Risedronate

⚠️ 3. Tahadhari & Madhara Yanayoweza Kutokea (Side Effects & Warnings)

6 ADVERSE REACTIONS Most common adverse reactions (greater than 5%) include: diarrhea, influenza, arthralgia, back pain, and abdominal pain (6.1) Hypersensitivity reactions (angioedema, generalized rash, bullous skin reactions, Stevens-Johnson syndrome, and toxic epidermal necrolysis), and eye inflammation (iritis, uveitis) have been reported rarely (6.2) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries Inc. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Treatment of Postmenopausal Osteoporosis Once-a-Week Dosing with Risedronate Sodium Delayed-Release tablets The safety of risedronate sodium delayed-release 35 mg once-a-week in the treatment of postmenopausal osteoporosis was assessed in a 1-year, double-blind, multicenter study comparing risedronate sodium delayed-release 35 mg once-a-week to risedronate sodium immediate-release 5 mg daily in postmenopausal women 50 years of age or older. Risedronate sodium delayed-release was administered either at least 30 minutes before (N = 308) or immediately following (N = 307) breakfast, and risedronate sodium immediate-release 5 mg daily (N = 307) was administered at least 30 minutes before breakfast. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors, and H 2 antagonists were included in this clinical trial. All women received daily supplementation with 1000 mg of elemental calcium plus 800 to 1000 international units vitamin D. As treatment with risedronate sodium resulted in a significantly higher incidence of abdominal pain when administered before breakfast under fasting conditions, safety results that follow refer only to risedronate sodium delayed-release 35 mg once-a-week immediately following breakfast and risedronate sodium immediate-release 5 mg daily. The incidence of all-cause mortality was 0.0% in the risedronate sodium delayed-release 35 mg once-a-week group and 0.3% in the risedronate sodium immediate-release 5 mg daily group. The incidence of serious adverse reactions was 6.5% in the risedronate sodium delayed-release 35 mg once-a-week group and 7.2% in the risedronate sodium immediate-release 5 mg daily group. The percentage of patients who withdrew from the study due to adverse reactions was 9.1% in the risedronate sodium delayed-release 35 mg once-a-week group and 8.1% in the risedronate sodium immediate-release 5 mg daily group. The overall safety and tolerability profiles of the two dosing regimens were similar. Table 1 lists adverse reactions reported in greater than or equal to 2% of patients. Adverse reactions are shown without attribution of causality. Table 1 Adverse Reactions Occurring at a Frequency of greater than or equal to 2% in Either Treatment Group System Organ Class Preferred Term 35 mg Risedronate sodium Delayed-release Weekly N = 307% 5 mg Risedronate sodium Immediate-release Daily N = 307% Gastrointestinal disorders Diarrhea 8.8 4.9 Abdominal pain 5.2 2.9 Constipation 4.9 2.9 Vomiting 4.9 1.6 Dyspepsia 3.9 3.9 Nausea 3.6 3.9 Abdominal pain upper 2.9 2.3 Infections and infestations Influenza 7.2 6.2 Bronchitis 3.9 4.2 Upper respiratory tract infection 3.6 2.6 Musculoskeletal and connective tissue disorders Arthralgia 6.8 7.8 Back pain 6.8 5.9 Pain in extremity 3.9 2.3 Musculoskeletal pain 2.0 1.6 Muscle spasms 1.0 2.3 Nervous system disorders Dizziness 2.6 3.3 Headache 2.6 4.9 Acute Phase Reactions: Symptoms consistent with acute phase reaction have been reported with bisphosphonate use. The overall incidence of acute phase reaction was 2.3% in the risedronate sodium delayed-release 35 mg once-a-week group and 1.3% in the risedronate sodium immediate-release 5 mg daily group. These incidence rates are based on reporting of one or more pre-specified acute phase reaction-like symptoms within 3 days of the first dose and for a duration of 7 days or less. Gastrointestinal Adverse Reactions : Adverse reactions related to the upper gastrointestinal tract occurred in 16% of subjects treated with risedronate sodium delayed-release 35 mg once-a-week and 15% of subjects treated with risedronate sodium immediate-release 5 mg daily. The incidence of upper gastrointestinal tract adverse reactions in the risedronate sodium delayed-release 35 mg once-a-week and risedronate sodium immediate-release 5 mg daily groups were: abdominal pain (5.2% versus 2.9%), dyspepsia (3.9% versus 3.9%), upper abdominal pain (2.9% versus 2.3%), gastritis (1.0% versus 1.0%), and gastroesophageal reflux disease (1.0% versus 1.6%). Study discontinuation due to abdominal pain occurred in 1.3% of the risedronate sodium delayed-release 35 mg once-a-week group and 0.7% of the risedronate sodium immediate-release 5 mg daily group. Musculoskeletal Adverse Reactions: Selected musculoskeletal adverse reactions were reported in 16% of subjects treated with risedronate sodium delayed-release 35 mg once-a-week and 15% of subjects treated with risedronate sodium immediate-release 5 mg daily. The incidence of musculoskeletal adverse reactions in the risedronate sodium delayed-release 35 mg once-a-week and risedronate sodium immediate-release 5 mg daily groups were: arthralgia (6.8% versus 7.8%), back pain (6.8% versus 5.9%), musculoskeletal pain (2.0% versus 1.6%), and myalgia (1.3% versus 1.0%). Laboratory Test Findings : Parathyroid hormone: The effect of risedronate sodium delayed-release 35 mg once-a-week and risedronate sodium immediate-release 5 mg daily on parathyroid hormone was evaluated in postmenopausal women with osteoporosis. At week 52, in subjects with normal levels at baseline, PTH levels greater than 65 pg/mL (upper limit of normal) were noted in 9% of subjects receiving risedronate sodium delayed-release 35 mg once-a-week and 8% of subjects receiving risedronate sodium immediate-release 5 mg daily. In subjects with normal levels at baseline, PTH levels greater than 97 pg/mL (1.5 times the upper limit of normal) were seen in 2% of subjects receiving risedronate sodium delayed-release 35 mg once-a-week and no subjects receiving risedronate sodium immediate-release 5 mg daily. There were no clinically significant differences between treatment groups for levels of calcium, phosphorus and magnesium. Daily Dosing with Risedronate Sodium Immediate-Release 5 mg tablets The safety of risedronate sodium immediate-release 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 immediate-release 5 mg daily. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors (PPIs), 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 immediate-release 5 mg daily group. The incidence of serious adverse reactions was 24.6% in the placebo group and 27.2% in the risedronate sodium immediate-release 5 mg daily group. The percentage of patients who withdrew from the study due to adverse reactions was 15.6% in the placebo group and 14.8% in the risedronate sodium immediate-release 5 mg daily group. The most common adverse reactions reported in greater than 10% of subjects were: back pain, arthralgia, abdominal pain and dyspepsia. Gastrointestinal Adverse Reactions: The incidence of adverse reactions in the placebo and risedronate sodium immediate-release 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 immediate-release 5 mg daily group (0.1% to 1%). In patients with active upper gastrointestinal disease at baseline, the incidence of upper gastrointestinal adverse reactions was similar between the placebo and risedronate sodium immediate-release 5 mg daily groups. Musculoskeletal Adverse Reactions: The incidence of adverse reactions in the placebo and risedronate sodium immediate-release 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 immediate-release 5 mg daily. There were no significant differences in serum calcium, phosphate, or PTH levels between placebo and risedronate sodium immediate-release 5 mg 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 immediate-release 5 mg 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 immediate-release 5 mg daily. There have been rare reports (less than 0.1%) of abnormal liver function tests. Endoscopic Findings : In the risedronate sodium immediate-release 5 mg daily 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 immediate-release 5 mg daily]. Clinically important findings (perforations, ulcers, or bleeding) among this symptomatic population were similar between groups (51% placebo; 39% risedronate sodium immediate-release 5 mg daily). 6.2 Postmarketing Experience The following adverse reactions have been reported with the use of risedronate sodium immediate-release. 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 Reactions Reactions involving upper gastrointestinal irritation, such as esophagitis and esophageal or gastric ulcers, have been reported [ see Warnings and Precautions (5.2) ]. Musculoskeletal Pain Bone, joint, or muscle pain, described as severe or incapacitating, have been reported rarely [ see Warnings and Precautions (5.5) ]. 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 (5.4) ]. Pulmonary Asthma exacerbations