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:

ACTONEL is a bisphosphonate indicated for: Treatment and prevention of postmenopausal osteoporosis Treatment to increase bone mass in men with osteoporosis Treatment and prevention of glucocorticoid-induced osteoporosis Treatment of Paget’s disease 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

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 ) ]

Osteoporosis in Men ACTONEL is indicated for treatment to increase bone mass in men with osteoporosis

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

Paget’s Disease ACTONEL is indicated for treatment of Paget’s disease of bone in men and women

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.

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

Treatment of Postmenopausal Osteoporosis: 5 mg daily, 35 mg once-a-week, 75 mg two consecutive days each month, 150 mg once-a-month Prevention of Postmenopausal Osteoporosis: 5 mg daily, 35 mg once-a-week Men with Osteoporosis: 35 mg once-a-week Glucocorticoid-Induced Osteoporosis: 5 mg daily Paget’s Disease: 30 mg daily for 2 months 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 Take supplemental calcium and vitamin D if dietary intake is inadequate 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 ] 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 ] 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 ] The recommended regimen is: one 5 mg tablet orally, taken daily 2.5 Treatment of Paget’s Disease [ see Indications and Usage ] 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

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 ] . 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 ] . 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

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.

Products Containing Same Active Ingredient : Patients receiving Atelvia should not be treated with ACTONEL Upper Gastrointestinal Adverse Reactions can occur. Instruct patients to follow dosing instructions. Discontinue use if new or worsening symptoms occur Hypocalcemia may worsen and must be corrected prior to use Osteonecrosis of the J aw has been reported S evere B one, J oint , M uscle P ain may occur. Discontinue use if severe symptoms develop Atypical Fractures Including Femoral F ractures have been reported. Patients with new thigh or groin pain should be evaluated to rule out a femoral fracture. Risk/benefit of continuing bisphosphonate therapy should be re-evaluated in these patients and interruption of bisphosphonate therapy should be considered 5.1 Drug Products with the Same Active Ingredient ACTONEL contains the same active ingredient found in Atelvia ® . A patient being treated with Atelvia should not receive ACTONEL. 5. 2 Upper Gastrointestinal Adverse Reactions ACTONEL, like other bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when ACTONEL is given to patients with active upper gastrointestinal problems (such as known Barrett’s esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis or ulcers) [ see Contraindications, Adverse Reactions , Information for Patients ( 17 ) ] . Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates. In some cases, these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue ACTONEL and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn. The risk of severe esophageal adverse experiences appears to be greater in patients who lie down after taking oral bisphosphonates and/or who fail to swallow it with the recommended full glass (6 to 8 ounces) of water, and/or who continue to take oral bisphosphonates after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient [ see Dosage and Administration ] . In patients who cannot comply with dosing instructions due to mental disability, therapy with ACTONEL should be used under appropriate supervision. There have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications, although no increased risk was observed in controlled clinical trials. 5. 3 Mineral Metabolism Hypocalcemia has been reported in patients taking ACTONEL. Treat hypocalcemia and other disturbances of bone and mineral metabolism before starting ACTONEL therapy. Instruct patients to take supplemental calcium and vitamin D if their dietary intake is inadequate. Adequate intake of calcium and vitamin D is important in all patients, especially in patients with Paget’s disease in whom bone turnover is significantly elevated [ see Contraindications , Adverse Reactions, Information for Patients ( 17 ) ] . 5. 4 J aw Osteonecrosis Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients taking bisphosphonates, including ACTONEL. Known risk factors for osteonecrosis of the jaw include invasive dental procedures (for example, tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (for example, chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and co-morbid disorders (for example, periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). The risk of ONJ may increase with duration of exposure to bisphosphonates. For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk for ONJ. Clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit/risk assessment. Patients who develop osteonecrosis of the jaw while on bisphosphonate therapy should receive care by an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of bisphosphonate therapy should be considered based on individual benefit/risk assessment [ see Adverse Reactions ] . 5. 5 Musculoskeletal Pain In postmarketing experience, there have been reports of severe and occasionally incapacitating bone, joint, and/or muscle pain in patients taking bisphosphonates [ see A dverse R eactions ] . The time to onset of symptoms varied from one day to several months after starting the drug. Most patients had relief of symptoms after stopping medication. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. Consider discontinuing use if severe symptoms develop. 5. 6 Atypical Fractures Including Femoral Fractures Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported during treatment with bisphosphonates, including risedronate, in patients with osteoporosis. Atypical femur and other fractures most commonly occur with minimal or no trauma to the affected area. These fractures occurred anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are traverse or short oblique in orientation without evidence of comminution. Atypical fractures of other bones have also been reported. They may be bilateral. These fractures can also occur in osteoporotic patients who have not been treated with bisphosphonates. Concomitant treatment with glucocorticoids may also induce these fractures. Prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs was reported by patients. Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Bony pain in other locations should also be considered for evaluation of atypical fracture. Patients presenting with an atypical fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Risk/benefit of continuing bisphosphonate therapy should be re-evaluated in these patients and interruption of bisphosphonate therapy should be considered. 5. 7 Renal I mpairment ACTONEL is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/min). 5. 8 Glucocorticoid-Induced Osteoporosis Before initiating ACTONEL treatment for the treatment and prevention of glucocorticoid-induced osteoporosis, the sex steroid hormonal status of both men and women should be ascertained and appropriate replacement considered. 5. 9 Laboratory Test Interactions Bisphosphonates are known to interfere with the use of bone-imaging agents. Specific studies with ACTONEL have not been performed.

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 Calcium Supplements/Antacids Co-administration of ACTONEL and calcium, antacids, or oral medications containing divalent cations will interfere with the absorption of ACTONEL

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

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%)

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.