Risedronate

1 INDICATIONS AND USAGE Risedronate sodium delayed-release tablets are bisphosphonate in a delayed-release formulation and is indicated for treatment of postmenopausal osteoporosis (1.1) 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 (1.2). 1.1 Postmenopausal Osteoporosis Risedronate sodium delayed-release tablets are indicated for the treatment of osteoporosis in postmenopausal women. In postmenopausal women, risedronate sodium has been shown to reduce the incidence of vertebral fractures and a composite endpoint of nonvertebral osteoporosis-related fractures [ see Clinical Studies (14.1) ]. 1.2 Important Limitations of Use The optimal duration of use has not been determined. The safety and effectiveness of risedronate sodium delayed-release tablets for the treatment of osteoporosis are based on clinical data of one year 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.

12.1 Mechanism of Action Risedronate has an affinity for hydroxyapatite crystals in bone and acts as an antiresorptive agent. At the cellular level, risedronate 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 risedronate treatment reduces bone turnover (activation frequency, that is, the rate at which bone remodeling sites are activated) and bone resorption at remodeling sites.

2 DOSAGE AND ADMINISTRATION One 35 mg delayed-release tablet once-a-week (2.1) Instruct patients to: • Take risedronate sodium delayed-release tablets in the morning immediately following breakfast with at least 4 ounces of plain water (2.2) • Avoid lying down for 30 minutes after taking risedronate sodium delayed-release tablets (2.2) • Take supplemental calcium and vitamin D if dietary intake is inadequate (2.3) 2.1 Treatment of Postmenopausal Osteoporosis [ see Indications and Usage (1.1) ] The recommended regimen is: • one 35 mg delayed-release tablet orally, taken once-a-week [see Indications and Usage (1.1)] 2.2 Important Administration Instructions Instruct patients to do the following: • Take risedronate sodium delayed-release tablets in the morning immediately following breakfast. Risedronate sodium delayed-release tablets should be taken immediately following breakfast and not under fasting conditions because of a higher risk of abdominal pain if taken before breakfast when fasting. • Swallow risedronate sodium delayed-release tablets whole while in an upright position and with at least 4 ounces of plain water to facilitate delivery to the stomach. Avoid lying down for 30 minutes after taking the medication [ see Warnings and Precautions (5.2) ]. • Do not chew, cut, or crush risedronate sodium delayed-release tablets. 2.3 Recommendations for Calcium and Vitamin D Supplementation Instruct patients to take supplemental calcium and vitamin D if dietary intake is inadequate [ see Warnings and Precautions (5.3) ] and to take calcium supplements, antacids, magnesium-based supplements or laxatives, and iron preparations at a different time of the day as they interfere with the absorption of risedronate sodium delayed-release tablets. 2.4 Administration Instructions for Missed Doses If the once-weekly dose is missed, instruct patients to take one tablet on the morning after they remember and return to taking one tablet once-a-week, as originally scheduled on their chosen day. Patients should not take two tablets on the same day.

6 ADVERSE REACTIONS Most common adverse reactions (greater than 5%) include: diarrhea, influenza, arthralgia, back pain, and abdominal pain (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 Sun Pharmaceutical Industries Inc. at 1-800-818-4555 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 Once-a-Week Dosing with Risedronate Sodium Delayed-Release tablets The safety of risedronate sodium delayed-release 35 mg once-a-week in the treatment of postmenopausal osteoporosis was assessed in a 1-year, double-blind, multicenter study comparing risedronate sodium delayed-release 35 mg once-a-week to risedronate sodium immediate-release 5 mg daily in postmenopausal women 50 years of age or older. Risedronate sodium delayed-release was administered either at least 30 minutes before (N = 308) or immediately following (N = 307) breakfast, and risedronate sodium immediate-release 5 mg daily (N = 307) was administered at least 30 minutes before breakfast. 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 daily supplementation with 1000 mg of elemental calcium plus 800 to 1000 international units vitamin D. As treatment with risedronate sodium resulted in a significantly higher incidence of abdominal pain when administered before breakfast under fasting conditions, safety results that follow refer only to risedronate sodium delayed-release 35 mg once-a-week immediately following breakfast and risedronate sodium immediate-release 5 mg daily. The incidence of all-cause mortality was 0.0% in the risedronate sodium delayed-release 35 mg once-a-week group and 0.3% in the risedronate sodium immediate-release 5 mg daily group. The incidence of serious adverse reactions was 6.5% in the risedronate sodium delayed-release 35 mg once-a-week group and 7.2% in the risedronate sodium immediate-release 5 mg daily group. The percentage of patients who withdrew from the study due to adverse reactions was 9.1% in the risedronate sodium delayed-release 35 mg once-a-week group and 8.1% in the risedronate sodium immediate-release 5 mg daily group. The overall safety and tolerability profiles of the two dosing regimens were similar. Table 1 lists adverse reactions reported in greater than or equal to 2% of patients. Adverse reactions are shown without attribution of causality. Table 1 Adverse Reactions Occurring at a Frequency of greater than or equal to 2% in Either Treatment Group System Organ Class Preferred Term 35 mg Risedronate sodium Delayed-release Weekly N = 307% 5 mg Risedronate sodium Immediate-release Daily N = 307% Gastrointestinal disorders Diarrhea 8.8 4.9 Abdominal pain 5.2 2.9 Constipation 4.9 2.9 Vomiting 4.9 1.6 Dyspepsia 3.9 3.9 Nausea 3.6 3.9 Abdominal pain upper 2.9 2.3 Infections and infestations Influenza 7.2 6.2 Bronchitis 3.9 4.2 Upper respiratory tract infection 3.6 2.6 Musculoskeletal and connective tissue disorders Arthralgia 6.8 7.8 Back pain 6.8 5.9 Pain in extremity 3.9 2.3 Musculoskeletal pain 2.0 1.6 Muscle spasms 1.0 2.3 Nervous system disorders Dizziness 2.6 3.3 Headache 2.6 4.9 Acute Phase Reactions: Symptoms consistent with acute phase reaction have been reported with bisphosphonate use. The overall incidence of acute phase reaction was 2.3% in the risedronate sodium delayed-release 35 mg once-a-week group and 1.3% in the

5 WARNINGS AND PRECAUTIONS • Products Containing Same Active Ingredient : Patients receiving Actonel should not be treated with risedronate sodium delayed-release tablets (5.1) • Upper Gastrointestinal Adverse Reactions can occur. Instruct patients to follow dosing instructions. Discontinue use if new or worsening symptoms occur (5.2) • Hypocalcemia may worsen and must be corrected prior to use (5.3) • Osteonecrosis of the Jaw has been reported (5.4) • Severe Bone, Joint, Muscle Pain may occur. Discontinue use if severe symptoms develop (5.5, 6.2) • Atypical Femur Fractures have been reported. Patients with new thigh or groin pain should be evaluated to rule out a femoral fracture (5.6) 5.1 Drug Products with the Same Active Ingredient Risedronate sodium delayed-release tablets contain the same active ingredient found in Actonel ® . A patient being treated with Actonel should not receive risedronate sodium delayed-release tablets. 5.2 Upper Gastrointestinal Adverse Reactions Risedronate sodium, like other bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when risedronate sodium is given to patients with active upper gastrointestinal problems (such as known Barrett’s esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis or ulcers) [ see Contraindications (4), Adverse Reactions (6.1), Information for Patients (17) ]. Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates. In some cases, these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue risedronate sodium 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 4 ounces of water, and/or who continue to take oral bisphosphonates after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient [ see Dosage and Administration (2) ]. In patients who cannot comply with dosing instructions due to mental disability, therapy with risedronate sodium should be used under appropriate supervision. There have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications, although no increased risk was observed in controlled clinical trials. 5.3 Mineral Metabolism Hypocalcemia has been reported in patients taking risedronate sodium delayed-release tablets. Treat hypocalcemia and other disturbances of bone and mineral metabolism should be effectively treated before starting risedronate sodium 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 [ see Contraindications (4), Adverse Reactions (6.1), Information for Patients (17) ]. 5.4 Jaw Osteonecrosis Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients taking bisphosphonates, including risedronate. Known risk factors for osteonecrosis of the jaw include invasive dental procedures (for example, tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (for example, chemotherapy, corticosteroids, angiogene

4 CONTRAINDICATIONS Risedronate sodium delayed-release tablets contraindicated in patients with the following conditions: 1. Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia [ see Warnings and Precautions (5.2) ] 2. Inability to stand or sit upright for at least 30 minutes [ see Dosage and Administration (2), Warnings and Precautions (5.2) ] 3. Hypocalcemia [ see Warnings and Precautions (5.3) ] 4. Known hypersensitivity to any component of this product. 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, 5.2) • Inability to stand or sit upright for at least 30 minutes (4, 5.2) • Hypocalcemia (4, 5.3) • Known hypersensitivity to any component of this product (4, 6.2)

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. While milk or antacids containing calcium may be given to bind risedronate sodium immediate-release and reduce absorption of the drug, the impact of this intervention for risedronate sodium delayed-release tablets has not been evaluated. 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 of risedronate 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 human Paget’s disease dose of 30 mg/day based on surface area (mg/m 2 ).