Background/Purpose: Indomethacin is prescribed to treat acute pain and inflammation but, like other NSAIDs, is associated with dose-dependent gastrointestinal, cardiovascular, and renal adverse events (AEs). A US Food and Drug Administration Public Health Advisory recommended that physicians use NSAIDs at “the lowest effective dose for the shortest duration consistent with individual patient treatment goals.” The efficacy of new, submicron particle NSAIDs with enhanced absorption is being evaluated at lower doses than commercially available NSAIDs. We present safety and tolerability data from two phase 3 studies evaluating the analgesic efficacy and safety of investigational, lower-dose indomethacin submicron particle capsules in patients with acute pain following elective surgery.

Methods: Two phase 3, randomized, multi-center, double-blind studies enrolled patients 18 to 65 years of age undergoing bunionectomy with osteotomy and internal fixation under regional anesthesia. Patients with a pain intensity rating of ≥40 mm/100-mm Visual Analog Scale following surgery received indomethacin submicron particle capsules (40 mg three times daily [TID] or twice daily [BID], or 20 mg TID), or placebo. One study included celecoxib (400 mg loading dose followed by 200 mg BID). Safety assessments included an overall summary of AEs by severity and seriousness.

Results: The pooled safety population included 835 patients. AEs were similar across treatment groups (Table). The most common AEs were nausea, post-procedural edema, headache, dizziness, vomiting, post-procedural hemorrhage, and constipation. There were no severe cardiovascular, gastrointestinal, or renal AEs. One serious AE, deep vein thrombosis, occurred in the indomethacin submicron particle capsules 40 mg BID treatment group and was determined by the investigator to be unrelated to the study drug. Seven patients withdrew from the trials due to an AE. AEs leading to withdrawal included one case each of uvulitis, angioedema, pyrexia, anxiety, and nausea, and 2 cases of urticaria.

Conclusion: Indomethacin submicron particle capsules were generally well-tolerated in two phase 3 studies in patients with acute pain following elective surgery. Based on emerging efficacy data, investigational, lower-dose indomethacin submicron particle capsules represent a potentially promising lower-dose option for treating acute pain.