Linaclotide (Linzess)
Linaclotide (synthetic 14-amino-acid guanylate cyclase-C agonist peptide)
Linaclotide is an FDA-approved 14-amino acid oral GC-C agonist indicated for IBS-C in adults and pediatric patients 7 years and older, chronic idiopathic constipation (CIC) in adults, and functional constipation (FC) in pediatric patients 6 years and older, increasing intestinal fluid secretion and reducing visceral pain (FDA label 2025; PMID 22986440).
Last updated: 2026-03-10
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).
Known Side Effects
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Who Should NOT Use This
Boxed warning: deaths due to dehydration were observed in neonatal mice given linaclotide. Contraindicated in patients less than 2 years of age (FDA label 2025).
Contraindicated in patients with known or suspected mechanical GI obstruction (FDA label 2025).
The FDA label advises suspending dosing and rehydrating the patient if severe diarrhea occurs. Post-marketing reports include severe diarrhea associated with dizziness, syncope, hypotension, and electrolyte abnormalities requiring hospitalization (FDA label 2025).
While linaclotide is minimally absorbed and maternal use is not expected to result in fetal exposure, available data are not sufficient to inform drug-associated risk for major birth defects and miscarriage. Severe maternal toxicity with fetal effects was observed in mice at very high doses. Use only if clearly needed (FDA label 2025).
Talk to Your Doctor
Before considering Linaclotide (Linzess), 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: [1-13]
Evidence Assessment
Linaclotide meets Tier 1: FDA-approved in August 2012 (NDA 202811) for IBS-C and CIC, with label expanded in November 2025 to include pediatric IBS-C (7+) and FC (6+). Approval was supported by multiple large Phase 3 RCTs (PMID 22986440; PMID 26222318) and is reinforced by a 2024 systematic review/meta-analysis (PMID 38166671) and large real-world safety data (N=2963; PMID 39917729). This represents the highest evidence tier: FDA-approved with multiple Phase 3 RCTs (FDA label 2025;).
1A 12-Week, Randomized, Controlled Trial With a 4-Week Randomized Withdrawal Period to Evaluate the Efficacy and Safety of Linaclotide in Irritable Bowel Syndrome With ConstipationNCT00948818PMID 22986440
Rao S et al. - American Journal of Gastroenterology (2012) - RCT (Phase 3) - N=800 (intent-to-treat population)
Linaclotide 290 mcg significantly improved the 12-week FDA composite endpoint responder rate vs placebo (33.6% vs 21.0%, p<0.0001). Most treated patients had an SBM within 24 hours of first dose (67.4% vs 43.8%). Abdominal pain improvement began in week 1 and peaked at weeks 6-8. Diarrhea in 19.5% vs 3.5% placebo; severe diarrhea in 2%; discontinuation due to diarrhea 5.7%.
Limitations: 12 weeks + 4-week withdrawal; US-centric population. Sponsored by Ironwood Pharmaceuticals and Forest Laboratories.
2Linaclotide in Chronic Idiopathic Constipation Patients with Moderate to Severe Abdominal Bloating: A Randomized, Controlled TrialNCT01642914PMID 26222318
Lacy BE et al. - PLOS One (2015) - RCT (Phase 3b) - N=483 (intent-to-treat population)
Linaclotide 145 mcg met the primary 9/12-week CSBM responder endpoint vs placebo. Median time to first SBM: 12.5 hours vs 28.1 hours with placebo. Bloating improvement from week 1. Diarrhea: 5.9% with 145 mcg, 16.9% with 290 mcg vs 2.3% placebo. No serious diarrhea-related AEs.
Limitations: CIC population enriched for bloating; 12-week duration. Industry-sponsored.
3Efficacy and Safety of Linaclotide in Patients with IBS-C: Chinese Sub-Cohort Analysis of a Phase III TrialNCT01880424PMID 35019221
Peng et al. - Journal of Digestive Diseases (2022) - RCT (Phase 3, sub-cohort analysis) - N=659 Chinese adults with IBS-C
12-week abdominal pain/discomfort responder rate 62.1% vs 53.3% placebo. IBS degree-of-relief responder rate 32.1% vs 16.7%. Symptom improvement began within 1-2 weeks. Diarrhea 8.3% vs 1.2%.
Limitations: Sub-cohort analysis, not standalone registration trial. Chinese population only.
4Randomised Clinical Trial: Linaclotide vs Placebo -- A Study of Bi-Directional Gut and Brain AxisNCT02078323PMID 32406112
Rao SSC et al. - Alimentary Pharmacology and Therapeutics (2020) - RCT (mechanistic) - N=39 IBS-C patients with rectal hypersensitivity
Linaclotide prolonged recto-cortical evoked potential latencies (P1: delta 19 +/- 6 ms, p<0.005; N1: delta 20 +/- 7 ms, p<0.02). Maximum tolerable rectal volume increased vs placebo (delta 29 +/- 10 vs 4 +/- 20 cc, p<0.03). CSBM frequency increased (p<0.001). IBS-QoL improved (p=0.01). Provides neurophysiological evidence for analgesic mechanism.
Limitations: Small sample (N=39). 10-week duration. Overall responder rate not significantly different (54% vs 23%, p=0.13) likely due to underpowering.
5Comparative Profiles of Lubiprostone, Linaclotide, and Elobixibat for Chronic Constipation: A Systematic Literature Review with Meta-Analysis and NNT/NNHPMID 38166671
Rao S et al. - BMC Gastroenterology (2024) - Systematic review and meta-analysis - 24 studies in systematic review, 17 RCTs in meta-analysis
Across chronic-constipation studies, linaclotide showed strong efficacy with among the lowest NNT values for global response and abdominal-pain improvement. Diarrhea remained the principal treatment-emergent harm signal.
Limitations: Indirect comparison across agents with heterogeneous populations, designs, and dose selections.
6Real-World Safety of Linaclotide in Chinese Patients with IBS-C: A Multicenter, Single-Arm, Prospective Observational StudyNCT04462900PMID 39917729
Xiao et al. - Therapeutic Advances in Gastroenterology (2025) - Prospective observational (real-world safety) - N=2963 (safety population)
AEs in 24.0% of patients (95% CI 22.5-25.6%), mostly mild (89.9%). Diarrhea in 10.0%, all mild or moderate. Discontinuation due to AEs only 2.4%. Treatment satisfaction increased from 2.8 at baseline to 3.9 at week 12. IBS-QoL improved. Two SAEs considered possibly related (hemorrhoid and spontaneous abortion).
Limitations: Single-arm, no placebo control. Chinese population. Only 23.7% completed full 12-week follow-up.
7Efficacy and Safety of Linaclotide for Opioid-Induced Constipation in Patients with Chronic Noncancer Pain Syndromes from a Phase 2 Randomized StudyNCT02270983PMID 32310620
Brenner DM et al. - Pain (2020) - RCT (Phase 2) - N=254 randomized adults with OIC
Mean SBM change from baseline: 2.9 and 3.5 per week with 145 mcg and 290 mcg vs 1.6 with placebo. Significant improvements in stool consistency, straining, abdominal bloating, and treatment satisfaction. No serious diarrhea-related AEs.
Limitations: Exploratory off-label indication. Modest sample size. Only 8 weeks. Manufacturer-sponsored.
8Phase 2b Study of Delayed-Release Linaclotide Formulations for IBS-CPMID 33065589
Brenner DM et al. - American Journal of Gastroenterology (2020) - RCT (Phase 2b) - Multiple dose cohorts
Delayed-release formulations designed for more distal gut release showed efficacy for IBS-C with potentially improved diarrhea rates vs immediate-release.
Limitations: Phase 2b; not yet approved. Manufacturer-sponsored.
9Effects of Linaclotide on Abdominal Symptoms in Patients with Chronic Constipation: Pooled Analysis of Two Phase 3 TrialsPMID 25312449
Rao S et al. - Digestive Diseases and Sciences (2014) - Pooled analysis of RCTs - Pooled from two Phase 3 CIC trials
Linaclotide 145 mcg significantly improved abdominal discomfort, bloating, and pain in CIC patients vs placebo. Effects observed as early as week 1.
Limitations: Post-hoc pooled analysis. Both source trials manufacturer-sponsored.
10Efficacy and Safety of Linaclotide as an Adjunct to Polyethylene Glycol in Bowel Preparation: A Meta-AnalysisPMID 40955723
Shafique M et al. - Journal of Gastroenterology and Hepatology (2025) - Meta-analysis of 11 RCTs - 11 RCTs, all from China
Linaclotide + PEG provided comparable overall bowel cleansing (RR 1.01, 95% CI 0.98-1.04). 3L PEG + linaclotide superior to 3L PEG alone for bowel prep adequacy (RR 1.11, 95% CI 1.01-1.23) and BBPS score (MD 0.44). Polyp detection improved in 3L PEG + linaclotide subgroup (RR 1.78, 95% CI 1.32-2.40). Reduced abdominal pain, bloating, nausea.
Limitations: All 11 RCTs from China; limited generalizability. Varying linaclotide doses (290-870 mcg). Off-label use.
11A Pharmacovigilance Study of the Association Between Linaclotide/Plecanatide and Muscle Spasms Based on FDA FAERSPMID 40843382
Not specified - Frontiers in Pharmacology (2025) - Pharmacovigilance / disproportionality analysis - 182 linaclotide-associated muscle spasm reports from 19M+ FAERS reports
Significant safety signal for muscle spasms with linaclotide (ROR 1.88, 95% CI 1.63-2.18). Females 72.3% of cases. Early failure-type pattern. Proposed mechanisms include electrolyte imbalance and neuro-reflex pathways.
Limitations: FAERS data subject to reporting bias, underreporting. No denominator for incidence. Mechanisms speculative.
12Partially Differentiated Ileal and Distal-Colonic Human F508del-CF-Enteroids Secrete Fluid in Response to Forskolin and LinaclotidePMID 40395669
Singh V et al. - iScience (Cell Press) (2025) - In vitro (human enteroids) - Enteroids from 3 F508del-CF patients + 3 healthy subjects
F508del-CF enteroids showed ~67% of normal linaclotide-induced swelling response. Linaclotide independently enhanced CFTR modulator-induced fluid secretion. Both CFTR and NHE3 contributed to linaclotide's secretory effect.
Limitations: In vitro only; no clinical data in CF patients. Small number of enteroid lines.
13Linaclotide for The Treatment of Refractory Lower Bowel Manifestations of Systemic Sclerosis
Dein E et al. - Research Square (preprint); subsequently published in BMC Gastroenterology 2021 (2020) - Retrospective case series - SSc patients with refractory lower GI disease
Linaclotide showed benefit in systemic sclerosis patients with refractory lower bowel manifestations. Responders maintained benefit at 12+ months.
Limitations: Small retrospective series. Single center (Johns Hopkins).