Ibandronate Sodium

1 INDICATIONS AND USAGE Ibandronate sodium injection is a bisphosphonate indicated for the treatment of osteoporosis in postmenopausal women. (1.1) Limitations of Use Optimal duration of use has not been determined. For patients at low-risk for fracture, consider drug discontinuation after 3 to 5 years of use (1.2) 1.1 Treatment of Postmenopausal Osteoporosis Ibandronate sodium injection is indicated for the treatment of osteoporosis in postmenopausal women. In postmenopausal women with osteoporosis, ibandronate sodium injection increases bone mineral density (BMD) and reduces the incidence of vertebral fractures [ see Clinical Studies (14) ] . 1.2 Important Limitations of Use The safety and effectiveness of ibandronate sodium injection for the treatment of osteoporosis are based on clinical data of one 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. Patients at low-risk for fracture should be considered for drug discontinuation after 3 to 5 years of use. Patients who discontinue therapy should have their risk for fracture re-evaluated periodically.

2 DOSAGE AND ADMINISTRATION 3 mg every 3 months administered intravenously over a period of 15 to 30 seconds (2.2) Dosing Instructions: Only administer intravenously by a 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 3 months. (2.2) Instruct patients to take supplemental calcium and vitamin D if dietary intake is inadequate 2.1 Important Administration Instructions Ibandronate sodium injection must be administered intravenously only by a 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 single-dose only. 2.2 Dosage Information The recommended dose of ibandronate sodium injection for the treatment of postmenopausal osteoporosis is 3 mg every 3 months administered intravenously over a period of 15 to 30 seconds. Do not administer more frequently than once every 3 months. 2.3 Laboratory Testing and Oral Examination Prior to Administration Prior to administration of each dose obtain a serum creatinine [ see Warnings and Precautions (5.3) ] . Given that bisphosphonates have been associated with osteonecrosis of the jaw (ONJ), perform a routine oral examination prior to administration of ibandronate sodium injection. 2.4 Calcium and Vitamin D Supplementation Instruct patients to take supplemental calcium and vitamin D if their dietary intake is inadequate [ see Warnings 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 3 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) [ see Warnings and Precautions (5.3) and CLINICAL 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) [see CLINICAL PHARMACOLOGY (12.3) ] .

5 WARNINGS AND PRECAUTIONS Hypocalcemia can worsen. Correct hypocalcemia prior to use. Adequately supplement patients with calcium and vitamin D (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 Fractures Including Femoral Fractures have been reported. Patients with new thigh or groin pain should be evaluated to rule out a femoral fracture. Risk/benefit of continuing bisphosphonate therapy should be re-evaluated in these patients and interruption of bisphosphonate therapy should be considered. (5.7) 5.1 Hypocalcemia and Mineral Metabolism Ibandronate sodium injection may cause a 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 D is important in all patients. It is recommended that patients receive supplemental calcium and vitamin D 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 was administered as a 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. A routine oral examination should be performed by the prescriber prior to initiation of bisphosphonate treatment. Consider a dental examination with appropriate preventive dentistry prior to treatment with bisphosphonates in patients with a history of concomitant…

4 CONTRAINDICATIONS Ibandronate sodium injection is contraindicated in patients with the following conditions: Hypocalcemia [ see Warnings and Precautions (5.1) ] Known hypersensitivity to ibandronate sodium injection or to any of its excipients. Cases of anaphylaxis, including fatal events, have been reported [ see Warnings and Precautions (5.2), Adverse Reactions (6.2) ] Hypocalcemia (4) Hypersensitivity to ibandronate sodium injection (4)

7 DRUG INTERACTIONS 7.1 Melphalan/Prednisolone Intravenous ibandronate (6 mg) did not interact with intravenous melphalan (10 mg/m 2 ) or oral prednisolone (60 mg/m 2 ). [ See Clinical Pharmacology (12.3) ] 7.2 Tamoxifen There was no interaction between oral 30 mg tamoxifen and intravenous 2 mg ibandronate. [ see Clinical Pharmacology (12.3) ] 7.3 Bone Imaging Agents Bisphosphonates are known to interfere with the use of bone-imaging agents. Specific studies with ibandronate have not been performed.

8.1 Pregnancy Risk Summary Ibandronate is not indicated for use in women of reproductive potential. There are no data with ibandronate use in pregnant women to inform any drug-associated risks. In reproductive toxicity studies in the rat, ibandronate caused obstruction of labor, with maternal periparturient mortality, pup loss and reduced pup weight at greater than or equal to 2 times human exposure at the recommended human intravenous dose of 3 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 5 times human exposure. In reproductive studies in the rabbit, ibandronate 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 ). Data Animal Data In pregnant rats given intravenous doses producing greater than or equal to 2 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 4 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 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 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 5 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 3 mg every 3 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 3 mg every 3 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 1 mg/kg/day in rats, and 0.03, 0.07, or 0.2 mg/kg/day in rabbits.

6 ADVERSE REACTIONS The following clinically significant adverse drug reactions are described elsewhere in the labeling: 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 Fractures Including 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 Eugia US LLC at 1-866-850-2876 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 a 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 a 1-year, double-blind, multicenter study comparing ibandronate sodium injection administered intravenously as 3 mg every 3 months to ibandronate 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 reactions was 8% in the ibandronate 2.5 mg daily group and 7.5% in the ibandronate sodium injection 3 mg once every 3 months group. The percentage of patients who withdrew from treatment due to adverse reactions was approximately 6.7% in the ibandronate 2.5 mg daily group and 8.5% in the ibandronate sodium injection 3 mg every 3 months group. Table 1 lists the adverse reactions reported in greater than 2% of patients. Table 1 Adverse Reactions With an Incidence of at Least 2% in Patients Treated with Ibandronate Sodium Injection (3 mg once every 3 months) or Ibandronate Daily Oral Tablet (2.5 mg) * Combination of abdominal pain and abdominal pain upper † Combination of influenza-like illness and acute phase reaction ‡ Combination of rash, rash pruritic, rash macular, dermatitis, dermatitis allergic, exanthema, erythema, rash papular, rash generalized, dermatitis medicamentosa, rash erythematous Body System/Adverse Reaction Ibandronate 2.5 mg Daily (Oral) % (n = 465) Ibandronate Sodium Injection 3 mg every 3 months (Intravenous) % (n = 469) Infections and Infestations Influenza 8 5 Nasopharyngitis 6 3 Cystitis 3 2 Gastroenteritis 3 2 Urinary Tract Infection 3 3 Bronchitis 3 2 Upper Respiratory Tract Infection 3 1 Gastrointestinal Disorders Abdominal Pain* 6 5 Dyspepsia 4 4 Nausea 4 2 Constipation 4 3 Diarrhea 2 3 Gastritis 2 2 Musculoskeletal and Connective Tissue Disorders Arthralgia 9 10 Back Pain 8 7 Localized Osteoarthritis 2 2 Pain in Extremity 2 3 Myalgia 1 3 Nervous System Disorders Dizziness 3 2 Headache 3 4 Psychiatric Disorders Insomnia 3 1 Depression 2 1 General Disorders and Administration Site Conditions Influenza-like Illness † 1 5 Fatigue 1 3 Skin and Subcutaneous Tissue Disorders Rash ‡ 3 2 Acute Phase Reaction-like Events Symptoms 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 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 upon reporting of any of 33 potential APR-like symptoms within 3 days of an intravenous dose and lasting 7 days or less. In most cases, no specific treatment was required and the symptoms subsided within 24 to 48 hours. Injection Site Reactions Local reactions at the injection site, such as redness or swelling, were observed at a higher in…