Actonel

6 ADVERSE REACTIONS Most common adverse reactions reported in greater than 10% of patients treated with ACTONEL 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 AbbVie at 1-800-678-1605 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 D aily Dosing The safety of ACTONEL 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 ACTONEL 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 ACTONEL 5 mg daily group. The incidence of serious adverse events was 24.6% in the placebo group and 27.2% in the ACTONEL 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 ACTONEL 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 ACTONEL 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 ACTONEL 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 ACTONEL 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 ACTONEL 5 mg daily groups. Musculoskeletal Adverse Events : The incidence of adverse events in the placebo and ACTONEL 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 ACTONEL 5 mg once daily. There were no significant differences in serum calcium, phosphate, or PTH levels between placebo and ACTONEL 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 ACTONEL 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 ACTONEL 5 mg once daily. There have been rare reports (less than 0.1%) of abnormal liver function tests. Endoscopic Findings : In the ACTONEL 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%) ACTONEL]. Clinically important findings (perforations, ulcers, or bleeding) among this symptomatic population were similar between groups (51% placebo; 39% ACTONEL). Once-a- W eek Dosing The safety of ACTONEL 35 mg once-a-week in the treatment of postmenopausal osteoporosis was assessed in a 1-year, double-blind, multicenter study comparing ACTONEL 5 mg daily and ACTONEL 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 ACTONEL 5 mg daily and 485 exposed to ACTONEL 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 ACTONEL 5 mg daily group and 1.0% in the ACTONEL 35 mg once-a-week group. The incidence of serious adverse events was 7.1% in the ACTONEL 5 mg daily group and 8.2% in the ACTONEL 35 mg once-a-week group. The percentage of patients who withdrew from the study due to adverse events was 11.9% in the ACTONEL 5 mg daily group and 11.5% in the ACTONEL 35 mg once-a-week group. The overall safety and tolerability profiles of the two dosing regimens were similar. Gastrointestinal Adverse E vents : The incidence of gastrointestinal adverse events was similar between the ACTONEL 5 mg daily group and the ACTONEL 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 ACTONEL 5 mg daily group and 14.2% of patients in the ACTONEL 35 mg once-a-week group. Myalgia was reported by 4.6% of patients in the ACTONEL 5 mg daily group and 6.2% of patients in the ACTONEL 35 mg once-a-week group. Laboratory Test Findings : The mean percent changes from baseline at 12 months were similar between the ACTONEL 5 mg daily and ACTONEL 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 ACTONEL 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 ACTONEL 5 mg daily and 616 were exposed to ACTONEL 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 ACTONEL 5 mg daily group and 0.5% for the ACTONEL 75 mg two consecutive days per month group. The incidence of serious adverse events was 10.8% in the ACTONEL 5 mg daily group and 14.4% in the ACTONEL 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 ACTONEL 5 mg daily group and 13.0% in the ACTONEL 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 ACTONEL 5 mg daily and 7.6% of patients on ACTONEL 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 ACTONEL 5 mg daily and 0.6% of patients on ACTONEL 75 mg two consecutive days per month. Gastrointestinal Adverse Events : The ACTONEL 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 ACTONEL 5 mg daily group. Most of these events occurred within a few days of dosing. Ocular Adverse Events : None of the patients treated with ACTONEL 75 mg two consecutive days per month reported ocular inflammation such as uveitis, scleritis, or iritis; 1 patient treated with ACTONEL 5 mg daily reported uveitis. Laboratory Test Findings : When ACTONEL 5 mg daily and ACTONEL 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 ACTONEL 5 mg daily group, ACTONEL 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%. Onc e-a- Month The safety of ACTONEL 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 ACTONEL 5 mg daily and 650 exposed to ACTONEL 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 ACTONEL 5 mg daily group and 0.0% for the ACTONEL 150 mg once-a-month group. The incidence of serious adverse events was 4.2% in the ACTONEL 5 mg daily group and 6.2% in the ACTONEL 150 mg once-a-month group. The percentage of patients who withdrew from treatment due to adverse events was 9.5% in the ACTONEL 5 mg daily group and 8.6% in the ACTONEL 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 ACTONEL 5 mg daily group and 5.2% in the ACTONEL 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 ACTONEL 5 mg daily and 1.4% of patients on ACTONEL 150 mg once-a-month. Gastrointestinal Adverse Events : A greater percentage of patients experienced diarrhea with ACTONEL 150 mg once-a-month compared to 5 mg daily (8.2% versus 4.7%, respectively). The ACTONEL 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 ACTONEL 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 ACTONEL 150 mg once-a-month reported ocular inflammation such as uveitis, scleritis, or iritis; 2 patients treated with ACTONEL 5 mg daily reported iritis. Laboratory Test Findings : When ACTONEL 5 mg daily and ACTONEL 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 ACTONEL 5 mg daily regimen, ACTONEL 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 D osing The safety of ACTONEL 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 ACTONEL-treated patients was included. The duration of the trial was one year, with 259 exposed to placebo and 261 patients exposed to ACTONEL 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 ACTONEL 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 ACTONEL 5 mg group. The incidence of serious adverse events was 8.9% in the placebo group and 5.4% in the ACTONEL 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 ACTONEL 5 mg group. Constipation was reported by 1.9% of the placebo group and 6.5% of ACTONEL 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 ACTONEL 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 ACTONEL 5 mg group. Nausea was reported by 6.4% of patients in the placebo group and 13.2% of patients in the ACTONEL 5 mg group. Once-a- W eek Dosing There were no deaths in a 1-year, double-blind, placebo-controlled study of ACTONEL 35 mg once-a-week for prevention of bone loss in 278 postmenopausal women without osteoporosis. More treated subjects on ACTONEL reported arthralgia (placebo 7.8%; ACTONEL 13.9%), myalgia (placebo 2.1%; ACTONEL 5.1%), and nausea (placebo 4.3%; ACTONEL 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 ACTONEL 35 mg once-a-week (N = 191). The overall safety and tolerability profile of ACTONEL in men with osteoporosis was similar to the adverse events reported in the ACTONEL postmenopausal osteoporosis clinical trials, with the addition of benign prostatic hyperplasia (placebo 3%; ACTONEL 35 mg 5%), nephrolithiasis (placebo 0%; ACTONEL 35 mg 3%), and arrhythmia (placebo 0%; ACTONEL 35 mg 2%). Treatment and Prevention of Glucocorticoid- I nduced Osteoporosis The safety of ACTONEL 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 ACTONEL 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 ACTONEL 5 mg daily group. The incidence of serious adverse events was 33.5% in the placebo group and 30.5% in the ACTONEL 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 ACTONEL 5 mg daily group. Back pain was reported in 8.8% of patients in the placebo group and 17.8% of patients in the ACTONEL 5 mg daily group. Arthralgia was reported in 14.7% of patients in the placebo group and 24.7% of patients in the ACTONEL 5 mg daily group. Treatment of Paget’s Disease ACTONEL has been studied in 392 patients with Paget’s disease of bone. As in trials of ACTONEL 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 ACTONEL 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 ACTONEL and 61 patients exposed to Didronel ® . The adverse event profile was similar for ACTONEL and Didronel: 6.6% (4/61) of patients treated with ACTONEL 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 ACTONEL-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 ACTONEL -Treated Patients* in Phase 3 Paget's Disease Trials Body System 30 mg/day x 2 months ACTONEL % (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 *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 ACTONEL group and 14.8% in the Didronel group; none were serious or resulted in withdrawal. Ocular Adverse Events : Three patients who received ACTONEL 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 ACTONEL 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 P recautions ( 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

4 CONTRAINDICATIONS ACTONEL is contraindicated in patients with the following conditions: Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia [ see Warnings and Precautions ( 5.1 ) ] Inability to stand or sit upright for at least 30 minutes [ see Dosage and Administration ( 2 ), Warnings and Precautions ( 5.1 ) ] Hypocalcemia [ see Warnings and Precautions ( 5.2 ) ] Known hypersensitivity to ACTONEL 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 )

11 DESCRIPTION ACTONEL (risedronate sodium) tablets is a pyridinyl bisphosphonate that inhibits osteoclast-mediated bone resorption and modulates bone metabolism. Each ACTONEL tablet for oral administration contains the equivalent of 5, 30, 35, 75, or 150 mg of anhydrous risedronate sodium in the form of the hemi-pentahydrate with small amounts of monohydrate. 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 is a fine, white to off-white, odorless, crystalline powder. It is soluble in water and in aqueous solutions, and essentially insoluble in common organic solvents. Inactive Ingredients All dose strengths contain: crospovidone, hydroxypropyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, silicon dioxide, titanium dioxide. Dose strength-specific ingredients include: 5 mg—ferric oxide yellow, lactose monohydrate; 30 mg—lactose monohydrate; 35 mg—ferric oxide red, ferric oxide yellow, lactose monohydrate; 75 mg—ferric oxide red; 150 mg—FD&C blue #2 aluminum lake. ACTONEL (risedronate sodium) tablets is a pyridinyl bisphosphonate that inhibits osteoclast-mediated bone resorption and modulates bone metabolism. Each ACTONEL tablet for oral administration contains the equivalent of 5, 30, 35, 75, or 150 mg of anhydrous risedronate sodium in the form of the hemi-pentahydrate with small amounts of monohydrate. The empirical formula for risedronate sodium hemi-pentahydrate is C7H10NO7P2Na •2.5 H2O. 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:

2 DOSAGE AND ADMINISTRATION 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 ACTONEL 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 ACTONEL 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 ACTONEL. 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 ACTONEL. 2. 8 Administration Instructions for Missed Doses Instruct patients about missing ACTONEL doses as follows: If a dose of ACTONEL 35 mg once-a-week is missed: 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. Do not take 2 tablets on the same day. If one or both tablets of ACTONEL 75 mg on two consecutive days per month are missed, and the next month’s scheduled doses are more than 7 days away: If both tablets are missed, take one ACTONEL 75 mg tablet in the morning after the day it is remembered and then the other tablet on the next consecutive morning. If only one ACTONEL 75 mg tablet is missed, take the missed tablet in the morning after the day it is remembered Return to taking their ACTONEL 75 mg on two consecutive days per month as originally scheduled. Do not take more than two 75 mg tablets within 7 days. If one or both tablets of ACTONEL 75 mg on two consecutive days per month are missed, and the next month's scheduled doses are within 7 days: Wait until their next month’s scheduled doses and then continue taking ACTONEL 75 mg on two consecutive days per month as originally scheduled. If the dose of ACTONEL 150 mg once-a-month is missed, and the next month’s scheduled dose is more than 7 days away: Take the missed tablet in the morning after the day it is remembered and then return to taking their ACTONEL 150 mg once-a-month as originally scheduled. Do not take more than one 150 mg tablet within 7 days. If the dose of ACTONEL 150 mg once-a-month is missed, and the next month's scheduled dose is within 7 days: Wait until their next month’s scheduled dose and then continue taking ACTONEL 150 mg once-a-month as originally scheduled.

1 INDICATIONS AND USAGE ACTONEL is 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 ACTONEL is indicated for the treatment and prevention of osteoporosis in postmenopausal women. In postmenopausal women with osteoporosis, ACTONEL reduces 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 ACTONEL is indicated for treatment to increase bone mass in men with osteoporosis. 1.3 Glucocorticoid-Induced Osteoporosis ACTONEL is 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 ACTONEL is 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 ACTONEL 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.

10 OVERDOSAGE Decreases in serum calcium and phosphorus following substantial overdose may be expected in some patients. Signs and symptoms of hypocalcemia may also occur in some of these patients. Milk or antacids containing calcium should be given to bind ACTONEL and reduce absorption of the drug. In cases of substantial overdose, gastric lavage may be considered to remove unabsorbed drug. Standard procedures that are effective for treating hypocalcemia, including the administration of calcium intravenously, would be expected to restore physiologic amounts of ionized calcium and to relieve signs and symptoms of hypocalcemia. Lethality after single oral doses was seen in female rats at 903 mg/kg and male rats at 1703 mg/kg. The minimum lethal dose in mice and rabbits was 4000 mg/kg and 1000 mg/kg, respectively. These values represent 320 to 620 times the 30 mg human dose based on surface area (mg/m 2 ).

7 DRUG INTERACTIONS 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 ACTONEL ( 7.1 ) 7.1 Calcium Supplements/Antacids Co-administration of ACTONEL and calcium, antacids, or oral medications containing divalent cations will interfere with the absorption of ACTONEL. 7.2 Hormone Replacement Therapy One study of about 500 early postmenopausal women has been conducted to date in which treatment with ACTONEL 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, ACTONEL may be used concomitantly with hormone replacement therapy. 7.3 Aspirin/Nonsteroidal Anti-Inflammatory Drugs Of over 5700 patients enrolled in the ACTONEL 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 ACTONEL-treated patients (24.5%). 7.4 H 2 Blockers and Proton Pump Inhibitors (PPIs) Of over 5700 patients enrolled in the ACTONEL 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 ACTONEL-treated patients.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action ACTONEL has an affinity for hydroxyapatite crystals in bone and acts as an antiresorptive agent. At the cellular level, ACTONEL inhibits osteoclasts. The osteoclasts adhere normally to the bone surface, but show evidence of reduced active resorption (for example, lack of ruffled border). Histomorphometry in rats, dogs, and minipigs showed that ACTONEL treatment reduces bone turnover (activation frequency, that is, the rate at which bone remodeling sites are activated) and bone resorption at remodeling sites. 12.2 Pharmacodynamics ACTONEL treatment decreases the elevated rate of bone turnover that is typically seen in postmenopausal osteoporosis. In clinical trials, administration of ACTONEL to postmenopausal women resulted in decreases in biochemical markers of bone turnover, including urinary deoxypyridinoline/creatinine and urinary collagen cross-linked N-telopeptide (markers of bone resorption) and serum bone-specific alkaline phosphatase (a marker of bone formation). At the 5 mg dose, decreases in deoxypyridinoline/creatinine were evident within 14 days of treatment. Changes in bone formation markers were observed later than changes in resorption markers, as expected, due to the coupled nature of bone resorption and bone formation; decreases in bone-specific alkaline phosphatase of about 20% were evident within 3 months of treatment. Bone turnover markers reached a nadir of about 40% below baseline values by the sixth month of treatment and remained stable with continued treatment for up to 3 years. Bone turnover is decreased as early as 14 days and maximally within about 6 months of treatment, with achievement of a new steady-state that more nearly approximates the rate of bone turnover seen in premenopausal women. In a 1-year study comparing daily versus weekly oral dosing regimens of ACTONEL for the treatment of osteoporosis in postmenopausal women, ACTONEL 5 mg daily and ACTONEL 35 mg once-a-week decreased urinary collagen cross-linked N-telopeptide by 60% and 61%, respectively. In addition, serum bone-specific alkaline phosphatase was also reduced by 42% and 41% in the ACTONEL 5 mg daily and ACTONEL 35 mg once-a-week groups, respectively. When postmenopausal women with osteoporosis were treated for 1 year with ACTONEL 5 mg daily or ACTONEL 75 mg two consecutive days per month, urinary collagen cross-linked N-telopeptide was decreased by 54% and 52%, respectively, and serum bone-specific alkaline phosphatase was reduced by 36% and 35%, respectively. In a 1–year study comparing ACTONEL 5 mg daily versus ACTONEL 150 mg once-a-month in women with postmenopausal osteoporosis, urinary collagen cross-linked N-telopeptide was decreased by 52% and 49%, respectively, and serum bone-specific alkaline phosphatase was reduced by 31% and 32%, respectively. Osteoporosis in Men In a 2-year study of men with osteoporosis, treatment with ACTONEL 35 mg once-a-week resulted in a mean decrease from baseline compared to placebo of 16% (placebo 20%; ACTONEL 35 mg 37%) for the bone resorption marker urinary collagen cross-linked N-telopeptide, 45% (placebo -6%; ACTONEL 35 mg 39%) for the bone resorption marker serum C-telopeptide, and 27% (placebo -2%; ACTONEL 35 mg 25%) for the bone formation marker serum bone-specific alkaline phosphatase. Glucocorticoid-Induced Osteoporosis Osteoporosis with glucocorticoid use occurs as a result of inhibited bone formation and increased bone resorption resulting in net bone loss. ACTONEL decreases bone resorption without directly inhibiting bone formation. In two 1-year clinical trials in the treatment and prevention of glucocorticoid-induced osteoporosis, ACTONEL 5 mg decreased urinary collagen cross-linked N-telopeptide (a marker of bone resorption), and serum bone-specific alkaline phosphatase (a marker of bone formation) by 50% to 55% and 25% to 30%, respectively, within 3 to 6 months after initiation of therapy. Paget’s Disease Paget’s disease of bone is a chronic, focal skeletal disorder characterized by greatly increased and disordered bone remodeling. Excessive osteoclastic bone resorption is followed by osteoblastic new bone formation, leading to the replacement of the normal bone architecture by disorganized, enlarged, and weakened bone structure. In pagetic patients treated with ACTONEL 30 mg daily for 2 months, bone turnover returned to normal in a majority of patients as evidenced by significant reductions in serum alkaline phosphatase (a marker of bone formation), and in urinary hydroxyproline/creatinine and deoxypyridinoline/creatinine (markers of bone resorption). 12.3 Pharmacokinetics Absorption Based on simultaneous modeling of serum and urine data, peak absorption after an oral dose is achieved at approximately 1 hour (T max ) and occurs throughout the upper gastrointestinal tract. The fraction of the dose absorbed is independent of dose over the range studied (single dose, from 2.5 mg to 30 mg; multiple dose, from 2.5 mg to 5 mg). Steady-state conditions in the serum are observed within 57 days of daily dosing. Mean absolute oral bioavailability of the 30 mg tablet is 0.63% (90% CI: 0.54% to 0.75%) and is comparable to a solution. Food Effect The extent of absorption of a 30 mg dose (three 10 mg tablets) when administered 0.5 hours before breakfast is reduced by 55% compared to dosing in the fasting state (no food or drink for 10 hours prior to or 4 hours after dosing). Dosing 1 hour prior to breakfast reduces the extent of absorption by 30% compared to dosing in the fasting state. Dosing either 0.5 hours prior to breakfast or 2 hours after dinner (evening meal) results in a similar extent of absorption. ACTONEL is effective when administered at least 30 minutes before breakfast. Distribution The mean steady-state volume of distribution for risedronate is 13.8 L/kg in humans. Human plasma protein binding of drug is about 24%. Preclinical studies in rats and dogs dosed intravenously with single doses of [ 14 C] risedronate indicate that approximately 60% of the dose is distributed to bone. The remainder of the dose is excreted in the urine. After multiple oral dosing in rats, the uptake of risedronate in soft tissues was in the range of 0.001% to 0.01%. Metabolism There is no evidence of systemic metabolism of risedronate. Excretion In young healthy subjects, approximately half of the absorbed dose of risedronate was excreted in urine within 24 hours, and 85% of an intravenous dose was recovered in the urine over 28 days. Based on simultaneous modeling of serum and urine data, mean renal clearance was 105 mL/min (CV = 34%) and mean total clearance was 122 mL/min (CV = 19%), with the difference primarily reflecting nonrenal clearance or clearance due to adsorption to bone. The renal clearance is not concentration dependent, and there is a linear relationship between renal clearance and creatinine clearance. Unabsorbed drug is eliminated unchanged in feces. In osteopenic postmenopausal women, the terminal exponential half-life was 561 hours, mean renal clearance was 52 mL/min (CV = 25%), and mean total clearance was 73 mL/min (CV = 15%). Specific Populations Pediatric : ACTONEL is not indicated for use in pediatric patients [see Pediatric Use ( 8.4 ) ]. Gender : Bioavailability and pharmacokinetics following oral administration are similar in men and women. Geriatric : Bioavailability and disposition are similar in elderly (greater than 60 years of age) and younger subjects. No dosage adjustment is necessary. Race : Pharmacokinetic differences due to race have not been studied. Renal Impairment : Risedronate is excreted unchanged primarily via the kidney. As compared to persons with normal renal function, the renal clearance of risedronate was decreased by about 70% in patients with creatinine clearance of approximately 30 mL/min. ACTONEL is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/min) because of lack of clinical experience. No dosage adjustment is necessary in patients with a creatinine clearance greater than or equal to 30 mL/min. Hepatic Impairment : No studies have been performed to assess risedronate’s safety or efficacy in patients with hepatic impairment. Risedronate is not metabolized in rat, dog, and human liver preparations. Insignificant amounts (less than 0.1% of intravenous dose) of drug are excreted in the bile in rats. Therefore, dosage adjustment is unlikely to be needed in patients with hepatic impairment. Drug Interactions : No specific drug-drug interaction studies were performed. Risedronate is not metabolized and does not induce or inhibit hepatic microsomal drug-metabolizing enzymes (Cytochrome P450) [ see Drug Interactions ( 7 ) ].

12.1 Mechanism of Action ACTONEL has an affinity for hydroxyapatite crystals in bone and acts as an antiresorptive agent. At the cellular level, ACTONEL inhibits osteoclasts. The osteoclasts adhere normally to the bone surface, but show evidence of reduced active resorption (for example, lack of ruffled border). Histomorphometry in rats, dogs, and minipigs showed that ACTONEL treatment reduces bone turnover (activation frequency, that is, the rate at which bone remodeling sites are activated) and bone resorption at remodeling sites.

12.2 Pharmacodynamics ACTONEL treatment decreases the elevated rate of bone turnover that is typically seen in postmenopausal osteoporosis. In clinical trials, administration of ACTONEL to postmenopausal women resulted in decreases in biochemical markers of bone turnover, including urinary deoxypyridinoline/creatinine and urinary collagen cross-linked N-telopeptide (markers of bone resorption) and serum bone-specific alkaline phosphatase (a marker of bone formation). At the 5 mg dose, decreases in deoxypyridinoline/creatinine were evident within 14 days of treatment. Changes in bone formation markers were observed later than changes in resorption markers, as expected, due to the coupled nature of bone resorption and bone formation; decreases in bone-specific alkaline phosphatase of about 20% were evident within 3 months of treatment. Bone turnover markers reached a nadir of about 40% below baseline values by the sixth month of treatment and remained stable with continued treatment for up to 3 years. Bone turnover is decreased as early as 14 days and maximally within about 6 months of treatment, with achievement of a new steady-state that more nearly approximates the rate of bone turnover seen in premenopausal women. In a 1-year study comparing daily versus weekly oral dosing regimens of ACTONEL for the treatment of osteoporosis in postmenopausal women, ACTONEL 5 mg daily and ACTONEL 35 mg once-a-week decreased urinary collagen cross-linked N-telopeptide by 60% and 61%, respectively. In addition, serum bone-specific alkaline phosphatase was also reduced by 42% and 41% in the ACTONEL 5 mg daily and ACTONEL 35 mg once-a-week groups, respectively. When postmenopausal women with osteoporosis were treated for 1 year with ACTONEL 5 mg daily or ACTONEL 75 mg two consecutive days per month, urinary collagen cross-linked N-telopeptide was decreased by 54% and 52%, respectively, and serum bone-specific alkaline phosphatase was reduced by 36% and 35%, respectively. In a 1–year study comparing ACTONEL 5 mg daily versus ACTONEL 150 mg once-a-month in women with postmenopausal osteoporosis, urinary collagen cross-linked N-telopeptide was decreased by 52% and 49%, respectively, and serum bone-specific alkaline phosphatase was reduced by 31% and 32%, respectively. Osteoporosis in Men In a 2-year study of men with osteoporosis, treatment with ACTONEL 35 mg once-a-week resulted in a mean decrease from baseline compared to placebo of 16% (placebo 20%; ACTONEL 35 mg 37%) for the bone resorption marker urinary collagen cross-linked N-telopeptide, 45% (placebo -6%; ACTONEL 35 mg 39%) for the bone resorption marker serum C-telopeptide, and 27% (placebo -2%; ACTONEL 35 mg 25%) for the bone formation marker serum bone-specific alkaline phosphatase. Glucocorticoid-Induced Osteoporosis Osteoporosis with glucocorticoid use occurs as a result of inhibited bone formation and increased bone resorption resulting in net bone loss. ACTONEL decreases bone resorption without directly inhibiting bone formation. In two 1-year clinical trials in the treatment and prevention of glucocorticoid-induced osteoporosis, ACTONEL 5 mg decreased urinary collagen cross-linked N-telopeptide (a marker of bone resorption), and serum bone-specific alkaline phosphatase (a marker of bone formation) by 50% to 55% and 25% to 30%, respectively, within 3 to 6 months after initiation of therapy. Paget’s Disease Paget’s disease of bone is a chronic, focal skeletal disorder characterized by greatly increased and disordered bone remodeling. Excessive osteoclastic bone resorption is followed by osteoblastic new bone formation, leading to the replacement of the normal bone architecture by disorganized, enlarged, and weakened bone structure. In pagetic patients treated with ACTONEL 30 mg daily for 2 months, bone turnover returned to normal in a majority of patients as evidenced by significant reductions in serum alkaline phosphatase (a marker of bone formation), and in urinary hydroxyproline/creatinine and deoxypyridinoline/creatinine (markers of bone resorption).

12.3 Pharmacokinetics Absorption Based on simultaneous modeling of serum and urine data, peak absorption after an oral dose is achieved at approximately 1 hour (T max ) and occurs throughout the upper gastrointestinal tract. The fraction of the dose absorbed is independent of dose over the range studied (single dose, from 2.5 mg to 30 mg; multiple dose, from 2.5 mg to 5 mg). Steady-state conditions in the serum are observed within 57 days of daily dosing. Mean absolute oral bioavailability of the 30 mg tablet is 0.63% (90% CI: 0.54% to 0.75%) and is comparable to a solution. Food Effect The extent of absorption of a 30 mg dose (three 10 mg tablets) when administered 0.5 hours before breakfast is reduced by 55% compared to dosing in the fasting state (no food or drink for 10 hours prior to or 4 hours after dosing). Dosing 1 hour prior to breakfast reduces the extent of absorption by 30% compared to dosing in the fasting state. Dosing either 0.5 hours prior to breakfast or 2 hours after dinner (evening meal) results in a similar extent of absorption. ACTONEL is effective when administered at least 30 minutes before breakfast. Distribution The mean steady-state volume of distribution for risedronate is 13.8 L/kg in humans. Human plasma protein binding of drug is about 24%. Preclinical studies in rats and dogs dosed intravenously with single doses of [ 14 C] risedronate indicate that approximately 60% of the dose is distributed to bone. The remainder of the dose is excreted in the urine. After multiple oral dosing in rats, the uptake of risedronate in soft tissues was in the range of 0.001% to 0.01%. Metabolism There is no evidence of systemic metabolism of risedronate. Excretion In young healthy subjects, approximately half of the absorbed dose of risedronate was excreted in urine within 24 hours, and 85% of an intravenous dose was recovered in the urine over 28 days. Based on simultaneous modeling of serum and urine data, mean renal clearance was 105 mL/min (CV = 34%) and mean total clearance was 122 mL/min (CV = 19%), with the difference primarily reflecting nonrenal clearance or clearance due to adsorption to bone. The renal clearance is not concentration dependent, and there is a linear relationship between renal clearance and creatinine clearance. Unabsorbed drug is eliminated unchanged in feces. In osteopenic postmenopausal women, the terminal exponential half-life was 561 hours, mean renal clearance was 52 mL/min (CV = 25%), and mean total clearance was 73 mL/min (CV = 15%). Specific Populations Pediatric : ACTONEL is not indicated for use in pediatric patients [see Pediatric Use ( 8.4 ) ]. Gender : Bioavailability and pharmacokinetics following oral administration are similar in men and women. Geriatric : Bioavailability and disposition are similar in elderly (greater than 60 years of age) and younger subjects. No dosage adjustment is necessary. Race : Pharmacokinetic differences due to race have not been studied. Renal Impairment : Risedronate is excreted unchanged primarily via the kidney. As compared to persons with normal renal function, the renal clearance of risedronate was decreased by about 70% in patients with creatinine clearance of approximately 30 mL/min. ACTONEL is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/min) because of lack of clinical experience. No dosage adjustment is necessary in patients with a creatinine clearance greater than or equal to 30 mL/min. Hepatic Impairment : No studies have been performed to assess risedronate’s safety or efficacy in patients with hepatic impairment. Risedronate is not metabolized in rat, dog, and human liver preparations. Insignificant amounts (less than 0.1% of intravenous dose) of drug are excreted in the bile in rats. Therefore, dosage adjustment is unlikely to be needed in patients with hepatic impairment. Drug Interactions : No specific drug-drug interaction studies were performed. Risedronate is not metabolized and does not induce or inhibit hepatic microsomal drug-metabolizing enzymes (Cytochrome P450) [ see Drug Interactions ( 7 ) ].

20231001

26

3 DOSAGE FORMS AND STRENGTHS 5 mg film-coated, oval, yellow tablet with RSN on 1 face and 5 mg on the other. 30 mg film-coated, oval, white tablet with RSN on 1 face and 30 mg on the other. 35 mg film-coated, oval, orange tablet with RSN on 1 face and 35 mg on the other. 75 mg film-coated, oval, pink tablet with RSN on 1 face and 75 mg on the other. 150 mg film-coated, oval, blue tablet with RSN on 1 face and 150 mg on the other. Tablets: 5, 30, 35, 75, and 150 mg ( 3 )

Actonel Risedronate Sodium RISEDRONATE SODIUM HEMI-PENTAHYDRATE RISEDRONIC ACID RISEDRONATE SODIUM ANHYDROUS RISEDRONATE SODIUM MONOHYDRATE RISEDRONIC ACID RISEDRONATE SODIUM ANHYDROUS CROSPOVIDONE HYDROXYPROPYL CELLULOSE (1600000 WAMW) HYPROMELLOSES MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE POLYETHYLENE GLYCOL, UNSPECIFIED SILICON DIOXIDE TITANIUM DIOXIDE FERRIC OXIDE YELLOW LACTOSE MONOHYDRATE RSN;5;MG Actonel Risedronate Sodium RISEDRONATE SODIUM HEMI-PENTAHYDRATE RISEDRONIC ACID RISEDRONATE SODIUM ANHYDROUS RISEDRONATE SODIUM MONOHYDRATE RISEDRONIC ACID RISEDRONATE SODIUM ANHYDROUS CROSPOVIDONE HYDROXYPROPYL CELLULOSE (1600000 WAMW) HYPROMELLOSES MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE POLYETHYLENE GLYCOL, UNSPECIFIED SILICON DIOXIDE TITANIUM DIOXIDE LACTOSE MONOHYDRATE RSN;30;MG Actonel Risedronate Sodium RISEDRONATE SODIUM HEMI-PENTAHYDRATE RISEDRONIC ACID RISEDRONATE SODIUM ANHYDROUS RISEDRONATE SODIUM MONOHYDRATE RISEDRONIC ACID RISEDRONATE SODIUM ANHYDROUS CROSPOVIDONE HYDROXYPROPYL CELLULOSE (1600000 WAMW) HYPROMELLOSES MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE POLYETHYLENE GLYCOL, UNSPECIFIED SILICON DIOXIDE TITANIUM DIOXIDE FERRIC OXIDE RED FERRIC OXIDE YELLOW LACTOSE MONOHYDRATE RSN;35;MG Actonel Risedronate Sodium RISEDRONATE SODIUM HEMI-PENTAHYDRATE RISEDRONIC ACID RISEDRONATE SODIUM ANHYDROUS RISEDRONATE SODIUM MONOHYDRATE RISEDRONIC ACID RISEDRONATE SODIUM ANHYDROUS CROSPOVIDONE HYDROXYPROPYL CELLULOSE (1600000 WAMW) HYPROMELLOSES MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE POLYETHYLENE GLYCOL, UNSPECIFIED SILICON DIOXIDE TITANIUM DIOXIDE FERRIC OXIDE RED RSN;75;MG Actonel Risedronate Sodium RISEDRONATE SODIUM HEMI-PENTAHYDRATE RISEDRONIC ACID RISEDRONATE SODIUM ANHYDROUS RISEDRONATE SODIUM MONOHYDRATE RISEDRONIC ACID RISEDRONATE SODIUM ANHYDROUS CROSPOVIDONE HYDROXYPROPYL CELLULOSE (1600000 WAMW) HYPROMELLOSES MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE POLYETHYLENE GLYCOL, UNSPECIFIED SILICON DIOXIDE TITANIUM DIOXIDE FD&C BLUE NO. 2 RSN;150;MG

13.2 Animal Toxicology and/or Pharmacology Risedronate demonstrated potent anti-osteoclast, antiresorptive activity in ovariectomized rats and minipigs. Bone mass and biomechanical strength were increased dose-dependently at daily oral doses up to 4 and 25 times the human recommended oral dose of 5 mg for rats and minipigs, respectively. Risedronate treatment maintained the positive correlation between BMD and bone strength and did not have a negative effect on bone structure or mineralization. In intact dogs, risedronate induced positive bone balance at the level of the bone remodeling unit at oral doses ranging from 0.5 to 1.5 times the 5 mg/day human daily dose. In dogs treated with an oral dose approximately 5 times the human daily dose, risedronate caused a delay in fracture healing of the radius. The observed delay in fracture healing is similar to other bisphosphonates. This effect did not occur at a dose approximately 0.5 times the human daily dose. The Schenk rat assay, based on histologic examination of the epiphyses of growing rats after drug treatment, demonstrated that risedronate did not interfere with bone mineralization even at the highest dose tested, which was approximately 3500 times the lowest antiresorptive dose in this model (1.5 mcg/kg/day) and approximately 800 times the human daily dose of 5 mg. This indicates that ACTONEL administered at the therapeutic dose is unlikely to induce osteomalacia. Dosing multiples provided above are based on the recommended human dose of 5 mg/day and normalized using body surface area (mg/m 2 ).

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a 104-week carcinogenicity study, rats were administered daily oral doses up to approximately 8 times the maximum recommended human daily dose. There were no significant drug-induced tumor findings in male or female rats. The high dose male group was terminated early in the study (Week 93) due to excessive toxicity, and data from this group were not included in the statistical evaluation of the study results. In an 80-week carcinogenicity study, mice were administered daily oral doses approximately 6.5 times the human dose. There were no significant drug-induced tumor findings in male or female mice. Mutagenesis Risedronate did not exhibit genetic toxicity in the following assays: In vitro bacterial mutagenesis in Salmonella and E. coli (Ames assay), mammalian cell mutagenesis in CHO/HGPRT assay, unscheduled DNA synthesis in rat hepatocytes and an assessment of chromosomal aberrations in vivo in rat bone marrow. Risedronate was positive in a chromosomal aberration assay in CHO cells at highly cytotoxic concentrations (greater than 675 mcg/mL, survival of 6% to 7%). When the assay was repeated at doses exhibiting appropriate cell survival (29%), there was no evidence of chromosomal damage. Impairment of Fertility In female rats, ovulation was inhibited at an oral dose approximately 5 times the human dose. Decreased implantation was noted in female rats treated with doses approximately 2.5 times the human dose. In male rats, testicular and epididymal atrophy and inflammation were noted at approximately 13 times the human dose. Testicular atrophy was also noted in male rats after 13 weeks of treatment at oral doses approximately 5 times the human dose. There was moderate-to-severe spermatid maturation block after 13 weeks in male dogs at an oral dose approximately 8 times the human dose. These findings tended to increase in severity with increased dose and exposure time. Dosing multiples provided above are based on the recommended human dose of 30 mg/day and normalized using body surface area (mg/m 2 ). Actual doses were 24 mg/kg/day in rats, 32 mg/kg/day in mice, and 8, 16 and 40 mg/kg/day in dogs.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a 104-week carcinogenicity study, rats were administered daily oral doses up to approximately 8 times the maximum recommended human daily dose. There were no significant drug-induced tumor findings in male or female rats. The high dose male group was terminated early in the study (Week 93) due to excessive toxicity, and data from this group were not included in the statistical evaluation of the study results. In an 80-week carcinogenicity study, mice were administered daily oral doses approximately 6.5 times the human dose. There were no significant drug-induced tumor findings in male or female mice. Mutagenesis Risedronate did not exhibit genetic toxicity in the following assays: In vitro bacterial mutagenesis in Salmonella and E. coli (Ames assay), mammalian cell mutagenesis in CHO/HGPRT assay, unscheduled DNA synthesis in rat hepatocytes and an assessment of chromosomal aberrations in vivo in rat bone marrow. Risedronate was positive in a chromosomal aberration assay in CHO cells at highly cytotoxic concentrations (greater than 675 mcg/mL, survival of 6% to 7%). When the assay was repeated at doses exhibiting appropriate cell survival (29%), there was no evidence of chromosomal damage. Impairment of Fertility In female rats, ovulation was inhibited at an oral dose approximately 5 times the human dose. Decreased implantation was noted in female rats treated with doses approximately 2.5 times the human dose. In male rats, testicular and epididymal atrophy and inflammation were noted at approximately 13 times the human dose. Testicular atrophy was also noted in male rats after 13 weeks of treatment at oral doses approximately 5 times the human dose. There was moderate-to-severe spermatid maturation block after 13 weeks in male dogs at an oral dose approximately 8 times the human dose. These findings tended to increase in severity with increased dose and exposure time. Dosing multiples provided above are based on the recommended human dose of 30 mg/day and normalized using body surface area (mg/m 2 ). Actual doses were 24 mg/kg/day in rats, 32 mg/kg/day in mice, and 8, 16 and 40 mg/kg/day in dogs. 13.2 Animal Toxicology and/or Pharmacology Risedronate demonstrated potent anti-osteoclast, antiresorptive activity in ovariectomized rats and minipigs. Bone mass and biomechanical strength were increased dose-dependently at daily oral doses up to 4 and 25 times the human recommended oral dose of 5 mg for rats and minipigs, respectively. Risedronate treatment maintained the positive correlation between BMD and bone strength and did not have a negative effect on bone structure or mineralization. In intact dogs, risedronate induced positive bone balance at the level of the bone remodeling unit at oral doses ranging from 0.5 to 1.5 times the 5 mg/day human daily dose. In dogs treated with an oral dose approximately 5 times the human daily dose, risedronate caused a delay in fracture healing of the radius. The observed delay in fracture healing is similar to other bisphosphonates. This effect did not occur at a dose approximately 0.5 times the human daily dose. The Schenk rat assay, based on histologic examination of the epiphyses of growing rats after drug treatment, demonstrated that risedronate did not interfere with bone mineralization even at the highest dose tested, which was approximately 3500 times the lowest antiresorptive dose in this model (1.5 mcg/kg/day) and approximately 800 times the human daily dose of 5 mg. This indicates that ACTONEL administered at the therapeutic dose is unlikely to induce osteomalacia. Dosing multiples provided above are based on the recommended human dose of 5 mg/day and normalized using body surface area (mg/m 2 ).

NDA020835

Actonel

Risedronate Sodium

0430-0472

HUMAN PRESCRIPTION DRUG

ORAL

5. 9 Laboratory Test Interactions Bisphosphonates are known to interfere with the use of bone-imaging agents. Specific studies with ACTONEL have not been performed.

PRINCIPAL DISPLAY PANEL Rx Only NDC 0430-0471-15 Actonel (risedronate sodium) tablets 5 mg 30 Tablets Rx Only NDC 0430-0471-15 Actonel (risedronate sodium) tablets 5 mg 30 Tablets

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling ( Medication Guide ) Instruct patients to read the Medication Guide before starting therapy with ACTONEL and to re-read it each time the prescription is renewed. Instruct patients that Atelvia and ACTONEL contain the same active ingredient and if they are taking Atelvia, they should not take ACTONEL [ see Warnings and Precautions ( 5.1 ) ]. Instruct patients to pay particular attention to the dosing instructions as clinical benefits may be compromised by failure to take the drug according to instructions. Specifically, ACTONEL should be taken at least 30 minutes before the first food or drink of the day other than water. Instruct patients to take ACTONEL while in an upright position (sitting or standing) with a full glass of plain water (6 to 8 ounces) to facilitate delivery to the stomach, and thus reduce the potential for esophageal irritation. Instruct patients not to lie down for 30 minutes after taking the medication [ see Warnings and Precautions ( 5.1 ) ]. Instruct patients not to chew or suck on the tablet because of a potential for oropharyngeal irritation. Instruct patients that if they develop symptoms of esophageal disease (such as difficulty or pain upon swallowing, retrosternal pain or severe persistent or worsening heartburn) they should consult their physician before continuing ACTONEL. Instruct patients about missing ACTONEL doses as follows: If a dose of ACTONEL 35 mg once-a-week is missed, they should 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. Patients should not take 2 tablets on the same day. If one or both tablets of ACTONEL 75 mg on two consecutive days per month are missed, and the next month’s scheduled doses are more than 7 days away, the patient should be instructed as follows: If both tablets are missed, take one ACTONEL 75 mg tablet in the morning after the day it is remembered and then the other tablet on the next consecutive morning. If only one ACTONEL 75 mg tablet is missed, take the missed tablet in the morning after the day it is remembered. Patients should then return to taking their ACTONEL 75 mg on two consecutive days per month as originally scheduled. Patients should not take more than two 75 mg tablets within 7 days. If one or both tablets of ACTONEL 75 mg on two consecutive days per month are missed, and the next month's scheduled doses are within 7 days, patients should wait until their next month’s scheduled doses and then continue taking ACTONEL 75 mg on two consecutive days per month as originally scheduled. If the dose of ACTONEL 150 mg once-a-month is missed, and the next month’s scheduled dose is more than 7 days away, the patient should be instructed to take the missed tablet in the morning after the day it is remembered. Patients should then return to taking their ACTONEL 150 mg once-a-month as originally scheduled. Patients should not take more than one 150 mg tablet within 7 days. If the dose of ACTONEL 150 mg once-a-month is missed, and the next month's scheduled dose is within 7 days, patients should wait until their next month’s scheduled dose and then continue taking ACTONEL 150 mg once-a-month as originally scheduled. Instruct patients to take supplemental calcium and vitamin D if dietary intake is inadequate [ see Warnings and Precautions ( 5.3 ) ]. Weight-bearing exercise should be considered along with the modification of certain behavioral factors, such as excessive cigarette smoking, and/or alcohol consumption, if these factors exist. Instruct patients to take calcium supplements or calcium-, aluminum-, and magnesium-containing medications at a different time of the day than ACTONEL as these medications may interfere with the absorption of ACTONEL. Remind patients to give all of their healthcare providers an accurate medication history. Instruct patients to tell all of their healthcare providers that they are taking ACTONEL. Patients should be instructed that any time they have a medical problem they think may be from ACTONEL, they should talk to their doctor. Distributed by: AbbVie Inc. North Chicago, Illinois 60064 © 2023 AbbVie. All rights reserved. Actonel and its design are trademarks of Allergan Pharmaceuticals International Limited, an AbbVie company. 20080025

Medication Guide ACTONEL ® ( AK - toh - nel ) ( risedronate sodium ) Tablets Read the Medication Guide that comes with ACTONEL ® before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or your treatment. Talk to your doctor if you have any questions about ACTONEL, there may be new information about it. What is the most important information I should know about ACTONEL? ACTONEL can cause serious side effects including : Esophagus problems Low calcium levels in your blood (hypocalcemia) Severe jaw bone problems (osteonecrosis) Bone, joint, or muscle pain Unusual thigh bone fractures 1. Esophagus problems. Some people who take ACTONEL may develop problems in the esophagus (the tube that connects the mouth and the stomach). These problems include irritation, inflammation, or ulcers of the esophagus which may sometimes bleed. It is important that you take ACTONEL exactly as prescribed to help lower your chance of getting esophagus problems. (See the section “How should I take ACTONEL ?”) Stop taking ACTONEL and call your doctor right away if you get chest pain, new or worsening heartburn, or have trouble or pain when you swallow. 2. Low calcium levels in your blood (hypocalcemia). ACTONEL may lower the calcium levels in your blood. If you have low blood calcium before you start taking ACTONEL, it may get worse during treatment. Your low blood calcium must be treated before you take ACTONEL. Most people with low blood calcium levels do not have symptoms, but some people may have symptoms. Call your doctor right away if you have symptoms of low blood calcium such as: Spasms, twitches, or cramps in your muscles Numbness or tingling in your fingers, toes, or around your mouth Your doctor may prescribe calcium and vitamin D to help prevent low calcium levels in your blood, while you take ACTONEL. Take calcium and vitamin D as your doctor tells you to. 3. Severe jaw bone problems (osteonecrosis). Severe jaw bone problems may happen when you take ACTONEL. Your doctor should examine your mouth before you start ACTONEL. Your doctor may tell you to see your dentist before you start ACTONEL. It is important for you to practice good mouth care during treatment with ACTONEL. 4. Bone, joint, or muscle pain. Some people who take ACTONEL develop severe bone, joint, or muscle pain. 5. Unusual thigh bone fractures. Some people have developed unusual fractures in their thigh bone. Symptoms of a fracture may include new or unusual pain in your hip, groin, or thigh. Call your doctor right away if you have any of these side effects. What is ACTONEL ? ACTONEL is a prescription medicine used to: Treat or prevent osteoporosis in women after menopause. ACTONEL helps increase bone mass and helps reduce the chance of having a spinal or non-spinal fracture (break). Increase bone mass in men with osteoporosis. Treat or prevent osteoporosis in either men or women who are taking corticosteroid medicines. Treat certain men and women who have Paget’s disease of the bone. It is not known how long ACTONEL works for the treatment and prevention of osteoporosis. You should see your doctor regularly to determine if ACTONEL is still right for you. ACTONEL is not for use in children. Who should not take ACTONEL ? Do not take ACTONEL if you : Have certain problems with your esophagus, the tube that connects your mouth with your stomach Cannot stand or sit upright for at least 30 minutes Have low levels of calcium in your blood Are allergic to ACTONEL or any of its ingredients. A list of ingredients is at the end of this leaflet. What should I tell my doctor before taking ACTONEL ? Before you start ACTONEL , be sure to talk to your doctor if you : Have problems with swallowing Have stomach or digestive problems Have low blood calcium Plan to have dental surgery or teeth removed Have kidney problems Have been told you have trouble absorbing minerals in your stomach or intestines (malabsorption syndrome) Are pregnant, plan to become pregnant, or suspect that you are pregnant. If you become pregnant while taking ACTONEL, stop taking it and contact your doctor. It is not known if ACTONEL can harm your unborn baby. Are breastfeeding or plan to breastfeed. It is not known if ACTONEL passes into your milk and may harm your baby. Especially tell your doctor if you take: antacids aspirin Nonsteroidal Anti-Inflammatory (NSAID) medicines Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Certain medicines may affect how ACTONEL works. Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist each time you get a new medicine. How should I take ACTONEL ? Take ACTONEL exactly as your doctor tells you. Your doctor may change your dose of ACTONEL if needed. ACTONEL works only if taken on an empty stomach. Take 1 ACTONEL tablet, after you get up for the day and before taking your first food, drink, or other medicine. Take ACTONEL while you are sitting or standing. Do not chew or suck on a tablet of ACTONEL . Swallow ACTONEL tablet with a full glass (6 to 8 ounces) of plain water only. Do not take ACTONEL with mineral water, coffee, tea, soda, or juice. After swallowing ACTONEL tablet, wait at least 30 minutes: Before you lie down. You may sit, stand or walk, and do normal activities like reading. Before you take your first food or drink except for plain water. Before you take other medicines, including antacids, calcium, and other supplements and vitamins. Do not lie down for at least 30 minutes after you take ACTONEL and after you eat your first food of the day. If you miss a dose of ACTONEL, do not take it later in the day. Take your missed dose the next morning and then return to your normal schedule. Do not take 2 doses at the same time. If you miss more than 2 doses of ACTONEL in a month, call your doctor for instructions. If you take too much ACTONEL, call your doctor. Do not try to vomit. Do not lie down. What are the possible side effects of ACTONEL ? ACTONEL may cause serious side effects: See “What is the most important information I should know about ACTONEL ? ” The most common side effects of ACTONEL are: pain, including back and joint pain stomach area (abdominal) pain heartburn You may get allergic reactions, such as hives, swelling of your face, lips, tongue, or throat. Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of ACTONEL. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store ACTONEL ? Store ACTONEL at room temperature, 68° F to 77° F (20° C to 25° C). Safely throw away medicine that is out of date or no longer needed. Keep ACTONEL and all medicines out of the reach of children. General information about the safe and effective use of ACTONEL . Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ACTONEL for a condition for which it was not prescribed. Do not give ACTONEL to other people, even if they have the same symptoms you have. It may harm them. This Medication Guide summarizes the most important information about ACTONEL. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about ACTONEL that is written for health professionals. For more information, go to www.Actonel.com or call 1-800-678-1605. What are the ingredients in ACTONEL ? Active ingredient: risedronate sodium Inactive ingredients in all dose strengths: crospovidone, hydroxypropyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, silicon dioxide, titanium dioxide. Inactive ingredients specific to a dose strength: 5 mg—ferric oxide yellow, lactose monohydrate; 30 mg—lactose monohydrate; 35 mg—ferric oxide red, ferric oxide yellow, lactose monohydrate; 75 mg—ferric oxide red; 150 mg—FD&C blue #2 aluminum lake. This Medication Guide has been approved by the U.S. Food and Drug Administration. Distributed by: AbbVie Inc. North Chicago, Illinois 60064 © 2023 AbbVie. All rights reserved. Actonel and its design are trademarks of Allergan Pharmaceuticals International Limited, an AbbVie company. Revised: 10/2023 20080025

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 D aily Dosing The safety of ACTONEL 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 ACTONEL 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 ACTONEL 5 mg daily group. The incidence of serious adverse events was 24.6% in the placebo group and 27.2% in the ACTONEL 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 ACTONEL 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 ACTONEL 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 ACTONEL 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 ACTONEL 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 ACTONEL 5 mg daily groups. Musculoskeletal Adverse Events : The incidence of adverse events in the placebo and ACTONEL 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 ACTONEL 5 mg once daily. There were no significant differences in serum calcium, phosphate, or PTH levels between placebo and ACTONEL 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 ACTONEL 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 ACTONEL 5 mg once daily. There have been rare reports (less than 0.1%) of abnormal liver function tests. Endoscopic Findings : In the ACTONEL 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%) ACTONEL]. Clinically important findings (perforations, ulcers, or bleeding) among this symptomatic population were similar between groups (51% placebo; 39% ACTONEL). Once-a- W eek Dosing The safety of ACTONEL 35 mg once-a-week in the treatment of postmenopausal osteoporosis was assessed in a 1-year, double-blind, multicenter study comparing ACTONEL 5 mg daily and ACTONEL 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 ACTONEL 5 mg daily and 485 exposed to ACTONEL 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 ACTONEL 5 mg daily group and 1.0% in the ACTONEL 35 mg once-a-week group. The incidence of serious adverse events was 7.1% in the ACTONEL 5 mg daily group and 8.2% in the ACTONEL 35 mg once-a-week group. The percentage of patients who withdrew from the study due to adverse events was 11.9% in the ACTONEL 5 mg daily group and 11.5% in the ACTONEL 35 mg once-a-week group. The overall safety and tolerability profiles of the two dosing regimens were similar. Gastrointestinal Adverse E vents : The incidence of gastrointestinal adverse events was similar between the ACTONEL 5 mg daily group and the ACTONEL 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 ACTONEL 5 mg daily group and 14.2% of patients in the ACTONEL 35 mg once-a-week group. Myalgia was reported by 4.6% of patients in the ACTONEL 5 mg daily group and 6.2% of patients in the ACTONEL 35 mg once-a-week group. Laboratory Test Findings : The mean percent changes from baseline at 12 months were similar between the ACTONEL 5 mg daily and ACTONEL 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 ACTONEL 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 ACTONEL 5 mg daily and 616 were exposed to ACTONEL 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 ACTONEL 5 mg daily group and 0.5% for the ACTONEL 75 mg two consecutive days per month group. The incidence of serious adverse events was 10.8% in the ACTONEL 5 mg daily group and 14.4% in the ACTONEL 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 ACTONEL 5 mg daily group and 13.0% in the ACTONEL 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 ACTONEL 5 mg daily and 7.6% of patients on ACTONEL 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 ACTONEL 5 mg daily and 0.6% of patients on ACTONEL 75 mg two consecutive days per month. Gastrointestinal Adverse Events : The ACTONEL 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 ACTONEL 5 mg daily group. Most of these events occurred within a few days of dosing. Ocular Adverse Events : None of the patients treated with ACTONEL 75 mg two consecutive days per month reported ocular inflammation such as uveitis, scleritis, or iritis; 1 patient treated with ACTONEL 5 mg daily reported uveitis. Laboratory Test Findings : When ACTONEL 5 mg daily and ACTONEL 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 ACTONEL 5 mg daily group, ACTONEL 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%. Onc e-a- Month The safety of ACTONEL 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 ACTONEL 5 mg daily and 650 exposed to ACTONEL 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 ACTONEL 5 mg daily group and 0.0% for the ACTONEL 150 mg once-a-month group. The incidence of serious adverse events was 4.2% in the ACTONEL 5 mg daily group and 6.2% in the ACTONEL 150 mg once-a-month group. The percentage of patients who withdrew from treatment due to adverse events was 9.5% in the ACTONEL 5 mg daily group and 8.6% in the ACTONEL 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 ACTONEL 5 mg daily group and 5.2% in the ACTONEL 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 ACTONEL 5 mg daily and 1.4% of patients on ACTONEL 150 mg once-a-month. Gastrointestinal Adverse Events : A greater percentage of patients experienced diarrhea with ACTONEL 150 mg once-a-month compared to 5 mg daily (8.2% versus 4.7%, respectively). The ACTONEL 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 ACTONEL 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 ACTONEL 150 mg once-a-month reported ocular inflammation such as uveitis, scleritis, or iritis; 2 patients treated with ACTONEL 5 mg daily reported iritis. Laboratory Test Findings : When ACTONEL 5 mg daily and ACTONEL 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 ACTONEL 5 mg daily regimen, ACTONEL 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 D osing The safety of ACTONEL 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 ACTONEL-treated patients was included. The duration of the trial was one year, with 259 exposed to placebo and 261 patients exposed to ACTONEL 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 ACTONEL 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 ACTONEL 5 mg group. The incidence of serious adverse events was 8.9% in the placebo group and 5.4% in the ACTONEL 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 ACTONEL 5 mg group. Constipation was reported by 1.9% of the placebo group and 6.5% of ACTONEL 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 ACTONEL 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 ACTONEL 5 mg group. Nausea was reported by 6.4% of patients in the placebo group and 13.2% of patients in the ACTONEL 5 mg group. Once-a- W eek Dosing There were no deaths in a 1-year, double-blind, placebo-controlled study of ACTONEL 35 mg once-a-week for prevention of bone loss in 278 postmenopausal women without osteoporosis. More treated subjects on ACTONEL reported arthralgia (placebo 7.8%; ACTONEL 13.9%), myalgia (placebo 2.1%; ACTONEL 5.1%), and nausea (placebo 4.3%; ACTONEL 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 ACTONEL 35 mg once-a-week (N = 191). The overall safety and tolerability profile of ACTONEL in men with osteoporosis was similar to the adverse events reported in the ACTONEL postmenopausal osteoporosis clinical trials, with the addition of benign prostatic hyperplasia (placebo 3%; ACTONEL 35 mg 5%), nephrolithiasis (placebo 0%; ACTONEL 35 mg 3%), and arrhythmia (placebo 0%; ACTONEL 35 mg 2%). Treatment and Prevention of Glucocorticoid- I nduced Osteoporosis The safety of ACTONEL 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 ACTONEL 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 ACTONEL 5 mg daily group. The incidence of serious adverse events was 33.5% in the placebo group and 30.5% in the ACTONEL 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 ACTONEL 5 mg daily group. Back pain was reported in 8.8% of patients in the placebo group and 17.8% of patients in the ACTONEL 5 mg daily group. Arthralgia was reported in 14.7% of patients in the placebo group and 24.7% of patients in the ACTONEL 5 mg daily group. Treatment of Paget’s Disease ACTONEL has been studied in 392 patients with Paget’s disease of bone. As in trials of ACTONEL 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 ACTONEL 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 ACTONEL and 61 patients exposed to Didronel ® . The adverse event profile was similar for ACTONEL and Didronel: 6.6% (4/61) of patients treated with ACTONEL 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 ACTONEL-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 ACTONEL -Treated Patients* in Phase 3 Paget's Disease Trials Body System 30 mg/day x 2 months ACTONEL % (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 *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 ACTONEL group and 14.8% in the Didronel group; none were serious or resulted in withdrawal. Ocular Adverse Events : Three patients who received ACTONEL 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 ACTONEL treatment and again during treatment with pamidronate. All patients were effectively treated with topical steroids.

8.5 Geriatric Use Of the patients receiving ACTONEL in postmenopausal osteoporosis studies [ see C linical S tudies ( 14 ) ], 47% were between 65 and 75 years of age, and 17% were over 75. The corresponding proportions were 26% and 11% in glucocorticoid-induced osteoporosis trials, and 40% and 26% in Paget’s disease trials. No overall differences in efficacy between geriatric and younger patients were observed in these studies. In the male osteoporosis trial, 28% of patients receiving ACTONEL were between 65 and 75 years of age and 9% were over 75. The lumbar spine BMD response for ACTONEL compared to placebo was 5.6% for subjects less than 65 years and 2.9% for subjects greater than or equal to 65 years. No overall differences in safety between geriatric and younger patients were observed in the ACTONEL trials, but greater sensitivity of some older individuals cannot be ruled out.

8.4 Pediatric Use ACTONEL is not indicated for use in pediatric patients. The safety and effectiveness of risedronate was assessed in a one-year, randomized, double-blind, placebo-controlled study of 143 pediatric patients (94 received risedronate) with osteogenesis imperfecta (OI). The enrolled population was predominantly patients with mild osteogenesis imperfecta (85% Type-I), aged 4 to less than 16 years, 50% male and 82% Caucasian, with a mean lumbar spine BMD Z-score of -2.08 (2.08 standard deviations below the mean for age-matched controls). Patients received either a 2.5 mg (less than or equal to 30 kg body weight) or 5 mg (greater than 30 kg body weight) daily oral dose. After one year, an increase in lumbar spine BMD in the risedronate group compared to the placebo group was observed. However, treatment with risedronate did not result in a reduction in the risk of fracture in pediatric patients with osteogenesis imperfecta. In ACTONEL-treated subjects, no mineralization defects were noted in paired bone biopsy specimens obtained at baseline and month 12. The overall safety profile of risedronate in OI patients treated for up to 12 months was generally similar to that of adults with osteoporosis. However, there was an increased incidence of vomiting compared to placebo. In this study, vomiting was observed in 15% of children treated with risedronate and 6% of patients treated with placebo. Other adverse events reported in greater than or equal to 10% of patients treated with risedronate and with a higher frequency than placebo were: pain in the extremity (21% with risedronate versus 16% with placebo), headache (20% versus 8%), back pain (17% versus 10%), pain (15% versus 10%), upper abdominal pain (11% versus 8%), and bone pain (10% versus 4%).

8.1 Pregnancy Risk Summary Available data on the use of ACTONEL in pregnant women are insufficient to inform a drug-associated risk of adverse maternal or fetal outcomes. Discontinue ACTONEL when pregnancy is recognized. In animal reproduction studies, daily oral administration of risedronate to pregnant rats during organogenesis decreased neonatal survival and body weight at doses approximately 5 and 26 times, respectively, the highest recommended human daily dose of 30 mg (based on body surface area, mg/m 2 ). A low incidence of cleft palate was observed in fetuses of dams treated at doses approximately equal to the 30 mg human daily dose. Delayed skeletal ossification was observed in fetuses of dams treated at approximately 2.5 to 5 times the 30 mg human daily dose. Periparturient mortality due to maternal hypocalcemia occurred in dams and neonates upon daily oral administration of risedronate to pregnant rats during mating and/or gestation starting at doses equivalent to the 30 mg daily human dose. Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over a period of years. The amount of bisphosphonate incorporated into adult bone and available for release into the systemic circulation is directly related to the dose and duration of bisphosphonate use. Consequently, based on the mechanism of action of bisphosphonates, there is a potential risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been studied. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In animal studies, pregnant rats received risedronate sodium during organogenesis at doses equivalent to 1 to 26 times the 30 mg human daily dose (based on body surface area, mg/m 2 ). Survival of neonates was decreased in dams treated during gestation with oral doses approximately 5 times the human dose, and body weight was decreased in neonates of dams treated with approximately 26 times the human dose. A low incidence of cleft palate was observed in fetuses of dams treated with oral doses approximately equal to the human dose. The number of fetuses exhibiting incomplete ossification of sternebrae or skull of dams treated with approximately 2.5 times the human dose was significantly increased compared to controls. Both incomplete ossification and unossified sternebrae were increased in fetuses of dams treated with oral doses approximately 5 times the human dose. No significant ossification effects were seen in fetuses of rabbits treated with oral doses approximately 7 times the human dose (the highest dose tested). However, 1 of 14 litters were aborted and 1 of 14 litters were delivered prematurely. Periparturient mortality due to maternal hypocalcemia occurred in dams and neonates when pregnant rats were treated daily during mating and/or gestation with oral doses equivalent to the human dose or higher.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Discontinue when pregnancy is recognized ( 8.1 ) ACTONEL is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/min) ( 5.6 , 8.6 , 12.3 ) ACTONEL is not indicated for use in pediatric patients ( 8.4 ) 8.1 Pregnancy Risk Summary Available data on the use of ACTONEL in pregnant women are insufficient to inform a drug-associated risk of adverse maternal or fetal outcomes. Discontinue ACTONEL when pregnancy is recognized. In animal reproduction studies, daily oral administration of risedronate to pregnant rats during organogenesis decreased neonatal survival and body weight at doses approximately 5 and 26 times, respectively, the highest recommended human daily dose of 30 mg (based on body surface area, mg/m 2 ). A low incidence of cleft palate was observed in fetuses of dams treated at doses approximately equal to the 30 mg human daily dose. Delayed skeletal ossification was observed in fetuses of dams treated at approximately 2.5 to 5 times the 30 mg human daily dose. Periparturient mortality due to maternal hypocalcemia occurred in dams and neonates upon daily oral administration of risedronate to pregnant rats during mating and/or gestation starting at doses equivalent to the 30 mg daily human dose. Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over a period of years. The amount of bisphosphonate incorporated into adult bone and available for release into the systemic circulation is directly related to the dose and duration of bisphosphonate use. Consequently, based on the mechanism of action of bisphosphonates, there is a potential risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been studied. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In animal studies, pregnant rats received risedronate sodium during organogenesis at doses equivalent to 1 to 26 times the 30 mg human daily dose (based on body surface area, mg/m 2 ). Survival of neonates was decreased in dams treated during gestation with oral doses approximately 5 times the human dose, and body weight was decreased in neonates of dams treated with approximately 26 times the human dose. A low incidence of cleft palate was observed in fetuses of dams treated with oral doses approximately equal to the human dose. The number of fetuses exhibiting incomplete ossification of sternebrae or skull of dams treated with approximately 2.5 times the human dose was significantly increased compared to controls. Both incomplete ossification and unossified sternebrae were increased in fetuses of dams treated with oral doses approximately 5 times the human dose. No significant ossification effects were seen in fetuses of rabbits treated with oral doses approximately 7 times the human dose (the highest dose tested). However, 1 of 14 litters were aborted and 1 of 14 litters were delivered prematurely. Periparturient mortality due to maternal hypocalcemia occurred in dams and neonates when pregnant rats were treated daily during mating and/or gestation with oral doses equivalent to the human dose or higher. 8. 2 Lactation Risk Summary There are no data on the presence of risedronate in human milk, the effects on the breastfed infant, or the effects on milk production. A small degree of lacteal transfer occurred in nursing rats. The concentration of the drug in animal milk does not necessarily predict the concentration of drug in human milk. However, when a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for ACTONEL and any potential adverse effects on the breast-fed child from ACTONEL or from the underlying maternal condition. Data Animal Data Risedronate was detected in neonates of lactating rats given a single oral dose of risedronate at 24-hours post-dosing, indicating a small degree of lacteal transfer. 8.4 Pediatric Use ACTONEL is not indicated for use in pediatric patients. The safety and effectiveness of risedronate was assessed in a one-year, randomized, double-blind, placebo-controlled study of 143 pediatric patients (94 received risedronate) with osteogenesis imperfecta (OI). The enrolled population was predominantly patients with mild osteogenesis imperfecta (85% Type-I), aged 4 to less than 16 years, 50% male and 82% Caucasian, with a mean lumbar spine BMD Z-score of -2.08 (2.08 standard deviations below the mean for age-matched controls). Patients received either a 2.5 mg (less than or equal to 30 kg body weight) or 5 mg (greater than 30 kg body weight) daily oral dose. After one year, an increase in lumbar spine BMD in the risedronate group compared to the placebo group was observed. However, treatment with risedronate did not result in a reduction in the risk of fracture in pediatric patients with osteogenesis imperfecta. In ACTONEL-treated subjects, no mineralization defects were noted in paired bone biopsy specimens obtained at baseline and month 12. The overall safety profile of risedronate in OI patients treated for up to 12 months was generally similar to that of adults with osteoporosis. However, there was an increased incidence of vomiting compared to placebo. In this study, vomiting was observed in 15% of children treated with risedronate and 6% of patients treated with placebo. Other adverse events reported in greater than or equal to 10% of patients treated with risedronate and with a higher frequency than placebo were: pain in the extremity (21% with risedronate versus 16% with placebo), headache (20% versus 8%), back pain (17% versus 10%), pain (15% versus 10%), upper abdominal pain (11% versus 8%), and bone pain (10% versus 4%). 8.5 Geriatric Use Of the patients receiving ACTONEL in postmenopausal osteoporosis studies [ see C linical S tudies ( 14 ) ], 47% were between 65 and 75 years of age, and 17% were over 75. The corresponding proportions were 26% and 11% in glucocorticoid-induced osteoporosis trials, and 40% and 26% in Paget’s disease trials. No overall differences in efficacy between geriatric and younger patients were observed in these studies. In the male osteoporosis trial, 28% of patients receiving ACTONEL were between 65 and 75 years of age and 9% were over 75. The lumbar spine BMD response for ACTONEL compared to placebo was 5.6% for subjects less than 65 years and 2.9% for subjects greater than or equal to 65 years. No overall differences in safety between geriatric and younger patients were observed in the ACTONEL trials, but greater sensitivity of some older individuals cannot be ruled out. 8. 6 Renal I mpairment ACTONEL is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/min) because of lack of clinical experience. No dosage adjustment is necessary in patients with a creatinine clearance greater than or equal to 30 mL/min. 8. 7 Hepatic I mpairment No studies have been performed to assess risedronate’s safety or efficacy in patients with hepatic impairment. Risedronate is not metabolized in human liver preparations. Dosage adjustment is unlikely to be needed in patients with hepatic impairment.

16 HOW SUPPLIED/STORAGE AND HANDLING ACTONEL ® is available as follows: 5 mg film-coated, oval, yellow tablets with RSN on 1 face and 5 mg on the other. NDC 0430-0471-15 bottle of 30 30 mg film-coated, oval, white tablets with RSN on 1 face and 30 mg on the other. NDC 0430-0470-15 bottle of 30 35 mg film-coated, oval, orange tablets with RSN on 1 face and 35 mg on the other. NDC 0430-0472-03 dose pack of 4 NDC 0430-0472-07 dose pack of 12 75 mg film-coated, oval, pink tablets with RSN on 1 face and 75 mg on the other. NDC 0430-0477-02 dose pack of 2 150 mg film-coated, oval, blue tablets with RSN on 1 face and 150 mg on the other. NDC 0430-0478-01 dose pack of 1 NDC 0430-0478-02 dose pack of 3 Store at controlled room temperature 20° to 25° C (68° to 77° F) [see USP].