Daily Dosing:

Osteoporosis:

ACTONEL has been studied in over 5700 patients enrolled in the Phase 3 glucocorticoid-induced osteoporosis clinical trials and in postmenopausal osteoporosis trials of up to 3-years duration. The overall adverse event profile of ACTONEL 5 mg in these studies was similar to that of placebo. Most adverse events were either mild or moderate and did not lead to discontinuation from the study. The incidence of serious adverse events in the placebo group was 24.9% and in the ACTONEL 5 mg group was 26.3%. The percentage of patients who withdrew from the study due to adverse events was 14.4% and 13.5% for the placebo and ACTONEL 5 mg groups, respectively. Table 5 lists adverse events from the Phase 3 osteoporosis trials reported in ≥ 2% of patients and in more ACTONEL-treated patients than placebo-treated patients. Adverse events are shown without attribution of causality.

Table 5 Adverse Events Occurring at a Frequency ≥ 2% and in More ACTONEL-Treated Patients than Placebo-Treated Patients; Combined Phase 3 Osteoporosis Trials

Duodenitis and glossitis have been reported uncommonly (0.1% to 1%). There have been rare reports (< 0.1%) of abnormal liver function tests.

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 5 mg once daily. There were no significant differences in serum calcium, phosphate, or PTH levels between ACTONEL 5 mg once daily and placebo at 3 years. Serum calcium levels below 8 mg/dL were observed in 18 patients, 9 (0.5%) in each treatment arm (ACTONEL 5 mg once daily and placebo). Serum phosphorus levels below 2 mg/dL were observed in 14 patients, 11 (0.6%) treated with ACTONEL 5 mg once daily and 3 (0.2%) treated with placebo.

Endoscopic Findings:

ACTONEL clinical studies enrolled over 5700 patients, many with pre-existing gastrointestinal disease and concomitant use of NSAIDs or aspirin. Investigators were encouraged to perform endoscopies in any patients with moderate-to-severe gastrointestinal complaints, while maintaining the blind. These endoscopies were ultimately performed on equal numbers of patients between the treated and placebo groups [75 (14.5%) placebo; 75 (11.9%) ACTONEL]. Across treatment groups, the percentage of patients with normal esophageal, gastric, and duodenal mucosa on endoscopy was similar (20% placebo; 21% ACTONEL). The number of patients who withdrew from the studies due to the event prompting endoscopy was similar across treatment groups. Positive findings on endoscopy were also generally comparable across treatment groups. There was a higher number of reports of mild duodenitis in the ACTONEL group, however there were more duodenal ulcers in the placebo group. Clinically important findings (perforations, ulcers, or bleeding) among this symptomatic population were similar between groups (51% placebo; 39% ACTONEL).

Once-A-Week Dosing:

In a 1-year, double-blind, multicenter study comparing ACTONEL 5 mg daily and ACTONEL 35 mg once a week in postmenopausal women, the overall safety and tolerability profiles of the 2 oral dosing regimens were similar. Table 6 lists the adverse events in ≥ 2% of patients from this trial. Events are shown without attribution of causality.

Table 6 Adverse Events Occurring in ≥ 2% of Patients of Either Treatment Group in the Daily vs. Weekly Osteoporosis Treatment Study in Postmenopausal Women

Laboratory Test Findings:

In a 1-year study comparing daily versus weekly oral dosing regimens of ACTONEL in postmenopausal women, the mean percent changes from baseline at 12 months were similar between the ACTONEL 5 mg daily and ACTONEL 35 mg once a week groups, respectively, for serum calcium (0.4% and 0.7%), phosphate (-3.8% and -2.6%) and PTH (6.4% and 4.2%).

Monthly Dosing:

One year of treatment with ACTONEL 5 mg daily was compared to ACTONEL 75 mg two consecutive days/month in a double-blind, multicenter study in postmenopausal women with osteoporosis. The overall safety and tolerability profiles of the 2 oral dosing regimens were similar. The incidence of serious adverse events was 4.7% in the ACTONEL 5 mg daily group and 7.5% in the ACTONEL 75 mg two consecutive days/month group. The percentage of patients who withdrew from treatment due to adverse events was 9.0% in the ACTONEL 5 mg daily group and 9.1% in the ACTONEL 75 mg two consecutive days/month group. Table 7 lists the adverse events in ≥ 2% of patients from this trial. Events are shown without attribution of causality.

Table 7 Adverse Events Occurring in ≥ 2% of Patients in Either Treatment Group in the Daily vs. the 2 Consecutive Days/Month Treatment Study in Postmenopausal Women (1-year data)

Acute Phase Reactions:

Acute phase reaction-like events, defined as adverse events of fever or influenza-like illness with onset within the first 5 days of treatment, were reported by 4 (0.6%) patients on ACTONEL 75 mg two consecutive days/month and no patients on ACTONEL 5 mg daily.

Gastrointestinal Adverse Events:

The ACTONEL 75 mg two consecutive days/month regimen resulted in a slightly higher incidence of discontinuation due to vomiting (1.0% vs. 0.0%) and diarrhea (0.8% vs. 0.0%) compared to the ACTONEL 5 mg once daily regimen. Most of these events occurred within a few days of dosing.

Ocular Adverse Events:

None of the patients treated with ACTONEL 75 mg two consecutive days/month experienced ocular inflammation such as uveitis or scleritis.

Laboratory Test Findings:

When ACTONEL 5 mg daily and ACTONEL 75 mg two consecutive days/month were compared in postmenopausal women with osteoporosis, the mean percent changes from baseline at 12 months were 0.2% and 0.8% for serum calcium, -1.9% and -1.1% for phosphate, and -3.0% and -11.7% for PTH, respectively. Compared to the ACTONEL 5 mg daily regimen, ACTONEL 75 mg two consecutive days/month resulted in a slightly higher incidence of hypocalcemia at the end of the first month of treatment (4.5% vs. 3.0%) Thereafter, the incidence of hypocalcemia with these regimens was similar at approximately 2%.

Osteoporosis Prevention:

There were no deaths in a 1-year, double-blind, placebo-controlled study of ACTONEL 35 mg once a week for prevention of bone loss in 278 postmenopausal women without osteoporosis. More treated subjects on risedronate experienced arthralgia (risedronate 13.9%; placebo 7.8%), myalgia (risedronate 5.1%; placebo 2.1%), and nausea (risedronate 7.3%; placebo 4.3%) than subjects on placebo.

Men With Osteoporosis:

In a 2-year, double-blind, multi-center study, 284 men with osteoporosis were treated with ACTONEL 35 mg once a week (n = 191) or placebo (n = 93). The overall safety and tolerability profile of ACTONEL in men with osteoporosis was similar to the adverse events reported in the ACTONEL postmenopausal osteoporosis clinical trials, with the addition of benign prostatic hyperplasia (ACTONEL 35 mg 5%; placebo 3%), nephrolithiasis (ACTONEL 35 mg 3%; placebo 0%), and arrhythmia (ACTONEL 35 mg 2%; placebo 0%).

Paget's Disease:

ACTONEL has been studied in 392 patients with Paget's disease of bone. As in trials of ACTONEL 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.

In a double-blind, active-controlled study, the adverse event profile was similar for ACTONEL and Didronel: 6.6% (4/61) of patients treated with ACTONEL 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 8 Adverse Events Reported in ≥ 2% of ACTONEL-Treated Patients* in Phase 3 Paget's Disease Trials

Ocular Adverse Events:

Three patients who received ACTONEL 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 treatment and again during treatment with pamidronate. All patients were effectively treated with topical steroids.

Post-Marketing Experience:

Very rare hypersensitivity and skin reactions have been reported, including angioedema, generalized rash and bullous skin reactions, some severe.

Musculoskeletal: bone, joint, or muscle pain, rarely described as severe or incapacitating (see PRECAUTIONS, Musculoskeletal Pain).

Very rare reactions of eye inflammation including iritis and uveitis have been reported.

Osteonecrosis of the jaw has been reported very rarely (see PRECAUTIONS, Jaw Osteonecrosis).

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

Calcium Supplements/Antacids:

Co-administration of ACTONEL and calcium, antacids, or oral medications containing divalent cations will interfere with the absorption of ACTONEL.

Hormone Replacement Therapy:

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

Aspirin/Nonsteroidal Anti-Inflammatory Drugs (NSAIDs):

Of over 5700 patients enrolled in the ACTONEL 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 ACTONEL-treated patients (24.5%) was similar to that in placebo-treated patients (24.8%).

H₂ Blockers And Proton Pump Inhibitors (PPIs):

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

Drug/Laboratory Test Interactions:

Bisphosphonates are known to interfere with the use of bone-imaging agents. Specific studies with ACTONEL have not been performed.

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