Plecanatide (Trulance)

Safety Summary

The overall safety profile of plecanatide is characterized by local GI adverse effects with negligible systemic exposure. Diarrhea is the only adverse event occurring in ≥2% of patients and greater than placebo across all four pivotal trials. Severe diarrhea leading to dehydration is the principal serious risk, requiring treatment suspension and rehydration per FDA label guidance. The boxed warning concerns risk of serious dehydration in pediatric patients <6 years based on fatal dehydration in juvenile mice at doses as low as 0.5 mg/kg on postnatal day 7. Discontinuation rates due to adverse events were 4% (CIC) and 2.5% (IBS-C) versus 2% and 0.4% for placebo, respectively, with diarrhea being the most common reason. FAERS pharmacovigilance analyses (PMC11625541; DOI 10.3389/fphar.2024.1500810) covering 861 reports through 2024 Q2 identified no new unexpected serious safety signals beyond known GI events. Most adverse events occurred early (within 7 days per FAERS analysis). A separate FAERS signal for muscle spasms was identified PMC12364702 but mechanism is unestablished. Nonclinical carcinogenicity studies showed no carcinogenic potential (FDA multidisciplinary review NDA 211801). No evidence of tolerance, tachyphylaxis, or withdrawal effects in long-term studies up to 52-72 weeks (PMID 30277094; PMID 29343131). Immunogenicity assays were required as a post-marketing commitment but no anti-plecanatide antibodies have been documented to date.