Ibandronate Sodium

1 INDICATIONS AND USAGE Ibandronate sodium is a bisphosphonate indicated for the treatment and prevention of postmenopausal 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 tablets increase bone mineral density (BMD) and reduce 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 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 is one 150 mg tablet taken once monthly on the same date each month. 2.2 Important Administration Instructions Instruct Patients to do the following: Take ibandronate sodium tablets 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 tablets (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 tablets. 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 tablets administration because co-administration of ibandronate sodium tablets 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 tablets 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 tablets day is only 1 to 7 days away, wait until the subsequent month’s scheduled ibandronate sodium tablets 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.

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, 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), diagnos…

4 CONTRAINDICATIONS Ibandronate sodium tablets are 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 tablets. (4)

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 Administration [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 H 2 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.

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 wer…

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 Aurobindo Pharma USA, Inc. 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. Treatment and Prevention of Postmenopausal Osteoporosis Daily Dosing 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 to 82 years. The duration of the trials was 2 to 3 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 H 2 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 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 group. The percentage of patients who withdrew from treatment due to adverse reactions was approximately 17% in both the ibandronate sodium 2.5 mg (ibandronate) 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 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 Sodiu m Than in Patients Treated with Placebo Daily in the Osteoporosis Treatment and Prevention Studies Body System Placebo % (n=1134) Ibandronate Sodium 2.5 mg (ibandronate) % (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 2.5 mg (ibandronate) 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 2.5 mg (ibandronate) 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 we…