Risedronate Sodium

5 WARNINGS AND PRECAUTIONS Products Containing Same Active Ingredient : Patients receiving Atelvia should not be treated with risedronate sodium tablets ( 5.1 ) Upper Gastrointestinal Adverse Reactions can occur. Instruct patients to follow dosing instructions. Discontinue use if new or worsening symptoms occur ( 5.2 ) Hypocalcemia may worsen and must be corrected prior to use ( 5.3 ) Osteonecrosis of the Jaw has been reported ( 5.4 ) Severe Bone, Joint, Muscle Pain may occur. Discontinue use if severe symptoms develop ( 5.5 , 6.2 ) 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 ( 5.6 ) 5.1 Drug Products with the Same Active Ingredient Risedronate sodium tablets contain the same active ingredient found in Atelvia ® . A patient being treated with Atelvia should not receive risedronate sodium tablets. 5.2 Upper Gastrointestinal Adverse Reactions Risedronate, 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 risedronate is given to patients with active upper gastrointestinal problems (such as known Barrett’s esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis or ulcers) [see Contraindications (4) , Adverse Reactions (6.1) , Information for Patients (17) ] . 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 risedronate 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 ounces) 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) ] . In patients who cannot comply with dosing instructions due to mental disability, therapy with risedronate 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. 5.3 Mineral Metabolism Hypocalcemia has been reported in patients taking risedronate. Treat hypocalcemia and other disturbances of bone and mineral metabolism before starting risedronate therapy. Instruct patients to take supplemental calcium and vitamin D if their dietary intake is inadequate. Adequate intake of calcium and vitamin D is important in all patients, especially in patients with Paget’s disease in whom bone turnover is significantly elevated [see Contraindications (4) , Adverse Reactions (6.1) , Information for Patients (17) ]. 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 risedronate. Known risk factors for osteonecrosis of the jaw include invasive dental procedures (for example, tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (for example, chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and co-morbid disorders (for example, 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 [see Adverse Reactions (6.2) ] . 5.5 Musculoskeletal Pain In postmarketing experience, there have been reports of severe and occasionally incapacitating bone, joint, and/or muscle pain in patients taking bisphosphonates [see Adverse Reactions (6.2) ] . 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 medication. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. Consider discontinuing use if severe symptoms develop. 5.6 Atypical Fractures Including Femoral Fractures Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported during treatment with bisphosphonates, including risedronate, 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. 5.7 Renal Impairment Risedronate is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/min). 5.8 Glucocorticoid-Induced Osteoporosis Before initiating risedronate treatment for the treatment and prevention of glucocorticoid-induced osteoporosis, the sex steroid hormonal status of both men and women should be ascertained and appropriate replacement considered. 5.9 Laboratory Test Interactions Bisphosphonates are known to interfere with the use of bone-imaging agents. Specific studies with risedronate have not been performed.

6 ADVERSE REACTIONS The following clinically significant adverse drug reactions are described elsewhere in the labeling: Drug Products with the Same Active Ingredient [see Warnings and Precautions (5.1) ] Upper Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.2) ] Mineral Metabolism [see Warnings and Precautions (5.3) ] Jaw Osteonecrosis [see Warnings and Precautions (5.4) ] Musculoskeletal Pain [see Warnings and Precautions (5.5) ] Atypical Fractures Including Femoral Fractures [see Warnings and Precautions (5.6) ] Renal Impairment [see Warnings and Precautions (5.7) ] Glucocorticoid-Induced Osteoporosis [see Warnings and Precautions (5.8) ] Laboratory Test Interactions [see Warnings and Precautions (5.9) ] Most common adverse reactions reported in greater than 10% of patients treated with risedronate and with a higher frequency than placebo are: back pain, arthralgia, abdominal pain, and dyspepsia (6.1) Hypersensitivity reactions (angioedema, generalized rash, bullous skin reactions, Stevens-Johnson syndrome, and toxic epidermal necrolysis), and eye inflammation (iritis, uveitis) have been reported rarely (6.2) 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 Studies 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 of Postmenopausal Osteoporosis Daily Dosing The safety of risedronate sodium tablets 5 mg once daily in the treatment of postmenopausal osteoporosis was assessed in four randomized, double-blind, placebo-controlled multinational trials of 3232 women aged 38 to 85 years with postmenopausal osteoporosis. The duration of the trials was up to three years, with 1619 patients exposed to placebo and 1613 patients exposed to risedronate sodium tablets 5 mg. 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 women received 1000 mg of elemental calcium plus vitamin D supplementation up to 500 international units per day if their 25-hydroxyvitamin D 3 level was below normal at baseline. The incidence of all-cause mortality was 2% in the placebo group and 1.7% in the risedronate sodium tablets 5 mg daily group. The incidence of serious adverse events was 24.6% in the placebo group and 27.2% in the risedronate sodium tablets 5 mg group. The percentage of patients who withdrew from the study due to adverse events was 15.6% in the placebo group and 14.8% in the risedronate sodium tablets 5 mg group. The most common adverse reactions reported in greater than 10 percent of subjects were: back pain, arthralgia, abdominal pain and dyspepsia. Table 1 lists adverse events from the Phase 3 postmenopausal osteoporosis trials reported in greater than or equal to 5% of patients. Adverse events are shown without attribution of causality. Table 1 Adverse Events Occurring at a Frequency greater than or equal to 5% in Either Treatment Group Combined Phase 3 Postmenopausal Osteoporosis Treatment Trials Body System Placebo N = 1619 5 mg Risedronate Sodium Tablets N = 1613 % % Body as a Whole Infection 29.9 31.1 Back Pain 26.1 28 Accidental Injury 16.8 16.9 Pain 14 14.1 Abdominal Pain 9.9 12.2 Flu Syndrome 11.6 10.5 Headache 10.8 9.9 Asthenia 4.5 5.4 Neck Pain 4.7 5.4 Chest Pain 5.1 5 Allergic Reaction Cardiovascular System 5.9 3.8 Hypertension Digestive System 9.8 10.5 Constipation 12.6 12.9 Diarrhea 10 10.8 Dyspepsia 10.6 10.8 Nausea Metabolic & Nutritional Disorders 11.2 10.5 Peripheral Edema Musculoskeletal System 8.8 7.7 Arthralgia 22.1 23.7 Arthritis 10.1 9.6 Traumatic Bone Fracture 12.3 9.3 Joint Disorder 5.3 7 Myalgia 6.2 6.7 Bone Pain Nervous System 4.8 5.3 Dizziness 5.7 7.1 Depression 6.1 6.8 Insomnia Respiratory System 4.6 5 Bronchitis 10.4 10 Sinusitis 9.1 8.7 Rhinitis 5.1 6.2 Pharyngitis 5 6 Increased Cough Skin and Appendages 6.3 5.9 Rash Special Senses 7.1 7.9 Cataract Urogenital System 5.7 6.5 Urinary Tract Infection 10.4 11.1 Gastrointestinal Adverse Events: The incidence of adverse events in the placebo and risedronate sodium tablets 5 mg daily groups were: abdominal pain (9.9% versus 12.2%), diarrhea (10% versus 10.8%), dyspepsia (10.6% versus 10.8%), and gastritis (2.3% versus 2.7%). Duodenitis and glossitis have been reported uncommonly in the risedronate sodium tablets 5 mg daily group (0.1% to 1%). In patients with active upper gastrointestinal disease at baseline, the incidence of upper gastrointestinal adverse events was similar between the placebo and risedronate sodium tablets 5 mg daily groups. Musculoskeletal Adverse Events: The incidence of adverse events in the placebo and risedronate sodium tablets 5 mg daily groups were: back pain (26.1% versus 28%), arthralgia (22.1% versus 23.7%), myalgia (6.2% versus 6.7%), and bone pain (4.8% versus 5.3%). Laboratory Test Findings: Throughout the Phase 3 studies, transient decreases from baseline in serum calcium (less than 1%) and serum phosphate (less than 3%) and compensatory increases in serum PTH levels (less than 30%) were observed within 6 months in patients in osteoporosis clinical trials treated with risedronate sodium tablets 5 mg once daily. There were no significant differences in serum calcium, phosphate, or PTH levels between placebo and risedronate sodium tablets 5 mg once daily at 3 years. Serum calcium levels below 8 mg/dL were observed in 18 patients, 9 (0.5%) in each treatment arm (placebo and risedronate sodium tablets 5 mg once daily). Serum phosphorus levels below 2 mg/dL were observed in 14 patients, 3 (0.2%) treated with placebo and 11 (0.6%) treated with risedronate sodium tablets 5 mg once daily. There have been rare reports (less than 0.1%) of abnormal liver function tests. Endoscopic Findings: In the risedronate sodium tablets clinical trials, endoscopic evaluation was encouraged in any patient with moderate-to-severe gastrointestinal complaints, while maintaining the blind. Endoscopies were performed on equal numbers of patients between the placebo and treated groups [75 (14.5%) placebo; 75 (11.9%) risedronate sodium tablets]. Clinically important findings (perforations, ulcers, or bleeding) among this symptomatic population were similar between groups (51% placebo; 39% risedronate sodium tablets). Once-a-Week Dosing The safety of risedronate sodium tablets 35 mg once-a-week in the treatment of postmenopausal osteoporosis was assessed in a 1-year, double-blind, multicenter study comparing risedronate sodium tablets 5 mg daily and risedronate sodium tablets 35 mg once-a-week in postmenopausal women aged 50 to 95 years. The duration of the trials was one year, with 480 patients exposed to risedronate sodium tablets 5 mg daily and 485 exposed to risedronate sodium tablets 35 mg once-a-week. 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 women received 1000 mg of elemental calcium plus vitamin D supplementation up to 500 international units per day if their 25-hydroxyvitamin D 3 level was below normal at baseline. The incidence of all-cause mortality was 0.4% in the risedronate sodium tablets 5 mg daily group and 1% in the risedronate sodium tablets 35 mg once-a-week group. The incidence of serious adverse events was 7.1% in the risedronate sodium tablets 5 mg daily group and 8.2% in the risedronate sodium tablets 35 mg once-a-week group. The percentage of patients who withdrew from the study due to adverse events was 11.9% in the risedronate sodium tablets 5 mg daily group and 11.5% in the risedronate sodium tablets 35 mg once-a-week group. The overall safety and tolerability profiles of the two dosing regimens were similar. Gastrointestinal Adverse Events: The incidence of gastrointestinal adverse events was similar between the risedronate sodium tablets 5 mg daily group and the risedronate sodium tablets 35 mg once-a-week group: dyspepsia (6.9% versus 7.6%), diarrhea (6.3% versus 4.9%), and abdominal pain (7.3% versus 7.6%). Musculoskeletal Adverse Events: Arthralgia was reported in 11.5% of patients in the risedronate sodium tablets 5 mg daily group and 14.2% of patients in the risedronate sodium tablets 35 mg once-a-week group. Myalgia was reported by 4.6% of patients in the risedronate sodium tablets 5 mg daily group and 6.2% of patients in the risedronate sodium tablets 35 mg once-a-week group. Laboratory Test Findings: The mean percent changes from baseline at 12 months were similar between the risedronate sodium tablets 5 mg daily and risedronate sodium tablets 35 mg once-a-week groups, respectively, for serum calcium (0.4% versus 0.7%), phosphate (-3.8% versus -2.6%) and PTH (6.4% versus 4.2%). Monthly Dosing Two Consecutive Days per Month The safety of risedronate sodium tablets 75 mg administered on two consecutive days per month for the treatment of postmenopausal osteoporosis was assessed in a double-blind, multicenter study in postmenopausal women aged 50 to 86 years. The duration of the trial was two years; 613 patients were exposed to risedronate sodium tablets 5 mg daily and 616 were exposed to risedronate sodium tablets 75 mg two consecutive days per month. 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 this clinical trial. All women received 1000 mg of elemental calcium plus 400 to 800 international units of vitamin D supplementation per day. The incidence of all-cause mortality was 1% for the risedronate sodium tablets 5 mg daily group and 0.5% for the risedronate sodium tablets 75 mg two consecutive days per month group. The incidence of serious adverse events was 10.8% in the risedronate sodium tablets 5 mg daily group and 14.4% in the risedronate sodium tablets 75 mg two consecutive days per month group. The percentage of patients who withdrew from treatment due to adverse events was 14.2% in the risedronate sodium tablets 5 mg daily group and 13% in the risedronate sodium tablets 75 mg two consecutive days per month group. The overall safety and tolerability profiles of the two dosing regimens were similar. Acute Phase Reactions: Symptoms consistent with acute phase reaction have been reported with bisphosphonate use. The overall incidence of acute phase reaction was 3.6% of patients on risedronate sodium tablets 5 mg daily and 7.6% of patients on risedronate sodium tablets 75 mg two consecutive days per month. These incidence rates are based on reporting of any of 33 acute phase reaction-like symptoms within 5 days of the first dose. Fever or influenza-like illness with onset within the same period were reported by 0% of patients on risedronate sodium tablets 5 mg daily and 0.6% of patients on risedronate sodium tablets 75 mg two consecutive days per month. Gastrointestinal Adverse Events: The risedronate sodium tablets 75 mg two consecutive days per month group resulted in a higher incidence of discontinuation due to vomiting (1% versus 0.2%) and diarrhea (1% versus 0.3%) compared to the risedronate sodium tablets 5 mg daily group. Most of these events occurred within a few days of dosing. Ocular Adverse Events: None of the patients treated with risedronate sodium tablets 75 mg two consecutive days per month reported ocular inflammation such as uveitis, scleritis, or iritis; 1 patient treated with risedronate sodium tablets 5 mg daily reported uveitis. Laboratory Test Findings: When risedronate sodium tablets 5 mg daily and risedronate sodium tablets 75 mg two consecutive days per month were compared in postmenopausal women with osteoporosis, the mean percent changes from baseline at 24 months were 0.2% and 0.8% for serum calcium, -1.9% and -1.3% for phosphate, and -10.4% and -17.2% for PTH, respectively. Compared to the risedronate sodium tablets 5 mg daily group, risedronate sodium tablets 75 mg two consecutive days per month resulted in a slightly higher incidence of hypocalcemia at the end of the first month of treatment (4.5% versus 3%). Thereafter, the incidence of hypocalcemia with these regimens was similar at approximately 2%. Once-a-Month The safety of risedronate sodium tablets 150 mg administered once-a-month for the treatment of postmenopausal osteoporosis was assessed in a double-blind, multicenter study in postmenopausal women aged 50 to 88 years. The duration of the trial was one year, with 642 patients exposed to risedronate sodium tablets 5 mg daily and 650 exposed to risedronate sodium tablets 150 mg once-a-month. 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 this clinical trial. All women received 1000 mg of elemental calcium plus up to 1000 international units of vitamin D supplementation per day. The incidence of all-cause mortality was 0.5% for the risedronate sodium tablets 5 mg daily group and 0% for the risedronate sodium tablets 150 mg once-a-month group. The incidence of serious adverse events was 4.2% in the risedronate sodium tablets 5 mg daily group and 6.2% in the risedronate sodium tablets 150 mg once-a-month group. The percentage of patients who withdrew from treatment due to adverse events was 9.5% in the risedronate sodium tablets 5 mg daily group and 8.6% in the risedronate sodium tablets 150 mg once-a-month group. The overall safety and tolerability profiles of the two dosing regimens were similar. Acute Phase Reactions: Symptoms consistent with acute phase reaction have been reported with bisphosphonate use. The overall incidence of acute phase reaction was 1.1% in the risedronate sodium tablets 5 mg daily group and 5.2% in the risedronate sodium tablets 150 mg once-a-month group. These incidence rates are based on reporting of any of 33 acute phase reaction-like symptoms within 3 days of the first dose and for a duration of 7 days or less. Fever or influenza-like illness with onset within the same period were reported by 0.2% of patients on risedronate sodium tablets 5 mg daily and 1.4% of patients on risedronate sodium tablets 150 mg once-a-month. Gastrointestinal Adverse Events: A greater percentage of patients experienced diarrhea with risedronate sodium tablets 150 mg once-a-month compared to 5 mg daily (8.2% versus 4.7%, respectively). The risedronate sodium tablets 150 mg once-a-month group resulted in a higher incidence of discontinuation due to abdominal pain upper (2.5% versus 1.4%) and diarrhea (0.8% versus 0%) compared to the risedronate sodium tablets 5 mg daily regimen. All of these events occurred within a few days of the first dose. The incidence of vomiting that led to discontinuation was the same in both groups (0.3% versus 0.3%). Ocular Adverse Events: None of the patients treated with risedronate sodium tablets 150 mg once-a-month reported ocular inflammation such as uveitis, scleritis, or iritis; 2 patients treated with risedronate sodium tablets 5 mg daily reported iritis. Laboratory Test Findings: When risedronate sodium tablets 5 mg daily and risedronate sodium tablets 150 mg once-a-month were compared in postmenopausal women with osteoporosis, the mean percent changes from baseline at 12 months were 0.1% and 0.3% for serum calcium, -2.3% and -2.3% for phosphate, and 8.3% and 4.8% for PTH, respectively. Compared to the risedronate sodium tablets 5 mg daily regimen, risedronate sodium tablets 150 mg once-a-month resulted in a slightly higher incidence of hypocalcemia at the end of the first month of treatment (0.2% versus 2.2%). Thereafter, the incidence of hypocalcemia with these regimens was similar at approximately 2%. Prevention of Postmenopausal Osteoporosis Daily Dosing The safety of risedronate sodium tablets 5 mg daily in the prevention of postmenopausal osteoporosis was assessed in two randomized, double-blind, placebo-controlled trials. In one study of postmenopausal women aged 37 to 82 years without osteoporosis, the use of estrogen replacement therapy in both placebo- and risedronate sodium tablets-treated patients was included. The duration of the trial was one year, with 259 exposed to placebo and 261 patients exposed to risedronate sodium tablets 5 mg. The second study included postmenopausal women aged 44 to 63 years without osteoporosis. The duration of the trial was one year, with 125 exposed to placebo and 129 patients exposed to risedronate sodium tablets 5 mg. All women received 1000 mg of elemental calcium per day. In the trial with estrogen replacement therapy, the incidence of all-cause mortality was 1.5% for the placebo group and 0.4% for the risedronate sodium tablets 5 mg group. The incidence of serious adverse events was 8.9% in the placebo group and 5.4% in the risedronate sodium tablets 5 mg group. The percentage of patients who withdrew from treatment due to adverse events was 18.9% in the placebo group and 10.3% in the risedronate sodium tablets 5 mg group. Constipation was reported by 1.9% of the placebo group and 6.5% of risedronate sodium tablets 5 mg group. In the second trial, the incidence of all-cause mortality was 0% for both groups. The incidence of serious adverse events was 17.6% in the placebo group and 9.3% in the risedronate sodium tablets 5 mg group. The percentage of patients who withdrew from treatment due to adverse events was 6.4% in the placebo group and 5.4% in the risedronate sodium tablets 5 mg group. Nausea was reported by 6.4% of patients in the placebo group and 13.2% of patients in the risedronate sodium tablets 5 mg group. Once-a-Week Dosing There were no deaths in a 1-year, double-blind, placebo-controlled study of risedronate sodium tablets 35 mg once-a-week for prevention of bone loss in 278 postmenopausal women without osteoporosis. More treated subjects on risedronate sodium tablets reported arthralgia (placebo 7.8%; risedronate sodium tablets 13.9%), myalgia (placebo 2.1%; risedronate sodium tablets 5.1%), and nausea (placebo 4.3%; risedronate sodium tablets 7.3%) than subjects on placebo. Treatment to Increase Bone Mass in Men with Osteoporosis In a 2-year, double-blind, multicenter study, 284 men with osteoporosis were treated with placebo (N = 93) or risedronate sodium tablets 35 mg once-a-week (N = 191). The overall safety and tolerability profile of risedronate sodium tablets in men with osteoporosis was similar to the adverse events reported in the risedronate sodium tablets postmenopausal osteoporosis clinical trials, with the addition of benign prostatic hyperplasia (placebo 3%; risedronate sodium tablets 35 mg 5%), nephrolithiasis (placebo 0%; risedronate sodium tablets 35 mg 3%), and arrhythmia (placebo 0%; risedronate sodium tablets 35 mg 2%). Treatment and Prevention of Glucocorticoid-Induced Osteoporosis The safety of risedronate sodium tablets 5 mg daily in the treatment and prevention of glucocorticoid-induced osteoporosis was assessed in two randomized, double-blind, placebo-controlled multinational trials of 344 patients [male (123) and female (221)] aged 18 to 85 years who had recently initiated oral glucocorticoid therapy (less than or equal to 3 months, prevention study) or were on long-term oral glucocorticoid therapy (greater than or equal to 6 months, treatment study). The duration of the trials was one year, with 170 patients exposed to placebo and 174 patients exposed to risedronate sodium tablets 5 mg daily. Patients in one study received 1000 mg elemental calcium plus 400 international units of vitamin D supplementation per day; patients in the other study received 500 mg calcium supplementation per day. The incidence of all-cause mortality was 2.9% in the placebo group and 1.1% in the risedronate sodium tablets 5 mg daily group. The incidence of serious adverse events was 33.5% in the placebo group and 30.5% in the risedronate sodium tablets 5 mg daily group. The percentage of patients who withdrew from the study due to adverse events was 8.8% in the placebo group and 7.5% in the risedronate sodium tablets 5 mg daily group. Back pain was reported in 8.8% of patients in the placebo group and 17.8% of patients in the risedronate sodium tablets 5 mg daily group. Arthralgia was reported in 14.7% of patients in the placebo group and 24.7% of patients in the risedronate sodium tablets 5 mg daily group. Treatment of Paget’s Disease Risedronate sodium tablets have been studied in 392 patients with Paget’s disease of bone. As in trials of risedronate sodium tablets for other indications, the adverse experiences reported in the Paget’s disease trials have generally been mild or moderate, have not required discontinuation of treatment, and have not appeared to be related to patient age, gender, or race. The safety of risedronate sodium tablets was assessed in a randomized, double-blind, active-controlled study of 122 patients aged 34 to 85 years. The duration of the trial was 540 days, with 61 patients exposed to risedronate sodium tablets and 61 patients exposed to Didronel ® . The adverse event profile was similar for risedronate sodium tablets and Didronel: 6.6% (4/61) of patients treated with risedronate sodium tablets 30 mg daily for 2 months discontinued treatment due to adverse events, compared to 8.2% (5/61) of patients treated with Didronel 400 mg daily for 6 months. Table 2 lists adverse events reported in greater than or equal to 5% of risedronate sodium tablets-treated patients in Phase 3 Paget's disease trials. Adverse events shown are considered to be possibly or probably causally related in at least one patient. Table 2 Adverse Events Reported in greater than or equal to 5% of R isedronate Sodium Tablets-Treated Patients* in Phase 3 Paget's Disease Trials Body System 30 mg/day x 2 months Risedronate Sodium Tablets % (N = 61) 400 mg/day x 6 months Didronel % (N = 61) Body as a Whole Flu Syndrome 9.8 1.6 Chest Pain Gastrointestinal 6.6 3.3 Diarrhea 19.7 14.8 Abdominal Pain 11.5 8.2 Nausea 9.8 9.8 Constipation Metabolic and Nutritional Disorders 6.6 8.2 Peripheral Edema Musculoskeletal 8.2 6.6 Arthralgia Nervous 32.8 29.5 Headache 18 16.4 Dizziness Skin and Appendages 6.6 4.9 Rash 11.5 8.2 *Considered to be possibly or probably causally related in at least one patient. Gastrointestinal Adverse Events: During the first year of the study (treatment and nontreatment follow-up), the proportion of patients who reported upper gastrointestinal adverse events was similar between the treatment groups; no patients reported severe upper gastrointestinal adverse events. The incidence of diarrhea was 19.7% in the risedronate sodium tablets group and 14.8% in the Didronel group; none were serious or resulted in withdrawal. Ocular Adverse Events: Three patients who received risedronate sodium tablets 30 mg daily experienced acute iritis in 1 supportive study. All 3 patients recovered from their events; however, in 1 of these patients, the event recurred during risedronate sodium tablets treatment and again during treatment with pamidronate. All patients were effectively treated with topical steroids. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of risedronate or bisphosphonate products. Because these adverse 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 Reactions Hypersensitivity and skin reactions have been reported, including angioedema, generalized rash, bullous skin reactions, Stevens-Johnson syndrome and toxic epidermal necrolysis. Gastrointestinal Adverse Events Events involving upper gastrointestinal irritation, such as esophagitis and esophageal or gastric ulcers, have been reported [see Warnings and Precautions (5.1) ]. Musculoskeletal Bone, joint, or muscle pain, described as severe or incapacitating, have been reported rarely [see Warnings and Precautions (5.4) ] ; low-energy femoral shaft and subtrochanteric fractures, and atypical fractures of other bones [see Warnings and Precautions (5.6) ]. Eye Inflammation Reactions of eye inflammation including iritis and uveitis have been reported rarely. Jaw Osteonecrosis Osteonecrosis of the jaw has been reported rarely [see Warnings and Precautions (5.3) ] . Pulmonary Asthma exacerbations

<table cellspacing="0" cellpadding="0" border="0" width="100%"><colgroup><col width="51.64%"/><col width="24.84%"/><col width="23.52%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3" align="center" valign="top"><content styleCode="bold"> Table 1</content> <content styleCode="bold">Adverse Events Occurring at a Frequency greater than or equal to 5% in Either Treatment Group Combined Phase 3 Postmenopausal Osteoporosis Treatment Trials</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" rowspan="2" valign="bottom"><content styleCode="bold">Body System </content> </td><td styleCode="Rrule" align="center" valign="top"><content styleCode="bold">Placebo </content> <content styleCode="bold">N = 1619 </content><content styleCode="bold"/> </td><td styleCode="Rrule" align="center" valign="top"><content styleCode="bold"> 5 mg </content><content styleCode="bold">Risedronate Sodium Tablets </content> <content styleCode="bold">N = 1613 </content><content styleCode="bold"/> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="middle"><content styleCode="bold"> %</content> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">%</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Body as a Whole </td><td styleCode="Rrule" align="center" valign="middle"> </td><td styleCode="Rrule" align="center" valign="middle"> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Infection </td><td styleCode="Rrule" align="center" valign="middle">29.9 </td><td styleCode="Rrule" align="center" valign="middle">31.1 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Back Pain </td><td styleCode="Rrule" align="center" valign="middle">26.1 </td><td styleCode="Rrule" align="center" valign="middle">28 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Accidental Injury </td><td styleCode="Rrule" align="center" valign="middle">16.8 </td><td styleCode="Rrule" align="center" valign="middle">16.9 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Pain </td><td styleCode="Rrule" align="center" valign="middle">14 </td><td styleCode="Rrule" align="center" valign="middle">14.1 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Abdominal Pain </td><td styleCode="Rrule" align="center" valign="middle">9.9 </td><td styleCode="Rrule" align="center" valign="middle">12.2 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Flu Syndrome </td><td styleCode="Rrule" align="center" valign="middle">11.6 </td><td styleCode="Rrule" align="center" valign="middle">10.5 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Headache </td><td styleCode="Rrule" align="center" valign="middle">10.8 </td><td styleCode="Rrule" align="center" valign="middle">9.9 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Asthenia </td><td styleCode="Rrule" align="center" valign="middle">4.5 </td><td styleCode="Rrule" align="center" valign="middle">5.4 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Neck Pain </td><td styleCode="Rrule" align="center" valign="middle">4.7 </td><td styleCode="Rrule" align="center" valign="middle">5.4 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Chest Pain </td><td styleCode="Rrule" align="center" valign="middle">5.1 </td><td styleCode="Rrule" align="center" valign="middle">5 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Allergic Reaction Cardiovascular System </td><td styleCode="Rrule" align="center" valign="top">5.9 </td><td styleCode="Rrule" align="center" valign="top">3.8 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Hypertension Digestive System </td><td styleCode="Rrule" align="center" valign="top">9.8 </td><td styleCode="Rrule" align="center" valign="top">10.5 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Constipation </td><td styleCode="Rrule" align="center" valign="middle">12.6 </td><td styleCode="Rrule" align="center" valign="middle">12.9 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Diarrhea </td><td styleCode="Rrule" align="center" valign="middle">10 </td><td styleCode="Rrule" align="center" valign="middle">10.8 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Dyspepsia </td><td styleCode="Rrule" align="center" valign="middle">10.6 </td><td styleCode="Rrule" align="center" valign="middle">10.8 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Nausea Metabolic &amp; Nutritional Disorders </td><td styleCode="Rrule" align="center" valign="top">11.2 </td><td styleCode="Rrule" align="center" valign="top">10.5 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Peripheral Edema Musculoskeletal System </td><td styleCode="Rrule" align="center" valign="top">8.8 </td><td styleCode="Rrule" align="center" valign="top">7.7 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Arthralgia </td><td styleCode="Rrule" align="center" valign="middle">22.1 </td><td styleCode="Rrule" align="center" valign="middle">23.7 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Arthritis </td><td styleCode="Rrule" align="center" valign="middle">10.1 </td><td styleCode="Rrule" align="center" valign="middle">9.6 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Traumatic Bone Fracture </td><td styleCode="Rrule" align="center" valign="middle">12.3 </td><td styleCode="Rrule" align="center" valign="middle">9.3 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Joint Disorder </td><td styleCode="Rrule" align="center" valign="middle">5.3 </td><td styleCode="Rrule" align="center" valign="middle">7 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Myalgia </td><td styleCode="Rrule" align="center" valign="middle">6.2 </td><td styleCode="Rrule" align="center" valign="middle">6.7 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Bone Pain Nervous System </td><td styleCode="Rrule" align="center" valign="top">4.8 </td><td styleCode="Rrule" align="center" valign="top">5.3 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Dizziness </td><td styleCode="Rrule" align="center" valign="middle">5.7 </td><td styleCode="Rrule" align="center" valign="middle">7.1 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Depression </td><td styleCode="Rrule" align="center" valign="middle">6.1 </td><td styleCode="Rrule" align="center" valign="middle">6.8 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Insomnia Respiratory System </td><td styleCode="Rrule" align="center" valign="top">4.6 </td><td styleCode="Rrule" align="center" valign="top">5 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Bronchitis </td><td styleCode="Rrule" align="center" valign="middle">10.4 </td><td styleCode="Rrule" align="center" valign="middle">10 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Sinusitis </td><td styleCode="Rrule" align="center" valign="middle">9.1 </td><td styleCode="Rrule" align="center" valign="middle">8.7 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Rhinitis </td><td styleCode="Rrule" align="center" valign="middle">5.1 </td><td styleCode="Rrule" align="center" valign="middle">6.2 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Pharyngitis </td><td styleCode="Rrule" align="center" valign="middle">5 </td><td styleCode="Rrule" align="center" valign="middle">6 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Increased Cough Skin and Appendages </td><td styleCode="Rrule" align="center" valign="top">6.3 </td><td styleCode="Rrule" align="center" valign="top">5.9 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Rash Special Senses </td><td styleCode="Rrule" align="center" valign="top">7.1 </td><td styleCode="Rrule" align="center" valign="top">7.9 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Cataract Urogenital System </td><td styleCode="Rrule" align="center" valign="top">5.7 </td><td styleCode="Rrule" align="center" valign="top">6.5 </td></tr><tr><td styleCode="Lrule Rrule" valign="middle">Urinary Tract Infection </td><td styleCode="Rrule" align="center" valign="middle">10.4 </td><td styleCode="Rrule" align="center" valign="middle">11.1 </td></tr></tbody></table>

<table cellspacing="0" cellpadding="0" border="0" width="100%"><colgroup><col width="50.2%"/><col width="25.46%"/><col width="24.34%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3" align="center" valign="top"><content styleCode="bold"> Table 2 </content> <content styleCode="bold">Adverse Events Reported in greater than or equal to 5% of R</content><content styleCode="bold">isedronate Sodium Tablets-Treated Patients* in Phase 3 Paget&apos;s Disease Trials</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="bottom">Body System </td><td styleCode="Rrule" align="center" valign="top">30 mg/day x 2 months Risedronate Sodium Tablets % (N = 61) </td><td styleCode="Rrule" align="center" valign="top">400 mg/day x 6 months Didronel % (N = 61) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Body as a Whole </td><td styleCode="Rrule" align="center" valign="middle"> </td><td styleCode="Rrule" align="center" valign="middle"> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Flu Syndrome </td><td styleCode="Rrule" align="center" valign="middle">9.8 </td><td styleCode="Rrule" align="center" valign="middle">1.6 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Chest Pain Gastrointestinal </td><td styleCode="Rrule" align="center" valign="top">6.6 </td><td styleCode="Rrule" align="center" valign="top">3.3 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Diarrhea </td><td styleCode="Rrule" align="center" valign="middle">19.7 </td><td styleCode="Rrule" align="center" valign="middle">14.8 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Abdominal Pain </td><td styleCode="Rrule" align="center" valign="middle">11.5 </td><td styleCode="Rrule" align="center" valign="middle">8.2 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Nausea </td><td styleCode="Rrule" align="center" valign="middle">9.8 </td><td styleCode="Rrule" align="center" valign="middle">9.8 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Constipation Metabolic and Nutritional Disorders </td><td styleCode="Rrule" align="center" valign="top">6.6 </td><td styleCode="Rrule" align="center" valign="top">8.2 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Peripheral Edema Musculoskeletal </td><td styleCode="Rrule" align="center" valign="top">8.2 </td><td styleCode="Rrule" align="center" valign="top">6.6 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Arthralgia Nervous </td><td styleCode="Rrule" align="center" valign="top">32.8 </td><td styleCode="Rrule" align="center" valign="top">29.5 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Headache </td><td styleCode="Rrule" align="center" valign="middle">18 </td><td styleCode="Rrule" align="center" valign="middle">16.4 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Dizziness Skin and Appendages </td><td styleCode="Rrule" align="center" valign="top">6.6 </td><td styleCode="Rrule" align="center" valign="top">4.9 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Rash </td><td styleCode="Rrule" align="center" valign="middle">11.5 </td><td styleCode="Rrule" align="center" valign="middle">8.2 </td></tr><tr><td styleCode="Lrule Rrule" colspan="3" valign="middle">*Considered to be possibly or probably causally related in at least one patient. </td></tr></tbody></table>