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 Actonel (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 Actonel (risedronate sodium) 5 mg. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal antiinflammatory drugs, proton pump inhibitors, and H2 antagonists were included in these clinical trials. All women received 1000 mg of elemental calcium plus vitamin D supplementation up to 500 IU per day if their 25-hydroxyvitamin D3 level was below normal at baseline.

The incidence of all-cause mortality was 2.0% in the placebo group and 1.7% in the Actonel (risedronate sodium) 5 mg daily group. The incidence of serious adverse events was 24.6% in the placebo group and 27.2% in the Actonel (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 Actonel (risedronate sodium) 5 mg group. Table 1 lists adverse events from the Phase 3 postmenopausal osteoporosis trials reported in ≥ 5% of patients. Adverse events are shown without attribution of causality.

Table 1 : Adverse Events Occurring at a Frequency ≥ 5% in Either Treatment Group Combined Phase 3 Postmenopausal Osteoporosis Treatment Trials

Gastrointestinal Adverse Events: The incidence of adverse events in the placebo and Actonel (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 Actonel (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 Actonel (risedronate sodium) 5 mg daily groups.

Musculoskeletal Adverse Events: The incidence of adverse events in the placebo and Actonel (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 ( < 1%) and serum phosphate ( < 3%) and compensatory increases in serum PTH levels ( < 30%) were observed within 6 months in patients in osteoporosis clinical trials treated with Actonel (risedronate sodium) 5 mg once daily. There were no significant differences in serum calcium, phosphate, or PTH levels between placebo and Actonel (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 Actonel (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 Actonel (risedronate sodium) 5 mg once daily. There have been rare reports ( < 0.1%) of abnormal liver function tests.

Endoscopic Findings: In the Actonel (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%) Actonel (risedronate sodium) ]. Clinically important findings (perforations, ulcers, or bleeding) among this symptomatic population were similar between groups (51% placebo; 39% Actonel (risedronate sodium) ).

Once-a-Week Dosing

The safety of Actonel (risedronate sodium) 35 mg once-a-week in the treatment of postmenopausal osteoporosis was assessed in a 1-year, double-blind, multicenter study comparing Actonel (risedronate sodium) 5 mg daily and Actonel (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 ACTONEL (risedronate sodium) 5 mg daily and 485 exposed to Actonel (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 H2 antagonists were included in these clinical trials. All women received 1000 mg of elemental calcium plus vitamin D supplementation up to 500 IU per day if their 25-hydroxyvitamin D3 level was below normal at baseline.

The incidence of all-cause mortality was 0.4% in the Actonel (risedronate sodium) 5 mg daily group and 1.0% in the Actonel (risedronate sodium) 35 mg once-a-week group. The incidence of serious adverse events was 7.1% in the Actonel (risedronate sodium) 5 mg daily group and 8.2% in the Actonel (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 Actonel (risedronate sodium) 5 mg daily group and 11.5% in the Actonel (risedronate sodium) 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 Actonel (risedronate sodium) 5 mg daily group and the Actonel (risedronate sodium) 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 Actonel (risedronate sodium) 5 mg daily group and 14.2% of patients in the Actonel (risedronate sodium) 35 mg once-a-week group. Myalgia was reported by 4.6% of patients in the Actonel (risedronate sodium) 5 mg daily group and 6.2% of patients in the Actonel (risedronate sodium) 35 mg once-a-week group.

Laboratory Test Findings: The mean percent changes from baseline at 12 months were similar between the Actonel (risedronate sodium) 5 mg daily and Actonel (risedronate sodium) 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 Actonel (risedronate sodium) 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 Actonel (risedronate sodium) 5 mg daily and 616 were exposed to Actonel (risedronate sodium) 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 H2 antagonists were included in this clinical trial. All women received 1000 mg of elemental calcium plus 400 to 800 IU of vitamin D supplementation per day.

The incidence of all-cause mortality was 1.0% for the Actonel (risedronate sodium) 5 mg daily group and 0.5% for the Actonel (risedronate sodium) 75 mg two consecutive days per month group. The incidence of serious adverse events was 10.8% in the Actonel (risedronate sodium) 5 mg daily group and 14.4% in the Actonel (risedronate sodium) 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 Actonel (risedronate sodium) 5 mg daily group and 13.0% in the Actonel (risedronate sodium) 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 Actonel (risedronate sodium) 5 mg daily and 7.6% of patients on Actonel (risedronate sodium) 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 0.0% of patients on Actonel (risedronate sodium) 5 mg daily and 0.6% of patients on Actonel (risedronate sodium) 75 mg two consecutive days per month.

Gastrointestinal Adverse Events: The Actonel (risedronate sodium) 75 mg two consecutive days per month group resulted in a higher incidence of discontinuation due to vomiting (1.0% versus 0.2%) and diarrhea (1.0% versus 0.3%) compared to the Actonel (risedronate sodium) 5 mg daily group. Most of these events occurred within a few days of dosing.

Ocular Adverse Events: None of the patients treated with Actonel (risedronate sodium) 75 mg two consecutive days per month reported ocular inflammation such as uveitis, scleritis, or iritis; 1 patient treated with Actonel (risedronate sodium) 5 mg daily reported uveitis.

Laboratory Test Findings: When Actonel (risedronate sodium) 5 mg daily and Actonel (risedronate sodium) 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 Actonel (risedronate sodium) 5 mg daily group, Actonel (risedronate sodium) 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 3.0%). Thereafter, the incidence of hypocalcemia with these regimens was similar at approximately 2%.

Once-a-Month

The safety of Actonel (risedronate sodium) 150 mg administered once a month for the treatment of postmenopausal osteoporosis was assessed in a double-blind, multicenter study in postmenopausal women aged 50 to 88 years. The duration of the trial was one year, with 642 patients exposed to Actonel (risedronate sodium) 5 mg daily and 650 exposed to Actonel (risedronate sodium) 150 mg once-a-month. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors, and H2 antagonists were included in this clinical trial. All women received 1000 mg of elemental calcium plus up to 1000 IU of vitamin D supplementation per day.

The incidence of all-cause mortality was 0.5% for the Actonel (risedronate sodium) 5 mg daily group and 0.0% for the Actonel (risedronate sodium) 150 mg once-a-month group. The incidence of serious adverse events was 4.2% in the Actonel (risedronate sodium) 5 mg daily group and 6.2% in the Actonel (risedronate sodium) 150 mg once-a-month group. The percentage of patients who withdrew from treatment due to adverse events was 9.5% in the Actonel (risedronate sodium) 5 mg daily group and 8.6% in the Actonel (risedronate sodium) 150 mg once-a-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 1.1% in the Actonel (risedronate sodium) 5 mg daily group and 5.2% in the Actonel (risedronate sodium) 150 mg once-a-month group. These incidence rates are based on reporting of any of 33 acute phase reaction-like symptoms within 3 days of the first dose and for a duration of 7 days or less. Fever or influenza-like illness with onset within the same period were reported by 0.2% of patients on Actonel (risedronate sodium) 5 mg daily and 1.4% of patients on Actonel (risedronate sodium) 150 mg once-a-month.

Gastrointestinal Adverse Events: A greater percentage of patients experienced diarrhea with Actonel (risedronate sodium) 150 mg once-a-month compared to 5 mg daily (8.2% versus 4.7%, respectively). The Actonel (risedronate sodium) 150 mg once-a-month group resulted in a higher incidence of discontinuation due to abdominal pain upper (2.5% versus 1.4%) and diarrhea (0.8% versus 0.0%) compared to the Actonel (risedronate sodium) 5 mg daily regimen. All of these events occurred within a few days of the first dose. The incidence of vomiting that led to discontinuation was the same in both groups (0.3% versus 0.3%).

Ocular Adverse Events: None of the patients treated with Actonel (risedronate sodium) 150 mg once-a-month reported ocular inflammation such as uveitis, scleritis, or iritis; 2 patients treated with Actonel (risedronate sodium) 5 mg daily reported iritis.

Laboratory Test Findings: When Actonel (risedronate sodium) 5 mg daily and Actonel (risedronate sodium) 150 mg once-a-month were compared in postmenopausal women with osteoporosis, the mean percent changes from baseline at 12 months were 0.1% and 0.3% for serum calcium, -2.3% and -2.3% for phosphate, and 8.3% and 4.8% for PTH, respectively. Compared to the Actonel (risedronate sodium) 5 mg daily regimen, Actonel (risedronate sodium) 150 mg once-a-month resulted in a slightly higher incidence of hypocalcemia at the end of the first month of treatment (0.2% versus 2.2%). Thereafter, the incidence of hypocalcemia with these regimens was similar at approximately 2%.

Prevention of Postmenopausal Osteoporosis

Daily Dosing

The safety of Actonel (risedronate sodium) 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 Actonel (risedronate sodium) -treated patients was included. The duration of the trial was one year, with 259 exposed to placebo and 261 patients exposed to Actonel (risedronate sodium) 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 Actonel (risedronate sodium) 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 Actonel (risedronate sodium) 5 mg group. The incidence of serious adverse events was 8.9% in the placebo group and 5.4% in the Actonel (risedronate sodium) 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 Actonel (risedronate sodium) 5 mg group. Constipation was reported by 1.9% of the placebo group and 6.5% of Actonel (risedronate sodium) 5 mg group.

In the second trial, the incidence of all-cause mortality was 0.0% for both groups. The incidence of serious adverse events was 17.6% in the placebo group and 9.3% in the Actonel (risedronate sodium) 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 Actonel (risedronate sodium) 5 mg group. Nausea was reported by 6.4% of patients in the placebo group and 13.2% of patients in the Actonel (risedronate sodium) 5 mg group.

Once-a-Week Dosing

There were no deaths in a 1-year, double-blind, placebo-controlled study of Actonel (risedronate sodium) 35 mg once a week for prevention of bone loss in 278 postmenopausal women without osteoporosis. More treated subjects on Actonel (risedronate sodium) reported arthralgia (placebo 7.8%; Actonel (risedronate sodium) 13.9%), myalgia (placebo 2.1%; Actonel (risedronate sodium) 5.1%), and nausea (placebo 4.3%; Actonel (risedronate sodium) 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 Actonel (risedronate sodium) 35 mg once-a-week (N = 191). The overall safety and tolerability profile of Actonel (risedronate sodium) in men with osteoporosis was similar to the adverse events reported in the Actonel (risedronate sodium) postmenopausal osteoporosis clinical trials, with the addition of benign prostatic hyperplasia (placebo 3%; Actonel (risedronate sodium) 35 mg 5%), nephrolithiasis (placebo 0%; Actonel (risedronate sodium) 35 mg 3%), and arrhythmia (placebo 0%; Actonel (risedronate sodium) 35 mg 2%).

Treatment and Prevention of Glucocorticoid-Induced Osteoporosis

The safety of Actonel (risedronate sodium) 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 ( ≤ 3 months, prevention study) or were on long-term oral glucocorticoid therapy ( ≥ 6 months, treatment study). The duration of the trials was one year, with 170 patients exposed to placebo and 174 patients exposed to Actonel (risedronate sodium) 5 mg daily. Patients in one study received 1000 mg elemental calcium plus 400 IU 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 Actonel (risedronate sodium) 5 mg daily group. The incidence of serious adverse events was 33.5% in the placebo group and 30.5% in the Actonel (risedronate sodium) 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 Actonel (risedronate sodium) 5 mg daily group. Back pain was reported in 8.8% of patients in the placebo group and 17.8% of patients in the Actonel (risedronate sodium) 5 mg daily group. Arthralgia was reported in 14.7% of patients in the placebo group and 24.7% of patients in the Actonel (risedronate sodium) 5 mg daily group.

Treatment of Paget's Disease

Actonel (risedronate sodium) has been studied in 392 patients with Paget's disease of bone. As in trials of Actonel (risedronate sodium) 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 Actonel (risedronate sodium) 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 Actonel (risedronate sodium) and 61 patients exposed to Didronel®. The adverse event profile was similar for Actonel (risedronate sodium) and Didronel: 6.6% (4/61) of patients treated with Actonel (risedronate sodium) 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 ≥ 5% of Actonel (risedronate sodium) 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 ≥ 5% of Actonel (risedronate sodium) -Treated Patients* in Phase 3 Paget's Disease Trials

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 Actonel (risedronate sodium) group and 14.8% in the Didronel group; none were serious or resulted in withdrawal.

Ocular Adverse Events: Three patients who received Actonel (risedronate sodium) 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 Actonel (risedronate sodium) treatment and again during treatment with pamidronate. All patients were effectively treated with topical steroids.

Postmarketing Experience

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 rarely, including angioedema, generalized rash and bullous skin reactions, some severe.

Gastrointestinal Adverse Events

Events involving upper gastrointestinal irritation, such as esophagitis and esophageal or gastric ulcers, have been reported [see WARNINGS AND PRECAUTIONS].

Musculoskeletal Pain

Bone, joint, or muscle pain, described as severe or incapacitating, have been reported rarely [see WARNINGS AND PRECAUTIONS].

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].

Read the Actonel (risedronate sodium) Side Effects Center for a complete guide to possible side effects »

No specific drug-drug interaction studies were performed. Risedronate is not metabolized and does not induce or inhibit hepatic microsomal drug-metabolizing enzymes (e.g., Cytochrome P450).

Calcium Supplements/Antacids

Co-administration of Actonel (risedronate sodium) and calcium, antacids, or oral medications containing divalent cations will interfere with the absorption of Actonel (risedronate sodium) .

Hormone Replacement Therapy

One study of about 500 early postmenopausal women has been conducted to date in which treatment with Actonel (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, Actonel (risedronate sodium) may be used concomitantly with hormone replacement therapy.

Aspirin/Nonsteroidal Anti-Inflammatory Drugs

Of over 5700 patients enrolled in the Actonel (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 Actonel (risedronate sodium) -treated patients (24.5%).

H₂ Blockers and Proton Pump Inhibitors (PPIs)

Of over 5700 patients enrolled in the Actonel (risedronate sodium) Phase 3 osteoporosis studies, 21% used H2 blockers and/or PPIs. Among these patients, the incidence of upper gastrointestinal adverse experiences in the placebo-treated patients was similar to that in Actonel (risedronate sodium) -treated patients.

Last reviewed on RxList: 3/10/2011
This monograph has been modified to include the generic and brand name in many instances.