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Plecanatide

Tier 1 · Human trials
Also known as Trulance · SP-304

Supported by multiple human randomized controlled trials (Phase 2b and two Phase III CIC studies, IBS-C trials), pooled analyses, subgroup analyses, guideline recommendations, and FDA approval. Mechanistic and pediatric-safety details draw on animal and theoretical/expert sources, but the strongest evidence present is Tier 1 human clinical/RCT data.

Half-life
Not recorded
Routes
Oral
Goals
Digestive/gastrointestinal function · Chronic constipation relief · IBS-C symptom management
Cost / mg
Not recorded

How it works

Plecanatide is a synthetic 16-amino-acid peptide that mimics a natural human hormone called uroguanylin. It works locally inside the gut by switching on a receptor (guanylate cyclase-C, or GC-C) on the surface of intestinal lining cells. This triggers the cells to pump chloride and bicarbonate into the intestine, which draws in more fluid, softens stool, and speeds up movement through the bowel. It is designed to stay in the gut and is barely absorbed into the bloodstream. Animal studies also suggest it can quiet pain-sensing nerves in the intestine.

Overview

Overview

Plecanatide (brand name Trulance, development code SP-304) is a synthetic 16-amino-acid peptide with two disulfide bonds that acts as a guanylate cyclase-C (GC-C) receptor agonist. It is a structural analog of the endogenous human hormone uroguanylin, differing by a single amino acid substitution that confers greater GC-C binding affinity. It is the second-in-class GC-C agonist, following linaclotide (a 14-amino-acid peptide).

Mechanism

As a luminally acting secretagogue, plecanatide binds GC-C on the apical surface of intestinal epithelial cells, increasing intracellular and extracellular cGMP. This activates the CFTR ion channel, promoting chloride and bicarbonate secretion into the intestinal lumen, which increases intestinal fluid and accelerates transit. In animal models it acts in a pH-sensitive manner within the small intestine. GC-C agonists as a class also provide visceral analgesia, and animal studies indicate plecanatide decreases the activity of pain-sensitive intestinal nerves.

Development & Approvals

Plecanatide was first developed in 2007 and received its first global approval (US FDA) in January 2017 for adult chronic idiopathic constipation (CIC). It was subsequently approved for irritable bowel syndrome with constipation (IBS-C) in adults (reported as January 2018 or 2018 depending on source). Marketed as TRULANCE, it is indicated in adults aged 18 and older for both CIC and IBS-C. It is offered as a prosecretory/secretagogue option for CIC patients not responding to traditional laxatives.

Clinical Evidence

  • A Phase 2b study in 951 CIC patients over 12 weeks tested 0.3, 1.0, and 3.0 mg once daily; the 3.0 mg dose gave the highest overall responder rate (19.0% vs 10.7% placebo, p=0.009), 0.3 mg was significant (p=0.016), and 1 mg was not (p=0.057).
  • Two Phase III CIC studies tested 3 mg and 6 mg over 12 weeks; both beat placebo, but no dose-response was observed between 3 mg and 6 mg.
  • Pooled CIC trials: durable overall CSBM responder rates of 21.0% (3 mg) and 19.5% (6 mg) vs 10.2% placebo (p<0.001); increased mean weekly CSBM by 2.5/week (3 mg) and 2.2/week (6 mg) vs 1.2/week placebo, and SBM by 3.2/3.1/week vs 1.3/week placebo.
  • Plecanatide significantly reduced straining, improved stool consistency, and reduced bloating, with high patient satisfaction and improved quality of life.
  • A subgroup analysis (N=2,639) showed benefit across most demographic groups; the 3 mg dose was also significantly superior in patients 65+, non-White individuals, and BMI ≥30.
  • In IBS-C patients with baseline bloating (605 adults), 3 mg over 12 weeks significantly improved abdominal pain, bloating, and CSBMs; composite response was 23.3% vs 13.4% (p=0.002).
  • A network meta-analysis (17,214 patients, 33 RCTs) found plecanatide superior to placebo on CSBM endpoints, like almost all drugs studied.
  • Guideline panels made a strong recommendation for plecanatide in CIC and a conditional recommendation with moderate-certainty evidence for IBS-C.

Epidemiologic Context

Chronic constipation affects roughly one-third of the US population, disproportionately the elderly and females; CIC pooled prevalence is about 14%, and around 60% of CIC patients are not satisfied by current prescribed treatment.

What the research shows

168 findings extracted from the 28 sources cited below, strongest evidence first within each group. Every one links to the source it came from.

What human studies found

Based on 45 human trial findings and 2 human study findings.

  • human trialThe 3.0 mg dose provided the highest overall responder rate (19.0% vs. 10.7% for placebo) and a statistically significant treatment difference compared to placebo (p = 0.009)1

  • human trial1 mg dose did not result in statistically significant difference from the placebo (p = 0.057)1

  • human trial0.3 mg dose level resulted in a statistically significant difference from the placebo (p = 0.016)1

  • human trialNo dose-response was observed between 3 mg and 6 mg doses for primary efficacy endpoint while both dose levels have shown statistically significant improvement over placebo1

  • human trialPlecanatide at 3 mg dose resulted in 21.0% durable overall complete spontaneous bowel movement (CSBM) responders over 12 weeks2

  • human trialPlecanatide at 6 mg dose resulted in 19.5% durable overall CSBM responders over 12 weeks2

  • human trialPlacebo resulted in 10.2% durable overall CSBM responders2

  • human trialPlecanatide 3 mg increased mean weekly CSBM frequency by 2.5/week from baseline2

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  • human trialPlecanatide 6 mg increased mean weekly CSBM frequency by 2.2/week from baseline2

  • human trialPlacebo increased mean weekly CSBM frequency by 1.2/week from baseline2

  • human trialPlecanatide 3 mg increased mean weekly spontaneous bowel movement frequency by 3.2/week2

  • human trialPlecanatide 6 mg increased mean weekly spontaneous bowel movement frequency by 3.1/week2

  • human trialPlacebo increased mean weekly spontaneous bowel movement frequency by 1.3/week2

  • human trialStudy duration was 12 weeks2

  • human trialRandomized clinical trial showed that plecanatide resulted in a significantly greater percentage of durable overall bowel movements and improved stool6

  • human trialFDA approved plecanatide for treatment of CIC in January 20178

  • human trialFDA approved plecanatide for treatment of IBS-C in January 20188

  • human trialLinaclotide and lubiprostone are pro-secretory agents that have been shown to be effective and well tolerated for treatment of CIC8

  • human trialBoth doses of plecanatide, 3 mg and 6 mg resulted in a significantly greater percentage of patients who were durable overall complete spontaneous bowel movement (CSBM) responders compared with those who received placebo11

  • human trialPlecanatide treatment significantly reduced the severity of other CIC symptoms (straining effort, stool consistency, bloating)11

  • human trialPlecanatide-treated patients reported high levels of satisfaction and improved QOL and desire to continue treatment11

  • human trialThe safety and effectiveness of TRULANCE have not been established in patients less than 18 years of age14

  • human trialPlecanatide was included in a systematic review and meta-analysis of pharmacological therapies for functional constipation in children15

  • human trialOne randomised controlled trial of plecanatide in children with functional constipation was identified in the systematic review15

  • human trialPlecanatide 3 mg significantly improved abdominal pain in IBS-C patients with baseline bloating compared to placebo over 12 weeks16

  • human trialPlecanatide 3 mg significantly improved bloating in IBS-C patients compared to placebo over 12 weeks16

  • human trialPlecanatide 3 mg significantly increased complete spontaneous bowel movements (CSBMs) per week in IBS-C patients compared to placebo over 12 weeks16

  • human trial23.3% of plecanatide-treated patients versus 13.4% of placebo-treated patients achieved ≥30% improvement in pain and bloating plus ≥1 CSBM/week increase16

  • human trial19.5% of plecanatide-treated patients versus 8.9% of placebo-treated patients achieved ≥30% improvement in pain and bloating plus ≥2 CSBMs/week increase16

  • human trialStrong recommendation for the use of plecanatide for CIC in adults based on available evidence17

  • human trialThe panel made a strong recommendation for the use of plecanatide for chronic idiopathic constipation in adults based on available evidence18

  • human trialCSBM responder rates were significantly greater with 3 mg of plecanatide and 6 mg of plecanatide vs placebo in subgroups younger than 65 years20

  • human trialCSBM responder rates were significantly greater with 3 mg of plecanatide and 6 mg of plecanatide vs placebo in female subgroups20

  • human trialCSBM responder rates were significantly greater with 3 mg of plecanatide and 6 mg of plecanatide vs placebo in White individuals20

  • human trialCSBM responder rates were significantly greater with 3 mg of plecanatide and 6 mg of plecanatide vs placebo in BMI <25 kg/m² and 25-30 kg/m²20

  • human trialFor 3 mg plecanatide, CSBM responder rates were significantly greater vs placebo in those 65 years or older20

  • human trialFor 3 mg plecanatide, CSBM responder rates were significantly greater vs placebo in non-White individuals20

  • human trialFor 3 mg plecanatide, CSBM responder rates were significantly greater vs placebo in BMI ≥30 kg/m²20

  • human trialImprovement from baseline in weekly CSBM and SBM frequency occurred in all subgroups for both plecanatide doses vs placebo at week 12, except those aged 65 years or older for 6 mg of plecanatide20

  • human trialPlecanatide is recommended conditionally for the management of patients with IBS-C21

  • human trialPlecanatide has moderate certainty evidence for IBS-C management21

  • human trialPlecanatide was included in a network meta-analysis comparing efficacy of drugs for chronic idiopathic constipation22

  • human trialPlecanatide was assessed in randomised controlled trials with minimum 4 weeks treatment duration22

  • human trialPlecanatide efficacy was evaluated based on endpoints of failure to achieve three or more complete spontaneous bowel movements per week or failure to achieve increase of one or more CSBM per week from baseline22

  • human trialAlmost all drugs studied including plecanatide were superior to placebo according to either endpoint measure22

  • human studyGC-C agonists improve stool consistency and number of bowel movements in subjects with chronic idiopathic constipation12

  • human studyGC-C agonists provide visceral analgesia12

How it works

Based on 2 human trial findings, 3 animal findings, 14 expert opinion findings and 4 theoretical findings.

  • human trialPlecanatide is a guanylate cyclase-C (GC-C) agonist and uroguanylin analog2

  • human trialPlecanatide works by increasing the fluid secretion of the bowels, which helps ease the passage of stools and relieve the symptoms of constipation7

  • animalStimulates fluid secretion and increases intestinal transit, as demonstrated in animal models5

  • animalActs in a pH-sensitive manner in the small intestine to facilitate fluid secretion5

  • animalDecreases the activity of pain-sensitive nerves in the intestine, based on animal studies5

  • expert opinionPlecanatide is a synthetic, 16-amino acid peptide with 2 disulfide bonds that is a second-in-class guanylate cyclase-C (GC-C) receptor agonist1

  • expert opinionTRULANCE (plecanatide) is a guanylate cyclase-C agonist3

  • expert opinionStructurally identical to human uroguanylin with the exception of a single amino acid substitution for greater GC-C binding affinity5

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  • expert opinionPlecanatide is a 16-amino-acid peptide8

  • expert opinionPlecanatide is a guanylate cyclase-C (GC-C) agonist8

  • expert opinionPlecanatide is a guanylate cyclase-C (GC-C) agonist that stimulates secretion of chloride and bicarbonate into intestinal lumen, which increases intestinal fluid and accelerates intestinal transit9

  • expert opinionPlecanatide is a Guanylate Cyclase-C Agonist10

  • expert opinionPlecanatide is a guanylate cyclase agonist11

  • expert opinionPlecanatide is a 16 amino acid synthetic peptide that is a structural analog of human uroguanylin11

  • expert opinionPlecanatide is a luminally acting secretagogue11

  • expert opinionPlecanatide is a second-in-class, US FDA-approved, synthetic GC-C agonist12

  • expert opinionPlecanatide is a 16-amino acid peptide analog to endogenous uroguanylin12

  • expert opinionPlecanatide is an oral guanylate cyclase-C agonist23

  • expert opinionPlecanatide is a synthetic analogue of human uroguanylin, a 16 amino acid peptide that regulates ion and fluid transport in the gastrointestinal tract23

  • theoreticalTRULANCE is a guanylate cyclase-C agonist4

  • theoreticalPlecanatide is a 16-amino acid peptide that serves as an agonist of guanylate cyclase-C (GC-C)24

  • theoreticalPlecanatide binds to GC-C located on the apical surface of intestinal epithelial cells, thereby leading to an increase in both intracellular and extracellular cyclic guanosine monophosphate (cGMP) levels24

  • theoreticalElevated cGMP activates the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel, promoting chloride and bicarbonate secretion into the intestinal lumen, which increases intestinal fluid and accelerates transit24

Dosing

Based on 10 human trial findings, 3 human study findings and 2 expert opinion findings.

  • human trialPhase 2b study evaluated 0.3, 1.0, and 3.0 mg QD oral doses of plecanatide versus placebo in a total of 951 CIC patients over a 12-week treatment period1

  • human trialTwo dose levels, 3 mg and 6 mg, were evaluated in 2 phase III studies in CIC patients with 12 weeks treatment period1

  • human trialPlecanatide is administered orally once daily2

  • human trialThe recommended adult dosage of plecanatide for CIC is 3 mg taken orally once daily3

  • human trialThe recommended adult dosage of plecanatide for IBS-C is 3 mg taken orally once daily3

  • human trialThe recommended adult dosage of TRULANCE is 3 mg taken orally once daily for CIC4

  • human trialThe recommended adult dosage of TRULANCE is 3 mg taken orally once daily for IBS-C4

  • human trialSwallow the tablet whole. Do not crush, break, or chew it. You may take this medicine with or without food7

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  • human trialIf you have trouble swallowing the tablet, you may mix the contents with applesauce or water7

  • human trialThe recommended adult dosage of TRULANCE is 3 mg taken orally once daily for both CIC and IBS-C14

  • human studyHigher dosage (6 mg daily) not recommended; provides no additional clinical benefit but may increase adverse effects9

  • human studyPlecanatide has been approved in the US for the treatment of irritable bowel syndrome with constipation at doses of 3 and 6 mg12

  • human studyPlecanatide has been approved in the US for the treatment of chronic idiopathic constipation at the 3 mg dosage12

  • expert opinionTRULANCE tablets can be crushed and administered orally in applesauce or with water for patients with swallowing difficulties4

  • expert opinionPlecanatide is available as 3 mg oral tablets10

How the body handles it

Based on 4 human trial findings and 1 human study finding.

  • human trialPlecanatide did not have measurable systemic exposure1

  • human trialPlecanatide can be taken with or without food3

  • human trialTRULANCE can be taken with or without food4

  • human trialTRULANCE can be taken with or without food14

  • human studyAdministration with meals may result in looser stools9

Safety and side effects

Based on 23 human trial findings, 6 human study findings, 9 animal findings and 7 expert opinion findings.

  • human trialDiarrhea occurred in 1.3% of placebo patients, 5.9% of 3 mg plecanatide patients, and 5.7% of 6 mg plecanatide patients2

  • human trialSafety and effectiveness of plecanatide have not been established in patients less than 18 years of age3

  • human trialPatients may experience severe diarrhea with plecanatide; if severe diarrhea occurs, suspend dosing and rehydrate the patient3

  • human trialThe most common adverse reaction to plecanatide (≥2%) is diarrhea3

  • human trialPlecanatide is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction3

  • human trialPatients may experience severe diarrhea from TRULANCE; if severe diarrhea occurs, suspend dosing and rehydrate the patient4

  • human trialMost common adverse reaction (≥2%) is diarrhea4

  • human trialUse of plecanatide is not recommended in children younger than 6 years of age7

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  • human trialSafety and efficacy have not been established in children 6 to 17 years of age7

  • human trialElderly patients are more likely to have kidney, liver, or heart problems, which may require caution and an adjustment in the dose for patients receiving plecanatide7

  • human trialThere are no adequate studies in women for determining infant risk when using this medication during breastfeeding7

  • human trialCall your doctor right away if you have severe diarrhea7

  • human trialSafety and efficacy not established in patients <18 years of age9

  • human trialPlecanatide is contraindicated in infants and children <6 years of age and should be avoided in children and adolescents 6 to <18 years of age9

  • human trialThe product monograph includes clinical trial adverse reactions data10

  • human trialThe rate of treatment-emergent adverse events with plecanatide was low, including rates of diarrhea11

  • human trialSafety of once-daily plecanatide was evaluated over 12 weeks of dosing based on TEAEs and vital signs13

  • human trialMost common adverse reaction (≥2%) is diarrhea14

  • human trialPatients may experience severe diarrhea with TRULANCE; if severe diarrhea occurs, dosing should be suspended and the patient rehydrated14

  • human trialAvoid use of TRULANCE in patients 6 years to less than 18 years of age14

  • human trialTRULANCE is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction14

  • human trialPlecanatide was well tolerated in IBS-C patients16

  • human trialThe most common adverse event was diarrhea with 3 mg plecanatide at 4.9%, 6 mg plecanatide at 5.4%, and placebo at 1.3%20

  • human studyDiarrhea resulting in drug discontinuance occurred in 2% of patients receiving 3-mg daily dosage, generally within 4 weeks of drug initiation9

  • human studySevere diarrhea reported in 0.6% of patients, generally within first 3 days of treatment9

  • human studyPlecanatide has very limited systemic absorption and appears safe in patients with CKD19

  • human studyA total of 861 cases associated with plecanatide were identified, including 2057 adverse event reports24

  • human studyCommon positive adverse events included diarrhea, constipation, abdominal distension, dissatisfaction with treatment, rectal tenesmus, increased fecal volume, abnormal gastrointestinal sounds, and gastrointestinal motility disorders24

  • human studyThe majority of adverse events related to plecanatide occurred within the first 7 days of treatment24

  • animalIn nonclinical studies in young juvenile mice, administration of a single oral dose of plecanatide caused deaths due to dehydration3

  • animalPlecanatide is contraindicated in patients less than 6 years of age due to risk of serious dehydration3

  • animalPlecanatide should be avoided in patients 6 years to less than 18 years of age3

  • animalTRULANCE is contraindicated in patients less than 6 years of age due to risk of serious dehydration; in nonclinical studies in young juvenile mice, administration of a single oral dose of plecanatide caused deaths due to dehydration4

  • animalIn nonclinical studies in young juvenile mice, administration of a single oral dose of plecanatide caused deaths due to dehydration5

  • animalSingle oral doses caused deaths due to dehydration in young juvenile mice9

  • animalNo evidence of adverse embryofetal developmental effects in studies in mice and rabbits9

  • animalNo developmental abnormalities and no effects on growth, learning and memory, or fertility observed in the offspring of exposed mice9

  • animalTRULANCE is contraindicated in patients less than 6 years of age; in nonclinical studies in young juvenile mice, administration of a single oral dose of plecanatide caused deaths due to dehydration14

  • expert opinionAvoid use of TRULANCE in patients 6 years to less than 18 years of age4

  • expert opinionThe safety and effectiveness of TRULANCE have not been established in patients less than 18 years of age4

  • expert opinionTrulance is contraindicated in patients less than 6 years of age5

  • expert opinionUse of TRULANCE should be avoided in patients 6 years to less than 18 years of age5

  • expert opinionThe safety and effectiveness of TRULANCE have not been established in patients less than 18 years of age5

  • expert opinionPlecanatide is contraindicated in known or suspected mechanical GI obstruction9

  • expert opinionThe product includes a Serious Warnings and Precautions Box10

What people use it for

Based on 19 human trial findings, 1 human study finding and 10 expert opinion findings.

  • human trialThe proposed indication for plecanatide is treatment of chronic idiopathic constipation in adults with 3 mg oral dose once daily1

  • human trialPlecanatide is approved for the treatment of chronic idiopathic constipation (CIC)2

  • human trialPlecanatide is indicated in adults for treatment of chronic idiopathic constipation (CIC)3

  • human trialPlecanatide is indicated in adults for treatment of irritable bowel syndrome with constipation (IBS-C)3

  • human trialTRULANCE (plecanatide) is indicated in adults for treatment of chronic idiopathic constipation (CIC)4

  • human trialTRULANCE (plecanatide) is indicated in adults for treatment of irritable bowel syndrome with constipation (IBS-C)4

  • human trialPlecanatide is used to treat chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C)7

  • human trialPlecanatide is indicated for the treatment of chronic idiopathic constipation (CIC) in adults8

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  • human trialPlecanatide is indicated for the treatment of irritable bowel syndrome with constipation (IBS-C) in patients 18 years of age and older8

  • human trialPlecanatide is indicated for symptomatic treatment of chronic idiopathic constipation in adults9

  • human trialPlecanatide is indicated for treatment of chronic idiopathic constipation (CIC) in adults10

  • human trialTRULANCE (plecanatide) is a guanylate cyclase-C agonist indicated in adults for treatment of chronic idiopathic constipation (CIC)14

  • human trialTRULANCE (plecanatide) is a guanylate cyclase-C agonist indicated in adults for treatment of irritable bowel syndrome with constipation (IBS-C)14

  • human trialPlecanatide is a secretagogue agent for pharmacological treatment of chronic idiopathic constipation (CIC) in adults17

  • human trialPlecanatide is a secretagogue agent for pharmacological treatment of chronic idiopathic constipation in adults18

  • human trialPlecanatide is effective for treatment of chronic idiopathic constipation20

  • human trialPlecanatide is one of several agents evaluated for pharmacological management of IBS-C21

  • human trialPlecanatide received its first global approval in the USA in January 2017 for the treatment of adult patients with chronic idiopathic constipation23

  • human trialPlecanatide is undergoing phase III investigation in irritable bowel syndrome with constipation23

  • human studyPlecanatide was approved by the US FDA for the treatment of chronic idiopathic constipation (3 mg) and IBS-C (3 and 6 mg) in patients aged >18 years12

  • expert opinionTrulance (plecanatide) 3 mg tablets are indicated in adults for the treatment of Chronic Idiopathic Constipation (CIC) and Irritable Bowel Syndrome with Constipation (IBS-C)5

  • expert opinionPlecanatide has been approved by the US Food and Drug Administration for the treatment of adults with chronic idiopathic constipation (CIC)11

  • expert opinionPlecanatide was first developed in 2007 and received FDA approval in January 2017 for the treatment of adult chronic idiopathic constipation (CIC)24

  • expert opinionIn 2018, plecanatide was further approved for the indication of irritable bowel syndrome with constipation (IBS-C)24

  • expert opinionChronic constipation affects one-third of the US population25

  • expert opinionChronic constipation occurs disproportionately in the elderly and female individuals25

  • expert opinionChronic constipation increases in older individuals who are institutionalized25

  • expert opinionChronic constipation has a significant impact on health care costs and quality of life25

  • expert opinionPelvic floor dysfunction is more common in elderly individuals and should be considered in diagnostic algorithms for constipation25

  • expert opinionPlecanatide is a prosecretory agent offered as treatment for chronic idiopathic constipation patients not responding to traditional laxatives26

Other findings

Based on 3 expert opinion findings.

  • expert opinionTrulance is the only FDA-approved structural analog of the human peptide uroguanylin5

  • expert opinionPlecanatide is the second-in-class GC-C agonist following linaclotide12

  • expert opinionClinicians need to consider primary as well as secondary causes of constipation in elderly individuals because the cause is often multifactorial25

Points of contention

Where the evidence is unsettled, thin, or says less than the popular claim — worth knowing before you draw conclusions.

Contested

Sources report slightly different dates for the IBS-C approval.

Most sources cite January 2017 for CIC approval; for IBS-C, Plecanatide (Trulance) for Chronic Idiopathic Constipation and Irritable Bowel Syndrome With Constipation states January 2018 while Frontiers | Assessing real-world safety of plecanatide: a pharmacovigilance study based on the FDA adverse event reporting system states 2018 more generally, and Plecanatide: First Global Approval. describes IBS-C as still under Phase III investigation (reflecting its earlier publication date).

Limited evidence

Pediatric use is not established and largely restricted.

Plecanatide is contraindicated under age 6 (based on juvenile mouse deaths from dehydration) and avoided in ages 6 to <18; safety and effectiveness under 18 have not been established. Only a single pediatric RCT was identified in a systematic review of functional constipation in children.

Single source

CKD safety and pharmacovigilance findings each come from one source.

The claim that plecanatide appears safe in CKD is from a single observational review (Constipation in Patients With Chronic Kidney Disease.), and the FAERS-style pharmacovigilance analysis of 861 cases is from a single tier-2 source (Frontiers | Assessing real-world safety of plecanatide: a pharmacovigilance study based on the FDA adverse event reporting system).

Limited evidence

No dose-response benefit above 3 mg despite 6 mg being studied and approved for IBS-C.

Phase III CIC trials showed no dose-response between 3 mg and 6 mg, and one source states the 6 mg dose provides no additional clinical benefit but may increase adverse effects; the recommended dose is 3 mg once daily.

Using it with other compounds

Check a stack
  • TeduglutideStack with caution

    Worth caution

    Both act locally in the intestine but pull in opposite directions on fluid handling. Teduglutide (a GLP-2 agonist) is used to help a compromised gut absorb more fluid and nutrients, while plecanatide deliberately increases fluid secretion into the gut lumen to loosen stool. Combining them could work against each other — a secretagogue like plecanatide may aggravate fluid loss in someone whose treatment goal is to retain fluid — so they should not be casually stacked without medical oversight.

    Tier 4Theoretical — not established

    What the research doesn't fully establish

    The proposed relationship claims shared dimensions of 'gut_barrier_integrity' and 'mucosal_repair,' but the mechanism descriptions do not support these as shared dimensions. Plecanatide's mechanisms focus on cGMP signaling, CFTR-mediated chloride/bicarbonate secretion, and increased intestinal fluid secretion—with no mention of barrier integrity or mucosal repair. Teduglutide explicitly targets mucosal repair, epithelial growth, and barrier function (tagged with gut_barrier_integrity and mucosal_repair). The mechanisms describe fundamentally different pathways and effects. While the explanation correctly identifies opposing effects on fluid handling (a valid clinical concern), this opposition does not constitute a shared dimension of barrier integrity or mucosal repair. The caution relationship may be clinically reasonable, but it is not justified by the claimed shared dimensions in the mechanism material provided.

    Shares gut barrier integrity · mucosal repair

  • LinaclotideSame mechanism

    Research does not support combining these

    Plecanatide and linaclotide are both guanylate cyclase-C (GC-C) agonists that drive the exact same cGMP/CFTR pathway to pull fluid into the gut and speed transit. Stacking them is redundant rather than additive, and combining two secretagogues would sharply raise the risk of watery diarrhea, dehydration and electrolyte loss. If you need a GC-C agonist, pick one — do not run both.

    Tier 4Theoretical — not established

    What the research doesn't fully establish

    Both peptides' mechanisms clearly establish the same primary pathway: GC-C receptor agonism → cGMP signaling → CFTR-mediated chloride/bicarbonate secretion → increased intestinal fluid secretion and accelerated transit. Linaclotide targets GC-C and activates cGMP/PKG/CFTR pathways; plecanatide targets GC-C and activates cGMP/CFTR pathways. Both produce overlapping clinical effects (increased fluid secretion, accelerated transit, improved bowel movements, reduced bloating). The mechanism descriptions support the claim that they engage the same downstream effector cascade, making redundancy and additive risk of adverse effects (watery diarrhea, dehydration) mechanistically justified. The 'same_mechanism' relationship is directly supported by the provided material.

    Timing Do not co-administer; choose one GC-C agonist.

Safety and side effects

Safety & Side Effects

Most common adverse reaction

Diarrhea is the most common adverse reaction (≥2%). In CIC trials it occurred in about 5.9% (3 mg) and 5.7% (6 mg) of patients versus 1.3% placebo (subgroup analysis: 4.9%, 5.4%, and 1.3% respectively).

  • Diarrhea leading to discontinuation occurred in about 2% of patients on the 3 mg dose (generally within 4 weeks).
  • Severe diarrhea was reported in about 0.6% of patients (generally within the first 3 days). If severe diarrhea occurs, dosing should be suspended and the patient rehydrated.

A pharmacovigilance analysis (2017 Q1–2024 Q2, single source) identified 861 cases and 2,057 adverse event reports, with common events including diarrhea, constipation, abdominal distension, treatment dissatisfaction, rectal tenesmus, increased fecal volume, abnormal GI sounds, and GI motility disorders; the majority occurred within the first 7 days.

Contraindications

  • Contraindicated in patients under 6 years of age due to risk of serious dehydration — in nonclinical studies a single oral dose caused deaths from dehydration in young juvenile mice.
  • Contraindicated in patients with known or suspected mechanical gastrointestinal obstruction.

Pediatric use

Use should be avoided in patients 6 to <18 years; safety and effectiveness under 18 have not been established. Only a single pediatric RCT was identified in a systematic review of functional constipation in children.

Special populations

  • Reproductive studies (animal): no evidence of adverse embryofetal effects in mice and rabbits, and no developmental abnormalities or effects on growth, learning/memory, or fertility in offspring of exposed mice.
  • Breastfeeding: no adequate studies of infant risk.
  • Elderly: may have kidney, liver, or heart problems warranting caution and possible dose adjustment.
  • Chronic kidney disease: because of very limited systemic absorption, plecanatide appears safe in CKD (based on a single observational review).

Dosing note

The higher 6 mg daily dose is not recommended — it provides no additional clinical benefit but may increase adverse effects.

Reconstitution and handling

Preparation & Dosing

Plecanatide is a commercially manufactured oral tablet (Trulance) and does not require reconstitution.

Recommended dosage

  • 3 mg orally once daily for both CIC and IBS-C in adults.

Administration

  • Tablets should be swallowed whole.
  • For patients with swallowing difficulties, tablets may be crushed/mixed and administered in applesauce or with water.
  • May be taken with or without food; administration with meals may result in looser stools.

Pharmacokinetic context

Plecanatide has no measurable systemic exposure and very limited systemic absorption, acting locally at the intestinal epithelium. The higher 6 mg dose is not recommended, as it offers no additional benefit over 3 mg but may increase side effects.

Sources

Ordered by evidence quality — the strongest first.

  1. 208745Orig1s000 - accessdata.fda.gov(opens in a new tab)
    Tier 1Web · accessdata.fda.gov
  2. A Randomized Phase III Clinical Trial of Plecanatide, a Uroguanylin Analog, in Patients With Chronic Idiopathic Constipation(opens in a new tab)
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