Trulance (Plecanatide)
plecanatide
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Chronic idiopathic constipation (CIC) | Adults (≥18 years) | Monotherapy | FDA Approved |
| Irritable bowel syndrome with constipation (IBS-C) | Adults (≥18 years) | Monotherapy | FDA Approved |
Plecanatide was first approved by the FDA in January 2017 for CIC in adults, followed by the IBS-C indication in January 2018. It is the only GC-C agonist that is a structural analog of the endogenous hormone uroguanylin, and unlike linaclotide, it exhibits pH-sensitive receptor binding that preferentially activates GC-C in the mildly acidic environment of the proximal small intestine. The AGA issued a conditional recommendation for plecanatide in IBS-C based on moderate-certainty evidence (AGA 2022), and the AGA/ACG jointly recommended plecanatide strongly for CIC in adults who do not respond to over-the-counter agents (AGA/ACG 2023). Plecanatide does not have any approved pediatric indications.
No well-established off-label indications exist for plecanatide. Anecdotal use parallels linaclotide off-label uses (e.g., opioid-induced constipation refractory to PAMORAs), but evidence is extremely limited. Evidence quality: Very low.
Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| CIC — adult | 3 mg once daily | 3 mg once daily | 3 mg/day | No titration required; take with or without food, any time of day 6 mg dose did not add clinical benefit and increased adverse events in trials |
| IBS-C — adult | 3 mg once daily | 3 mg once daily | 3 mg/day | Same dose as CIC; single strength simplifies prescribing Addresses both abdominal pain and stool frequency in IBS-C |
| Swallowing difficulty — crushed tablet | 3 mg once daily | 3 mg once daily | 3 mg/day | Crush tablet and mix with 1 tsp applesauce or dissolve in 30 mL water; consume immediately Can also be given via NG or gastric tube with 30 mL water |
A key practical advantage of plecanatide over linaclotide is that it can be taken with or without food, at any time of day. Linaclotide must be taken on an empty stomach at least 30 minutes before the first meal. For patients who find fasting requirements burdensome or who eat at irregular times, plecanatide offers greater dosing flexibility. The single 3 mg dose for both indications also eliminates the need to distinguish between CIC and IBS-C dosing.
Pharmacology
Mechanism of Action
Plecanatide is a 16-amino-acid synthetic peptide that is structurally nearly identical to human uroguanylin, differing by only a single amino acid substitution designed to enhance GC-C binding affinity. Like its endogenous counterpart, plecanatide functions as a guanylate cyclase-C agonist, binding to GC-C receptors on the luminal surface of the intestinal epithelium. This binding is pH-sensitive, with higher affinity in the mildly acidic environment of the proximal small intestine (pH ~5–6), which mirrors how endogenous uroguanylin normally regulates intestinal fluid balance. Activation of GC-C increases both intracellular and extracellular cyclic guanosine monophosphate (cGMP). Intracellular cGMP stimulates chloride and bicarbonate secretion through the CFTR ion channel, increasing intestinal fluid and accelerating transit. Extracellular cGMP reduces the activity of visceral pain-sensing afferent neurons in animal models, contributing to abdominal pain relief in IBS-C.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Negligible systemic absorption; plasma concentrations below limit of quantitation in the majority of samples after 3 mg dosing | Standard PK parameters (AUC, Cmax, t½) cannot be calculated; drug action is entirely local in the GI lumen |
| Distribution | Minimally distributed to tissues; negligible binding to human serum albumin and α-1-acid glycoprotein | No dose adjustment required for renal or hepatic impairment; systemic off-target effects not expected |
| Metabolism | Metabolized in the GI tract by loss of the terminal leucine to form an active metabolite; both parent and metabolite are proteolytically degraded to smaller peptides and amino acids | No CYP2C9 or CYP3A4 inhibition; no CYP3A4 induction; not a P-gp or BCRP substrate or inhibitor |
| Elimination | No human excretion studies conducted; drug and metabolite not measurable in plasma at recommended doses | Entirely degraded within the intestinal lumen; renal and hepatic clearance pathways not relevant |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Diarrhea | 5% (CIC); 4.3% (IBS-C) | The only adverse effect reported at ≥2% in any trial; placebo rate was 1% in both populations; notably lower diarrhea rate than linaclotide (16–20%) |
| Nausea | 1–2% (IBS-C) | Reported in 1–<2% of IBS-C patients at a rate exceeding placebo |
| Nasopharyngitis | 1–2% (IBS-C) | Likely coincidental; observed in IBS-C trials |
| Upper respiratory tract infection | <2% (both CIC and IBS-C) | Reported at incidence exceeding placebo in both trial populations |
| Abdominal distension | <2% (CIC) | Noted in CIC trials at a rate above placebo |
| Flatulence | <2% (CIC) | Reported in CIC trials; self-limiting in most patients |
| Dizziness | 1–2% (IBS-C) | Reported in the IBS-C trials at incidence exceeding placebo |
| Urinary tract infection | 1–2% (IBS-C) | Likely coincidental; no plausible pharmacological mechanism |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Severe diarrhea with dehydration | 0.6% (CIC); 1% (IBS-C) | Within first 3 days (CIC); within first day (IBS-C) | Suspend dosing immediately; rehydrate orally or parenterally; monitor electrolytes |
| Elevated hepatic transaminases (ALT >5× ULN) | Rare (2–3 patients per trial population) | Variable | Monitor LFTs; discontinue if clinically significant elevation persists; evaluate alternative causes |
| Hypersensitivity reactions (pruritus, urticaria, rash) | Very rare (postmarketing) | Any time | Discontinue; standard allergy management; do not rechallenge if severe |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Diarrhea | 2% (CIC); 1.2% (IBS-C) | Placebo comparator: 0.5% (CIC), 0% (IBS-C); notably lower discontinuation rate than linaclotide |
Diarrhea is the primary tolerability concern with plecanatide, though its overall incidence (4–5%) and discontinuation rate (1–2%) are substantially lower than those reported with linaclotide (16–20% incidence, 2–5% discontinuation). Most cases begin within the first 4 weeks. In the CIC trials, severe diarrhea occurred within the first 3 days. If severe diarrhea occurs, suspend dosing and ensure adequate rehydration. Post-marketing experience has confirmed a low real-world diarrhea rate, with reports indicating a rate under 0.5% and no cases of severe diarrhea requiring hospitalization.
Drug Interactions
Plecanatide has an exceptionally clean drug interaction profile due to its local GI activity and negligible systemic absorption. In vitro studies confirmed that neither plecanatide nor its active metabolite inhibits CYP2C9 or CYP3A4, induces CYP3A4, or acts as a substrate or inhibitor of P-glycoprotein or BCRP transporters. No formal drug-drug interaction studies were deemed necessary by the FDA. Additionally, a pooled analysis of Phase 3 CIC trial data demonstrated that concomitant use of acid suppression therapy (PPIs and H2RAs) did not diminish plecanatide efficacy or alter its safety profile.
The absence of CYP, transporter, and systemic pharmacokinetic interactions, combined with confirmed safety alongside acid suppression therapy, makes plecanatide particularly suitable for patients on polypharmacy regimens. No dose adjustments are needed for any concomitant medication.
Monitoring
-
Stool Pattern
Weeks 1–4, then as needed
Routine Assess stool frequency, consistency, and presence of diarrhea. Most diarrhea begins within the first 4 weeks. In CIC trials, severe diarrhea occurred within the first 3 days. If severe, suspend dosing and rehydrate. -
Hydration Status
First 4 weeks, then as needed
Routine Monitor for signs of dehydration, particularly in elderly patients and those on diuretics. Parenteral rehydration may be necessary in severe cases. -
Hepatic Function
If symptoms arise
Trigger-based Elevated ALT (>5–15× ULN) and AST (>5× ULN) were reported in a small number of patients in clinical trials. Check LFTs if hepatic symptoms develop; no routine baseline LFTs are mandated by the label. -
Abdominal Symptoms
Baseline, then 4–8 weeks
Routine Track abdominal pain severity and bloating in IBS-C patients. In trials, improvement in CSBM frequency was observed as early as week 1. Reassess treatment if no benefit after 4–6 weeks. -
Treatment Efficacy
4–8 weeks after initiation
Routine Evaluate whether the patient has met treatment goals for bowel frequency (target ≥3 CSBMs/week). In clinical trials, TRULANCE-treated patients returned to baseline within 2 weeks of stopping treatment.
Contraindications & Cautions
Absolute Contraindications
- Age <6 years: Contraindicated due to risk of fatal dehydration from GC-C agonism-induced fluid secretion in immature intestine (FDA Boxed Warning).
- Known or suspected mechanical gastrointestinal obstruction: Secretory effects may worsen obstruction-related complications.
Relative Contraindications (Specialist Input Recommended)
- Age 6 to <18 years: The FDA label explicitly states to avoid use in this population. Safety and efficacy have not been established in any pediatric age group. Although no deaths occurred in older juvenile mice, the lack of clinical data in children warrants avoidance.
- Known hypersensitivity to plecanatide or any excipient: Pruritus, urticaria, and rash have been reported postmarketing.
Use with Caution
- Elderly patients on diuretics or with limited fluid intake: Higher susceptibility to dehydration from drug-induced diarrhea.
- Patients with inflammatory bowel disease: Not studied in IBD; theoretical concern that increased secretion could exacerbate diarrhea in active disease.
- Pregnancy: No adequate human data, though negligible systemic absorption suggests low fetal risk. Use only if benefit justifies potential risk.
- Lactation: Plecanatide and its metabolite were not detected in breast milk after 3 mg daily for 2 weeks, but potential for adverse effects in breastfed infants exists due to GC-C sensitivity in neonates.
Plecanatide is contraindicated in patients less than 6 years of age. In nonclinical studies, a single oral dose of plecanatide caused deaths due to dehydration in young juvenile mice (human age equivalent of approximately 1 month to less than 2 years) as a consequence of GC-C stimulation. Due to increased intestinal expression of GC-C, children under 6 years are at disproportionate risk of severe diarrhea and life-threatening dehydration. Use should also be avoided in patients 6 to less than 18 years of age given the absence of pediatric clinical data. Accidental ingestion by young children can be life-threatening; patients must store the medication securely out of reach of children.
Patient Counselling
Purpose of Therapy
Plecanatide works directly in the intestine to increase fluid secretion, soften stools, and speed up bowel transit. In patients with IBS-C, it also helps reduce abdominal pain by mimicking a natural hormone (uroguanylin) that regulates gut fluid. Most patients begin to notice improvement in stool frequency within the first week of treatment.
How to Take
Take one 3 mg tablet once daily, with or without food, at any convenient time of day. Swallow the tablet whole. If you cannot swallow tablets, you can crush the tablet and mix it with a teaspoon of applesauce (swallow immediately) or dissolve it in 30 mL of room-temperature water. If you miss a dose, skip it and take the next one at your regular time.
Sources
- TRULANCE (plecanatide) tablets, for oral use. Full Prescribing Information. Salix Pharmaceuticals (originally Synergy Pharmaceuticals Inc.). Initial approval January 2017; IBS-C indication added January 2018; label updated through April 2021. DailyMedPrimary source for all dosing, adverse reaction rates, contraindications, and pharmacokinetic data. Lactation and postmarketing data from 2020–2021 label revisions.
- Trulance (plecanatide) FDA Approval History. Drugs.com. Accessed April 2026. Drugs.comTimeline of FDA regulatory actions from CIC approval (Jan 2017) through IBS-C approval (Jan 2018).
- Miner PB Jr, Koltun WD, Wiener GJ, et al. A randomized phase III clinical trial of plecanatide, a uroguanylin analog, in patients with chronic idiopathic constipation. Am J Gastroenterol. 2017;112(4):613–621. DOIPivotal Phase 3 CIC trial (Study 1, N=1394) establishing efficacy of plecanatide 3 mg (21% vs 10.2% placebo responder rate).
- DeMicco M, Barrow L, Hickey B, et al. Randomized clinical trial: efficacy and safety of plecanatide in the treatment of chronic idiopathic constipation. Therap Adv Gastroenterol. 2017;10(11):837–851. DOISecond pivotal Phase 3 CIC trial (Study 2, N=1337) confirming durable CSBM response (21% vs 13% placebo).
- Brenner DM, Fogel R, Dorn SD, et al. Efficacy, safety, and tolerability of plecanatide in patients with irritable bowel syndrome with constipation: results of two phase 3 randomized clinical trials. Am J Gastroenterol. 2018;113(5):735–745. DOITwo pivotal Phase 3 IBS-C trials (Studies 3 and 4, N=2189 total) establishing combined responder rates of 30% and 21% vs placebo.
- Brenner DM, Sharma A, Rao SSC, et al. Plecanatide improves abdominal bloating and bowel symptoms of irritable bowel syndrome with constipation. Dig Dis Sci. 2024;69(5):1731–1738. DOIPooled Phase 3 post-hoc analysis demonstrating plecanatide efficacy in IBS-C patients with moderate-to-severe bloating.
- Chang L, Sultan S, Lembo A, et al. AGA Clinical Practice Guideline on the pharmacological management of irritable bowel syndrome with constipation. Gastroenterology. 2022;163(1):118–136. DOIConditional recommendation for plecanatide in IBS-C based on moderate-certainty evidence.
- Chang L, Chey WD, Imdad A, et al. AGA–ACG Clinical Practice Guideline: pharmacological management of chronic idiopathic constipation. Gastroenterology. 2023;164(7):1086–1106. DOIStrong recommendation for plecanatide for CIC after OTC agent failure, based on moderate-certainty evidence.
- Lacy BE, Pimentel M, Brenner DM, et al. ACG Clinical Guideline: management of irritable bowel syndrome. Am J Gastroenterol. 2021;116(1):17–44. DOIACG guideline recommending GC-C agonists (including plecanatide) for IBS-C based on high-quality evidence.
- Shailubhai K, Comiskey S, Foss JA, et al. Plecanatide, an oral guanylate cyclase C agonist acting locally in the gastrointestinal tract, is safe and well-tolerated in single doses. Dig Dis Sci. 2013;58(9):2580–2586. DOIPhase 1 study confirming local GI action, negligible systemic absorption, and safety in healthy volunteers.
- Boulete IM, Thadi A, Beaufrand C, et al. Oral treatment with plecanatide or dolcanatide attenuates visceral hypersensitivity via activation of guanylate cyclase-C in rat models. World J Gastroenterol. 2018;24(17):1888–1900. DOIPreclinical evidence that GC-C agonism with plecanatide reduces visceral pain signaling in animal models.
- Moshiree B, Schoenfeld P, Franklin H, et al. The effect of acid suppression therapy on the safety and efficacy of plecanatide: analysis of randomized phase III trials. Clin Ther. 2022;44(1):98–110.e1. DOIPooled Phase 3 analysis confirming that concomitant PPI/H2RA use does not affect plecanatide efficacy or safety.
- Menees SB, Franklin H, Chey WD. Evaluation of plecanatide for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation in patients 65 years or older. Clin Ther. 2020;42(7):1406–1414.e4. DOIPooled Phase 3 analysis in elderly patients (≥65 years) confirming comparable efficacy and safety to the younger population.