Plecanatide (Trulance)
Plecanatide; SP-304; synonyms: plecanatide acetate. UNII: 7IK8Z952OK. DrugBank: DB13170. NDA 208745.
Plecanatide (Trulance) is an FDA-approved oral 16-amino acid synthetic analog of human uroguanylin that activates guanylate cyclase-C receptors on intestinal epithelial cells, increasing fluid secretion and accelerating transit for treatment of chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C) in adults (FDA label NDA 208745; PMC6009086; PMID 28169285).
Last updated: 2026-03-13
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.
Known Side Effects
common
uncommon
uncommon
uncommon
uncommon
uncommon
uncommon
rare
rare
rare
rare
Who Should NOT Use This
Boxed warning. In nonclinical studies, single oral doses of plecanatide at 0.5 mg/kg and 10 mg/kg caused mortality in young juvenile mice on postnatal days 7 and 14 (human age equivalent approximately 1 month to <2 years) apparently due to dehydration from increased intestinal GC-C expression. Contraindicated due to risk of serious dehydration and death (FDA label NDA 208745;).
Avoid use. Safety and effectiveness not established in patients <18 years. Given deaths in younger juvenile mice and lack of clinical data, FDA label advises avoiding use in this age group (FDA label;).
Contraindicated per FDA label because plecanatide increases intestinal fluid secretion which could worsen obstruction symptoms and risk serious complications (FDA label;).
If severe diarrhea occurs, suspend dosing and rehydrate the patient. Most severe diarrhea occurred within the first 3 days of treatment (FDA label Section 5.2;).
Talk to Your Doctor
Before considering Plecanatide (Trulance), discuss it with your healthcare provider. Ask about potential interactions with your current medications, whether it is appropriate for your health conditions, and what monitoring may be needed.
Sources: [1-10]
Evidence Assessment
Plecanatide (Trulance) is FDA-approved (NDA 208745, January 19, 2017) for CIC in adults and (supplemental approval January 24, 2018) for IBS-C in adults. Approval was based on four pivotal Phase III randomized, double-blind, placebo-controlled trials enrolling over 3,000 patients in the efficacy population: two CIC trials (Study 1 NCT01982240 n=1394; Study 2 n=1410) and two IBS-C trials (Study 3 and Study 4, combined n=~2189). All demonstrated statistically significant superiority over placebo for primary endpoints. Additionally approved in Canada (NOC October 10, 2019) and marketed in India (as Plectide). A 2025 systematic review and meta-analysis (PMID 41604554) confirmed efficacy. Evidence quality is high with consistent results across multiple large RCTs.
1A Randomized Phase III Clinical Trial of Plecanatide, a Uroguanylin Analog, in Patients With Chronic Idiopathic ConstipationNCT01982240PMID 28169285
Miner PB Jr, Koltun WD, Wiber GJ, et al. - American Journal of Gastroenterology (2017) - Phase III RCT, double-blind, placebo-controlled - n=1394 randomized (3 arms: plecanatide 3 mg, 6 mg, placebo)
Durable overall CSBM responder rate: 21.0% (3 mg) and 19.5% (6 mg) vs 10.2% (placebo), p<0.001. Significant improvement in SBM frequency, stool consistency, straining. Diarrhea AE: 5.9% (3 mg), 5.7% (6 mg) vs 1.3% placebo.
Limitations: Industry-sponsored (Synergy Pharmaceuticals). 12-week treatment duration. Excluded severe comorbidities.
2Randomized clinical trial: efficacy and safety of plecanatide in the treatment of chronic idiopathic constipationPMID 29147135
DeMicco M, Barrow L, Hickey B, Shailubhai K, Griffin P. - Therapeutic Advances in Gastroenterology (2017) - Phase III RCT, double-blind, placebo-controlled - n=1410 (3 mg and 6 mg vs placebo)
Confirmed CIC efficacy: durable CSBM responder rates significantly higher for plecanatide vs placebo. Consistent safety profile with diarrhea as most common AE.
Limitations: Industry-sponsored. 12-week treatment. Limited diversity data.
3Efficacy, safety, and tolerability of plecanatide in patients with irritable bowel syndrome with constipation: results of two phase 3 randomized clinical trialsPMID 29545635
Brenner DM, Fogel R, Dorn SD, et al. - American Journal of Gastroenterology (2018) - Pooled analysis of two Phase III RCTs for IBS-C - n=~2189 randomized across two trials
Overall composite responder rates (>=30% pain reduction + >=1 CSBM increase >=6/12 weeks): 21-30% plecanatide vs 14-18% placebo. Significant improvement in abdominal pain, bloating, and bowel symptoms. Diarrhea AE 4.3% vs 1%.
Limitations: Industry-sponsored. 12-week treatment. No head-to-head comparison with linaclotide.
4Long-term treatment with plecanatide was safe and tolerable in patients with irritable bowel syndrome with constipationPMID 30277094
Barish CF, et al. - Digestive Diseases and Sciences (2019) - Open-label extension study - Patients from Phase III IBS-C trials, up to 52 weeks
Safety profile consistent with short-term trials. Low discontinuation rate (~4.3% due to AEs). Diarrhea incidence tended to decline over time. No evidence of tolerance or withdrawal effects.
Limitations: Open-label design. No placebo comparator in extension phase.
5Long-term safety and efficacy data for plecanatide in CICPMID 29343131
Not specified in raw data - Not specified in raw data (2018) - Long-term extension study for CIC - Not specified in raw data
Confirmed long-term safety consistent with 12-week trials. No cumulative toxicity, tolerance, or withdrawal effects observed.
Limitations: Details limited in available raw data sources.
6Efficacy and tolerability of plecanatide for irritable bowel syndrome with constipation and chronic idiopathic constipation: a systematic review and meta-analysisPMID 41604554
Not specified in raw data - Not specified in raw data (2025) - Systematic review and meta-analysis - Pooled data from multiple RCTs
Confirmed efficacy of plecanatide for both CIC and IBS-C across pooled data. Consistent with individual trial results.
Limitations: Details limited in available raw data sources.
7Assessing real-world safety of plecanatide: a pharmacovigilance study based on the FDA adverse event reporting system
Zhang Z, Yao Y, Zhu L. - Frontiers in Pharmacology (2024) - FAERS pharmacovigilance analysis - 861 FAERS reports through 2024 Q2
Diarrhea most frequently reported AE (~20% of reports). Most events within 7 days of initiation. No new unexpected serious safety signals. Death (4.1%) and hospitalization (4.3%) in FAERS reports but no causal attribution established beyond known GI risks.
Limitations: FAERS is voluntary spontaneous reporting; subject to reporting bias, cannot establish causality or incidence rates.
8Efficacy and Safety of Plecanatide Comparing With Placebo in the Treatment of Functional Constipation in Chinese PatientsNCT05151328
Shandong Luoxin Pharmaceutical Group Stock Co., Ltd. - ClinicalTrials.gov (2022) - Phase III RCT, double-blind, placebo-controlled (Chinese population) - n=648 enrolled (320 plecanatide, 320 placebo)
Trial completed October 2023. Results not yet published in available data sources.
Limitations: Results not yet publicly available in peer-reviewed literature.
9Pilot Study of GCC Agonists to Identify a Cyclic-GMP Signal in Duodenal Tissue of VolunteersNCT05107219
University of Wisconsin, Madison; NCI - ClinicalTrials.gov (2022) - Early Phase I pilot, randomized, parallel (plecanatide vs linaclotide vs no agent) - n=43 enrolled
Active, not recruiting. Evaluating cGMP accumulation and VASP phosphorylation in duodenal tissue biopsies after single dose of plecanatide 3 mg or linaclotide 145 mcg vs no agent. Estimated completion February 2026. Exploratory cancer prevention angle.
Limitations: Small pilot study. Not powered for clinical endpoints. Results pending.
10Plecanatide, an oral guanylate cyclase C agonist acting locally in the gastrointestinal tract, is safe and well-tolerated in single dosesPMID 23625291
Shailubhai K, Comiskey S, Foss JA, et al. - Digestive Diseases and Sciences (2013) - Phase I single-dose safety study - Healthy volunteers, small (n<100)
Plecanatide was safe and well-tolerated in single oral doses up to 48.6 mg. No measurable plasma concentrations at any dose, confirming negligible systemic absorption.
Limitations: Small Phase I study. Single-dose only. Healthy volunteers, not patients.