RISEDRONATE SODIUM

Risedronate sodium tablets, USP are pyridinyl bisphosphonates that inhibit osteoclast-mediated bone resorption and modulate bone metabolism. Each risedronate sodium tablet, USP for oral administration contains the equivalent of 35, 75, or 150 mg of anhydrous risedronate sodium in the form of the hemi-pentahydrate. The empirical formula for risedronate sodium hemi-pentahydrate is C 7 H 10 NO 7 P 2 Na •2.5 H 2 O. The chemical name of risedronate sodium is [1-hydroxy-2-(3-pyridinyl)ethylidene]bis[phosphonic acid] monosodium salt. The chemical structure of risedronate sodium hemi-pentahydrate is the following: Molecular Weight: Anhydrous: 305.10 Hemi-pentahydrate: 350.13 Risedronate sodium, USP is a white powder. It is soluble in water and essentially insoluble in common organic solvents. Inactive Ingredients All dose strengths contain: anhydrous lactose, crospovidone, hydroxypropyl cellulose, hypromellose, magnesium stearate, polyethylene glycol, silicon dioxide, and titanium dioxide. Dose strength-specific ingredients include: 35 mg—ferric oxide red, ferric oxide yellow; 75 mg—ferric oxide red; 150 mg -FD&C blue #2, sodium phosphate monobasic monohydrate, sodium phosphate dibasic. risedronatestructure

Risedronate sodium tablets, USP are a bisphosphonate indicated for: Treatment and prevention of postmenopausal osteoporosis ( 1.1 ) Treatment to increase bone mass in men with osteoporosis ( 1.2 ) • Treatment and prevention of glucocorticoid-induced osteoporosis ( 1.3 ) • Treatment of Paget's disease ( 1.4 ) Limitations of Use 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. ( 1.5 ) 1.1 Postmenopausal Osteoporosis Risedronate sodium tablets, USP are indicated for the treatment and prevention of osteoporosis in postmenopausal women. In postmenopausal women with osteoporosis, risedronate sodium tablets, USP reduce the incidence of vertebral fractures and a composite endpoint of nonvertebral osteoporosis-related fractures [ see Clinical Studies ( 14.1 , 14.2 ) ]. 1.2 Osteoporosis in Men Risedronate sodium tablets, USP are indicated for treatment to increase bone mass in men with osteoporosis. 1.3 Glucocorticoid-Induced Osteoporosis Risedronate sodium tablets, USP are indicated for the treatment and prevention of glucocorticoid-induced osteoporosis in men and women who are either initiating or continuing systemic glucocorticoid treatment (daily dosage of greater than or equal to 7.5 mg of prednisone or equivalent) for chronic diseases. Patients treated with glucocorticoids should receive adequate amounts of calcium and vitamin D. 1.4 Paget's Disease Risedronate sodium tablets, USP are indicated for treatment of Paget’s disease of bone in men and women. 1.5 Important Limitations of Use The optimal duration of use has not been determined. The safety and effectiveness of risedronate sodium tablets, USP 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.

Treatment of Postmenopausal Osteoporosis: 5 mg daily, 35 mg once-a-week, 75 mg two consecutive days each month, 150 mg once-a-month ( 2.1 ) Prevention of Postmenopausal Osteoporosis: 5 mg daily, 35 mg once-a-week ( 2.2 ) Men with Osteoporosis: 35 mg once-a-week ( 2.3 ) Glucocorticoid-Induced Osteoporosis: 5 mg daily ( 2.4 ) Paget's Disease: 30 mg daily for 2 months ( 2.5 ) Instruct patients to: • Swallow tablet whole with 6 to 8 ounces of plain water, at least 30 minutes before the first food, beverage, or medication of the day. • Avoid lying down for 30 minutes ( 2 ) • Take supplemental calcium and vitamin D if dietary intake is inadequate ( 2.7 ) 2.1 Treatment of Postmenopausal Osteoporosis [see Indications and Usage (1.1)] The recommended regimen is: • one 5 mg tablet orally, taken daily or • one 35 mg tablet orally, taken once-a-week or • one 75 mg tablet orally, taken on two consecutive days for a total of two tablets each month or • one 150 mg tablet orally, taken once-a-month 2.2 Prevention of Postmenopausal Osteoporosis [see Indications and Usage (1.1)] The recommended regimen is: • one 5 mg tablet orally, taken daily or • one 35 mg tablet orally, taken once-a-week or • alternatively, one 75 mg tablet orally, taken on two consecutive days for a total of two tablets each month may be considered or • alternatively, one 150 mg tablet orally, taken once-a-month may be considered 2.3 Treatment to Increase Bone Mass in Men with Osteoporosis [see Indications and Usage (1.2)] The recommended regimen is: • one 35 mg tablet orally, taken once-a-week 2.4 Treatment and Prevention of Glucocorticoid-Induced Osteoporosis [see Indications and Usage (1.3)] The recommended regimen is: • one 5 mg tablet orally, taken daily 2.5 Treatment of Paget's Disease [see Indications and Usage (1.4)] The recommended treatment regimen is 30 mg orally once daily for 2 months. Retreatment may be considered (following post-treatment observation of at least 2 months) if relapse occurs, or if treatment fails to normalize serum alkaline phosphatase. For retreatment, the dose and duration of therapy are the same as for initial treatment. No data are available on more than 1 course of retreatment. 2.6 Important Administration Instructions Instruct patients to do the following: • Take risedronate sodium tablets at least 30 minutes before the first food or drink of the day other than water, and 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 risedronate sodium tablets whole with a full glass of plain water (6 to 8 ounces). Avoid lying down for 30 minutes after taking the medication [ see Warnings and Precautions ( 5.1 ) ]. Do not chew or suck the tablet because of a potential for oropharyngeal ulceration. • Do not eat or drink anything except plain water, or take other medications for at least 30 minutes after taking risedronate sodium tablets. 2.7 Recommendations for Calcium and Vitamin D Supplementation Instruct patients to take supplemental calcium and vitamin D if their dietary intake is inadequate; and to take calcium supplements, antacids, magnesium-based supplements or laxatives, and iron preparations at a different time of the day as they interfere with the absorption of risedronate sodium tablets. 2.8 Administration Instructions for Missed Doses Instruct patients about missing risedronate sodium tablet doses as follows: • If a dose of risedronate sodium tablet 35 mg once-a-week is missed: o Take 1 tablet on the morning after they remember and return to taking 1 tablet once-a-‑week, as originally scheduled on their chosen day. o Do not take 2 tablets on the same day. • If one or both tablets of risedronate sodium tablets 75 mg on two consecutive days per month are missed, and the next month’s scheduled doses are more than 7 days away: o If both tablets are missed, take one risedronate sodium 75 mg tablet in the morning after the day it is remembered and then the other tablet on the next consecutive morning. o If only one risedronate sodium 75 mg tablet is missed, take the missed tablet in the morning after the day it is remembered o Return to taking their risedronate sodium 75 mg tablets on two consecutive days per month as originally scheduled. o Do not take more than two 75 mg tablets within 7 days. • If one or both tablets of risedronate sodium 75 mg tablets on two consecutive days per month are missed, and the next month's scheduled doses are within 7 days: o Wait until their next month’s scheduled doses and then continue taking risedronate sodium 75 mg tablets on two consecutive days per month as originally scheduled. • If the dose of risedronate sodium tablets 150 mg once-a-month is missed, and the next month’s scheduled dose is more than 7 days away: o Take the missed tablet in the morning after the day it is remembered and then return to taking their risedronate sodium tablet 150 mg once-a-month as originally scheduled. o Do not take more than one 150 mg tablet within 7 days. • If the dose of risedronate sodium 150 mg tablet once-a-month is missed, and the next month's scheduled dose is within 7 days: o Wait until their next month’s scheduled dose and then continue taking risedronate sodium 150 mg tablets once-a-month as originally scheduled.

Risedronate 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 30 minutes [see Dosage and Administration ( 2 ), Warnings and Precautions ( 5.1 )] • Hypocalcemia [see Warnings and Precautions ( 5.2 )] • Known hypersensitivity to risedronate sodium tablets or any of its excipients. Angioedema, generalized rash, bullous skin reactions, Stevens-Johnson syndrome and toxic epidermal necrolysis 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 30 minutes ( 4 , 5.1 ) Hypocalcemia ( 4 , 5.2 ) Known hypersensitivity to any component of this product ( 4 , 6.2 )

Most common adverse reactions reported in greater than 10% of patients treated with risedronate sodium tablets 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 Apotex Corp at 1-800-706-5575 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 2.0% 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 28.0 Accidental Injury 16.8 16.9 Pain 14.0 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 5.0 Allergic Reaction 5.9 3.8 Cardiovascular System Hypertension 9.8 10.5 Digestive System Constipation 12.6 12.9 Diarrhea 10.0 10.8 Dyspepsia 10.6 10.8 Nausea 11.2 10.5 Metabolic & Nutritional Disorders Peripheral Edema 8.8 7.7 Musculoskeletal System Arthralgia 22.1 23.7 Arthritis 10.1 9.6 Traumatic Bone Fracture 12.3 9.3 Joint Disorder 5.3 7.0 Myalgia 6.2 6.7 Bone Pain 4.8 5.3 Nervous System Dizziness 5.7 7.1 Depression 6.1 6.8 Insomnia 4.6 5.0 Respiratory System Bronchitis 10.4 10.0 Sinusitis 9.1 8.7 Rhinitis 5.1 6.2 Pharyngitis 5.0 6.0 Increased Cough 6.3 5.9 Skin and Appendages Rash 7.1 7.9 Special Senses Cataract 5.7 6.5 Urogenital System 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 (10.0% 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 28.0%), 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 1.0% 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 1.0% 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 13.0% 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 0.0% 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 (1.0% versus 0.2%) and diarrhea (1.0% 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 3.0%). 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 0.0% 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 0.0%) 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-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 0.0% 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 13.9%), myalgia (placebo 2.1%; risedronate sodium 5.1%), and nausea (placebo 4.3%; risedronate sodium 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 Risedronate Sodium-Treated Patients Considered to be possibly or probably causally related in at least one patient. in Phase 3 Paget's Disease Trials Body System 30 mg/day x 2 months Risedronate sodium % (N = 61) 400 mg/day x 6 months Didronel % (N = 61) Body as a Whole Flu Syndrome 9.8 1.6 Chest Pain 6.6 3.3 Gastrointestinal Diarrhea 19.7 14.8 Abdominal Pain 11.5 8.2 Nausea 9.8 9.8 Constipation 6.6 8.2 Metabolic and Nutritional Disorders Peripheral Edema 8.2 6.6 Musculoskeletal Arthralgia 32.8 29.5 Nervous Headache 18.0 16.4 Dizziness 6.6 4.9 Skin and Appendages Rash 11.5 8.2 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 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 treatment and again during treatment with pamidronate. All patients were effectively treated with topical steroids. 6.2 Postmarketing Experience 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 Pain Bone, joint, or muscle pain, described as severe or incapacitating, have been reported rarely [see Warnings and Precautions ( 5.4 )]. 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

No specific drug-drug interaction studies were performed. Risedronate is not metabolized and does not induce or inhibit hepatic microsomal drug-metabolizing enzymes (for example, Cytochrome P450). Calcium, antacids, or oral medications containing divalent cations interfere with the absorption of risedronate sodium ( 7.1 ) 7.1 Calcium Supplements/Antacids Co-administration of risedronate sodium tablets and calcium, antacids, or oral medications containing divalent cations will interfere with the absorption of risedronate sodium tablets. 7.2 Hormone Replacement Therapy One study of about 500 early postmenopausal women has been conducted to date in which treatment with risedronate sodium tablets 5 mg daily plus estrogen replacement therapy was compared to estrogen replacement therapy alone. Exposure to study drugs was approximately 12 to 18 months and the primary endpoint was change in BMD. If considered appropriate, risedronate sodium tablets may be used concomitantly with hormone replacement therapy. 7.3 Aspirin/Nonsteroidal Anti-Inflammatory Drugs Of over 5700 patients enrolled in the risedronate sodium tablets Phase 3 osteoporosis studies, aspirin use was reported by 31% of patients, 24% of whom were regular users (3 or more days per week). Forty-eight percent of patients reported NSAID use, 21% of whom were regular users. Among regular aspirin or NSAID users, the incidence of upper gastrointestinal adverse experiences in placebo-treated patients (24.8%) was similar to that in risedronate sodium-treated patients (24.5%). 7.4 H 2 Blockers and Proton Pump Inhibitors (PPIs) Of over 5700 patients enrolled in the risedronate sodium tablets Phase 3 osteoporosis studies, 21% used H 2 blockers and/or PPIs. Among these patients, the incidence of upper gastrointestinal adverse experiences in the placebo-treated patients was similar to that in risedronate sodium-treated patients.