Actonel Side Effects, and Drug Interactions - Risedronate

Actonel Side Effects, and Drug Interactions - Risedronate

SIDE EFFECTS

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.

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

Asymptomatic and small decreases were observed in serum calcium and phosphorus levels. Overall, mean decreases of 0.8% in serum calcium and of 2.7% in phosphorus were observed at 6 months in patients receiving ACTONEL. Throughout the Phase 3 studies, serum calcium levels below 8 mg/dL were observed in 18 patients, 9 (0.5%) in each treatment arm (ACTONEL and placebo). Serum phosphorus levels below 2 mg/dL were observed in 14 patients, 11 (0.6%) treated with ACTONEL and 3 (0.2%) treated with placebo.

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).

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 ³2% of patients from this trial. Events are shown without attribution of causality.

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/day for 2 months discontinued treatment due to adverse events, compared to 8.2% (5/61) of patients treated with Didronel 400 mg/day for 6 months.

Three patients who received ACTONEL 30 mg/day 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.

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/day) 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.