intake is inadequate. 2.1 Important Administration Instructions. Ibandronate Sodium Injection must be administered intravenously only by health care professional. Care must be taken not to administer intra-arterially or paravenously as this could lead to tissue damage [see Warnings and Precautions (5.4)] .Appropriate medical support and monitoring measures should be readily available when ibandronate sodium injection is administered. If anaphylactic or other severe hypersensitivity/allergic reactions occur, immediately discontinue the injection and initiate appropriate treatment [see Warnings and Precautions (5.2) .Visually inspect the liquid in the prefilled syringe for particulate matter and discoloration before administration. Do not use prefilled syringes with particulate matter or discoloration.Administer only with the enclosed needle.Discard any unused portion.Do not mix with calcium-containing solutions or other intravenously administered drugs.Prefilled syringes are for single use only.. Appropriate medical support and monitoring measures should be readily available when ibandronate sodium injection is administered. If anaphylactic or other severe hypersensitivity/allergic reactions occur, immediately discontinue the injection and initiate appropriate treatment [see Warnings and Precautions (5.2) .. Visually inspect the liquid in the prefilled syringe for particulate matter and discoloration before administration. Do not use prefilled syringes with particulate matter or discoloration.. Administer only with the enclosed needle.. Discard any unused portion.. Do not mix with calcium-containing solutions or other intravenously administered drugs.. Prefilled syringes are for single use only.. 2.2 Dosage Information. The recommended dose of ibandronate sodium injection for the treatment of postmenopausal osteoporosis is mg (ibandronate) every months administered intravenously over period of 15 to 30 seconds. Do not administer more frequently than once every months.. 2.3 Laboratory Testing and Oral Examination Prior to Administration. Prior to administration of each dose obtain serum creatinine [seeWarnings and Precautions (5.3)] Given that bisphosphonates have been associated with osteonecrosis of the jaw (ONJ), perform routine oral examination prior to administration of ibandronate sodium injection.. 2.4 Calcium and Vitamin Supplementation. Instruct patients to take supplemental calcium and vitamin if their dietary intake is inadequate [seeWarnings and Precautions (5.1)] .. 2.5 Dosing After Missed Dose. If the dose is missed, administer as soon as it can be re-scheduled. Thereafter, ibandronate sodium injection should be scheduled every months from the date of the last injection.. 2.6 Dosage Modifications in Patients with Renal Impairment. Do not administer to patients with severe renal impairment (creatinine clearance less than 30 mL/minute) [seeWarnings and Precautions (5.3)andClinical Pharmacology (12.3)] No dose adjustment is necessary for patients with mild or moderate renal impairment (creatinine clearance greater than or equal to 30 mL/min) [seeClinical Pharmacology (12.3)].

INSTRUCTIONS FOR USE SECTION.

BD Vacutainer (R) Safety-Lok(TM) For Short Term IV Adminstration Instructions for Use: IV AdministrationAseptic technique, proper skin preparation and continued protection of the site are essential. Observe Universal Precautions on all patients.Caution: Keep hands behind the needle at all times during use and disposal.Instructions for Device AssemblyOpen the package.Remove the rubber cap from the tip of the syringe containing the Ibandronate Sodium Injection (Fig.1 ), and remove the protective cap at the end of the tubing opposite the butterfly needle Fig.2 ).Insert the tip of the syringe into the hub (Luer adaptor) and twist as firm pressure is applied to assure tight connection Fig.3 ).Proceed with priming the system with medication in accordance with recommended procedure and confirm that administration fluid comes from the needle. Ensure that there is no air in the system. Priming VolumeGaugeTubingVolume (mL)2512 inches(30.48 cm)0.33Venipuncture and AdministrationGrasp wings securely.Remove the needle protector (Fig.4 ). Caution: Care should be taken not to touch the needle.Insert needle in vein by holding wings (Fig.5 )Carefully allow wings to return to starting position and conform to the shape of the skin.Confirm proper positioning of the needle in the vein.Further secure the position of the winged infusion set per facility protocol.Administer over period of 15 to 30 seconds.After UseRemove tape, if present, from wings.Apply pressure to site using your fingers as shown Fig.6 ). Grasp the translucent yellow safety shield grip area with the thumb and index finger. Completely remove the needle from the puncture site and apply digital pressure to the site using sterile gauze pad held in the opposite hand.Hold tubing in hand and advance translucent yellow safety shield with thumb and index finger until the safety shield is locked in place over needle tip Fig.7).Visually confirm activation of the safety feature Fig.8).Dispose of used needles and materials following the policies and procedures of your facility, as well as federal and local regulations for Sharps Disposal. 10/20192620000000U535. Open the package.. Remove the rubber cap from the tip of the syringe containing the Ibandronate Sodium Injection (Fig.1 ), and remove the protective cap at the end of the tubing opposite the butterfly needle Fig.2 ).. Insert the tip of the syringe into the hub (Luer adaptor) and twist as firm pressure is applied to assure tight connection Fig.3 ).. Proceed with priming the system with medication in accordance with recommended procedure and confirm that administration fluid comes from the needle. Ensure that there is no air in the system. Priming VolumeGaugeTubingVolume (mL)2512 inches(30.48 cm)0.33. Grasp wings securely.. Remove the needle protector (Fig.4 ). Caution: Care should be taken not to touch the needle.. Insert needle in vein by holding wings (Fig.5 ). Carefully allow wings to return to starting position and conform to the shape of the skin.. Confirm proper positioning of the needle in the vein.. Further secure the position of the winged infusion set per facility protocol.. Administer over period of 15 to 30 seconds.. Remove tape, if present, from wings.. Apply pressure to site using your fingers as shown Fig.6 ). Grasp the translucent yellow safety shield grip area with the thumb and index finger. Completely remove the needle from the puncture site and apply digital pressure to the site using sterile gauze pad held in the opposite hand.. Hold tubing in hand and advance translucent yellow safety shield with thumb and index finger until the safety shield is locked in place over needle tip Fig.7).. Visually confirm activation of the safety feature Fig.8).. Dispose of used needles and materials following the policies and procedures of your facility, as well as federal and local regulations for Sharps Disposal. 064fc02-436b-4bdb-9534-9884f7895ab0.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisIn 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 and times, respectively, human exposure). There were no significant drug-related tumor findings in male or female rats. In 78-week carcinogenicity study, doses of 5, 20, or 40 mg/kg/day were administered by oral gavage to NMRI mice (exposures in males and females up to 96 and 14 times, respectively, human exposure). There were no significant drug-related tumor findings in male or female mice. In 90-week carcinogenicity study, doses of 5, 20, or 80 mg/kg/day were administered in the drinking water to NMRI mice. 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 human exposure). The relevance of these findings to humans is unknown.Exposure multiples comparing human and rodent doses were calculated using human exposure at the recommended intravenous dose of mg ibandronate every months, based on cumulative AUC comparison.. MutagenesisThere was no evidence for mutagenic or clastogenic potential of ibandronate in the following assays: in vitro bacterial mutagenesis assay inSalmonella typhimuriumandEscherichia 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 FertilityIn 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 intravenous dose of 1.2 mg/kg/day (117 times human exposure). In male rats treated for 28 days prior to mating, decrease in sperm production and altered sperm morphology were observed at intravenous doses greater than or equal to 0.3 mg/kg/day (greater than or equal to 40 times human exposure).Exposure multiples comparing human and rat doses were calculated using human exposure at the recommended intravenous dose of mg ibandronate every months, based on cumulative AUC comparison.. 13.2 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 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 ibandronate sodium injection administered at 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 to times the human intravenous dose of mg ibandronate every 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 SECTION.

12.3 Pharmacokinetics. DistributionArea under the serum ibandronate concentrations versus time curve increases in dose proportional manner after administration of mg to mg ibandronate by intravenous 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 one study, 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 intravenous bolus administration).. MetabolismThere is no evidence that ibandronate is metabolized in humans. Ibandronate does not inhibit human P450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 isozymes in vitro.Ibandronate does not undergo hepatic metabolism and does not inhibit the hepatic cytochrome P450 system. Ibandronate is eliminated by renal excretion. Based on rat study, the ibandronate secretory pathway does not appear to include known acidic or basic transport systems involved in the excretion of other drugs.. EliminationThe 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 intravenous dose).The plasma elimination of ibandronate is multiphasic. Its renal clearance and distribution into bone accounts for rapid and early decline in plasma concentrations, reaching 10% of Cmax within or hours after intravenous or oral administration, respectively. This is followed by 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 intravenous and mg ibandronate after hours of infusion ranges from 4.6 to 15.3 hours and to 25.5 hours, 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.. Pharmacokinetics in Specific Populations. PediatricsThe pharmacokinetics of ibandronate have not been studied in patients less than 18 years of age.. GenderThe pharmacokinetics of ibandronate are similar in both men and women.. GeriatricSince 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 seeUse in Specific Populations (8.5)] .. RacePharmacokinetic differences due to race have not been studied.. Renal ImpairmentRenal clearance of ibandronate in patients with various degrees of renal impairment is linearly related to creatinine clearance (CLcr).Following single dose of 0.5 mg ibandronate by intravenous administration, patients with creatinine clearance 40 to 70 mL/min had 55% higher exposure (AUC ) than the exposure observed in patients with creatinine clearance higher than 90 mL/min. Patients with severe renal impairment (creatinine clearance below 30 mL/min) had more than two-fold increase in exposure compared to the exposure for patients with creatinine clearance equal to or higher than 80 mL/min [seeDosage and Administration (2.6)andUse in Specific Populations (8.6)] .. Hepatic ImpairmentNo studies have been performed to assess the pharmacokinetics of ibandronate in patients with hepatic impairment since ibandronate is not metabolized in the human liver.. Drug Interaction. Melphalan/PrednisoloneA pharmacokinetic interaction study in multiple myeloma patients demonstrated that intravenous melphalan (10 mg/m2) and oral prednisolone (60 mg/m2) did not interact with mg ibandronate upon intravenous coadministration. Ibandronate did not interact with melphalan or prednisolone.. TamoxifenA pharmacokinetic interaction study in healthy postmenopausal women demonstrated that there was no interaction between oral 30 mg tamoxifen and intravenous mg ibandronate.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryIbandronate Sodium is not indicated for use in women of reproductive potential. There are no data with ibandronate sodium use in pregnant women to inform any drug-associated risks.In reproductive toxicity studies in the rat, ibandronate sodium caused obstruction of labor, with maternal periparturient mortality, pup loss and reduced pup weight at greater than or equal to times human exposure at the recommended human intravenous dose of mg. Abnormal pup odontogeny was observed at greater than or equal to 18 times human exposure. In rats dosed during pregnancy, kidney developmental toxicity occurred in offspring at greater than or equal to 47 times human exposure. Also, fetal weight and pup growth were reduced at greater than or equal to times human exposure. In reproductive studies in the rabbit, ibandronate sodium caused maternal mortality, reduced maternal body weight gain, decreased litter size due to increased resorption rate, and decreased fetal weight at 19 times the recommended human dose (see Data).DataAnimal DataIn pregnant rats given intravenous doses producing greater than or equal to times human exposure from Day 17 post-coitum until Day 20 post-partum, ibandronate treatment resulted in dystocia, maternal mortality, and early postnatal pup loss in all dose groups. Reduced body weight at birth was observed at greater than or equal to times the human exposure. Pups exhibited abnormal odontogeny that decreased food consumption and body weight gain at greater than or equal to 18 times human exposure. Periparturient mortality has also been observed with other bisphosphonates and appears to be 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 intravenous dose producing greater than or equal to 47 times human exposure. In this spontaneous delivery study, dystocia was counteracted by perinatal calcium supplementation. In rat studies with intravenous dosing during gestation, fetal weight and pup growth were reduced at doses producing greater than or equal to times human exposure.In pregnant rabbits given intravenous doses 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 19 times the recommended human intravenous dose.Exposure multiples for the rat studies were calculated using human exposure at the recommended intravenous dose of mg ibandronate every months and were based on cumulative area under the curve (AUC) comparison. Exposure multiples for the rabbit study were calculated for the recommended human intravenous dose of mg ibandronate every months and were based on cumulative dose/[body surface area] comparison. Doses in pregnant animals were 0.05, 0.1, 0.15, 0.3, 0.5 or mg/kg/day in rats, and 0.03, 0.07, or 0.2 mg/kg/day in rabbits.

SPL MEDGUIDE SECTION.

MEDICATION GUIDEIBANDRONATE SODIUM(eye-BAN-droe-nate SOE-dee-um)Injection for intravenous useRead the Medication Guide that comes with ibandronate sodium before you start taking it and each time you get refill. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or treatment. Talk to your doctor if you have any questions about ibandronate sodium.What is the most important information should know about ibandronate sodiumIbandronate Sodium Injection is given in your vein (intravenously) and only given by healthcare provider. Do not give ibandronate sodium Injection to yourself.Ibandronate Sodium may cause serious side effects including:Low calcium levels in your blood (hypocalcemia)Severe allergic reaction (anaphylactic reaction)Severe kidney problemsSevere jaw bone problems (osteonecrosis)Bone, joint or muscle painUnusual thigh bone fracturesLow calcium levels in your blood (hypocalcemia). Ibandronate Sodium may lower the calcium levels in your blood. If you have low blood calcium before you start taking ibandronate sodium, it may get worse during treatment. Your low blood calcium must be treated before you receive ibandronate sodium. Most people with low blood calcium levels do not have symptoms, but some people may have symptoms. Call your doctor right away if you have symptoms of low blood calcium such as:Spasms, twitches, or cramps in your musclesNumbness or tingling in your fingers, toes, or around your mouthYour doctor may prescribe calcium and vitamin to help prevent low calcium levels in your blood, while you receive ibandronate sodium. Take calcium and vitamin as your doctor tells you to.Severe allergic reactions. Some people who received ibandronate sodium injection had severe allergic reactions (anaphylactic reactions) that led to death. Get medical help right away if you have any of the symptoms of serious allergic reaction such as:Swelling of your face, lips, mouth or tongueTrouble breathingWheezingSevere itchingSkin rash, redness or swellingDizziness or faintingFast heartbeat or pounding in your chestSweatingSevere kidney problems. Severe kidney problems, including kidney failure, may happen when you receive ibandronate sodium. Your doctor should do blood tests to check your kidneys before you receive each dose of ibandronate sodium.Severe jaw bone problems (osteonecrosis). Severe jaw bone problems may happen when you receive ibandronate sodium. Your doctor may examine your mouth before you start ibandronate sodium. Your doctor may tell you to see your dentist before you start ibandronate sodium. It is important for you to practice good mouth care during treatment with ibandronate sodium.Bone, joint, or muscle pain. Some people who receive ibandronate sodium develop severe bone, joint, or muscle pain.Unusual thigh bone fractures. Some people have developed unusual fractures in their thigh bone. Symptoms of fracture may include new or unusual pain in your hip, groin, or thigh.Call your doctor right away if you have any of these side effects.What is ibandronate sodiumIbandronate Sodium is prescription medicine used to treat osteoporosis in women after menopause. Ibandronate Sodium helps increase bone mass and helps reduce the chance of having spinal fracture (break).It is not known how long ibandronate sodium works for the treatment of osteoporosis. You should see your doctor regularly to determine if ibandronate sodium is still right for you.It is not known if ibandronate sodium is safe and effective in children.Who should not receive ibandronate sodiumDo not receive ibandronate sodium if you:Have low levels of calcium in your bloodAre allergic to ibandronate sodium or any of the ingredients in ibandronate sodium. See the end of this leaflet for complete list of ingredients in ibandronate sodium.What should tell my healthcare provider before receiving ibandronate sodiumBefore you receive ibandronate sodium, tell your doctor if you:Have low blood calciumPlan to have dental surgery or teeth removedHave kidney problems or other problems that may affect your kidneysHave been told you have trouble absorbing minerals in your stomach or intestines (malabsorption syndrome)Are pregnant or plan to become pregnant. It is not known if ibandronate sodium can harm your unborn baby.Are breast-feeding or plan to breast-feed. It is not known if ibandronate sodium passes into your milk and may harm your baby.Tell your doctor and dentist about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements.Know the medicines you take. Keep list of them and show it to your healthcare provider and pharmacist each time you get new medicine.How should receive ibandronate sodiumIbandronate Sodium Injection is given time every months by healthcare provider.If you miss dose of ibandronate sodium, call your doctor or healthcare provider to schedule your next dose.What are the possible side effects of ibandronate sodiumIbandronate Sodium may cause serious side effects.See What is the most important information should know about ibandronate sodium The most common side effects of ibandronate sodium include:Pain in your bones, joints or musclesBack painAbdominal painFlu-like symptoms may happen within days after you receive ibandronate sodium. Symptoms include:feverchillsbone, joint, or muscle painfatigueIf you have flu-like symptoms, they should get better within 24 to 48 hours.Some people have pain or sore that will not heal in their mouth or jaw while they receive ibandronate sodium. Tell your doctor or dentist if you have mouth or jaw problems.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 ibandronate sodium. 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 TAGI Pharma, Inc. at 1-855-225-8244.How should store ibandronate sodium if need to pick it up from pharmacyStore ibandronate sodium injection at room temperature between 68 and 77 (20 and 25 C).Keep ibandronate sodium injection and all medicines out of the reach of children.General information about the safe and effective use of ibandronate sodium.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use ibandronate sodium for condition for which it was not prescribed. Do not give ibandronate sodium 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 ibandronate sodium. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about ibandronate sodium that is written for health professionals.What are the ingredients in ibandronate sodiumActive ingredient: ibandronate sodiumInactive ingredients: sodium chloride, glacial acetic acid, sodium acetate and waterThis Medication Guide has been approved by the U.S. Food and Drug Administration.. Low calcium levels in your blood (hypocalcemia)Severe allergic reaction (anaphylactic reaction)Severe kidney problemsSevere jaw bone problems (osteonecrosis)Bone, joint or muscle painUnusual thigh bone fractures. Low calcium levels in your blood (hypocalcemia). Severe allergic reaction (anaphylactic reaction). Severe kidney problems. Severe jaw bone problems (osteonecrosis). Bone, joint or muscle pain. Unusual thigh bone fractures. Low calcium levels in your blood (hypocalcemia). Ibandronate Sodium may lower the calcium levels in your blood. If you have low blood calcium before you start taking ibandronate sodium, it may get worse during treatment. Your low blood calcium must be treated before you receive ibandronate sodium. Most people with low blood calcium levels do not have symptoms, but some people may have symptoms. Call your doctor right away if you have symptoms of low blood calcium such as:Spasms, twitches, or cramps in your musclesNumbness or tingling in your fingers, toes, or around your mouthYour doctor may prescribe calcium and vitamin to help prevent low calcium levels in your blood, while you receive ibandronate sodium. Take calcium and vitamin as your doctor tells you to.. Spasms, twitches, or cramps in your muscles. Numbness or tingling in your fingers, toes, or around your mouth. Severe allergic reactions. Some people who received ibandronate sodium injection had severe allergic reactions (anaphylactic reactions) that led to death. Get medical help right away if you have any of the symptoms of serious allergic reaction such as:Swelling of your face, lips, mouth or tongueTrouble breathingWheezingSevere itchingSkin rash, redness or swellingDizziness or faintingFast heartbeat or pounding in your chestSweating. Swelling of your face, lips, mouth or tongue. Trouble breathing. Wheezing. Severe itching. Skin rash, redness or swelling. Dizziness or fainting. Fast heartbeat or pounding in your chest. Sweating. Severe kidney problems. Severe kidney problems, including kidney failure, may happen when you receive ibandronate sodium. Your doctor should do blood tests to check your kidneys before you receive each dose of ibandronate sodium.. Severe jaw bone problems (osteonecrosis). Severe jaw bone problems may happen when you receive ibandronate sodium. Your doctor may examine your mouth before you start ibandronate sodium. Your doctor may tell you to see your dentist before you start ibandronate sodium. It is important for you to practice good mouth care during treatment with ibandronate sodium.. Bone, joint, or muscle pain. Some people who receive ibandronate sodium develop severe bone, joint, or muscle pain.. Unusual thigh bone fractures. Some people have developed unusual fractures in their thigh bone. Symptoms of fracture may include new or unusual pain in your hip, groin, or thigh.. Have low levels of calcium in your blood. Are allergic to ibandronate sodium or any of the ingredients in ibandronate sodium. See the end of this leaflet for complete list of ingredients in ibandronate sodium.. Have low blood calcium. Plan to have dental surgery or teeth removed. Have kidney problems or other problems that may affect your kidneys. Have been told you have trouble absorbing minerals in your stomach or intestines (malabsorption syndrome). Are pregnant or plan to become pregnant. It is not known if ibandronate sodium can harm your unborn baby.. Are breast-feeding or plan to breast-feed. It is not known if ibandronate sodium passes into your milk and may harm your baby.. Ibandronate Sodium Injection is given time every months by healthcare provider.. If you miss dose of ibandronate sodium, call your doctor or healthcare provider to schedule your next dose.. See What is the most important information should know about ibandronate sodium . Pain in your bones, joints or muscles. Back pain. Abdominal pain. Flu-like symptoms may happen within days after you receive ibandronate sodium. Symptoms include:feverchillsbone, joint, or muscle painfatigueIf you have flu-like symptoms, they should get better within 24 to 48 hours.. fever. chills. bone, joint, or muscle pain. fatigue. Store ibandronate sodium injection at room temperature between 68 and 77 (20 and 25 C).

TERATOGENIC EFFECTS SECTION.

Risk SummaryIbandronate Sodium is not indicated for use in women of reproductive potential. There are no data with ibandronate sodium use in pregnant women to inform any drug-associated risks.In reproductive toxicity studies in the rat, ibandronate sodium caused obstruction of labor, with maternal periparturient mortality, pup loss and reduced pup weight at greater than or equal to times human exposure at the recommended human intravenous dose of mg. Abnormal pup odontogeny was observed at greater than or equal to 18 times human exposure. In rats dosed during pregnancy, kidney developmental toxicity occurred in offspring at greater than or equal to 47 times human exposure. Also, fetal weight and pup growth were reduced at greater than or equal to times human exposure. In reproductive studies in the rabbit, ibandronate sodium caused maternal mortality, reduced maternal body weight gain, decreased litter size due to increased resorption rate, and decreased fetal weight at 19 times the recommended human dose (see Data).DataAnimal DataIn pregnant rats given intravenous doses producing greater than or equal to times human exposure from Day 17 post-coitum until Day 20 post-partum, ibandronate treatment resulted in dystocia, maternal mortality, and early postnatal pup loss in all dose groups. Reduced body weight at birth was observed at greater than or equal to times the human exposure. Pups exhibited abnormal odontogeny that decreased food consumption and body weight gain at greater than or equal to 18 times human exposure. Periparturient mortality has also been observed with other bisphosphonates and appears to be 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 intravenous dose producing greater than or equal to 47 times human exposure. In this spontaneous delivery study, dystocia was counteracted by perinatal calcium supplementation. In rat studies with intravenous dosing during gestation, fetal weight and pup growth were reduced at doses producing greater than or equal to times human exposure.In pregnant rabbits given intravenous doses 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 19 times the recommended human intravenous dose.Exposure multiples for the rat studies were calculated using human exposure at the recommended intravenous dose of mg ibandronate every months and were based on cumulative area under the curve (AUC) comparison. Exposure multiples for the rabbit study were calculated for the recommended human intravenous dose of mg ibandronate every months and were based on cumulative dose/[body surface area] comparison. Doses in pregnant animals were 0.05, 0.1, 0.15, 0.3, 0.5 or mg/kg/day in rats, and 0.03, 0.07, or 0.2 mg/kg/day in rabbits.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryIbandronate Sodium is not indicated for use in women of reproductive potential. There are no data with ibandronate sodium use in pregnant women to inform any drug-associated risks.In reproductive toxicity studies in the rat, ibandronate sodium caused obstruction of labor, with maternal periparturient mortality, pup loss and reduced pup weight at greater than or equal to times human exposure at the recommended human intravenous dose of mg. Abnormal pup odontogeny was observed at greater than or equal to 18 times human exposure. In rats dosed during pregnancy, kidney developmental toxicity occurred in offspring at greater than or equal to 47 times human exposure. Also, fetal weight and pup growth were reduced at greater than or equal to times human exposure. In reproductive studies in the rabbit, ibandronate sodium caused maternal mortality, reduced maternal body weight gain, decreased litter size due to increased resorption rate, and decreased fetal weight at 19 times the recommended human dose (see Data).DataAnimal DataIn pregnant rats given intravenous doses producing greater than or equal to times human exposure from Day 17 post-coitum until Day 20 post-partum, ibandronate treatment resulted in dystocia, maternal mortality, and early postnatal pup loss in all dose groups. Reduced body weight at birth was observed at greater than or equal to times the human exposure. Pups exhibited abnormal odontogeny that decreased food consumption and body weight gain at greater than or equal to 18 times human exposure. Periparturient mortality has also been observed with other bisphosphonates and appears to be 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 intravenous dose producing greater than or equal to 47 times human exposure. In this spontaneous delivery study, dystocia was counteracted by perinatal calcium supplementation. In rat studies with intravenous dosing during gestation, fetal weight and pup growth were reduced at doses producing greater than or equal to times human exposure.In pregnant rabbits given intravenous doses 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 19 times the recommended human intravenous dose.Exposure multiples for the rat studies were calculated using human exposure at the recommended intravenous dose of mg ibandronate every months and were based on cumulative area under the curve (AUC) comparison. Exposure multiples for the rabbit study were calculated for the recommended human intravenous dose of mg ibandronate every months and were based on cumulative dose/[body surface area] comparison. Doses in pregnant animals were 0.05, 0.1, 0.15, 0.3, 0.5 or mg/kg/day in rats, and 0.03, 0.07, or 0.2 mg/kg/day in rabbits.. 8.2 Lactation. Risk SummaryIbandronate Sodium 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 this data is unclear.DataAnimal DataIn lactating rats treated with intravenous doses of 0.08 mg/kg, ibandronate was present in breast milk at concentrations of 8.1 to 0.4 ng/mL from to 24 hours after dose administration. Concentrations in milk averaged 1.5 times plasma concentrations.. 8.4 Pediatric Use. Safety and effectiveness of ibandronate sodium in pediatric patients have not been established.. 8.5 Geriatric Use. Of the patients receiving ibandronate sodium injection mg (ibandronate) every months for year, 51% were over 65 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.. 8.6 Renal Impairment. Ibandronate Sodium Injection should not be administered to patients with severe renal impairment (creatinine clearance less than 30 mL/min) [seeWarnings and Precautions (5.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypocalcemia can worsen. Correct hypocalcemia prior to use.Adequately supplement patients with calcium and vitamin ( 5.1 )Anaphylaxis including fatal events, has been reported. 5.2 )Renal Toxicity may be greater in patients with underlying renal impairment. Do not administer ibandronate sodium injection to patients with severe renal impairment (creatinine clearance less than 30 mL/min). Monitor serum creatinine prior to each dose. 5.3 )Tissue Damage with Inappropriate Drug Administration can occur. Do not administer ibandronate sodium injection intra-arterially or paravenously. 5.4 )Osteonecrosis of the jaw (ONJ) has been reported. 5.5 )Severe Bone, Joint, and/or Muscle Pain may occur, consider discontinuing use if symptoms occur. 5.6 )Atypical Femur Fractures have been reported. Patients with new thigh or groin pain should be evaluated to rule out femoral fracture. 5.7 ). Hypocalcemia can worsen. Correct hypocalcemia prior to use.Adequately supplement patients with calcium and vitamin ( 5.1 ). Anaphylaxis including fatal events, has been reported. 5.2 ). Renal Toxicity may be greater in patients with underlying renal impairment. Do not administer ibandronate sodium injection to patients with severe renal impairment (creatinine clearance less than 30 mL/min). Monitor serum creatinine prior to each dose. 5.3 ). Tissue Damage with Inappropriate Drug Administration can occur. Do not administer ibandronate sodium injection intra-arterially or paravenously. 5.4 ). Osteonecrosis of the jaw (ONJ) has been reported. 5.5 ). Severe Bone, Joint, and/or Muscle Pain may occur, consider discontinuing use if symptoms occur. 5.6 ). Atypical Femur Fractures have been reported. Patients with new thigh or groin pain should be evaluated to rule out femoral fracture. 5.7 ). 5.1 Hypocalcemia and Mineral Metabolism. Ibandronate Sodium Injection may cause decrease in serum calcium values. Treat hypocalcemia, hypovitaminosis D, and other disturbances of bone and mineral metabolism before starting ibandronate sodium injection therapy.Adequate intake of calcium and vitamin is important in all patients. It is recommended that patients receive supplemental calcium and vitamin if dietary intake is inadequate.. 5.2 Anaphylactic Reaction. Cases of anaphylaxis, including fatal events, have been reported in patients treated with ibandronate sodium injection.Appropriate medical support and monitoring measures should be readily available when ibandronate sodium injection is administered. If anaphylactic or other severe hypersensitivity/allergic reactions occur, immediately discontinue the injection and initiate appropriate treatment.. 5.3 Renal Impairment. Treatment with intravenous bisphosphonates has been associated with renal toxicity manifested as deterioration in renal function and acute renal failure. Although no cases of acute renal failure were observed in controlled clinical trials in which intravenous ibandronate sodium was administered as 15- to 30-second bolus, acute renal failure has been reported postmarketing. Do not administer ibandronate sodium injection to patients with severe renal impairment (creatinine clearance less than 30 mL/min).Obtain serum creatinine prior to each ibandronate sodium injection. After ibandronate sodium injection, assess renal function, as clinically appropriate, in patients with concomitant diseases or taking medications that have the potential for adverse effects on the kidney. IBANDRONATE SODIUM Injection should be withheld in patients with renal deterioration.. 5.4 Tissue Damage Related to Inappropriate Drug Administration. Ibandronate Sodium Injection must only be administered intravenously. Care must be taken not to administer ibandronate sodium injection intra-arterially or paravenously as this could lead to tissue damage.Do not administer ibandronate sodium injection by any other route of administration. The safety and efficacy of ibandronate sodium injection following non-intravenous routes of administration have not been established.. 5.5 Osteonecrosis of the Jaw. Osteonecrosis of the jaw (ONJ) has been reported in patients treated with bisphosphonates, including ibandronate sodium injection. Most cases have been in cancer patients treated with intravenous bisphosphonates undergoing dental procedures. Some cases have occurred in patients with postmenopausal osteoporosis treated with either oral or intravenous bisphosphonates. routine oral examination should be performed by the prescriber prior to initiation of bisphosphonate treatment. Consider dental examination with appropriate preventive dentistry prior to treatment with bisphosphonates in patients with history of concomitant risk factors (e.g., cancer, chemotherapy, angiogenesis inhibitors, radiotherapy, corticosteroids, poor oral hygiene, pre-existing dental disease or infection, anemia, coagulopathy). Concomitant administration of drugs associated with ONJ may increase the risk of developing ONJ. The risk of ONJ may increase with duration of exposure to bisphosphonates.While on treatment, patients with concomitant risk factors should avoid invasive dental procedures if possible. For patients who develop 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. The clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment seeAdverse Reactions (6.1) ].. 5.6 Musculoskeletal Pain. Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking ibandronate sodium and other bisphosphonates seeAdverse Reactions (6.2) ]. 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 the bisphosphonate. subset of patients had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. Discontinue ibandronate sodium if severe symptoms develop.. 5.7 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 complete fracture occurs. number of reports note that patients were also receiving treatment with glucocorticoids (e.g., prednisone) at the time of fracture.Any patient with 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 risk/benefit assessment, on an individual basis.