Safety and tolerability of linaclotide for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation: pooled Phase 3 analysis

Background: Linaclotide is approved for treating irritable bowel syndrome with constipation (IBS-C; 290 mu g QD) and chronic idiopathic constipation (CIC; 145 mu g or 72 mu g QD). These analyses aimed to assess linaclotide safety in a large, pooled Phase 3 population. Methods: In six randomized controlled trials (RCTs), patients received linaclotide (72 mu g, 145 mu g, 290 mu g) or placebo daily for 12-26 weeks; in two long-term safety (LTS) studies, patients received open-label linaclotide for <= 78 additional weeks. Laboratory values, vital signs, and treatment-emergent adverse events (TEAEs) were assessed. Results: Overall, 3853 patients received >= 1 dose of linaclotide. The most common TEAE was diarrhea (majority [90.5% in RCTs] mild/moderate). Linaclotide patients experienced 1.1 diarrhea TEAE per patient-year in the RCTs (0.2 in placebo), and 0.3 in the LTS studies. In RCTs, 6.9% linaclotide and 3.0% placebo patients discontinued due to any adverse event (AE); 4.0% linaclotide and 0.3% placebo patients discontinued due to diarrhea. In LTS studies, 9.4% patients discontinued due to any AE, and 3.8% due to diarrhea. Serious AEs (SAEs) were rare and similar across treatment groups; there were no SAEs of diarrhea. Conclusion: These pooled analyses of patients treated for <= 104 weeks confirm linaclotide's overall safety.