Ibandronate

5 WARNINGS AND PRECAUTIONS Upper gastrointestinal Adverse Reactions can occur. Instruct patients to follow dosing instructions and discontinue use if new or worsening symptoms occur. ( 5.1 ) Hypocalcemia may worsen during treatment. Correct hypocalcemia before use. ( 5.2 ) Severe Bone, Joint, and Muscle Pain may occur. Consider discontinuing use if symptoms develop. ( 5.3 ) Osteonecrosis of the Jaw has been reported. ( 5.4 ) 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. ( 5.5 ) 5.1 Upper Gastrointestinal Adverse Reactions Ibandronate sodium tablets, like other bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when ibandronate sodium tablets are given to patients with active upper gastrointestinal problems (such as known Barrett’s esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis or ulcers). Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates. In some cases, these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue ibandronate sodium tablets and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn. The risk of severe esophageal adverse experiences appears to be greater in patients who lie down after taking oral bisphosphonates and/or who fail to swallow it with the recommended full glass (6 to 8 oz) of water, and/or who continue to take oral bisphosphonates after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient (see Dosage and Administration [2.2] ) . In patients who cannot comply with dosing instructions due to mental disability, therapy with ibandronate sodium tablets should be used under appropriate supervision. There have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications, although no increased risk was observed in controlled clinical trials. 5.2 Hypocalcemia and Mineral Metabolism Hypocalcemia has been reported in patients taking ibandronate sodium tablets. Treat hypocalcemia and other disturbances of bone and mineral metabolism before starting ibandronate sodium tablets therapy. Instruct patients to take supplemental calcium and vitamin D if their dietary intake is inadequate (see Dosage and Administration [2.3] ) . 5.3 Musculoskeletal Pain Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking ibandronate sodium tablets and other bisphosphonates (see Adverse Reactions [6] ) . The time to onset of symptoms varied from one day to several months after starting the drug. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. Consider discontinuing use if severe symptoms develop. 5.4 Jaw Osteonecrosis Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients taking bisphosphonates, including ibandronate sodium. Known risk factors for osteonecrosis of the jaw include invasive dental procedures (e.g., tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and co-morbid disorders (e.g., periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). The risk of ONJ may increase with duration of exposure to bisphosphonates. For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk for ONJ. Clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit/risk assessment. Patients who develop osteonecrosis of the jaw while on bisphosphonate therapy should receive care by an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of bisphosphonate therapy should be considered based on individual benefit/risk assessment. 5.5 Atypical Fractures Including Femoral Fractures Atypical, low-energy, or low-trauma fractures of the femoral shaft have been reported during treatment with bisphosphonates including ibandronate in patients with osteoporosis. Atypical femur and other fractures most commonly occur with minimal or no trauma to the affected area. These fractures occurred anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are traverse or short oblique in orientation without evidence of comminution. Atypical fractures of other bones have also been reported. They may be bilateral. These fractures can also occur in osteoporotic patients who have not been treated with bisphosphonates. Concomitant treatment with glucocorticoids may also induce these fractures. Prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs was reported by patients. Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Bony pain in other locations should also be considered for evaluation of atypical fracture. Patients presenting with an atypical fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Risk/benefit of continuing bisphosphonate therapy should be re-evaluated in these patients and interruption of bisphosphonate therapy should be considered. 5.6 Severe Renal Impairment Ibandronate sodium tablets are not recommended for use in patients with severe renal impairment (creatinine clearance of less than 30 mL/min).

5.5 Atypical Fractures Including Femoral Fractures Atypical, low-energy, or low-trauma fractures of the femoral shaft have been reported during treatment with bisphosphonates including ibandronate in patients with osteoporosis. Atypical femur and other fractures most commonly occur with minimal or no trauma to the affected area. These fractures occurred anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are traverse or short oblique in orientation without evidence of comminution. Atypical fractures of other bones have also been reported. They may be bilateral. These fractures can also occur in osteoporotic patients who have not been treated with bisphosphonates. Concomitant treatment with glucocorticoids may also induce these fractures. Prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs was reported by patients. Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Bony pain in other locations should also be considered for evaluation of atypical fracture. Patients presenting with an atypical fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Risk/benefit of continuing bisphosphonate therapy should be re-evaluated in these patients and interruption of bisphosphonate therapy should be considered.

6 ADVERSE REACTIONS The following clinically significant adverse drug reactions are described elsewhere in the labeling: Upper Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.1 )] Hypocalcemia and Mineral Metabolism [see Warnings and Precautions ( 5.2 )] Musculoskeletal [see Warnings and Precautions ( 5.3 )] Jaw Osteonecrosis [see Warnings and Precautions ( 5.4 )] Atypical Fractures Including Femoral Fractures [see Warnings and Precautions ( 5.5 )] Severe Renal Impairment [see Warnings and Precautions ( 5.6 )] The most common adverse reactions (greater than 5%) are back pain, dyspepsia, pain in extremity, diarrhea, headache, and myalgia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 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. Treatment and Prevention of Postmenopausal Osteoporosis Daily Dosing The safety of ibandronate sodium tablets 2.5 mg once daily in the treatment and prevention of postmenopausal osteoporosis was assessed in 3577 patients aged 41 – 82 years. The duration of the trials was 2 to 3 years, with 1134 patients exposed to placebo and 1140 exposed to ibandronate sodium tablets 2.5 mg. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors and H2 antagonists were included in these clinical trials. All patients received 500 mg calcium plus 400 international units vitamin D supplementation daily. The incidence of all-cause mortality was 1% in the placebo group and 1.2% in the ibandronate sodium tablets 2.5 mg daily group. The incidence of serious adverse reactions was 20% in the placebo group and 23% in the ibandronate sodium tablets 2.5 mg daily group. The percentage of patients who withdrew from treatment due to adverse reactions was approximately 17% in both the ibandronate sodium tablets 2.5 mg daily group and the placebo group. Table 1 lists adverse reactions from the treatment and prevention studies reported in greater than or equal to 2% of patients and more frequently in patients treated daily with ibandronate sodium tablets than patients treated with placebo. Table 1 Adverse Reactions Occurring at an Incidence Greater Than or Equal to 2% and in More Patients Treated with Ibandronate Sodium Tablets Than in Patients Treated with Placebo Daily in the Osteoporosis Treatment and Prevention Studies Body System Placebo % (n=1134) Ibandronate Sodium Tablets 2.5 mg % (n=1140) Body as a Whole Back Pain 12 14 Pain in Extremity 6 8 Asthenia 2 4 Allergic Reaction 2 3 Digestive System Dyspepsia 10 12 Diarrhea 5 7 Tooth Disorder 2 4 Vomiting 2 3 Gastritis 2 2 Musculoskeletal System Myalgia 5 6 Joint Disorder 3 4 Arthritis 3 3 Nervous System Headache 6 7 Dizziness 3 4 Vertigo 3 3 Respiratory System Upper Respiratory Infection 33 34 Bronchitis 7 10 Pneumonia 4 6 Pharyngitis 2 3 Urogenital System Urinary Tract Infection 4 6 Gastrointestinal Adverse Reactions The incidence of selected gastrointestinal adverse reactions in the placebo and ibandronate sodium tablets 2.5 mg daily groups were: dyspepsia (10% vs. 12%), diarrhea (5% vs. 7%), and abdominal pain (5% vs. 6%). Musculoskeletal Adverse Reactions The incidence of selected musculoskeletal adverse reactions in the placebo and ibandronate sodium tablets 2.5 mg daily groups were: back pain (12% vs. 14%), arthralgia (14% vs. 14%) and myalgia (5% vs. 6%). Ocular Adverse Events Reports in the medical literature indicate that bisphosphonates may be associated with ocular inflammation such as iritis and scleritis. In some cases, these events did not resolve until the bisphosphonate was discontinued. There were no reports of ocular inflammation in studies with ibandronate sodium tablets 2.5 mg daily. Monthly Dosing The safety of ibandronate sodium tablets 150 mg once monthly in the treatment of postmenopausal osteoporosis was assessed in a two year trial which enrolled 1583 patients aged 54 to 81 years, with 395 patients exposed to ibandronate sodium tablets 2.5 mg daily and 396 exposed to ibandronate sodium tablets 150 mg monthly. Patients with active or significant pre-existing gastrointestinal disease were excluded from this trial. Patients with dyspepsia or concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors and H2 antagonists were included in this study. All patients received 500 mg calcium plus 400 international units vitamin D supplementation daily. After one year, the incidence of all-cause mortality was 0.3% in both the ibandronate sodium tablets 2.5 mg daily group and the ibandronate sodium tablets 150 mg monthly group. The incidence of serious adverse events was 5% in the ibandronate sodium tablets 2.5 mg daily group and 7% in the ibandronate sodium tablets 150 mg monthly group. The percentage of patients who withdrew from treatment due to adverse events was 9% in the ibandronate sodium tablets 2.5 mg daily group and 8% in the ibandronate sodium tablets 150 mg monthly group. Table 2 lists the adverse events reported in greater than or equal to 2% of patients. Table 2 Adverse Events with an Incidence of at Least 2% in Patients Treated with Ibandronate Sodium Tablets 2.5 mg Daily or 150 mg Once-Monthly for Treatment of Postmenopausal Osteoporosis Body System/Adverse Event Ibandronate sodium tablets 2.5 mg Daily % (n=395) Ibandronate sodium tablets 150 mg Monthly % (n=396) Vascular Disorders Hypertension 7.3 6.3 Gastrointestinal Disorders Dyspepsia 7.1 5.6 Nausea 4.8 5.1 Diarrhea 4.1 5.1 Constipation 2.5 4.0 Abdominal Pain a 5.3 7.8 Musculoskeletal and Connective Tissue Disorders Arthralgia 3.5 5.6 Back Pain 4.3 4.5 Pain in Extremity 1.3 4.0 Localized Osteoarthritis 1.3 3.0 Myalgia 0.8 2.0 Muscle Cramp 2.0 1.8 Infections and Infestations Influenza 3.8 4.0 Nasopharyngitis 4.3 3.5 Bronchitis 3.5 2.5 Urinary Tract Infection 1.8 2.3 Upper Respiratory Tract Infection 2.0 2.0 Nervous System Disorders Headache 4.1 3.3 Dizziness 1.0 2.3 General Disorders and Administration Site Conditions Influenza-like Illness b 0.8 3.3 Skin and Subcutaneous Tissue Disorders Rash c 1.3 2.3 Psychiatric Disorders Insomnia 0.8 2.0 a Combination of abdominal pain and abdominal pain upper b Combination of influenza-like illness and acute phase reaction c Combination of rash pruritic, rash macular, rash papular, rash generalized, rash erythematous, dermatitis, dermatitis allergic, dermatitis medicamentosa, erythema and exanthema Gastrointestinal Adverse Events The incidence of adverse events in the ibandronate sodium tablets 2.5 mg daily and ibandronate sodium tablets 150 mg monthly groups were: dyspepsia (7% vs. 6%), diarrhea (4% vs. 5%), and abdominal pain (5% vs. 8%). Musculoskeletal Adverse Events The incidence of adverse events in the ibandronate sodium tablets 2.5 mg daily and ibandronate sodium tablets 150 mg monthly groups were: back pain (4% vs. 5%), arthralgia (4% vs. 6%) and myalgia (1% vs. 2%). Acute Phase Reactions Symptoms consistent with acute phase reactions have been reported with bisphosphonate use. Over the two years of the study, the overall incidence of acute phase reaction symptoms was 3% in the ibandronate sodium tablets 2.5 mg daily group and 9% in the ibandronate sodium tablets 150 mg monthly group. These incidence rates are based on the reporting of any of 33 acute-phase reaction like symptoms within 3 days of the monthly dosing and lasting 7 days or less. Influenza like illness was reported in no patients in the ibandronate sodium tablets 2.5 mg daily group and 2% in the ibandronate sodium tablets 150 mg monthly group. Ocular Adverse Events Two patients who received ibandronate sodium tablets 150 mg once-monthly experienced ocular inflammation, one was a case of uveitis and the other scleritis. One hundred sixty (160) postmenopausal women without osteoporosis participated in a 1-year, double-blind, placebo-controlled study of ibandronate sodium tablets 150 mg once-monthly for prevention of bone loss. Seventy-seven subjects received ibandronate sodium tablets and 83 subjects received placebo. The overall pattern of adverse events was similar to that previously observed. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ibandronate sodium tablets or bisphosphonate products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity Allergic reactions including anaphylactic reaction/shock with fatalities, angioedema, bronchospasm, asthma exacerbations, rash, Stevens-Johnson syndrome, erythema multiforme, and dermatitis bullous have been reported (see CONTRAINDICATIONS [4] ) . Hypocalcemia Hypocalcemia has been reported in patients treated with ibandronate sodium tablets (see WARNINGS AND PRECAUTIONS [5.2] ) . Musculoskeletal Bone, joint, or muscle pain, described as severe or incapacitating, has been reported rarely (see WARNINGS AND PRECAUTIONS [5.3] ) ; low-energy femoral shaft and subtrochanteric fractures, and atypical fractures of other bones [see Warnings and Precautions ( 5.5 )] . Jaw Osteonecrosis Osteonecrosis of the jaw and other oro-facial sites, including the external auditory canal, have been reported in patients treated with ibandronate sodium tablets (see WARNINGS AND PRECAUTIONS [5.4] ) .

Treatment and Prevention of Postmenopausal Osteoporosis Daily Dosing The safety of ibandronate sodium tablets 2.5 mg once daily in the treatment and prevention of postmenopausal osteoporosis was assessed in 3577 patients aged 41 – 82 years. The duration of the trials was 2 to 3 years, with 1134 patients exposed to placebo and 1140 exposed to ibandronate sodium tablets 2.5 mg. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors and H2 antagonists were included in these clinical trials. All patients received 500 mg calcium plus 400 international units vitamin D supplementation daily. The incidence of all-cause mortality was 1% in the placebo group and 1.2% in the ibandronate sodium tablets 2.5 mg daily group. The incidence of serious adverse reactions was 20% in the placebo group and 23% in the ibandronate sodium tablets 2.5 mg daily group. The percentage of patients who withdrew from treatment due to adverse reactions was approximately 17% in both the ibandronate sodium tablets 2.5 mg daily group and the placebo group. Table 1 lists adverse reactions from the treatment and prevention studies reported in greater than or equal to 2% of patients and more frequently in patients treated daily with ibandronate sodium tablets than patients treated with placebo. Table 1 Adverse Reactions Occurring at an Incidence Greater Than or Equal to 2% and in More Patients Treated with Ibandronate Sodium Tablets Than in Patients Treated with Placebo Daily in the Osteoporosis Treatment and Prevention Studies Body System Placebo % (n=1134) Ibandronate Sodium Tablets 2.5 mg % (n=1140) Body as a Whole Back Pain 12 14 Pain in Extremity 6 8 Asthenia 2 4 Allergic Reaction 2 3 Digestive System Dyspepsia 10 12 Diarrhea 5 7 Tooth Disorder 2 4 Vomiting 2 3 Gastritis 2 2 Musculoskeletal System Myalgia 5 6 Joint Disorder 3 4 Arthritis 3 3 Nervous System Headache 6 7 Dizziness 3 4 Vertigo 3 3 Respiratory System Upper Respiratory Infection 33 34 Bronchitis 7 10 Pneumonia 4 6 Pharyngitis 2 3 Urogenital System Urinary Tract Infection 4 6 Gastrointestinal Adverse Reactions The incidence of selected gastrointestinal adverse reactions in the placebo and ibandronate sodium tablets 2.5 mg daily groups were: dyspepsia (10% vs. 12%), diarrhea (5% vs. 7%), and abdominal pain (5% vs. 6%). Musculoskeletal Adverse Reactions The incidence of selected musculoskeletal adverse reactions in the placebo and ibandronate sodium tablets 2.5 mg daily groups were: back pain (12% vs. 14%), arthralgia (14% vs. 14%) and myalgia (5% vs. 6%). Ocular Adverse Events Reports in the medical literature indicate that bisphosphonates may be associated with ocular inflammation such as iritis and scleritis. In some cases, these events did not resolve until the bisphosphonate was discontinued. There were no reports of ocular inflammation in studies with ibandronate sodium tablets 2.5 mg daily. Monthly Dosing The safety of ibandronate sodium tablets 150 mg once monthly in the treatment of postmenopausal osteoporosis was assessed in a two year trial which enrolled 1583 patients aged 54 to 81 years, with 395 patients exposed to ibandronate sodium tablets 2.5 mg daily and 396 exposed to ibandronate sodium tablets 150 mg monthly. Patients with active or significant pre-existing gastrointestinal disease were excluded from this trial. Patients with dyspepsia or concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors and H2 antagonists were included in this study. All patients received 500 mg calcium plus 400 international units vitamin D supplementation daily. After one year, the incidence of all-cause mortality was 0.3% in both the ibandronate sodium tablets 2.5 mg daily group and the ibandronate sodium tablets 150 mg monthly group. The incidence of serious adverse events was 5% in the ibandronate sodium tablets 2.5 mg daily group and 7% in the ibandronate sodium tablets 150 mg monthly group. The percentage of patients who withdrew from treatment due to adverse events was 9% in the ibandronate sodium tablets 2.5 mg daily group and 8% in the ibandronate sodium tablets 150 mg monthly group. Table 2 lists the adverse events reported in greater than or equal to 2% of patients. Table 2 Adverse Events with an Incidence of at Least 2% in Patients Treated with Ibandronate Sodium Tablets 2.5 mg Daily or 150 mg Once-Monthly for Treatment of Postmenopausal Osteoporosis Body System/Adverse Event Ibandronate sodium tablets 2.5 mg Daily % (n=395) Ibandronate sodium tablets 150 mg Monthly % (n=396) Vascular Disorders Hypertension 7.3 6.3 Gastrointestinal Disorders Dyspepsia 7.1 5.6 Nausea 4.8 5.1 Diarrhea 4.1 5.1 Constipation 2.5 4.0 Abdominal Pain a 5.3 7.8 Musculoskeletal and Connective Tissue Disorders Arthralgia 3.5 5.6 Back Pain 4.3 4.5 Pain in Extremity 1.3 4.0 Localized Osteoarthritis 1.3 3.0 Myalgia 0.8 2.0 Muscle Cramp 2.0 1.8 Infections and Infestations Influenza 3.8 4.0 Nasopharyngitis 4.3 3.5 Bronchitis 3.5 2.5 Urinary Tract Infection 1.8 2.3 Upper Respiratory Tract Infection 2.0 2.0 Nervous System Disorders Headache 4.1 3.3 Dizziness 1.0 2.3 General Disorders and Administration Site Conditions Influenza-like Illness b 0.8 3.3 Skin and Subcutaneous Tissue Disorders Rash c 1.3 2.3 Psychiatric Disorders Insomnia 0.8 2.0 a Combination of abdominal pain and abdominal pain upper b Combination of influenza-like illness and acute phase reaction c Combination of rash pruritic, rash macular, rash papular, rash generalized, rash erythematous, dermatitis, dermatitis allergic, dermatitis medicamentosa, erythema and exanthema Gastrointestinal Adverse Events The incidence of adverse events in the ibandronate sodium tablets 2.5 mg daily and ibandronate sodium tablets 150 mg monthly groups were: dyspepsia (7% vs. 6%), diarrhea (4% vs. 5%), and abdominal pain (5% vs. 8%). Musculoskeletal Adverse Events The incidence of adverse events in the ibandronate sodium tablets 2.5 mg daily and ibandronate sodium tablets 150 mg monthly groups were: back pain (4% vs. 5%), arthralgia (4% vs. 6%) and myalgia (1% vs. 2%). Acute Phase Reactions Symptoms consistent with acute phase reactions have been reported with bisphosphonate use. Over the two years of the study, the overall incidence of acute phase reaction symptoms was 3% in the ibandronate sodium tablets 2.5 mg daily group and 9% in the ibandronate sodium tablets 150 mg monthly group. These incidence rates are based on the reporting of any of 33 acute-phase reaction like symptoms within 3 days of the monthly dosing and lasting 7 days or less. Influenza like illness was reported in no patients in the ibandronate sodium tablets 2.5 mg daily group and 2% in the ibandronate sodium tablets 150 mg monthly group. Ocular Adverse Events Two patients who received ibandronate sodium tablets 150 mg once-monthly experienced ocular inflammation, one was a case of uveitis and the other scleritis. One hundred sixty (160) postmenopausal women without osteoporosis participated in a 1-year, double-blind, placebo-controlled study of ibandronate sodium tablets 150 mg once-monthly for prevention of bone loss. Seventy-seven subjects received ibandronate sodium tablets and 83 subjects received placebo. The overall pattern of adverse events was similar to that previously observed.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ibandronate sodium tablets or bisphosphonate products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity Allergic reactions including anaphylactic reaction/shock with fatalities, angioedema, bronchospasm, asthma exacerbations, rash, Stevens-Johnson syndrome, erythema multiforme, and dermatitis bullous have been reported (see CONTRAINDICATIONS [4] ) . Hypocalcemia Hypocalcemia has been reported in patients treated with ibandronate sodium tablets (see WARNINGS AND PRECAUTIONS [5.2] ) . Musculoskeletal Bone, joint, or muscle pain, described as severe or incapacitating, has been reported rarely (see WARNINGS AND PRECAUTIONS [5.3] ) ; low-energy femoral shaft and subtrochanteric fractures, and atypical fractures of other bones [see Warnings and Precautions ( 5.5 )] . Jaw Osteonecrosis Osteonecrosis of the jaw and other oro-facial sites, including the external auditory canal, have been reported in patients treated with ibandronate sodium tablets (see WARNINGS AND PRECAUTIONS [5.4] ) .

8 USE IN SPECIFIC POPULATIONS Ibandronate sodium tablets are not recommended in patients with severe renal impairment (creatinine clearance less than 30 mL/min). ( 5.6 , 8.6 ) 8.1 Pregnancy Risk Summary Ibandronate sodium tablets 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 post-implantation loss and obstruction of labor with maternal and fetal periparturient mortality at greater than or equal to 3 times human exposure at the recommended 2.5 mg daily oral dose, or at greater than or equal to 1 times human exposure at the recommended 150 mg once-monthly oral dose. In pregnant rats, kidney developmental toxicity occurred in offspring at greater than or equal to 30 times the daily 2.5 mg human dose or at greater than or equal to 9 times the once-monthly 150 mg human dose. In rat reproductive studies, impaired pup neuromuscular development was observed at 45 times the daily 2.5 mg dose and 13 times the once-monthly 150 mg dose. In reproductive studies in the rabbit, ibandronate sodium caused maternal mortality at greater than or equal to 8 times the daily 2.5 mg dose and greater than or equal to 4 times the once-monthly 150 mg dose ( see Data ). Data Animal Data In female rats given ibandronate at oral doses greater than or equal to 3 times human exposure at the recommended daily oral dose of 2.5 mg or greater than or equal to 1 times human exposure at the recommended once-monthly oral dose of 150 mg beginning 14 days before mating and continuing through lactation, maternal deaths were observed at the time of delivery in all dose groups. Perinatal pup loss in dams given doses producing 45 times human exposure at the recommended daily dose and 13 times human exposure at the recommended once-monthly dose was likely related to maternal dystocia. Calcium supplementation did not completely prevent dystocia and periparturient mortality in any of the treated groups at greater than or equal to 16 times the recommended daily dose and greater than or equal to 4.6 times the recommended once-monthly dose. A low incidence of postimplantation loss was observed in rats treated from 14 days before mating throughout lactation or during gestation, only at doses causing maternal dystocia and periparturient mortality. In pregnant rats dosed orally from gestation day 17 through lactation day 21 (following closure of the hard palate through weaning), maternal toxicity, including dystocia and mortality, fetal perinatal and postnatal mortality, were observed at doses equivalent to human exposure at the recommended daily dose and greater than or equal to 4 times the recommended once-monthly dose. Periparturient mortality has also been observed with other bisphosphonates and appears to be a class effect related to inhibition of skeletal calcium mobilization resulting in hypocalcemia and dystocia. Exposure of pregnant rats during the period of organogenesis resulted in an increased fetal incidence of RPU (renal pelvis ureter) syndrome at oral doses producing 30 times human exposure at the recommended daily oral dose of 2.5 mg and greater than or equal to 9 times human exposure at the recommended once-monthly oral dose of 150 mg. Impaired pup neuromuscular development (cliff avoidance test) was observed at 45 times human exposure at the daily dose and 13 times the once-monthly dose. In pregnant rabbits treated orally with ibandronate during gestation at doses greater than or equal to 8 times the recommended human daily oral dose of 2.5 mg and greater than or equal to 4 times the recommended human once-monthly oral dose of 150 mg, dose-related maternal mortality was observed in all treatment groups. The deaths occurred prior to parturition and were associated with lung edema and hemorrhage. No significant fetal anomalies were observed. Exposure multiples for the rat studies were calculated for the recommended daily oral dose of 2.5 mg or once-monthly dose of 150 mg based on area under the curve (AUC) comparison. Exposure multiples for the rabbit study were calculated for the recommended human daily oral dose of 2.5 mg or once-monthly dose of 150 mg based on dose/body surface area comparison. Doses used in pregnant animals were 1, 4, 5, 6, 16, 10, 20, 30, 60 or 100 mg/kg/day in rats, and 1, 4 or 20 mg/kg/day in rabbits. 8.2Lactation Risk Summary Ibandronate sodium tablets is not indicated for use in women of reproductive potential. There is no information on the presence of ibandronate in human milk, the effects of ibandronate on the breastfed infant, or the effects of ibandronate on milk production. Ibandronate is present in rat milk (see Data) . The clinical relevance of these data is unclear. Data Animal Data In lactating rats treated with intravenous doses of 0.08 mg/kg, ibandronate was present in breast milk from 2 to 24 hours after dose administration. Concentrations in milk averaged 1.5 times plasma concentrations. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Of the patients receiving ibandronate sodium tablets 2.5 mg daily in postmenopausal osteoporosis studies, 52% were over 65 years of age, and 10% were over 75 years of age. Of the patients receiving ibandronate sodium tablets 150 mg once-monthly in the postmenopausal osteoporosis 1-year study, 52% were over 65 years of age, and 9% were over 75 years of age. No overall differences in effectiveness or safety were observed between these patients and younger patients but greater sensitivity in some older individuals cannot be ruled out. 8.6 Renal Impairment Ibandronate sodium tablets are not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/min).

8.1 Pregnancy Risk Summary Ibandronate sodium tablets 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 post-implantation loss and obstruction of labor with maternal and fetal periparturient mortality at greater than or equal to 3 times human exposure at the recommended 2.5 mg daily oral dose, or at greater than or equal to 1 times human exposure at the recommended 150 mg once-monthly oral dose. In pregnant rats, kidney developmental toxicity occurred in offspring at greater than or equal to 30 times the daily 2.5 mg human dose or at greater than or equal to 9 times the once-monthly 150 mg human dose. In rat reproductive studies, impaired pup neuromuscular development was observed at 45 times the daily 2.5 mg dose and 13 times the once-monthly 150 mg dose. In reproductive studies in the rabbit, ibandronate sodium caused maternal mortality at greater than or equal to 8 times the daily 2.5 mg dose and greater than or equal to 4 times the once-monthly 150 mg dose ( see Data ). Data Animal Data In female rats given ibandronate at oral doses greater than or equal to 3 times human exposure at the recommended daily oral dose of 2.5 mg or greater than or equal to 1 times human exposure at the recommended once-monthly oral dose of 150 mg beginning 14 days before mating and continuing through lactation, maternal deaths were observed at the time of delivery in all dose groups. Perinatal pup loss in dams given doses producing 45 times human exposure at the recommended daily dose and 13 times human exposure at the recommended once-monthly dose was likely related to maternal dystocia. Calcium supplementation did not completely prevent dystocia and periparturient mortality in any of the treated groups at greater than or equal to 16 times the recommended daily dose and greater than or equal to 4.6 times the recommended once-monthly dose. A low incidence of postimplantation loss was observed in rats treated from 14 days before mating throughout lactation or during gestation, only at doses causing maternal dystocia and periparturient mortality. In pregnant rats dosed orally from gestation day 17 through lactation day 21 (following closure of the hard palate through weaning), maternal toxicity, including dystocia and mortality, fetal perinatal and postnatal mortality, were observed at doses equivalent to human exposure at the recommended daily dose and greater than or equal to 4 times the recommended once-monthly dose. Periparturient mortality has also been observed with other bisphosphonates and appears to be a class effect related to inhibition of skeletal calcium mobilization resulting in hypocalcemia and dystocia. Exposure of pregnant rats during the period of organogenesis resulted in an increased fetal incidence of RPU (renal pelvis ureter) syndrome at oral doses producing 30 times human exposure at the recommended daily oral dose of 2.5 mg and greater than or equal to 9 times human exposure at the recommended once-monthly oral dose of 150 mg. Impaired pup neuromuscular development (cliff avoidance test) was observed at 45 times human exposure at the daily dose and 13 times the once-monthly dose. In pregnant rabbits treated orally with ibandronate during gestation at doses greater than or equal to 8 times the recommended human daily oral dose of 2.5 mg and greater than or equal to 4 times the recommended human once-monthly oral dose of 150 mg, dose-related maternal mortality was observed in all treatment groups. The deaths occurred prior to parturition and were associated with lung edema and hemorrhage. No significant fetal anomalies were observed. Exposure multiples for the rat studies were calculated for the recommended daily oral dose of 2.5 mg or once-monthly dose of 150 mg based on area under the curve (AUC) comparison. Exposure multiples for the rabbit study were calculated for the recommended human daily oral dose of 2.5 mg or once-monthly dose of 150 mg based on dose/body surface area comparison. Doses used in pregnant animals were 1, 4, 5, 6, 16, 10, 20, 30, 60 or 100 mg/kg/day in rats, and 1, 4 or 20 mg/kg/day in rabbits.