Risedronate Sodium

Risedronate Sodium 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 Risedronate Sodium is indicated for the treatment and prevention of osteoporosis in postmenopausal women. In postmenopausal women with osteoporosis, Risedronate Sodium 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 Risedronate Sodium is indicated for treatment to increase bone mass in men with osteoporosis.

1.3 Glucocorticoid-Induced Osteoporosis Risedronate Sodium 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 Risedronate Sodium 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 Risedronate Sodium 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 ( 3 )

Risedronate Sodium 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 Risedronate Sodium 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 , 5.3 ) Known hypersensitivity to any component of this product ( 4 , 6.2 )

Products Containing Same Active Ingredient : Patients receiving Atelvia should not be treated with Risedronate Sodium ( 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 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 contains the same active ingredient found in Atelvia. A patient being treated with Atelvia should not receive Risedronate Sodium.

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 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 ( 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. Treat hypocalcemia and other disturbances of bone and mineral metabolism 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, especially in patients with Paget’s disease in whom bone turnover is significantly elevated [ 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 Sodium. 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 ( 6.2 ) ].

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 Adverse Reactions ( 6.2 ) ]. 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 Impairment Risedronate Sodium 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 Risedronate Sodium 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 Risedronate Sodium have not been performed.

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 Sodium 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 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 Daily Dosing The safety of Risedronate Sodium 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 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 Risedronate Sodium 5 mg daily group. The incidence of serious adverse events was 24.6% in the placebo group and 27.2% in the Risedronate Sodium 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 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 Risedronate Sodium 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 Risedronate Sodium 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 Risedronate Sodium 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 Risedronate Sodium 5 mg daily groups. Musculoskeletal Adverse Events : The incidence of adverse events in the placebo and Risedronate Sodium 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 Risedronate Sodium 5 mg once daily. There were no significant differences in serum calcium, phosphate, or PTH levels between placebo and Risedronate Sodium 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 Risedronate Sodium 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 Risedronate Sodium 5 mg once daily. There have been rare reports (less than 0.1%) of abnormal liver function tests. Endoscopic Findings : In the Risedronate Sodium 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%) Risedronate Sodium]. Clinically important findings (perforations, ulcers, or bleeding) among this symptomatic population were similar between groups (51% placebo; 39% Risedronate Sodium). Once-a-Week Dosing The safety of Risedronate Sodium 35 mg once-a-week in the treatment of postmenopausal osteoporosis was assessed in a 1-year, double-blind, multicenter study comparing Risedronate Sodium 5 mg daily and Risedronate Sodium 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 Risedronate Sodium 5 mg daily and 485 exposed to Risedronate Sodium 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 Risedronate Sodium 5 mg daily group and 1.0% in the Risedronate Sodium 35 mg once-a-week group. The incidence of serious adverse events was 7.1% in the Risedronate Sodium 5 mg daily group and 8.2% in the Risedronate Sodium 35 mg once-a-week group. The percentage of patients who withdrew from the study due to adverse events was 11.9% in the Risedronate Sodium 5 mg daily group and 11.5% in the Risedronate Sodium 35 mg once-a-week group. The overall safety and tolerability profiles of the two dosing regimens were similar. […]

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 ( 7.1 )

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

7.2 Hormone Replacement Therapy One study of about 500 early postmenopausal women has been conducted to date in which treatment with Risedronate Sodium 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 may be used concomitantly with hormone replacement therapy.

7.3 Aspirin/Nonsteroidal Anti-Inflammatory Drugs Of over 5700 patients enrolled in the Risedronate Sodium 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-treated patients (24.5%). 7.4 H 2 Blockers and Proton Pump Inhibitors (PPIs) Of over 5700 patients enrolled in the Risedronate Sodium 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-treated patients.

Pregnancy: Discontinue when pregnancy is recognized ( 8.1 ) Risedronate Sodium is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/min) ( 5.7 , 8.6 , 12.3 ) Risedronate Sodium is not indicated for use in pediatric patients ( 8.4 )

8.1 Pregnancy Risk Summary Available data on the use of Risedronate Sodium in pregnant women are insufficient to inform a drug-associated risk of adverse maternal or fetal outcomes. Discontinue Risedronate Sodium 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 breastfeeding should be considered along with the mother’s clinical need for Risedronate Sodium and any potential adverse effects on the breast-fed child from Risedronate Sodium 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 Risedronate Sodium 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 Risedronate Sodium-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 Risedronate Sodium in postmenopausal osteoporosis studies [ see Clinical Studies ( 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 Risedronate Sodium were between 65 and 75 years of age and 9% were over 75. The lumbar spine BMD response for Risedronate Sodium 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 Risedronate Sodium trials, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Renal Impairment Risedronate Sodium 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 Impairment 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.

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