Risedronate Sodium

Warnings and Precautions, Atypical Fractures Including Femoral Fractures ( 5.6 ) ..................................................................................... 02/2026

1 INDICATIONS AND USAGE Risedronate sodium tablets, USP are a bisphosphonate indicated for: Treatment and prevention of postmenopausal osteoporosis ( 1.1 ) Treatment to increase bone mass in men with osteoporosis ( 1.2 ) • Treatment and prevention of glucocorticoid-induced osteoporosis ( 1.3 ) • Treatment of Paget's disease ( 1.4 ) Limitations of Use Optimal duration of use has not been determined. For patients at low-risk for fracture, consider drug discontinuation after 3 to 5 years of use. ( 1.5 ) 1.1 Postmenopausal Osteoporosis Risedronate sodium tablets, USP are indicated for the treatment and prevention of osteoporosis in postmenopausal women. In postmenopausal women with osteoporosis, risedronate sodium tablets, USP reduce the incidence of vertebral fractures and a composite endpoint of nonvertebral osteoporosis-related fractures [ see Clinical Studies ( 14.1 , 14.2 ) ]. 1.2 Osteoporosis in Men Risedronate sodium tablets, USP are indicated for treatment to increase bone mass in men with osteoporosis. 1.3 Glucocorticoid-Induced Osteoporosis Risedronate sodium tablets, USP are indicated for the treatment and prevention of glucocorticoid-induced osteoporosis in men and women who are either initiating or continuing systemic glucocorticoid treatment (daily dosage of greater than or equal to 7.5 mg of prednisone or equivalent) for chronic diseases. Patients treated with glucocorticoids should receive adequate amounts of calcium and vitamin D. 1.4 Paget's Disease Risedronate sodium tablets, USP are indicated for treatment of Paget’s disease of bone in men and women. 1.5 Important Limitations of Use The optimal duration of use has not been determined. The safety and effectiveness of risedronate sodium tablets, USP for the treatment of osteoporosis are based on clinical data of three years duration. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis. Patients at low-risk for fracture should be considered for drug discontinuation after 3 to 5 years of use. Patients who discontinue therapy should have their risk for fracture re-evaluated periodically.

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 risedronate sodium tablets at least 30 minutes before the first food or drink of the day other than water, and before taking any oral medication or supplementation, including calcium, antacids, or vitamins to maximize absorption and clinical benefit, [ see Drug Interactions ( 7.1 ) ]. Avoid the use of water with supplements, including mineral water, because they may have a higher concentration of calcium. • Swallow risedronate sodium tablets whole with a full glass of plain water (6 to 8 ounces). Avoid lying down for 30 minutes after taking the medication [ see Warnings and Precautions ( 5.1 ) ]. Do not chew or suck the tablet because of a potential for oropharyngeal ulceration. • Do not eat or drink anything except plain water, or take other medications for at least 30 minutes after taking risedronate sodium tablets. 2.7 Recommendations for Calcium and Vitamin D Supplementation Instruct patients to take supplemental calcium and vitamin D if their dietary intake is inadequate; and to take calcium supplements, antacids, magnesium-based supplements or laxatives, and iron preparations at a different time of the day as they interfere with the absorption of risedronate sodium tablets. 2.8 Administration Instructions for Missed Doses Instruct patients about missing risedronate sodium tablet doses as follows: • If a dose of risedronate sodium tablet 35 mg once-a-week is missed: o Take 1 tablet on the morning after they remember and return to taking 1 tablet once-a-‐week, as originally scheduled on their chosen day. o Do not take 2 tablets on the same day. • If one or both tablets of risedronate sodium tablets 75 mg on two consecutive days per month are misse …

3 DOSAGE FORMS AND STRENGTHS 5 mg film-coated, round, yellow tablets debossed ‘5’ on one side and ‘S’ on other side. 30 mg film-coated, round, white tablets debossed ‘667’ on one side and ‘S’ on other side. 35 mg film-coated, round, brown tablets debossed ‘668’ on one side and ‘S’ on other side. 75 mg film-coated, round, pink tablets debossed ‘727’ on one side and ‘S’ on other side. 150 mg film-coated, round, blue tablets debossed ‘928’ on one side and ‘S’ on other side. Tablets: 5 mg, 30 mg, 35 mg, 75 mg, and 150 mg ( 3 )

4 CONTRAINDICATIONS Risedronate sodium tablets are contraindicated in patients with the following conditions: • Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia [ see Warnings and Precautions (5.1 ) ] • Inability to stand or sit upright for at least 30 minutes [ see Dosage and Administration (2 ) , Warnings and Precautions (5.1 ) ] • Hypocalcemia [ see Warnings and Precautions (5.2) ] • Known hypersensitivity to risedronate sodium tablets or any of its excipients.Angioedema, generalized rash, bullous skin reactions, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported [ see Adverse Reactions (6.2 ) ] • Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia ( 4 , 5.1 ) • Inability to stand or sit upright for at least 30 minutes ( 4 , 5.1 ) • Hypocalcemia ( 4 , 5.2 ) • Known hypersensitivity to any component of this product ( 4 , 6.2 )

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) ] Glucocorticoid-Induced Osteoporosis [see Warnings and Precautions (5.8) ] Laboratory Test Interactions [see Warnings and Precautions (5.9) ] Most common adverse reactions reported in greater than 10% of patients treated with risedronate 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 Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Treatment of Postmenopausal Osteoporosis Daily Dosing The safety of risedronate sodium tablets 5 mg once daily in the treatment of postmenopausal osteoporosis was assessed in four randomized, double-blind, placebo-controlled multinational trials of 3232 women aged 38 to 85 years with postmenopausal osteoporosis. The duration of the trials was up to three years, with 1619 patients exposed to placebo and 1613 patients exposed to risedronate sodium tablets 5 mg. Patients with pre-existing gastrointestinal disease and concomitant use of non­-steroidal anti-inflammatory drugs, proton pump inhibitors, and H 2 antagonists were included in these clinical trials. All women received 1000 mg of elemental calcium plus vitamin D supplementation up to 500 international units per day if their 25-hydroxyvitamin D 3 level was below normal at baseline. The incidence of all-cause mortality was 2% in the placebo group and 1.7% in the risedronate sodium tablets 5 mg daily group. The incidence of serious adverse events was 24.6% in the placebo group and 27.2% in the risedronate sodium tablets 5 mg group. The percentage of patients who withdrew from the study due to adverse events was 15.6% in the placebo group and 14.8% in the risedronate sodium tablets 5 mg group. The most common adverse reactions reported in greater than 10 percent of subjects were: back pain, arthralgia, abdominal pain and dyspepsia. Table 1 lists adverse events from the Phase 3 postmenopausal osteoporosis trials reported in greater than or equal to 5% of patients. Adverse events are shown without attribution of causality. Table 1 Adverse Events Occurring at a Frequency greater than or equal t o 5% in Either Treatment Group Combined Phase 3 Postmenopausal Osteoporosis Treatment Trials Body System Placebo N = 1619 % 5 mg Risedronate Sodium Tablets N = 1613 % Body as a Whole Infection 29.9 31.1 Back Pain 26.1 28 Accidental Injury 16.8 16.9 Pain 14 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 Allergic Reaction 5.9 3.8 Cardiovascular System Hypertension 9.8 10.5 Digestive System Constipation 12.6 12.9 Diarrhea 10 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 Myalgia 6.2 6.7 Bone Pa …

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 risedronate sodium tablets ( 7.1 ) 7.1 Calcium Supplements/Antacids Co-administration of risedronate sodium tablets and calcium, antacids, or oral medications containing divalent cations will interfere with the absorption of risedronate sodium tablets. 7.2 Hormone Replacement Therapy One study of about 500 early postmenopausal women has been conducted to date in which treatment with risedronate sodium tablets 5 mg daily plus estrogen replacement therapy was compared to estrogen replacement therapy alone. Exposure to study drugs was approximately 12 to 18 months and the primary endpoint was change in BMD. If considered appropriate, risedronate sodium tablets may be used concomitantly with hormone replacement therapy. 7.3 Aspirin/Nonsteroidal Anti-Inflammatory Drugs Of over 5700 patients enrolled in the risedronate sodium tablets Phase 3 osteoporosis studies, aspirin use was reported by 31% of patients, 24% of whom were regular users (3 or more days per week). Forty-eight percent of patients reported NSAID use, 21% of whom were regular users. Among regular aspirin or NSAID users, the incidence of upper gastrointestinal adverse experiences in placebo-treated patients (24.8%) was similar to that in risedronate sodium tablets-treated patients (24.5%). 7.4 H 2 Blockers and Proton Pump Inhibitors (PPIs) Of over 5700 patients enrolled in the risedronate sodium tablets Phase 3 osteoporosis studies, 21% used H 2 blockers and/or PPIs. Among these patients, the incidence of upper gastrointestinal adverse experiences in the placebo-treated patients was similar to that in risedronate sodium tablets-treated patients.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Discontinue when pregnancy is recognized ( 8.1 ) Risedronate sodium tablets are not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/min) ( 5.6 , 8.6 , 12.3 ) Risedronate sodium tablets are not indicated for use in pediatric patients ( 8.4 ) 8.1 Pregnancy Risk Summary Available data on the use of risedronate sodium tablets in pregnant women are insufficient to inform a drug-associated risk of adverse maternal or fetal outcomes. Discontinue risedronate sodium tablets 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 to 4% and 15 to 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 mi …

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

11 DESCRIPTION Risedronate Sodium tablets is a pyridinyl bisphosphonate that inhibits osteoclast-mediated bone resorption and modulates bone metabolism. Each Risedronate Sodium 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. The chemical structure of Risedronate Sodium hemi-pentahydrate is a pyridinyl bisphosphonate that inhibits osteoclast-mediated bone resorption and modulates bone metabolism. Each Risedronate Sodium 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.

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 risedronate sodium tablets 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 ).

16 HOW SUPPLIED/STORAGE AND HANDLING Risedronate sodium tablets, USP are available as follows: 5 mg film-coated, round, yellow tablets debossed ‘5’ on one side and ‘S’ on other side. Bottles of 30 with Child-resistant cap, NDC 47335-666-83 Bottles of 100 with Child-resistant cap, NDC 47335-666-88 Bottles of 100, NDC 47335-666-08 Bottles of 1000, NDC 47335-666-18 30 mg film-coated, round, white tablets debossed ‘667’ on one side and ‘S’ on other side. Bottles of 30 with Child-resistant cap, NDC 47335-667-83 Bottles of 100 with Child-resistant cap, NDC 47335-667-88 Bottles of 100, NDC 47335-667-08 Bottles of 1000, NDC 47335-667-18 35 mg film-coated, round, brown tablets debossed ‘668’ on one side and ‘S’ on other side. Unit-dose blister package of 4............................. NDC 47335-668-68 Unit-dose blister package of 12........................... NDC 47335-668-62 75 mg film-coated, round, pink tablets debossed ‘727’ on one side and ‘S’ on other side. Unit-dose blister package of 2............................. NDC 47335-727-98 150 mg film-coated, round, blue tablets debossed ‘928’ on one side and ‘S’ on other side. Unit-dose blister package of 1............................. NDC 47335-928-60 Unit-dose blister package of 3............................. NDC 47335-928-67 Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature]. Dispense in well-closed containers as defined in USP.