IBANDRONATE SODIUM

Ibandronate sodium is a nitrogen-containing bisphosphonate that inhibits osteoclast-mediated bone resorption. The chemical name for ibandronate sodium is 3-(N-methyl-N-pentyl) amino-1-hydroxypropane-1,1diphosphonic acid, monosodium salt, with the molecular formula C 9 H 22 NO 7 P 2 Na and a molecular weight of 341. Ibandronate sodium is an off-white to white colored powder. It is sparingly soluble in water. Ibandronate sodium has the following structural formula: Ibandronate sodium tablets are available as a white, capsule shaped 150-mg coated tablets for once-monthly oral administration. One 150 mg coated tablet contains 160.33 mg ibandronate sodium, equivalent to 150 mg of ibandronic acid. Ibandronate sodium tablets also contains the following inactive ingredients: colloidal silicon dioxide, crospovidone, croscarmellose sodium, lactose monohydrate, microcrystalline cellulose, povidone, and sodium stearyl fumarate. The tablet coating contains hypromellose, polyethylene glycol 400, and titanium dioxide. Imprinting ink contains: ammonium hydroxide, black iron oxide, propylene glycol and shellac.

Ibandronate sodium tablet 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 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.

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 tablet 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 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 every month on their previous chosen day.

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)

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 Dr. Reddy’s Laboratories Inc. at 1-888-375-3784 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 DosingThe safety of ibandronate sodium 2.5 mg 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. Patients with pre-existing gastrointestinal diseaseand 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 2.5 mg daily group. The incidence of serious adverse reactions was 20% in the placebo group and 23% in the ibandronate sodium2.5 mg 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 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 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 Than in Patients Treated with Placebo Daily in the Osteoporosis Treatment and Prevention Studies Body System Placebo % (n=1134) Ibandronate Sodium 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 2.5 mg daily groups were: dyspepsia (10% vs. 12%), diarrhea (5% vs. 7%), and abdominal pain (5% vs. 6%). M usculoskeletal Adverse Reactions The incidence of selected musculoskeletal adverse reactions in the placebo and ibandronate sodium 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 2.5 mg daily. Monthly Dosing The safety of ibandronate sodium 150 mg once monthly in the treatment of postmenopausal osteoporosis was assessed in a two year trial which enrolled 1,583 patients aged 54 to 81 years, with 395 patients exposed to ibandronate sodium 2.5 mg daily and 396 exposed to ibandronate sodium 150 mg monthly. Patients with active or significant pre-existing gastrointestinal disease were excluded from this trial. Patients with dyspepsia or concomitant use of nonsteroidal 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 daily group and the ibandronate sodium 150 mg monthly group. The incidence of serious adverse events was 5% in the ibandronate sodium 2.5 mg daily group and 7% in the ibandronate sodium 150 mg monthly group. The percentage of patients who withdrew from treatment due to adverse events was 9% in the ibandronate sodium 2.5 mg daily group and 8% in the ibandronate sodium 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 the Ibandronate Sodium 2.5 mg Daily or Ibandronate Sodium 150 mg Once-Monthly for Treatment of Postmenopausal Osteoporosis Body System/Adverse Event Ibandronate Sodium 2.5 mg Daily % (n=395) Ibandronate Sodium 150 mg Monthly % (n=396) Vascular Disorders Hypertension 7.3 6.3 Gastrointestinal Disorders Dyspepsia Nausea Diarrhea Constipation Abdominal Pain a 7.1 4.8 4.1 2.5 5.3 5.6 5.1 5.1 4.0 7.8 Musculoskeletal and Connective Tissue Disorders Arthralgia Back Pain Pain in Extremity Localized Osteoarthritis Myalgia Muscle Cramp 3.5 4.3 1.3 1.3 0.8 2.0 5.6 4.5 4.0 3.0 2.0 1.8 Infections and Infestations Influenza Nasopharyngitis Bronchitis Urinary Tract Infection Upper Respiratory Tract Infection 3.8 4.3 3.5 1.8 2.0 4.0 3.5 2.5 2.3 2.0 Nervous System Disorders Headache Dizziness 4.1 1.0 3.3 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 2.5 mg daily and ibandronate sodium 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 2.5 mg daily and ibandronate sodium 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 2.5 mg daily group and 9% in the ibandronate sodium 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 2.5 mg daily group and 2% in the ibandronate sodium 150 mg monthly group. Ocular Adverse Events Two patients who received ibandronate sodium 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 150 mg 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 muliforme, 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] ).

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 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.