Linaclotide

What it is

Linaclotide is a manufactured peptide of fourteen amino acids, taken as a capsule. The label describes it as a guanylate cyclase-C agonist structurally related to the human hormones guanylin and uroguanylin. It is not absorbed to any useful degree: plasma concentrations after normal doses are below the limit of measurement, so standard pharmacokinetic figures cannot even be calculated. It works inside the gut and leaves in the stool.

What the research says

It makes the bowel wetter and faster. In adults with irritable bowel syndrome with constipation, a network meta-analysis of 15 trials and 8,462 patients ranked linaclotide 290 micrograms once daily first on the endpoint the FDA recommends, and the pivotal 12-week trial met that endpoint in 33.6% on linaclotide against 21.0% on placebo, a number needed to treat of 8. In chronic idiopathic constipation it was one of the better drugs but prucalopride ranked first at 12 weeks. It also reduces bloating specifically, with a number needed to treat of 7. The price is diarrhoea: 20% of adults versus 3% on placebo, and 5% stopped because of it. It is contraindicated under two years of age because linaclotide killed neonatal mice by dehydration.

Evidence grade: Well established.

How it works

Drug class: Guanylate cyclase-C (GC-C) agonist; a minimally absorbed 14-amino-acid peptide secretagogue that acts on the gut lining

Linaclotide is a short peptide built to resemble two natural gut hormones, guanylin and uroguanylin. Taken by mouth it stays in the gut and binds a receptor called guanylate cyclase-C on the inner surface of the intestinal lining. That pushes up a signalling molecule, cyclic GMP, inside and outside the cells, which drives chloride and bicarbonate out into the gut through the CFTR channel. Fluid follows the salt, so the contents become wetter and move faster. In animal models the extra cyclic GMP outside the cells also damped down pain-sensing nerves, which is the proposed reason it eases abdominal pain as well as constipation. (Source 1)

Boxed warning

WARNING: RISK OF SERIOUS DEHYDRATION IN PEDIATRIC PATIENTS LESS THAN 2 YEARS OF AGE

(Source 2)

What it is used for

• A network meta-analysis of randomised trials put linaclotide 290 micrograms once daily first in efficacy on the FDA's recommended endpoint, on each trial's own primary endpoint, on abdominal pain and on complete spontaneous bowel movements. The pivotal 12-week trial of 800 patients met the FDA endpoint in a third of linaclotide patients against a fifth on placebo. Evidence: established. (Source 3)
• In a network meta-analysis of 33 trials and 17,214 patients, almost all drugs beat placebo. Linaclotide 290 micrograms once daily had efficacy similar to prucalopride 2 mg at 12 weeks on the endpoint of achieving at least one extra complete spontaneous bowel movement per week, but prucalopride ranked first and the reviewers judged it the most likely to be most efficacious. Evidence: established. (Source 4)
• A network meta-analysis of 13 trials and 10,091 patients looking specifically at bloating found linaclotide gave the greatest improvement, with a relative risk of failing to improve of 0.78 and a number needed to treat of 7. Indirect comparison showed no significant difference between the licensed drugs. Evidence: established. (Source 5)
• A phase 3 trial in 330 children aged 6 to 17 increased spontaneous bowel movements by 1.17 per week more than placebo and improved stool consistency. The label extends the indication down to 2 years on the basis of adult and paediatric studies. The trial was funded by the manufacturers. Evidence: limited. (Source 6)
• The label records this indication from 7 years of age and reports a 12-week double-blind trial in children aged 7 to 17, in which diarrhoea was the most common adverse reaction, at 7% on the recommended 145 microgram dose. No independent systematic review of this paediatric use was reached in this run. Evidence: limited. (Source 7)

Interactions

• A high-fat meal (pharmacokinetic study): Taken straight after a high-fat breakfast, linaclotide produced looser stools and more of them than when taken fasting. This is why the label says to take it on an empty stomach at least 30 minutes before food. It is a change in effect rather than a change in blood levels, because the drug is not absorbed. (Source 8)
• Other medicines taken by mouth, including supplements (pharmacokinetic study): Linaclotide is not measurably absorbed, so it is not expected to reach the liver enzymes or transporters where most drug interactions happen. The current label carries no drug interactions section at all. The practical caution is indirect: anything that is itself affected by faster gut transit or by diarrhoea could behave differently. (Source 9)
• Alcohol (theoretical): No study of alcohol with linaclotide was found in this run, and the label does not mention it. Because linaclotide stays in the gut and is not measurably absorbed, a pharmacokinetic interaction is not expected; any overlap would be on gut symptoms, which has not been tested. (Source 9)

Stopping it

• There is no withdrawal syndrome and no taper in the evidence read. The pivotal trial tested stopping deliberately: people switched from linaclotide to placebo for four weeks had their symptoms come back, but not worse than their own baseline. (Source 10)
• The trial authors state the same conclusion in their own words, that there was no worsening compared with baseline after linaclotide was stopped. (Source 11)
• Stopping for a different reason, severe diarrhoea, is written into the label as an instruction to suspend the drug and rehydrate rather than to continue through it. (Source 12)

What goes wrong

Diarrhoea was about seven times more common on linaclotide than on placebo in the pooled pivotal trials, and one in twenty stopped treatment because of it. (Source 13)

• Official position, Certainty not rated.
• Size: Pooled placebo-controlled trials in adults with IBS-C summarised in the label.
• Who: Adults with irritable bowel syndrome with constipation.
• How long: Not stated in this section of the label; the majority of diarrhoea cases began within the first 2 weeks of treatment.
• Result: Diarrhoea 20% versus 3%; severe diarrhoea 2% versus under 1%; discontinuation for diarrhoea 5% versus under 1%; most cases began in the first 2 weeks.
• Funding: industry-funded (manufacturer's prescribing information)

Limit of this finding: These are pooled figures from the manufacturer's own pivotal trials as summarised in the label, with no trial duration given in this section and no confidence intervals. The comparison that matters is given, 20% against 3% on placebo, so the excess attributable to the drug is about 17 in every 100 people treated.

In these trials, 20% of LINZESS-treated patients reported diarrhea compared to 3% of placebo-treated patients. Severe diarrhea was reported in 2% of the LINZESS-treated patients versus less than 1% of the placebo-treated patients, and 5% of LINZESS-treated patients discontinued due to diarrhea vs less than 1% of placebo-treated patients. The majority of reported cases of diarrhea started within the first 2 weeks of LINZESS treatment

Nine per cent of linaclotide patients stopped the drug early for adverse reactions against 3% on placebo, and in long-term open-label use 29% had the dose reduced or suspended. (Source 13)

• Official position, Certainty not rated.
• Size: Placebo-controlled trials in adults with IBS-C, plus 2147 patients in open-label long-term trials.
• Who: Adults with irritable bowel syndrome with constipation.
• How long: Up to 18 months in the open-label long-term trials.
• Result: Early discontinuation 9% versus 3% on placebo; commonest reasons diarrhoea 5% and abdominal pain 1%; in the open-label trials 29% of 2147 patients had the dose reduced or suspended because of adverse reactions, mostly diarrhoea or other gut effects.
• Funding: industry-funded (manufacturer's prescribing information)

Limit of this finding: The 29% figure comes from open-label trials with no placebo group, so it cannot be compared with what would have happened without the drug; it is still the only figure here that covers use beyond a few months. The 9% against 3% comparison is from the placebo-controlled trials and is a like-for-like comparison.

In placebo-controlled trials in patients with IBS-C, 9% of patients treated with LINZESS and 3% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LINZESS-treatment group, the most common reasons for discontinuation due to adverse reactions were diarrhea (5%) and abdominal pain (1%). In comparison, less than 1% of patients in the placebo group withdrew due to diarrhea or abdominal pain. Adverse Reactions Leading to Dose Reductions In the open-label, long-term trials, 2147 patients with IBS-C received 290 mcg of LINZESS daily for up to 18 months. In these trials, 29% of patients had their dose reduced or suspended secondary to adverse reactions, the majority of which were diarrhea or other GI adverse reactions.

Across the trial network, total adverse events were significantly greater with linaclotide than placebo, and diarrhoea was significantly more common with it. (Source 3)

• Systematic review, Moderate certainty.
• Size: 8,462 patients across 15 randomised controlled trials.
• Who: Adults with irritable bowel syndrome with constipation.
• How long: 12 weeks.
• Result: Total adverse events significantly larger with linaclotide 290 and 500 micrograms once daily; plecanatide 6 mg ranked first for safety.
• Funding: not stated.

Limit of this finding: The ranking is a P-score, a probability of being the better option across the network, not an observed event rate, and the network contains no head-to-head trials of one drug against another, as the review says itself. Ranking first is therefore an ordering, not a demonstration that linaclotide beats the other drugs. All data were taken at 12 weeks. The adverse-event comparison is against placebo, not against the other drugs.

Total numbers of adverse events were significantly larger with linaclotide (290 and 500 μg once daily) and plecanatide (3 mg once daily) compared with placebo. However, plecanatide 6 mg once daily ranked first for safety. Diarrhea was significantly more common with all drugs, except lubiprostone (8

After marketing, severe diarrhoea with dizziness, fainting, low blood pressure and low potassium or sodium has needed hospital admission or intravenous fluids. (Source 12)

• Case series, Very low certainty.
• Size: Not stated; spontaneous post-marketing reports summarised in the label.
• Who: Patients treated with linaclotide.
• How long: Not stated.
• Result: No rate can be calculated from spontaneous reports.
• Funding: industry-funded (manufacturer's prescribing information)

Limit of this finding: These are spontaneous post-marketing reports. They establish that severe diarrhoea with dehydration and electrolyte disturbance has happened and has needed hospital treatment, but no rate can be calculated from them and no comparison with placebo is possible.

In post-marketing experience, severe diarrhea associated with dizziness, syncope, hypotension and electrolyte abnormalities (hypokalemia and hyponatremia) requiring hospitalization or intravenous fluid administration have been reported in patients treated with LINZESS. If severe diarrhea occurs, suspend dosing and rehydrate the patient

In newborn mice a single oral dose of linaclotide at ten micrograms per kilogram per day caused deaths from rapid, severe dehydration, which is why the drug is contraindicated under two years of age. (Source 14)

• Animal study, Certainty not rated.
• Size: Not stated; neonatal and juvenile mouse toxicology studies.
• Who: Neonatal mice, human age equivalent about 0 to 28 days, and 2- and 3-week-old mice.
• How long: Deaths on post-natal day 7.
• Result: Deaths at 10 micrograms per kilogram per day in neonatal mice; 2-week-old mice tolerated 50 micrograms per kilogram per day but died after a single 100 microgram per kilogram dose; 3-week-old mice tolerated 100 micrograms per kilogram per day but died after a single 600 microgram per kilogram dose.
• Funding: industry-funded (manufacturer's prescribing information)

Limit of this finding: These are mouse studies. They are the stated reason for the human contraindication below two years of age, but a dose that kills a newborn mouse is not a human finding, and no human data on harm in children under two exist.

In toxicology studies in neonatal mice, oral administration of linaclotide at 10 mcg/kg/day caused deaths on post-natal day 7 (human age equivalent of approximately 0 to 28 days). These deaths were due to rapid and severe dehydration produced by significant fluid shifts into the intestinal lumen resulting from GC-C agonism in neonatal mice [see Contraindications (4) and Warnings and Precautions (5.1)]. Tolerability to linaclotide increases with age in juvenile mice. In 2-week-old mice, linaclotide was well tolerated at a dose of 50 mcg/kg/day, but deaths occurred after a single oral dose of 100 mcg/kg. In 3-week-old mice, linaclotide was well tolerated at 100 mcg/kg/day, but deaths occurred after a single oral dose of 600 mcg/kg

In the paediatric trial one 17-year-old girl had treatment-related severe diarrhoea with dehydration needing hospital admission. (Source 6)

• Randomized trial, Moderate certainty.
• Size: 328 children analysed for safety.
• Who: Children aged 6 to 17 with functional constipation.
• How long: 12 weeks.
• Result: Diarrhoea in 7 of 164 (4%) on linaclotide versus 3 of 164 (2%) on placebo; one serious adverse event of special interest; no deaths.
• Funding: industry-funded (AbbVie and Ironwood Pharmaceuticals)

Limit of this finding: The journal sets decimals with a middle dot, as in '1·28' and 'p<0·0001', and the quotation keeps that. The trial was 12 weeks long and was paid for by the two companies that sell the drug. One serious event in 164 children cannot be turned into a rate, and 12 weeks says nothing about longer use.

One serious adverse event of special interest (treatment-related severe diarrhoea resulting in dehydration and hospitalisation) occurred in a female patient aged 17 years in the linaclotide group; this case resolved without sequelae after administration of intravenous fluids. No deaths occurred during the study

The reason for the under-two contraindication is partly an absence of data: the label states there was insufficient information on receptor expression in children under two to assess their risk of diarrhoea. (Source 15)

• Official position, Certainty not rated.
• Size: Clinical GC-C expression study in children 2 to less than 18 years of age.
• Who: Children under 2 years of age, in whom the drug is contraindicated.
• How long: Deaths in neonatal mice occurred within the first 24 hours.
• Result: No age-dependent trend in receptor expression was seen from 2 to under 18 years; below 2 years the data were insufficient to assess risk.
• Funding: industry-funded (manufacturer's prescribing information)

Limit of this finding: The contraindication rests on an absence of evidence rather than on evidence of harm in humans: the deaths were in newborn mice, and the label states there were not enough human data below two years of age to judge the risk. That is a reason for caution, not a measured human risk.

In neonatal mice (human age equivalent of approximately 0 to 28 days), linaclotide increased fluid secretion as a consequence of age-dependent elevated GC-C agonism which was associated with increased mortality within the first 24 hours due to dehydration. There was no age-dependent trend in GC-C intestinal expression in a clinical study of children 2 to less than 18 years of age; however, there are insufficient data available on GC-C intestinal expression in children less than 2 years of age to assess the risk of developing diarrhea and its potentially serious consequences in these patients

In children the label reports diarrhoea in 7% and 8% at the two tested doses for IBS-C and in 4% for functional constipation, with severe cases in both trials. (Source 12)

• Official position, Certainty not rated.
• Size: Trials in children aged 7 to 17 with IBS-C and 6 to 17 with functional constipation.
• Who: Children aged 6 to 17.
• How long: 12 weeks, double blind.
• Result: Diarrhoea 7% at 145 micrograms and 8% at 290 micrograms in IBS-C; 4% at 72 micrograms in functional constipation.
• Funding: industry-funded (manufacturer's prescribing information)

Limit of this finding: These are the label's figures from the paediatric trials, with no placebo rates given alongside them in this section, so they are incidences on treatment rather than excess over placebo.

In a double-blind trial of patients 7 to 17 years of age with IBS-C, diarrhea was reported in 7% and 8% of patients treated with LINZESS 145 mcg and 290 mcg once daily, respectively. One severe case of diarrhea was reported in the IBS-C trial at a dosage higher than the recommended LINZESS 145 mcg once daily dosage for IBS-C. • In a double-blind trial of patients 6 to 17 years of age with FC treated with LINZESS 72 mcg once daily, diarrhea was reported in 4% of patients, and one case of severe diarrhea was reported

The label's basis for the under-two contraindication includes a clinical study of receptor expression in 99 children from six months of age, which did not produce enough data below two years to judge the risk of diarrhoea and severe dehydration. (Source 16)

• Official position, Certainty not rated.
• Size: 99 children aged 6 months to less than 18 years.
• Who: Children, with duodenal and colonic samples measured for GC-C mRNA expression.
• How long: Not stated; the neonatal mouse deaths occurred within 24 hours.
• Result: No usable estimate below 2 years of age: the label records insufficient data on GC-C intestinal expression to assess the risk of diarrhoea and its potentially serious consequences in children under 2.
• Funding: industry-funded (manufacturer's prescribing information)

Limit of this finding: This is a measurement of receptor expression, not of harm: nobody under two was given the drug. The contraindication therefore rests on newborn mouse deaths plus an admitted gap in the human data, which is a reason for caution rather than a measured human risk.

In a clinical GC-C ontogeny study in children 6 months to less than 18 years of age (N=99) to measure GC-C mRNA expression levels in duodenal and colonic samples to evaluate the risk of diarrhea and severe dehydration due to GC-C agonism, there was insufficient data on GC-C intestinal expression to assess the risk of developing diarrhea and its potentially serious consequences in children less than 2 years of age

The same label section reports four further adverse reactions, each in under 2% of linaclotide-treated patients but more often than on placebo. (Source 13)

• Official position, Certainty not rated.
• Size: Pooled IBS-C pivotal placebo-controlled trials; denominators not given in this paragraph.
• Who: Adults with IBS-C in the pooled pivotal placebo-controlled trials.
• How long: Trial length not stated in this paragraph.
• Result: Defecation urgency, faecal incontinence, vomiting and gastro-oesophageal reflux disease each in <2% of the linaclotide group, at a higher incidence than placebo.
• Funding: industry-funded (manufacturer's prescribing information)

Limit of this finding: The label gives these as "<2%" with no numerator, no denominator and no placebo figure, so the size of the difference from placebo cannot be read from it.

Defecation urgency, fecal incontinence, vomiting, and gastroesophageal reflux disease were reported in <2% of patients in the LINZESS-treatment group and at an incidence greater than in the placebo treatment group.

In the pivotal 12-week trial diarrhoea was the most common adverse event and led 5.7% of linaclotide patients to stop, against 0.3% on placebo. (Source 10)

• Randomized trial, Moderate certainty.
• Size: 800 patients (405 linaclotide, 395 placebo)
• Who: Adults with IBS-C (mean age 43.5 years, 90.5% female)
• How long: 12-week treatment period followed by a 4-week randomised withdrawal period.
• Result: Discontinuation for diarrhoea 5.7% on linaclotide versus 0.3% on placebo, a difference of about 5.4 percentage points.
• Funding: industry-funded (Ironwood/Forest phase 3 programme; the paper's own funding statement is not inside this block)

Limit of this finding: The spacing around the numbers and the percent signs is the journal record's own. This is one trial, and the figure is the proportion who stopped the drug because of diarrhoea, not the proportion who had it.

Diarrhea, the most common AE, resulted in discontinuation of 5.7 % of linaclotide and 0.3 % of placebo patients.

What the evidence supports

A network meta-analysis of secretagogue trials in irritable bowel syndrome with constipation ranked linaclotide 290 micrograms once daily first in efficacy on four separate endpoints. (Source 3)

• Systematic review, Moderate certainty.
• Size: 8,462 patients across 15 randomised controlled trials.
• Who: Adults with irritable bowel syndrome with constipation.
• How long: Data extracted at 12 weeks.
• Result: Ranked first by P score on the FDA endpoint, each trial's primary endpoint, abdominal pain and complete spontaneous bowel movements; relative risks reported per comparison rather than as a single pooled figure in this passage.
• Funding: not stated.

Limit of this finding: The ranking is a P-score, a probability of being the better option across the network, not an observed event rate, and the network contains no head-to-head trials of one drug against another, as the review says itself. Ranking first is therefore an ordering, not a demonstration that linaclotide beats the other drugs. All data were taken at 12 weeks.

Linaclotide, lubiprostone, plecanatide, and tenapanor were superior to placebo for the treatment of IBS-C. Linaclotide (290 μg once daily) was ranked first in efficacy based on the end point recommended by the Food and Drug Administration for trials in IBS-C, the primary end point used in each trial, abdominal pain, and complete spontaneous bowel movements

The pivotal 12-week randomised trial met the composite FDA endpoint in a third of linaclotide patients against a fifth on placebo, a number needed to treat of 8. (Source 10)

• Randomized trial, Moderate certainty.
• Size: 800 patients (405 linaclotide, 395 placebo)
• Who: Adults with irritable bowel syndrome with constipation, mean age 43.5, 90.5% female, 76.9% white.
• How long: 12 weeks of treatment plus a 4-week randomised withdrawal period.
• Result: 33.6% versus 21.0%, P < 0.0001, number needed to treat 8.0 (95% CI 5.4 to 15.5)
• Funding: industry-funded (trial reported by the manufacturers' investigators; the paper's own funding statement was not in the record read)

Limit of this finding: This journal sets its abstract with spaces around the punctuation, as in '90.5 % ,', '136 / 405' and 'FDA ’ s', and the quotation keeps that exactly as printed. The spacing is the journal's typography, not a transcription error, and none of the figures is affected. The trial population was 90.5% female, so it says little about men. It was reported by the manufacturer's investigators.

The FDA end point was met by 136 / 405 linaclotide-treated patients (33.6 % ), compared with 83 / 395 placebo-treated patients (21.0 % ) ( P < 0.0001) (number needed to treat: 8.0, 95 % confidence interval: 5.4, 15.5)

In the same trial, half of linaclotide patients reported at least a 30% reduction in abdominal pain for at least six of twelve weeks, against 37.5% on placebo. (Source 10)

• Randomized trial, Moderate certainty.
• Size: 800 patients.
• Who: Adults with irritable bowel syndrome with constipation.
• How long: 12 weeks.
• Result: Abdominal pain reduction 50.1% versus 37.5%, P = 0.0003; increase of at least one complete spontaneous bowel movement 48.6% versus 29.6%, P < 0.0001.
• Funding: industry-funded (trial reported by the manufacturers' investigators)

Limit of this finding: This journal sets its abstract with spaces around the punctuation, as in '90.5 % ,', '136 / 405' and 'FDA ’ s', and the quotation keeps that exactly as printed. The spacing is the journal's typography, not a transcription error, and none of the figures is affected.

A greater percentage of linaclotide patients, compared with placebo patients, reported for at least 6 / 12 treatment period weeks, a reduction of ≥ 30 % in abdominal pain (50.1 vs. 37.5 % , P = 0.0003) and an increase of ≥ 1 CSBM from baseline (48.6 vs. 29.6 % , P < 0.0001)

In chronic idiopathic constipation, linaclotide 290 micrograms once daily had efficacy similar to prucalopride 2 mg at 12 weeks but did not rank first. (Source 4)

• Systematic review, Moderate certainty.
• Size: 17,214 patients across 33 randomised controlled trials.
• Who: Adults with chronic idiopathic constipation.
• How long: Endpoints at 4 weeks, 12 weeks or both; most trials 4 to 12 weeks.
• Result: On failure to achieve an increase of one or more complete spontaneous bowel movement per week, prucalopride 4 mg ranked first at 12 weeks (RR 0.74, 95% CI 0.66 to 0.83, P-score 0.79); linaclotide 290 micrograms had a P-score of 0.76.
• Funding: independent (the review reports its funding as none)

Limit of this finding: This passage keeps two things the journal prints: 'falilure' for 'failure', and a doubled 'or or'. Both are the source's own and neither changes a figure. The P-scores are ranking probabilities rather than event rates, and the network contains no head-to-head trials.

although linaclotide 290 μg once daily and prucalopride 2 mg once daily had similar efficacy (P-scores of 0·76 and 0·71, respectively)

In a bloating-specific network meta-analysis, linaclotide produced the greatest improvement in abdominal bloating, with a number needed to treat of 7. (Source 5)

• Systematic review, Moderate certainty.
• Size: 10,091 patients across 13 randomised controlled trials.
• Who: Patients with irritable bowel syndrome with constipation.
• How long: Not stated in this passage.
• Result: Relative risk of failure to achieve an improvement in bloating 0.78, 95% CI 0.74 to 0.83, number needed to treat 7, P-score 0.97.
• Funding: not stated.

Limit of this finding: The 0.78 is a risk ratio of FAILING to improve, so a value below 1 favours linaclotide; shortened to 'RR 0.78' it would read backwards. The review also reports that indirect comparison found no significant difference between the individual drugs, so linaclotide's first place is a ranking, not a proven advantage over the alternatives. The source writes the patient total with a space as its thousands separator, '10 091', and the quotation keeps that.

Linaclotide demonstrated the greatest improvement in abdominal bloating in both pairwise and network meta-analysis (RR of failure to achieve an improvement in abdominal bloating = 0.78; 95% CI 0.74-0.83, number needed to treat = 7, P-score 0.97)

A phase 3 trial in children aged 6 to 17 with functional constipation increased weekly spontaneous bowel movements by about one more than placebo. (Source 6)

• Randomized trial, Moderate certainty.
• Size: 330 randomised, 328 analysed (164 per group)
• Who: Children aged 6 to 17 meeting modified Rome III criteria for functional constipation, 64 sites in seven countries.
• How long: 12 weeks.
• Result: Least-squares mean change from baseline 2.22 versus 1.05 spontaneous bowel movements per week, difference 1.17 (95% CI 0.65 to 1.69), p<0.0001; stool consistency difference 0.42 (95% CI 0.21 to 0.64), p=0.0001.
• Funding: industry-funded (AbbVie and Ironwood Pharmaceuticals)

Limit of this finding: The journal sets decimals with a middle dot, as in '1·28' and 'p<0·0001', and the quotation keeps that. The trial was 12 weeks long and was paid for by the two companies that sell the drug.

Compared with placebo (least-squares mean [LSM] CFB 1·05 SBMs per week [SE 0·19]), patients treated with linaclotide showed significant improvement in SBM frequency (LSM CFB 2·22 SBMs per week [0·19]; LSM CFB difference 1·17 SBMs per week [95% CI 0·65-1·69]; p<0·0001)

What the evidence does not support

The same network meta-analysis found no clear separation between the individual secretagogues on most endpoints, so linaclotide's first place does not mean it is better than the alternatives. (Source 17)

• Systematic review, Moderate certainty.
• Size: 8,462 patients across 15 randomised controlled trials.
• Who: Adults with irritable bowel syndrome with constipation.
• How long: 12 weeks.
• Result: Reported as similar efficacy among individual drugs and dosages for most endpoints, with no head-to-head trials in the network.
• Funding: not stated.

Limit of this finding: The ranking is a P-score, a probability of being the better option across the network, not an observed event rate, and the network contains no head-to-head trials of one drug against another, as the review says itself. Ranking first is therefore an ordering, not a demonstration that linaclotide beats the other drugs. All data were taken at 12 weeks.

we found all drugs to be superior to placebo. Efficacy was similar among individual drugs and dosages for most end points. However, data were extracted at the 12-week time point, so the long-term relative efficacy of these drugs is unknown

Reviewers of the bloating evidence state that indirect comparison showed no significant differences between the individual licensed drugs. (Source 5)

• Systematic review, Moderate certainty.
• Size: 10,091 patients across 13 randomised controlled trials.
• Who: Patients with irritable bowel syndrome with constipation.
• How long: Not stated.
• Result: No significant differences on indirect comparison between linaclotide, lubiprostone, tenapanor and tegaserod.
• Funding: not stated.

Limit of this finding: The 0.78 is a risk ratio of FAILING to improve, so a value below 1 favours linaclotide; shortened to 'RR 0.78' it would read backwards. The review also reports that indirect comparison found no significant difference between the individual drugs, so linaclotide's first place is a ranking, not a proven advantage over the alternatives. The source writes the patient total with a space as its thousands separator, '10 091', and the quotation keeps that.

We identified 13 eligible RCTs, containing 10 091 patients. Linaclotide 290 µg o.d., lubiprostone 8 µg b.d., tenapanor 50 mg b.d. and tegaserod 6 mg b.d. were all superior to placebo for abdominal bloating in patients with IBS-C, in both pairwise and the network meta-analyses

In chronic idiopathic constipation the reviewers judged prucalopride, not linaclotide, the drug most likely to be most efficacious, and said long-term relative efficacy is unknown. (Source 18)

• Systematic review, Moderate certainty.
• Size: 17,214 patients across 33 randomised controlled trials.
• Who: Adults with chronic idiopathic constipation.
• How long: Treatment in most trials 4 to 12 weeks.
• Result: Ranking judgement rather than a pooled estimate; no trial ran long enough to compare long-term efficacy.
• Funding: independent (the review reports its funding as none)

Limit of this finding: This passage keeps two things the journal prints: 'falilure' for 'failure', and a doubled 'or or'. Both are the source's own and neither changes a figure. The P-scores are ranking probabilities rather than event rates, and the network contains no head-to-head trials.

Prucalopride ranked first at 12 weeks, and many of the included trials recruited patients who previously did not respond to laxatives, suggesting that this drug is likely to be the most efficacious for patients with chronic idiopathic constipation. However, because treatment duration in most trials was 4-12 weeks, the long-term relative efficacy of these drugs is unknown

For functional constipation the label states that safety and effectiveness have not been established in children under 2 years of age. (Source 19)

• Official position, Certainty not rated.
• Size: Not stated; regulatory position on a paediatric indication.
• Who: Children less than 2 years of age with functional constipation.
• How long: Not stated.
• Result: No efficacy or safety estimate is given for this age group; the label states the indication is established only from 2 years of age.
• Funding: industry-funded (manufacturer's prescribing information)

Limit of this finding: This is the prescribing information, a regulatory position rather than a measurement. "Have not been established" means the trials needed to show it were not done or did not show it in that age group; it is not a finding that the drug does not work there.

The safety and effectiveness of LINZESS for the treatment of FC have not been established in pediatric patients less than 2 years of age.

For irritable bowel syndrome with constipation the label states that safety and effectiveness have not been established in children under 7 years of age. (Source 19)

• Official position, Certainty not rated.
• Size: Not stated; regulatory position on a paediatric indication.
• Who: Children less than 7 years of age with IBS-C.
• How long: Not stated.
• Result: No efficacy or safety estimate is given for this age group; the label states the indication is established only from 7 years of age.
• Funding: industry-funded (manufacturer's prescribing information)

Limit of this finding: This is the prescribing information, a regulatory position rather than a measurement. "Have not been established" means the trials needed to show it were not done or did not show it in that age group; it is not a finding that the drug does not work there.

The safety and effectiveness of LINZESS for the treatment of IBS-C have not been established in pediatric patients less than 7 years of age.

Where the evidence is mixed

The paediatric trial was paid for by the two companies that sell the drug, and its authors conclude in favour of it. (Source 20)

• Randomized trial, Moderate certainty.
• Size: 330 patients.
• Who: Children aged 6 to 17 with functional constipation.
• How long: 12 weeks.
• Result: No independent replication of this trial was found in this run.
• Funding: industry-funded (AbbVie and Ironwood Pharmaceuticals)

Limit of this finding: This is the authors' own interpretation sentence, not a result, and the funding line is printed immediately after it. No independent replication of this trial was found for this entry.

INTERPRETATION: Linaclotide is an efficacious and well tolerated treatment for functional constipation in paediatric patients and has subsequently been approved by the US Food and Drug Administration for this indication. FUNDING: AbbVie and Ironwood Pharmaceuticals

The current label (revised 2026) licenses linaclotide down to 2 years of age for functional constipation and 7 years for IBS-C, a wider paediatric range than earlier versions of the label carried. (Source 7)

• Official position, Certainty not rated.
• Size: Not stated; regulatory position.
• Who: Adults and children from 2 or 7 years depending on the condition.
• How long: Not stated.
• Result: No effect estimate; this is the indication statement itself.
• Funding: industry-funded (manufacturer's prescribing information)

Limit of this finding: This is the indication statement itself, not evidence. It records what the regulator approved and the ages it covers; it carries no effect size and no comparison.

LINZESS is indicated for the treatment of: • irritable bowel syndrome with constipation (IBS-C) in adults and pediatric patients 7 years of age and older • chronic idiopathic constipation (CIC) in adults • functional constipation (FC) in pediatric patients 2 years of age and older

The pivotal adult trial set four primary endpoints rather than one, which raises the chance that at least one would be met. (Source 21)

• Randomized trial, Moderate certainty.
• Size: 800 patients.
• Who: Adults with irritable bowel syndrome with constipation.
• How long: 12 weeks plus 4-week randomised withdrawal.
• Result: Four primary endpoints: the FDA composite responder definition plus three based on abdominal pain and complete spontaneous bowel movements over 9 of 12 weeks.
• Funding: industry-funded (trial reported by the manufacturers' investigators)

Limit of this finding: This journal sets its abstract with spaces around the punctuation, as in '90.5 % ,', '136 / 405' and 'FDA ’ s', and the quotation keeps that exactly as printed. The spacing is the journal's typography, not a transcription error, and none of the figures is affected. Four co-primary endpoints raise the chance that at least one is met, which is why this is recorded as a limitation rather than a benefit.

There were four primary end points, the Food and Drug Administration ’ s (FDA ’ s) primary end point for IBS-C (responder: improvement of ≥ 30 % in average daily worst abdominal pain score and increase by ≥ 1 complete spontaneous bowel movement (CSBM) from baseline (same week) for at least 50 % of weeks assessed) and three other primary end points, based on improvements in abdominal pain and CSBMs for 9 / 12 weeks

The label makes the conditions of taking the capsule part of the instruction: on an empty stomach at least 30 minutes before a meal, not crushed or chewed, and swallowed whole, with numbered steps for opening it into applesauce or water when it cannot be swallowed. (Source 22)

• Official position, Certainty not rated.
• Size: Not stated; regulatory administration instruction.
• Who: Anyone prescribed linaclotide, including people who cannot swallow a capsule.
• How long: Each dose, at approximately the same time each day.
• Result: No effect estimate; this is the administration condition under which the trials were run and under which the label approves use.
• Funding: industry-funded (manufacturer's prescribing information)

Limit of this finding: This is an instruction, not a finding, and it matters because the pharmacodynamic food-effect study showed looser and more frequent stools when the capsule was taken straight after a high-fat breakfast. The preparation steps are numbered 1, 2, 3 in the label itself because they are coded there as an ordered list, and the quotation preserves that coding.

Take LINZESS on an empty stomach, at least 30 minutes prior to a meal at approximately the same time each day. • If a dose is missed, skip the missed dose and take the next dose at the regular time. Do not take 2 doses at the same time. • Do not crush or chew LINZESS capsule or capsule contents. • Swallow LINZESS capsule whole.

The paediatric trial randomised 330 children, two of whom never received treatment, and 89% completed the twelve weeks, with just over half the participants female. (Source 6)

• Randomized trial, Moderate certainty.
• Size: 330 randomised (166 linaclotide, 164 placebo); 328 analysed; 293 completed.
• Who: Children aged 6 to 17 with functional constipation, 64 sites in seven countries.
• How long: 12 weeks.
• Result: 293 of 330 (89%) completed the 12-week treatment period, 148 on linaclotide and 145 on placebo; 181 of 328 (55%) were female and 147 (45%) male.
• Funding: industry-funded (AbbVie and Ironwood Pharmaceuticals)

Limit of this finding: These are the denominators behind the effect sizes and they were missing from the quoted passage. 37 of the 330 children did not complete the trial, which is the figure to weigh against the one-extra-bowel-movement-per-week result. The journal sets decimals with a middle dot, as in '1·28' and 'p<0·0001', and the quotation keeps that. The trial was 12 weeks long and was paid for by the two companies that sell the drug.

FINDINGS: Between Oct 1, 2019, and March 21, 2022, 330 patients were enrolled and randomly assigned to linaclotide (n=166) or placebo (n=164). Two patients in the linaclotide group did not receive any treatment; thus, efficacy and safety endpoints were assessed in 328 patients (164 patients in each group). 293 (89%) patients completed the 12-week treatment period (148 in the linaclotide group and 145 in the placebo group). 181 (55%) of 328 patients were female and 147 (45%) were male.

The reviewers of the bloating evidence conclude that linaclotide appeared the most efficacious but that longer-term efficacy still needs research and the mechanism is not understood. (Source 5)

• Systematic review, Moderate certainty.
• Size: 10,091 patients across 13 randomised controlled trials.
• Who: Patients with irritable bowel syndrome with constipation.
• How long: Not stated; the review notes long-term efficacy has not been assessed.
• Result: Narrative conclusion with no additional estimate.
• Funding: not stated.

Limit of this finding: The 0.78 is a risk ratio of FAILING to improve, so a value below 1 favours linaclotide; shortened to 'RR 0.78' it would read backwards. The review also reports that indirect comparison found no significant difference between the individual drugs, so linaclotide's first place is a ranking, not a proven advantage over the alternatives. The source writes the patient total with a space as its thousands separator, '10 091', and the quotation keeps that.

CONCLUSIONS: We found all licensed drugs for IBS-C to be superior to placebo for abdominal bloating. Linaclotide appeared to be the most efficacious at relieving abdominal bloating. Further research is needed to assess long-term efficacy of these agents and to better understand the precise mechanism of improving bloating.

Where the research disagrees

Which drug should rank first for chronic idiopathic constipation

• Black and colleagues, network meta-analysis of secretagogues in IBS-C, Gastroenterology 2018, Network meta-analysis of 15 randomised trials, with no head-to-head trials in the network, data at 12 weeks: Linaclotide (290 μg once daily) was ranked first in efficacy based on the end point recommended by the Food and Drug Administration for trials in IBS-C, the primary end point used in each trial, abdominal pain, and complete spontaneous bowel movements (Source 3)
• Luthra and colleagues, network meta-analysis of drugs for chronic idiopathic constipation, Lancet Gastroenterology and Hepatology 2019, Network meta-analysis of 33 randomised trials in a different condition, chronic idiopathic constipation rather than IBS-C: Prucalopride ranked first at 12 weeks, and many of the included trials recruited patients who previously did not respond to laxatives, suggesting that this drug is likely to be the most efficacious for patients with chronic idiopathic constipation (Source 18)

How much

• Reference intake: There is no dietary reference intake for linaclotide: it is a prescription medicine and the dose is set by the prescriber. As a position, the current label (DailyMed SPL, revised 2026) records 290 micrograms once daily for adults with IBS-C, 145 micrograms once daily for adults with chronic idiopathic constipation with a 72 microgram option, and 72 micrograms once daily for children from 2 years with functional constipation. (Source 23)
• Upper limit: No tolerable upper intake level exists. The highest dose in the label is 290 micrograms once daily, for IBS-C in adults; a dosage of 72 micrograms once daily is offered for adults with chronic idiopathic constipation based on individual presentation or tolerability. (Source 23)
• Studied: The pivotal adult trial gave 290 micrograms of oral linaclotide once daily on an empty stomach for 12 weeks, then re-randomised to placebo for 4 weeks. (Source 21)
• Studied: The paediatric functional constipation trial gave oral linaclotide 72 micrograms once daily for 12 weeks to children aged 6 to 17. (Source 6)
• Studied: The label records that in clinical trials linaclotide was given on an empty stomach, at least 30 minutes before a meal, at about the same time each day, and that is the condition the label carries into use. (Source 22)

A common belief, and what the research shows

The belief: Coming off linaclotide causes a rebound, leaving your bowel worse than before you started.

What the research shows: The pivotal trial was designed to test exactly that, with a four-week randomised withdrawal period. Its result: "patients re-randomized from linaclotide to placebo showed return of symptoms, but without worsening of symptoms relative to baseline". Symptoms come back, which is not the same as rebound.

Questions and answers

What is it?

Linaclotide is a manufactured peptide taken as a capsule, not a nutrient and not something the body makes. It is built to resemble guanylin and uroguanylin, two hormones the human gut already produces, and it acts on the same receptor they do, guanylate cyclase-C, on the inner lining of the intestine. It is barely absorbed, so almost all of it stays inside the gut and leaves in the stool. (Source 1)

What does it do in the body?

It makes the gut secrete fluid. Binding its receptor raises a signalling molecule called cyclic GMP inside the lining cells, which pushes chloride and bicarbonate out into the gut through the CFTR channel; water follows, so the contents are wetter and move faster. In animal models the cyclic GMP that leaks outside the cells also quietened pain-sensing nerves and reduced abdominal muscle contraction, which is the proposed explanation for the reduction in abdominal pain seen in the human trials. (Source 1)

Is it good or bad for you?

For the adults it is licensed for it does more good than harm on the trial evidence, with roughly one extra responder for every eight treated and a clear reduction in bloating. The harm is concentrated in one place, the bowel: a fifth of adults get diarrhoea against 3% on placebo, and after marketing there have been cases severe enough to need admission. For the very young it is dangerous, and the label says so in a boxed warning: it is contraindicated below two years of age because a single adult-equivalent dose killed neonatal mice through dehydration. (Source 2)

How do you get more of it?

There is nothing to get more of from food or behaviour: linaclotide exists only as a prescribed capsule. As a position, the label records the doses: 290 micrograms once daily for adults with IBS-C, 145 micrograms for adults with chronic idiopathic constipation, and 72 micrograms for children from two years with functional constipation. The label also records that it must be swallowed whole on an empty stomach at least 30 minutes before a meal. (Source 23)

If it is harmful, what reduces it?

Stopping the capsule is the whole of it. Because linaclotide is not absorbed into the bloodstream, there is nothing to clear from the body, and the drug and its active metabolite are broken down inside the gut and passed in the stool. When the problem is severe diarrhoea, the label's instruction is to suspend dosing and rehydrate rather than push on. (Source 24)

Why might someone be low in it or missing it?

The question does not apply. Nobody is deficient in linaclotide, because it is a manufactured peptide and not a substance the body makes or stores. The body does make the two natural hormones it imitates, guanylin and uroguanylin, which act on the same receptor; a shortage of those is a separate question that the sources read here do not address. (Source 1)

Which whole foods contain it or feed it?

No food contains linaclotide and no food feeds it. Food matters for a different reason: taking the capsule straight after a high-fat breakfast produced looser and more frequent stools than taking it fasting, so the trials were all run with the drug given on an empty stomach at least 30 minutes before eating. (Source 8)

What happens if you do not have it?

Nothing happens from never having it, since it is not needed for health. For someone who has been taking it and stops, the question has actually been tested: in the pivotal trial's four-week randomised withdrawal period, people moved from linaclotide to placebo had their symptoms return, but not worse than their own baseline, while those kept on it held their improvement. In other words the constipation and pain come back to roughly where they started, rather than overshooting. (Source 10)

How can you test for it?

There is no blood test for linaclotide, and the reason is in the label: after normal doses, neither the drug nor its active metabolite can be measured in plasma at all, so even the standard pharmacokinetic numbers cannot be calculated. Nothing in the sources read describes a validated test to predict who will respond or to monitor treatment; response is judged on symptoms. (Source 9)

We searched: Searched the current DailyMed label for LINZESS (setid 09beda19-56d6-4a56-afdc-9a77b70b2ef3) section by section, including clinical pharmacology and pharmacokinetics, plus PubMed via eutils for linaclotide biomarker and response-prediction studies; nothing describing a validated test was found.

References

1. DailyMed (US National Library of Medicine) SPL, Allergan, Inc.. LINZESS (linaclotide) capsules - US prescribing information: 12.1 Mechanism of Action. 2026. Read the source
2. DailyMed (US National Library of Medicine) SPL, Allergan, Inc.. LINZESS (linaclotide) capsules, for oral use - US prescribing information: boxed warning (LOINC 34066-1). 2026. Read the source
3. Gastroenterology. Efficacy of Secretagogues in Patients With Irritable Bowel Syndrome With Constipation: Systematic Review and Network Meta-analysis. 2018. PMID 30144426, DOI 10.1053/j.gastro.2018.08.021. Read the source
4. The Lancet Gastroenterology & Hepatology. Efficacy of drugs in chronic idiopathic constipation: a systematic review and network meta-analysis. 2019. PMID 31474542, DOI 10.1016/S2468-1253(19)30246-8. Read the source
5. Alimentary Pharmacology & Therapeutics. Systematic review and network meta-analysis: efficacy of licensed drugs for abdominal bloating in irritable bowel syndrome with constipation. 2021. PMID 34114657, DOI 10.1111/apt.16437. Read the source
6. The Lancet Gastroenterology & Hepatology. Efficacy and safety of linaclotide in treating functional constipation in paediatric patients: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. 2024. PMID 38211604, DOI 10.1016/S2468-1253(23)00398-9. Read the source
7. DailyMed (US National Library of Medicine) SPL, Allergan, Inc.. LINZESS (linaclotide) capsules - US prescribing information: 1 INDICATIONS AND USAGE. 2026. Read the source
8. DailyMed (US National Library of Medicine) SPL, Allergan, Inc.. LINZESS (linaclotide) capsules - US prescribing information: 12.2 Pharmacodynamics, Food Effect. 2026. Read the source
9. DailyMed (US National Library of Medicine) SPL, Allergan, Inc.. LINZESS (linaclotide) capsules - US prescribing information: 12.3 Pharmacokinetics, Absorption through Distribution. 2026. Read the source
10. The American Journal of Gastroenterology. A 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 constipation. 2012. PMID 22986440, DOI 10.1038/ajg.2012.255. Read the source
11. The American Journal of Gastroenterology. A 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 constipation. 2012. PMID 22986440, DOI 10.1038/ajg.2012.255. Read the source
12. DailyMed (US National Library of Medicine) SPL, Allergan, Inc.. LINZESS (linaclotide) capsules - US prescribing information: 5.2 Diarrhea. 2026. Read the source
13. DailyMed (US National Library of Medicine) SPL, Allergan, Inc.. LINZESS (linaclotide) capsules - US prescribing information: 6.1 Clinical Trials Experience, diarrhoea, discontinuations, dose reductions and less common adverse reactions in adults with IBS-C. 2026. Read the source
14. DailyMed (US National Library of Medicine) SPL, Allergan, Inc.. LINZESS (linaclotide) capsules - US prescribing information: 8.4 Pediatric Use, Juvenile Animal Toxicity Data. 2026. Read the source
15. DailyMed (US National Library of Medicine) SPL, Allergan, Inc.. LINZESS (linaclotide) capsules - US prescribing information: 5.1 Risk of Serious Dehydration in Pediatric Patients Less Than 2 Years of Age. 2026. Read the source
16. DailyMed (US National Library of Medicine) SPL, Allergan, Inc.. LINZESS (linaclotide) capsules - US prescribing information: 8.4 Pediatric Use, contraindication and GC-C ontogeny study. 2026. Read the source
17. Gastroenterology. Efficacy of Secretagogues in Patients With Irritable Bowel Syndrome With Constipation: Systematic Review and Network Meta-analysis. 2018. PMID 30144426, DOI 10.1053/j.gastro.2018.08.021. Read the source
18. The Lancet Gastroenterology & Hepatology. Efficacy of drugs in chronic idiopathic constipation: a systematic review and network meta-analysis. 2019. PMID 31474542, DOI 10.1016/S2468-1253(19)30246-8. Read the source
19. DailyMed (US National Library of Medicine) SPL, Allergan, Inc.. LINZESS (linaclotide) capsules - US prescribing information: 8.4 Pediatric Use, the Functional Constipation and Irritable Bowel Syndrome with Constipation established-use paragraphs. 2026. Read the source
20. The Lancet Gastroenterology & Hepatology. Efficacy and safety of linaclotide in treating functional constipation in paediatric patients: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. 2024. PMID 38211604, DOI 10.1016/S2468-1253(23)00398-9. Read the source
21. The American Journal of Gastroenterology. A 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 constipation. 2012. PMID 22986440, DOI 10.1038/ajg.2012.255. Read the source
22. DailyMed (US National Library of Medicine) SPL, Allergan, Inc.. LINZESS (linaclotide) capsules - US prescribing information: 2.2 Preparation and Administration Instructions. 2026. Read the source
23. DailyMed (US National Library of Medicine) SPL, Allergan, Inc.. LINZESS (linaclotide) capsules - US prescribing information: 2.1 Recommended Dosage. 2026. Read the source
24. DailyMed (US National Library of Medicine) SPL, Allergan, Inc.. LINZESS (linaclotide) capsules - US prescribing information: 12.3 Pharmacokinetics, Elimination. 2026. Read the source