Linaclotide (Linzess)

Safety Summary

Diarrhea is the dominant tolerability issue across all clinical trials and real-world data. In the pivotal Phase 3 IBS-C trial PMID 22986440, diarrhea occurred in 19.5% of linaclotide-treated patients vs 3.5% placebo, with severe diarrhea in 2% and discontinuation due to diarrhea in 5.7%. In pooled IBS-C trials (FDA label Table 1), diarrhea was reported in 20% vs 3%. In the Phase 3b adult CIC bloating trial, diarrhea rates were 5.9% with 145 mcg and 16.9% with 290 mcg vs 2.3% with placebo, with no serious diarrhea-related AEs PMID 26222318. In the large Chinese real-world study (N=2963), diarrhea was reported in 10.0%, all mild or moderate, with 1.8% discontinuing due to diarrhea PMID 39917729. In pediatric FC trials, diarrhea occurred in 4% with 72 mcg vs 2% placebo; in pediatric IBS-C, 7% with 145 mcg (FDA label 2025). The current FDA label warns that severe diarrhea can occur and instructs suspension plus rehydration if it does. URTI (5% vs 4%) and sinusitis (3% vs 2%) were reported at ≥2% incidence in CIC trials (FDA label Table 2). A pharmacovigilance study identified a signal for muscle spasms associated with linaclotide (ROR 1.88, 95% CI 1.63-2.18), predominantly in females and early in treatment PMID 40843382. Overall only 2.4% of patients in the real-world study discontinued due to any adverse event PMID 39917729.