Risedronate Sodium
Generic: RISEDRONATE SODIUM
Basic Information
Manufacturer
Aurobindo Pharma Limited
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
ORAL
FDA Set ID
89896dfe-f69d-4cb3-bb71-7a7c611071fa
Indications & Usage
1 INDICATIONS AND USAGE Risedronate sodium tablets 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 are indicated for the treatment and prevention of osteoporosis in postmenopausal women.
In postmenopausal women with osteoporosis, risedronate sodium tablets 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 are indicated for treatment to increase bone mass in men with osteoporosis.
1.3 Glucocorticoid-Induced Osteoporosis Risedronate sodium tablets 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 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 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.
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 are indicated for the treatment and prevention of osteoporosis in postmenopausal women.
In postmenopausal women with osteoporosis, risedronate sodium tablets 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 are indicated for treatment to increase bone mass in men with osteoporosis.
1.3 Glucocorticoid-Induced Osteoporosis Risedronate sodium tablets 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 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 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.
Adverse Reactions
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 Pain 4.8 5.3 Nervous System Dizziness 5.7 7.1 Depression 6.1 6.8 Insomnia 4.6 5 Respiratory System Bronchitis 10.4 10 Sinusitis 9.1 8.7 Rhinitis 5.1 6.2 Pharyngitis 5 6 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 tablets 5 mg daily groups were: abdominal pain (9.9% versus 12.2%), diarrhea (10% 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 tablets 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 tablets 5 mg daily groups.
Musculoskeletal Adverse Events: The incidence of adverse events in the placebo and risedronate sodium tablets 5 mg daily groups were: back pain (26.1% versus 28%), 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 tablets 5 mg once daily.
There were no significant differences in serum calcium, phosphate, or PTH levels between placebo and risedronate sodium tablets 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 tablets 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 tablets 5 mg once daily.
There have been rare reports (less than 0.1%) of abnormal liver function tests.
Endoscopic Findings: In the risedronate 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].
Clinically important findings (perforations, ulcers, or bleeding) among this symptomatic population were similar between groups (51% placebo; 39% risedronate).
Once-a-Week Dosing The safety of risedronate sodium tablets 35 mg once-a-week in the treatment of postmenopausal osteoporosis was assessed in a 1-year, double-blind, multicenter study comparing risedronate sodium tablets 5 mg daily and risedronate sodium tablets 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 tablets 5 mg daily and 485 exposed to risedronate sodium tablets 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 tablets 5 mg daily group and 1% in the risedronate sodium tablets 35 mg once-a-week group.
The incidence of serious adverse events was 7.1% in the risedronate sodium tablets 5 mg daily group and 8.2% in the risedronate sodium tablets 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 tablets 5 mg daily group and 11.5% in the risedronate sodium tablets 35 mg once-a-week group.
The overall safety and tolerability profiles of the two dosing regimens were similar.
Gastrointestinal Adverse Events: The incidence of gastrointestinal adverse events was similar between the risedronate sodium tablets 5 mg daily group and the risedronate sodium tablets 35 mg once-a-week group: dyspepsia (6.9% versus 7.6%), diarrhea (6.3% versus 4.9%), and abdominal pain (7.3% versus 7.6%).
Musculoskeletal Adverse Events: Arthralgia was reported in 11.5% of patients in the risedronate sodium tablets 5 mg daily group and 14.2% of patients in the risedronate sodium tablets 35 mg once-a-week group.
Myalgia was reported by 4.6% of patients in the risedronate sodium tablets 5 mg daily group and 6.2% of patients in the risedronate sodium tablets 35 mg once-a-week group.
Laboratory Test Findings: The mean percent changes from baseline at 12 months were similar between the risedronate sodium tablets 5 mg daily and risedronate sodium tablets 35 mg once-a-week groups, respectively, for serum calcium (0.4% versus 0.7%), phosphate (-3.8% versus -2.6%) and PTH (6.4% versus 4.2%).
Monthly Dosing Two Consecutive Days per Month The safety of risedronate sodium tablets 75 mg administered on two consecutive days per month for the treatment of postmenopausal osteoporosis was assessed in a double-blind, multicenter study in postmenopausal women aged 50 to 86 years.
The duration of the trial was two years; 613 patients were exposed to risedronate sodium tablets 5 mg daily and 616 were exposed to risedronate sodium tablets 75 mg two consecutive days per month.
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 1000 mg of elemental calcium plus 400 to 800 international units of vitamin D supplementation per day.
The incidence of all-cause mortality was 1% for the risedronate sodium tablets 5 mg daily group and 0.5% for the risedronate sodium tablets 75 mg two consecutive days per month group.
The incidence of serious adverse events was 10.8% in the risedronate sodium tablets 5 mg daily group and 14.4% in the risedronate sodium tablets 75 mg two consecutive days per month group.
The percentage of patients who withdrew from treatment due to adverse events was 14.2% in the risedronate sodium tablets 5 mg daily group and 13% in the risedronate sodium tablets 75 mg two consecutive days per month group.
The overall safety and tolerability profiles of the two dosing regimens were similar.
Acute Phase Reactions: Symptoms consistent with acute phase reaction have been reported with bisphosphonate use.
The overall incidence of acute phase reaction was 3.6% of patients on risedronate sodium tablets 5 mg daily and 7.6% of patients on risedronate sodium tablets 75 mg two consecutive days per month.
These incidence rates are based on reporting of any of 33 acute phase reaction-like symptoms within 5 days of the first dose.
Fever or influenza-like illness with onset within the same period were reported by 0% of patients on risedronate sodium tablets 5 mg daily and 0.6% of patients on risedronate sodium tablets 75 mg two consecutive days per month.
Gastrointestinal Adverse Events: The risedronate sodium tablets 75 mg two consecutive days per month group resulted in a higher incidence of discontinuation due to vomiting (1% versus 0.2%) and diarrhea (1% versus 0.3%) compared to the risedronate sodium tablets 5 mg daily group.
Most of these events occurred within a few days of dosing.
Ocular Adverse Events: None of the patients treated with risedronate sodium tablets 75 mg two consecutive days per month reported ocular inflammation such as uveitis, scleritis, or iritis; 1 patient treated with risedronate sodium tablets 5 mg daily reported uveitis.
Laboratory Test Findings: When risedronate sodium tablets 5 mg daily and risedronate sodium tablets 75 mg two consecutive days per month were compared in postmenopausal women with osteoporosis, the mean percent changes from baseline at 24 months were 0.2% and 0.8% for serum calcium, -1.9% and -1.3% for phosphate, and -10.4% and -17.2% for PTH, respectively.
Compared to the risedronate sodium tablets 5 mg daily group, risedronate sodium tablets 75 mg two consecutive days per month resulted in a slightly higher incidence of hypocalcemia at the end of the first month of treatment (4.5% versus 3%).
Thereafter, the incidence of hypocalcemia with these regimens was similar at approximately 2%.
Prevention of Postmenopausal Osteoporosis Daily Dosing The safety of risedronate sodium tablets 5 mg daily in the prevention of postmenopausal osteoporosis was assessed in two randomized, double-blind, placebo-controlled trials.
In one study of postmenopausal women aged 37 to 82 years without osteoporosis, the use of estrogen replacement therapy in both placebo- and risedronate-treated patients was included.
The duration of the trial was one year, with 259 exposed to placebo and 261 patients exposed to risedronate sodium tablets 5 mg.
The second study included postmenopausal women aged 44 to 63 years without osteoporosis.
The duration of the trial was one year, with 125 exposed to placebo and 129 patients exposed to risedronate sodium tablets 5 mg.
All women received 1000 mg of elemental calcium per day.
In the trial with estrogen replacement therapy, the incidence of all-cause mortality was 1.5% for the placebo group and 0.4% for the risedronate sodium tablets 5 mg group.
The incidence of serious adverse events was 8.9% in the placebo group and 5.4% in the risedronate sodium tablets 5 mg group.
The percentage of patients who withdrew from treatment due to adverse events was 18.9% in the placebo group and 10.3% in the risedronate sodium tablets 5 mg group.
Constipation was reported by 1.9% of the placebo group and 6.5% of risedronate sodium tablets 5 mg group.
In the second trial, the incidence of all-cause mortality was 0% for both groups.
The incidence of serious adverse events was 17.6% in the placebo group and 9.3% in the risedronate sodium tablets 5 mg group.
The percentage of patients who withdrew from treatment due to adverse events was 6.4% in the placebo group and 5.4% in the risedronate sodium tablets 5 mg group.
Nausea was reported by 6.4% of patients in the placebo group and 13.2% of patients in the risedronate sodium tablets 5 mg group.
Once-a-Week Dosing There were no deaths in a 1-year, double-blind, placebo-controlled study of risedronate sodium tablets 35 mg once-a-week for prevention of bone loss in 278 postmenopausal women without osteoporosis.
More treated subjects on risedronate reported arthralgia (placebo 7.8%; risedronate 13.9%), myalgia (placebo 2.1%; risedronate 5.1%), and nausea (placebo 4.3%; risedronate 7.3%) than subjects on placebo.
Treatment to Increase Bone Mass in Men with Osteoporosis In a 2-year, double-blind, multicenter study, 284 men with osteoporosis were treated with placebo (N = 93) or risedronate sodium tablets 35 mg once-a-week (N = 191).
The overall safety and tolerability profile of risedronate in men with osteoporosis was similar to the adverse events reported in the risedronate postmenopausal osteoporosis clinical trials, with the addition of benign prostatic hyperplasia (placebo 3%; risedronate sodium tablets 35 mg 5%), nephrolithiasis (placebo 0%; risedronate sodium tablets 35 mg 3%), and arrhythmia (placebo 0%; risedronate sodium tablets 35 mg 2%).
Treatment and Prevention of Glucocorticoid-Induced Osteoporosis The safety of risedronate sodium tablets 5 mg daily in the treatment and prevention of glucocorticoid-induced osteoporosis was assessed in two randomized, double-blind, placebo-controlled multinational trials of 344 patients [male (123) and female (221)] aged 18 to 85 years who had recently initiated oral glucocorticoid therapy (less than or equal to 3 months, prevention study) or were on long-term oral glucocorticoid therapy (greater than or equal to 6 months, treatment study).
The duration of the trials was one year, with 170 patients exposed to placebo and 174 patients exposed to risedronate sodium tablets 5 mg daily.
Patients in one study received 1000 mg elemental calcium plus 400 international units of vitamin D supplementation per day; patients in the other study received 500 mg calcium supplementation per day.
The incidence of all-cause mortality was 2.9% in the placebo group and 1.1% in the risedronate sodium tablets 5 mg daily group.
The incidence of serious adverse events was 33.5% in the placebo group and 30.5% in the risedronate sodium tablets 5 mg daily group.
The percentage of patients who withdrew from the study due to adverse events was 8.8% in the placebo group and 7.5% in the risedronate sodium tablets 5 mg daily group.
Back pain was reported in 8.8% of patients in the placebo group and 17.8% of patients in the risedronate sodium tablets 5 mg daily group.
Arthralgia was reported in 14.7% of patients in the placebo group and 24.7% of patients in the risedronate sodium tablets 5 mg daily group.
Treatment of Paget’s Disease Risedronate has been studied in 392 patients with Paget’s disease of bone.
As in trials of risedronate for other indications, the adverse experiences reported in the Paget’s disease trials have generally been mild or moderate, have not required discontinuation of treatment, and have not appeared to be related to patient age, gender, or race.
The safety of risedronate was assessed in a randomized, double-blind, active-controlled study of 122 patients aged 34 to 85 years.
The duration of the trial was 540 days, with 61 patients exposed to risedronate and 61 patients exposed to Didronel ® .
The adverse event profile was similar for risedronate and Didronel: 6.6% (4/61) of patients treated with risedronate sodium tablets 30 mg daily for 2 months discontinued treatment due to adverse events, compared to 8.2% (5/61) of patients treated with Didronel 400 mg daily for 6 months.
Table 2 lists adverse events reported in greater than or equal to 5% of risedronate-treated patients in Phase 3 Paget's disease trials.
Adverse events shown are considered to be possibly or probably causally related in at least one patient.
Table 2 Adverse Events Reported in greater than or equal to 5% of Risedronate-Treated Patients* in Phase 3 Paget's Disease Trials Body System 30 mg/day x 2 months Risedronate % (N = 61) 400 mg/day x 6 months Didronel % (N = 61) Body as a Whole Flu Syndrome 9.8 1.6 Chest Pain 6.6 3.3 Gastrointestinal Diarrhea 19.7 14.8 Abdominal Pain 11.5 8.2 Nausea 9.8 9.8 Constipation 6.6 8.2 Metabolic and Nutritional Disorders Peripheral Edema 8.2 6.6 Musculoskeletal Arthralgia 32.8 29.5 Nervous Headache 18 16.4 Dizziness 6.6 4.9 Skin and Appendages Rash 11.5 8.2 *Considered to be possibly or probably causally related in at least one patient.
Gastrointestinal Adverse Events: During the first year of the study (treatment and nontreatment follow-up), the proportion of patients who reported upper gastrointestinal adverse events was similar between the treatment groups; no patients reported severe upper gastrointestinal adverse events.
The incidence of diarrhea was 19.7% in the risedronate group and 14.8% in the Didronel group; none were serious or resulted in withdrawal.
Ocular Adverse Events: Three patients who received risedronate sodium tablets 30 mg daily experienced acute iritis in 1 supportive study.
All 3 patients recovered from their events; however, in 1 of these patients, the event recurred during risedronate treatment and again during treatment with pamidronate.
All patients were effectively treated with topical steroids.
6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of risedronate or bisphosphonate products.
Because these adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Hypersensitivity Reactions Hypersensitivity and skin reactions have been reported, including angioedema, generalized rash, bullous skin reactions, Stevens-Johnson syndrome and toxic epidermal necrolysis.
Gastrointestinal Adverse Events Events involving upper gastrointestinal irritation, such as esophagitis and esophageal or gastric ulcers, have been reported [see Warnings and Precautions (5.1) ].
Musculoskeletal Bone, joint, or muscle pain, described as severe or incapacitating, have been reported rarely [see Warnings and Precautions (5.4) ] ; low-energy femoral shaft and subtrochanteric fractures, and atypical fractures of other bones [see Warnings and Precautions (5.6) ].
Eye Inflammation Reactions of eye inflammation including iritis and uveitis have been reported rarely.
Jaw Osteonecrosis Osteonecrosis of the jaw has been reported rarely [see Warnings and Precautions (5.3) ] .
Pulmonary Asthma exacerbations
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 Pain 4.8 5.3 Nervous System Dizziness 5.7 7.1 Depression 6.1 6.8 Insomnia 4.6 5 Respiratory System Bronchitis 10.4 10 Sinusitis 9.1 8.7 Rhinitis 5.1 6.2 Pharyngitis 5 6 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 tablets 5 mg daily groups were: abdominal pain (9.9% versus 12.2%), diarrhea (10% 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 tablets 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 tablets 5 mg daily groups.
Musculoskeletal Adverse Events: The incidence of adverse events in the placebo and risedronate sodium tablets 5 mg daily groups were: back pain (26.1% versus 28%), 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 tablets 5 mg once daily.
There were no significant differences in serum calcium, phosphate, or PTH levels between placebo and risedronate sodium tablets 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 tablets 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 tablets 5 mg once daily.
There have been rare reports (less than 0.1%) of abnormal liver function tests.
Endoscopic Findings: In the risedronate 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].
Clinically important findings (perforations, ulcers, or bleeding) among this symptomatic population were similar between groups (51% placebo; 39% risedronate).
Once-a-Week Dosing The safety of risedronate sodium tablets 35 mg once-a-week in the treatment of postmenopausal osteoporosis was assessed in a 1-year, double-blind, multicenter study comparing risedronate sodium tablets 5 mg daily and risedronate sodium tablets 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 tablets 5 mg daily and 485 exposed to risedronate sodium tablets 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 tablets 5 mg daily group and 1% in the risedronate sodium tablets 35 mg once-a-week group.
The incidence of serious adverse events was 7.1% in the risedronate sodium tablets 5 mg daily group and 8.2% in the risedronate sodium tablets 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 tablets 5 mg daily group and 11.5% in the risedronate sodium tablets 35 mg once-a-week group.
The overall safety and tolerability profiles of the two dosing regimens were similar.
Gastrointestinal Adverse Events: The incidence of gastrointestinal adverse events was similar between the risedronate sodium tablets 5 mg daily group and the risedronate sodium tablets 35 mg once-a-week group: dyspepsia (6.9% versus 7.6%), diarrhea (6.3% versus 4.9%), and abdominal pain (7.3% versus 7.6%).
Musculoskeletal Adverse Events: Arthralgia was reported in 11.5% of patients in the risedronate sodium tablets 5 mg daily group and 14.2% of patients in the risedronate sodium tablets 35 mg once-a-week group.
Myalgia was reported by 4.6% of patients in the risedronate sodium tablets 5 mg daily group and 6.2% of patients in the risedronate sodium tablets 35 mg once-a-week group.
Laboratory Test Findings: The mean percent changes from baseline at 12 months were similar between the risedronate sodium tablets 5 mg daily and risedronate sodium tablets 35 mg once-a-week groups, respectively, for serum calcium (0.4% versus 0.7%), phosphate (-3.8% versus -2.6%) and PTH (6.4% versus 4.2%).
Monthly Dosing Two Consecutive Days per Month The safety of risedronate sodium tablets 75 mg administered on two consecutive days per month for the treatment of postmenopausal osteoporosis was assessed in a double-blind, multicenter study in postmenopausal women aged 50 to 86 years.
The duration of the trial was two years; 613 patients were exposed to risedronate sodium tablets 5 mg daily and 616 were exposed to risedronate sodium tablets 75 mg two consecutive days per month.
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 1000 mg of elemental calcium plus 400 to 800 international units of vitamin D supplementation per day.
The incidence of all-cause mortality was 1% for the risedronate sodium tablets 5 mg daily group and 0.5% for the risedronate sodium tablets 75 mg two consecutive days per month group.
The incidence of serious adverse events was 10.8% in the risedronate sodium tablets 5 mg daily group and 14.4% in the risedronate sodium tablets 75 mg two consecutive days per month group.
The percentage of patients who withdrew from treatment due to adverse events was 14.2% in the risedronate sodium tablets 5 mg daily group and 13% in the risedronate sodium tablets 75 mg two consecutive days per month group.
The overall safety and tolerability profiles of the two dosing regimens were similar.
Acute Phase Reactions: Symptoms consistent with acute phase reaction have been reported with bisphosphonate use.
The overall incidence of acute phase reaction was 3.6% of patients on risedronate sodium tablets 5 mg daily and 7.6% of patients on risedronate sodium tablets 75 mg two consecutive days per month.
These incidence rates are based on reporting of any of 33 acute phase reaction-like symptoms within 5 days of the first dose.
Fever or influenza-like illness with onset within the same period were reported by 0% of patients on risedronate sodium tablets 5 mg daily and 0.6% of patients on risedronate sodium tablets 75 mg two consecutive days per month.
Gastrointestinal Adverse Events: The risedronate sodium tablets 75 mg two consecutive days per month group resulted in a higher incidence of discontinuation due to vomiting (1% versus 0.2%) and diarrhea (1% versus 0.3%) compared to the risedronate sodium tablets 5 mg daily group.
Most of these events occurred within a few days of dosing.
Ocular Adverse Events: None of the patients treated with risedronate sodium tablets 75 mg two consecutive days per month reported ocular inflammation such as uveitis, scleritis, or iritis; 1 patient treated with risedronate sodium tablets 5 mg daily reported uveitis.
Laboratory Test Findings: When risedronate sodium tablets 5 mg daily and risedronate sodium tablets 75 mg two consecutive days per month were compared in postmenopausal women with osteoporosis, the mean percent changes from baseline at 24 months were 0.2% and 0.8% for serum calcium, -1.9% and -1.3% for phosphate, and -10.4% and -17.2% for PTH, respectively.
Compared to the risedronate sodium tablets 5 mg daily group, risedronate sodium tablets 75 mg two consecutive days per month resulted in a slightly higher incidence of hypocalcemia at the end of the first month of treatment (4.5% versus 3%).
Thereafter, the incidence of hypocalcemia with these regimens was similar at approximately 2%.
Prevention of Postmenopausal Osteoporosis Daily Dosing The safety of risedronate sodium tablets 5 mg daily in the prevention of postmenopausal osteoporosis was assessed in two randomized, double-blind, placebo-controlled trials.
In one study of postmenopausal women aged 37 to 82 years without osteoporosis, the use of estrogen replacement therapy in both placebo- and risedronate-treated patients was included.
The duration of the trial was one year, with 259 exposed to placebo and 261 patients exposed to risedronate sodium tablets 5 mg.
The second study included postmenopausal women aged 44 to 63 years without osteoporosis.
The duration of the trial was one year, with 125 exposed to placebo and 129 patients exposed to risedronate sodium tablets 5 mg.
All women received 1000 mg of elemental calcium per day.
In the trial with estrogen replacement therapy, the incidence of all-cause mortality was 1.5% for the placebo group and 0.4% for the risedronate sodium tablets 5 mg group.
The incidence of serious adverse events was 8.9% in the placebo group and 5.4% in the risedronate sodium tablets 5 mg group.
The percentage of patients who withdrew from treatment due to adverse events was 18.9% in the placebo group and 10.3% in the risedronate sodium tablets 5 mg group.
Constipation was reported by 1.9% of the placebo group and 6.5% of risedronate sodium tablets 5 mg group.
In the second trial, the incidence of all-cause mortality was 0% for both groups.
The incidence of serious adverse events was 17.6% in the placebo group and 9.3% in the risedronate sodium tablets 5 mg group.
The percentage of patients who withdrew from treatment due to adverse events was 6.4% in the placebo group and 5.4% in the risedronate sodium tablets 5 mg group.
Nausea was reported by 6.4% of patients in the placebo group and 13.2% of patients in the risedronate sodium tablets 5 mg group.
Once-a-Week Dosing There were no deaths in a 1-year, double-blind, placebo-controlled study of risedronate sodium tablets 35 mg once-a-week for prevention of bone loss in 278 postmenopausal women without osteoporosis.
More treated subjects on risedronate reported arthralgia (placebo 7.8%; risedronate 13.9%), myalgia (placebo 2.1%; risedronate 5.1%), and nausea (placebo 4.3%; risedronate 7.3%) than subjects on placebo.
Treatment to Increase Bone Mass in Men with Osteoporosis In a 2-year, double-blind, multicenter study, 284 men with osteoporosis were treated with placebo (N = 93) or risedronate sodium tablets 35 mg once-a-week (N = 191).
The overall safety and tolerability profile of risedronate in men with osteoporosis was similar to the adverse events reported in the risedronate postmenopausal osteoporosis clinical trials, with the addition of benign prostatic hyperplasia (placebo 3%; risedronate sodium tablets 35 mg 5%), nephrolithiasis (placebo 0%; risedronate sodium tablets 35 mg 3%), and arrhythmia (placebo 0%; risedronate sodium tablets 35 mg 2%).
Treatment and Prevention of Glucocorticoid-Induced Osteoporosis The safety of risedronate sodium tablets 5 mg daily in the treatment and prevention of glucocorticoid-induced osteoporosis was assessed in two randomized, double-blind, placebo-controlled multinational trials of 344 patients [male (123) and female (221)] aged 18 to 85 years who had recently initiated oral glucocorticoid therapy (less than or equal to 3 months, prevention study) or were on long-term oral glucocorticoid therapy (greater than or equal to 6 months, treatment study).
The duration of the trials was one year, with 170 patients exposed to placebo and 174 patients exposed to risedronate sodium tablets 5 mg daily.
Patients in one study received 1000 mg elemental calcium plus 400 international units of vitamin D supplementation per day; patients in the other study received 500 mg calcium supplementation per day.
The incidence of all-cause mortality was 2.9% in the placebo group and 1.1% in the risedronate sodium tablets 5 mg daily group.
The incidence of serious adverse events was 33.5% in the placebo group and 30.5% in the risedronate sodium tablets 5 mg daily group.
The percentage of patients who withdrew from the study due to adverse events was 8.8% in the placebo group and 7.5% in the risedronate sodium tablets 5 mg daily group.
Back pain was reported in 8.8% of patients in the placebo group and 17.8% of patients in the risedronate sodium tablets 5 mg daily group.
Arthralgia was reported in 14.7% of patients in the placebo group and 24.7% of patients in the risedronate sodium tablets 5 mg daily group.
Treatment of Paget’s Disease Risedronate has been studied in 392 patients with Paget’s disease of bone.
As in trials of risedronate for other indications, the adverse experiences reported in the Paget’s disease trials have generally been mild or moderate, have not required discontinuation of treatment, and have not appeared to be related to patient age, gender, or race.
The safety of risedronate was assessed in a randomized, double-blind, active-controlled study of 122 patients aged 34 to 85 years.
The duration of the trial was 540 days, with 61 patients exposed to risedronate and 61 patients exposed to Didronel ® .
The adverse event profile was similar for risedronate and Didronel: 6.6% (4/61) of patients treated with risedronate sodium tablets 30 mg daily for 2 months discontinued treatment due to adverse events, compared to 8.2% (5/61) of patients treated with Didronel 400 mg daily for 6 months.
Table 2 lists adverse events reported in greater than or equal to 5% of risedronate-treated patients in Phase 3 Paget's disease trials.
Adverse events shown are considered to be possibly or probably causally related in at least one patient.
Table 2 Adverse Events Reported in greater than or equal to 5% of Risedronate-Treated Patients* in Phase 3 Paget's Disease Trials Body System 30 mg/day x 2 months Risedronate % (N = 61) 400 mg/day x 6 months Didronel % (N = 61) Body as a Whole Flu Syndrome 9.8 1.6 Chest Pain 6.6 3.3 Gastrointestinal Diarrhea 19.7 14.8 Abdominal Pain 11.5 8.2 Nausea 9.8 9.8 Constipation 6.6 8.2 Metabolic and Nutritional Disorders Peripheral Edema 8.2 6.6 Musculoskeletal Arthralgia 32.8 29.5 Nervous Headache 18 16.4 Dizziness 6.6 4.9 Skin and Appendages Rash 11.5 8.2 *Considered to be possibly or probably causally related in at least one patient.
Gastrointestinal Adverse Events: During the first year of the study (treatment and nontreatment follow-up), the proportion of patients who reported upper gastrointestinal adverse events was similar between the treatment groups; no patients reported severe upper gastrointestinal adverse events.
The incidence of diarrhea was 19.7% in the risedronate group and 14.8% in the Didronel group; none were serious or resulted in withdrawal.
Ocular Adverse Events: Three patients who received risedronate sodium tablets 30 mg daily experienced acute iritis in 1 supportive study.
All 3 patients recovered from their events; however, in 1 of these patients, the event recurred during risedronate treatment and again during treatment with pamidronate.
All patients were effectively treated with topical steroids.
6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of risedronate or bisphosphonate products.
Because these adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Hypersensitivity Reactions Hypersensitivity and skin reactions have been reported, including angioedema, generalized rash, bullous skin reactions, Stevens-Johnson syndrome and toxic epidermal necrolysis.
Gastrointestinal Adverse Events Events involving upper gastrointestinal irritation, such as esophagitis and esophageal or gastric ulcers, have been reported [see Warnings and Precautions (5.1) ].
Musculoskeletal Bone, joint, or muscle pain, described as severe or incapacitating, have been reported rarely [see Warnings and Precautions (5.4) ] ; low-energy femoral shaft and subtrochanteric fractures, and atypical fractures of other bones [see Warnings and Precautions (5.6) ].
Eye Inflammation Reactions of eye inflammation including iritis and uveitis have been reported rarely.
Jaw Osteonecrosis Osteonecrosis of the jaw has been reported rarely [see Warnings and Precautions (5.3) ] .
Pulmonary Asthma exacerbations