Risedronate Sodium

1 INDICATIONS AND USAGE Risedronate sodium is a 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 is 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 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.

2 DOSAGE AND ADMINISTRATION One 35 mg delayed-release tablet once-a-week ( 2.1 ) Instruct patients to: Take Risedronate sodium delayed-release 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 ( 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 2. 2 Important Administration Instructions Instruct patients to do the following: Take Risedronate sodium delayed-release in the morning immediately following breakfast. Risedronate sodium delayed-release 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 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. 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.

5 WARNINGS AND PRECAUTIONS Products Containing Same Active Ingredient : Patients receiving Risedronate sodium immediate-release should not be treated with Risedronate sodium delayed-release ( 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 J aw has been reported ( 5.4 ) Severe B one, J oint, M uscle P ain may occur. Discontinue use if severe symptoms develop ( 5.5 , 6.2 ) Atypical Fractures Including Fem oral Fractures have been reported. Patients with new thigh or groin pain should be evaluated to rule out a femoral fracture. Risk/benefit of continuing bisphosphonate therapy should be re-evaluated in these patients and interruption of bisphosphonate therapy should be considered ( 5.6 ) 5.1 Drug Products with the Same Active Ingredient Risedronate sodium delayed-release contains the same active ingredient found in Risedronate sodium immediate-release. A patient being treated with Risedronate sodium immediate-release should not receive Risedronate sodium delayed-release. 5. 2 Upper Gastrointestinal Adverse Reactions Risedronate sodium delayed-release, 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 delayed-release 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 delayed-release 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 delayed-release 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. Treat hypocalcemia and other disturbances of bone and mineral metabolism should be effectively treated before starting Risedronate sodium delayed-release 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 J aw Osteonecrosis Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healin…

4 CONTRAINDICATIONS Risedronate sodium delayed-release 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 (5.2) ] Inability to stand or sit upright for at least 30 minutes [ see Dosage and Administration (2) , Warnings and Precautions (5.2) ] Hypocalcemia [ see Warnings and Precautions (5.3) ] 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 )

7 DRUG INTERACTIONS Risedronate is not metabolized and does not induce or inhibit hepatic microsomal drug-metabolizing enzymes (for example, Cytochrome P450). Calcium supplements, antacids, proton pump inhibitors (PPIs), H 2 blockers, magnesium-based supplements or laxatives, and iron preparations interfere with the absorption of Risedronate sodium delayed-release ( 7.1 , 7.2 ) 7.1 Calcium Supplements/Antacids When Risedronate sodium delayed-release was administered following breakfast, the co-administration of a tablet containing 600 mg of elemental calcium and 400 international units vitamin D reduced risedronate bioavailability by approximately 38% [ see Clinical Pharmacology (12.3) ] . Calcium supplements, antacids, magnesium-based supplements or laxatives, and iron preparations interfere with the absorption of Risedronate sodium delayed-release and should not be taken together. 7.2 Histamine 2 (H 2 ) Blockers and Proton Pump Inhibitors (PPIs) Drugs that raise stomach pH (for example, PPIs or H 2 blockers) may cause faster drug release from enteric coated (delayed-release) drug products such as Risedronate sodium delayed-release. Co-administration of Risedronate sodium delayed-release with the PPI, esomeprazole, increased risedronate bioavailability. The maximum plasma concentration (C max ) and the area under the plasma concentration (AUC) were increased by 60 percent and 22 percent, respectively. Concomitant administration of Risedronate sodium delayed-release and H 2 blockers or PPIs is not recommended. 7. 3 Hormone Therapy Concomitant use of Risedronate sodium delayed-release with estrogens and estrogen agonist/antagonists has not been studied. 7. 4 Aspirin/Nonsteroidal Anti-Inflammatory Drugs In the Phase 3 study comparing Risedronate sodium delayed-release 35 mg once-a-week immediately following breakfast and risedronate sodium 5 mg daily, 18% of NSAID users (any use) in both groups developed upper gastrointestinal adverse reactions. Among non-users, 13% of patients taking Risedronate sodium delayed-release 35 mg once-a-week immediately following breakfast developed upper gastrointestinal adverse reactions, compared to 12% taking risedronate sodium 5 mg daily.

8.1 Pregnancy Risk Summary Available data on use of Risedronate sodium delayed-release in pregnant women are insufficient to inform drug-associated risk of adverse maternal or fetal outcomes. Discontinue Risedronate sodium delayed-release 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 ), the dose indicated for treatment of Paget’s disease. 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 weeks to years. The amount of bisphosphonate incorporated into adult bone available for release into the systemic circulation is directly related to the dose and duration of bisphosphonate use. Consequently, based on 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 d ata In animal studies, pregnant rats received risedronate sodium during organogenesis at doses 1 to 26 times the human Paget’s disease dose of 30 mg/day (based on body surface area, mg/m 2 ). Survival of neonates was decreased in rats treated during gestation with oral doses approximately 5 times the human dose and body weight was decreased in neonates from dams treated with approximately 26 times the human dose. A low incidence of cleft palate was observed in fetuses from female rats 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.

6 ADVERSE REACTIONS The following clinically significant adverse drug reactions are described elsewhere in the labeling: Drug Products with the Same Active Ingredient [see Warnings and Precautions (5.1) ] Upper Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.2) ] Mineral Metabolism [see Warnings and Precautions (5.3) ] Jaw Osteonecrosis [ see Warnings and Precautions (5.4) ] Musculoskeletal Pain [see Warnings and Precautions (5.5) ] Atypical Fractures Including Femoral Fractures [see Warnings and Precautions (5.6) ] Renal Impairment [see Warnings and Precautions (5.7) ] Laboratory Test Interactions [see Warnings and Precautions (5.8) ] 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 Viatris at 1-877-446-3679 (1-877-4-INFO-RX) 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 delayed-release 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 35 mg Risedronate sodium d elayed -release 5 mg Risedronate sodium I mmediate - release Weekly Daily System Organ Class N = 307 N = 307 Preferred Term % % Gastrointestinal disorders Diarrhea 8.8 4.9 Abdominal pain 5.2 2.9 Constipation 4.9 …