IBANDRONATE SODIUM

1 INDICATIONS AND USAGE Ibandronate Sodium Tablets are a bisphosphonate indicated for the treatment and prevention of post-menopausal osteoporosis. ( 1.1 ) Limitations of Use The 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 and Prevention of Postmenopausal Osteoporosis Ibandronate Sodium Tablets are indicated for the treatment and prevention of osteoporosis in postmenopausal women. Ibandronate sodium increases bone mineral density (BMD) and reduces the incidence of vertebral fractures. 1.2 Important Limitations of Use The optimal duration of use has not been determined. The safety and effectiveness of Ibandronate Sodium Tablets for the treatment of osteoporosis are based on clinical data of three years duration. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis. Patients at low-risk for fracture should be considered for drug discontinuation after 3 to 5 years of use. Patients who discontinue therapy should have their risk for fracture re-evaluated periodically.

2 DOSAGE AND ADMINISTRATION • Take one 150 mg tablet as ibandronic acid once monthly on the same day each month ( 2.1 ) • Instruct patient to: ( 2.2 ) • Swallow whole tablet with 6 to 8 oz of plain water only, at least 60 minutes before the first food, beverage, or medication of day. Avoid lying down for at least 60 minutes after taking Ibandronate Sodium Tablets. • Do not eat, drink (except for water), or take other medication for 60 minutes after taking Ibandronate Sodium Tablets. • Take supplemental calcium and vitamin D if dietary intake inadequate ( 2.3 ) 2.1 Dosage Information The dose of Ibandronate Sodium Tablet is one 150 mg tablet as ibandronic acid taken once monthly on the same date each month. 2.2 Important Administration Instructions Instruct Patients to do the following: • Take Ibandronate Sodium Tablet at least 60 minutes before the first food or drink (other than water) of the day or before taking any oral medication or supplementation, including calcium, antacids, or vitamins to maximize absorption and clinical benefit, (see DRUG INTERACTIONS [ 7.1 ]) . Avoid the use of water with supplements including mineral water because they may have a higher concentration of calcium. • Swallow Ibandronate Sodium Tablets whole with a full glass of plain water (6 to 8 oz) while standing or sitting in an upright position to reduce the potential for esophageal irritation. Avoid lying down for 60 minutes after taking Ibandronate Sodium Tablet (see WARNINGS AND PRECAUTIONS [ 5.1 ]) . Do not chew or suck the tablet because of a potential for oropharyngeal ulceration. • Do not eat, drink anything except plain water, or take other medications for at least 60 minutes after taking Ibandronate Sodium Tablet. 2.3 Recommendations for Calcium and Vitamin D Supplementation Instruct patients to take supplemental calcium and vitamin D if their dietary intake is inadequate. Avoid the use of calcium supplements within 60 minutes of Ibandronate Sodium Tablet administration because co-administration of Ibandronate Sodium Tablet and calcium may interfere with the absorption of ibandronate sodium (see DRUG INTERACTIONS [7.1]) . 2.4 Administration Instructions for Missed Once-Monthly Doses If the once-monthly dose is missed, instruct patients to do the following: • If the next scheduled Ibandronate Sodium Tablet day is more than 7 days away, take one Ibandronate Sodium Tablet 150 mg (ibandronate) in the morning following the date that it is remembered. • If the next scheduled Ibandronate Sodium Tablet day is only 1 to 7 days away, wait until the subsequent month’s scheduled Ibandronate Sodium Tablet day to take their tablet. For subsequent monthly doses for both of the above scenarios, instruct patients to return to their original schedule by taking one Ibandronate Sodium Tablet 150 mg (ibandronate) every month on their previous chosen day.

4 CONTRAINDICATIONS Ibandronate sodium is contraindicated in patients with the following conditions: • Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia (see Warnings and Precautions [ 5.1 ]) • Inability to stand or sit upright for at least 60 minutes (see Dosage and Administration [2.2], and Warnings and Precautions [ 5.1 ]) • Hypocalcemia (see Warnings and Precautions [ 5.2 ]) • Known hypersensitivity to ibandronate sodium tablets or to any of its excipients. Cases of anaphylaxis have been reported. (see Adverse Reactions [6.2]) . • Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia ( 4 , 5.1 ) • Inability to stand or sit upright for at least 60 minutes ( 4 , 5.1 ) • Hypocalcemia ( 4 ) • Hypersensitivity to ibandronate sodium ( 4 )

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 Femur Fractures have been reported. Patients with new thigh or groin pain should be evaluated to rule out a femoral fracture. (5.5) 5.1 Upper Gastrointestinal Adverse Reactions Ibandronate sodium, 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 is given to patients with active upper gastrointestinal problems (such as known Barrett’s esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis or ulcers). Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates. In some cases, these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue ibandronate sodium 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 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. Treat hypocalcemia and other disturbances of bone and mineral metabolism before starting ibandronate sodium 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 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 Subtrochanteric and Diaphyseal Femoral Fractures Atypical, low-energy, or low-trauma fractures of the femoral shaft have been reported in bisphosphonate-treated patients. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with bisphosphonates. Atypical femur fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g., prednisone) at the time of fracture. Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patients presenting with an atypical fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of bisphosphonate therapy should be considered, pending a risk/benefit assessment, on an individual basis. 5.6 Severe Renal Impairment Ibandronate sodium is not recommended for use in patients with severe renal impairment (creatinine clearance of less than 30 mL/min).

7 DRUG INTERACTIONS • Calcium supplements, antacids and some oral medications may interfere with absorption of ibandronate. Do not take within 60 minutes of dosing ( 7.1 ) • Use caution when co-prescribing aspirin/nonsteroidal anti-inflammatory drugs that may worsen gastrointestinal irritation. ( 7.2 ) 7.1 Calcium Supplements/Antacids Products containing calcium and other multivalent cations (such as aluminum, magnesium, iron) are likely to interfere with absorption of ibandronate sodium. Therefore, instruct patients to take ibandronate sodium at least 60 minutes before any oral medications, including medications containing multivalent cations (such as antacids, supplements or vitamins). Also, patients should wait at least 60 minutes after dosing before taking any other oral medications (see DOSAGE AND ADMINSTRATION [2.3]) . 7.2 Aspirin/Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Because aspirin, NSAIDs, and bisphosphonates are all associated with gastrointestinal irritation, caution should be exercised in the concomitant use of aspirin or NSAIDs with ibandronate sodium. 7.3 H2 Blockers In healthy volunteers, co-administration with ranitidine resulted in a 20% increased bioavailability of ibandronate, which was not considered to be clinically relevant (see CLINICAL PHARMACOLOGY [12.3]) . 7.4 Drug/Laboratory Test Interactions Bisphosphonates are known to interfere with the use of bone-imaging agents. Specific studies with ibandronate have not been performed.

6 ADVERSE REACTIONS 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 Bionpharma Inc. at 1-888-235-BION or 1-888-235-2466 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 Monthly Dosing The safety of ibandronate sodium 150 mg as ibandronic acid 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 2.5 mg as ibandronic acid daily and 396 exposed to ibandronate sodium 150 mg as ibandronic acid 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 2.5 mg as ibandronic acid daily group and the ibandronate sodium 150 mg as ibandronic acid monthly group. The incidence of serious adverse events was 5% in the ibandronate sodium 2.5 mg as ibandronic acid daily group and 7% in the ibandronate sodium 150 mg as ibandronic acid monthly group. The percentage of patients who withdrew from treatment due to adverse events was 9% in the ibandronate sodium 2.5 mg as ibandronic acid daily group and 8% in the ibandronate sodium 150 mg as ibandronic acid 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 2.5 mg as Ibandronic Acid Daily or 150 mg as Ibandronic Acid Once - Monthly for Treatment of Postmenopausal Osteoporosis Ibandronate sodium 2.5 mg as Ibandronic acid Daily % Ibandronate sodium 150 mg as Ibandronic acid Monthly % Body System/Adverse Event (n=395) (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 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 Localized Osteoarthritis 1.3 3 Myalgia 0.8 2 Muscle Cramp 2 1.8 Infections and Infestations Influenza 3.8 4 Nasopharyngitis 4.3 3.5 Bronchitis 3.5 2.5 Urinary Tract Infection 1.8 2.3 Upper Respiratory Tract Infection 2 2 Nervous System Disorders Headache 4.1 3.3 Dizziness 1 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 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 2.5 mg as ibandronic acid daily and ibandronate sodium 150 mg as ibandronic acid 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 2.5 mg as ibandronic acid daily and ibandronate sodium 150 mg as ibandronic acid 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 2.5 mg as ibandronic acid daily group and 9% in the ibandronate sodium 150 mg as ibandronic acid 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 2.5 mg as ibandronic acid daily group and 2% in the ibandronate sodium 150 mg as ibandronic acid monthly group. Ocular Adverse Events Two patients who received ibandronate sodium 150 mg as ibandronic acid 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 150 mg as ibandronic acid once-monthly for prevention of bone loss. Seventy-seven subjects received ibandronate sodium 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. 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 (see WARNINGS AND PRECAUTIONS [5.2]) . Musculoskeletal Pain Bone, joint, or muscle pain (musculoskeletal pain), described as severe or incapacitating, has been reported (see WARNINGS AND PRECAUTIONS [ 5.3] ) . 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 (see WARNINGS AND PRECAUTIONS [5.4]) . Atypical Femoral Shaft Fracture Atypical, low-energy, or low-trauma fractures of the femoral shaft (see WARNINGS AND PRECAUTIONS [ 5.5 ]) .

8.1 Pregnancy Risk Summary Ibandronate 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 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.