Linaclotide (LINZESS): A Pricey Constipation Drug Whose Benefits Do Not Outweigh Its Risks

In 2012 the Food and Drug Administration (FDA) approved linaclotide (LINZESS) to manage symptoms of irritable bowel syndrome (IBS) with constipation and chronic idiopathic constipation in adults.[1] Subsequently, the agency also approved this oral, once-daily drug for functional constipation in children aged 6 to 17 years.[2]

According to its manufacturer, linaclotide increases intestinal fluid and accelerates gastrointestinal transit. However, the clinical significance of such actions is not clear, and the drug does not cure the underlying cause of constipation.

In 2023 the wholesale price for a 30-day supply of linaclotide was about $515.[3] Between November 2023 and October 2024, Medicare spent $1.94 billion on linaclotide for 627,000 enrollees.[4] In January 2025 the Centers for Medicare and Medicaid Services (CMS) selected linaclotide as one of 15 drugs for the current round of Medicare drug-price negotiations. The negotiated prices are expected to go into effect in 2027.

Public Citizen’s Health Research Group submitted comments to assist CMS with its decisions regarding the price negotiations of linaclotide.[5] Mainly, we have designated linaclotide as a Do Not Use drug because the randomized, placebo-controlled clinical trials supporting its approval demonstrated that its limited benefit (symptomatic relief of constipation in about one of five users) is offset by its diarrhea adverse effects (also reported in about one of five users). Linaclotide also has other serious risks, which are described below.

Limited benefits

The approval of linaclotide was based on evidence from four clinical trials — lasting only three to six months — that demonstrated more frequent symptomatic relief of constipation in linaclotide-treated patients than in those taking a placebo.[6],[7] According to FDA reviewers, up to 20% of IBS participants treated with linaclotide reported having at least three complete spontaneous bowel movements (CSBM) and an increase of at least one additional CSBM from baseline per week compared with up to 6% of those taking a placebo.

In contrast, diarrhea was reported in nearly 20% of linaclotide users, compared with only 3% of those who received a placebo. Importantly, participants in the preapproval trials were asked not to change their dietary or lifestyle habits or their dosage of other constipation medications. They were permitted to take the stimulant laxative bisacodyl (DULCOLAX, others and generics) as “rescue” treatment during the trials. This may have falsely inflated the observed benefit of linaclotide. In addition, in at least one of linaclotide’s preapproval trials, abdominal pain and constipation recurred after linaclotide was stopped, demonstrating the limited benefit of the drug.

To our knowledge, linaclotide has not been compared with older laxatives in clinical trials, so it is not clear whether its benefit-risk profile is better than the profiles of these drugs.

In 2019, Fukudo et al. reported results from an industry-funded, randomized, placebo-controlled trial that enrolled 186 Japanese participants with chronic constipation.[8] At the first week, the CSBM responder rate was significantly higher among participants who took linaclotide (53%) than among those who took a placebo (26%). Although this trial was extended to 52 weeks, its placebo subjects were switched to linaclotide after the fourth week, precluding the ability to compare the long-term effect of the drug with a placebo.

Clinical guidelines by the U.K.’s National Institute for Health and Care Management do not recommend linaclotide for IBS patients unless they have had constipation for more than 12 months and they were not helped by the maximum or optimal tolerated doses of other laxatives.[9] These guidelines also recommend regular follow-up of linaclotide users who have been taking linaclotide for more than three months.

Serious risks

At least three cases of ischemic colitis (a potentially fatal inflammatory condition that develops when there is insufficient blood flow to the colon, often due to intestinal obstruction) have been reported among linaclotide users in the drug’s preapproval trials. Ischemic colitis can lead to rectal bleeding or bloody stools, as well as inflammation and perforation of the colon. In severe cases, the condition may necessitate surgery.

Therefore, the FDA clinical reviewer advocated for the inclusion of ischemic colitis in the safety warning of linaclotide’s label.[10] However, such warning was not adopted by the agency. Instead, linaclotide’s medication guide only warns about the risk of intestinal blockage and instructs patients who “develop unusual or severe stomach-area (abdomen) pain, especially [with] bright red, bloody stools or black stools that look like tar” to immediately seek emergency care.[11]

Linaclotide’s label also fails to disclose additional potential adverse gastrointestinal effects associated with its use, including diverticulitis (inflammation of the small, bulging pouches [diverticula] in the lining of the colon) and related diverticular perforation and bleeding. The label only indicates that linaclotide should not be used in patients with intestinal obstruction.

Peritonitis (a potentially fatal infection of the abdominal cavity) was reported in a participant taking linaclotide in preapproval trials.[12] No such adverse event was reported in participants who took a placebo.

Because linaclotide is a synthetic, therapeutic protein drug, it can induce an immune response called “immunogenicity” in which the body reacts against the drug, rendering it less effective. Linaclotide mimics naturally occurring proteins called guanylins that are distributed throughout the body and are essential to the functioning of the heart, brain and lungs.[13] Thus, this immune response could hypothetically also deactivate these natural hormones, potentially causing serious adverse effects.

Despite these safety concerns, the FDA did not require linaclotide’s manufacturer to conduct immunogenicity testing before approval. Linaclotide’s manufacturer convinced the FDA that linaclotide is only minimally absorbed from the intestines and, therefore, is unlikely to cause an immune reaction that could block naturally occurring guanylins in other parts of the body.

Additionally, linaclotide is associated with serious allergic reactions, such as anaphylaxis (a severe, life-threatening allergic reaction), hives or skin rash.

What You Can Do

Due to its serious safety concerns and its limited benefits, we recommend against using linaclotide.

To prevent or manage constipation, increase your intake of dietary fiber with foods such as beans, vegetables, fresh and dried fruits, and whole grains; drink plenty of sugar-free, nonalcoholic liquids (six to eight glasses per day); avoid highly processed foods and drinks; and exercise daily. If constipation persists, try a bulk-forming laxative, such as psyllium (METAMUCIL, others and generics), for a short time. Consult your clinician if you experience severe or prolonged constipation.

If you experience IBS with constipation, consume foods high in soluble fiber (such as beans, barley and oats) and avoid insoluble fiber (such as bran).[14] Because stress can trigger or worsen IBS symptoms, it also is important to manage your stress level with adequate uninterrupted sleep, deep breathing, regular exercise, and finding effective ways to relax. Do not hesitate to seek support from family and friends or talk with a counselor.
 

References

[1] Food and Drug Administration. Division director summary review for LINZESS (linaclotide) NDA 202811. August 2012. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202811Orig1s000SumR.pdf. Accessed August 4, 2025.

[2] AbbVie. Label: linaclotide (LINZESS). June 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/202811s021lbl.pdf. Accessed August 4, 2025.

[3] Linaclotide (Linzess) for functional constipation. 2023. Med Lett Drugs Ther. 2023;65(1683):135-136.

[4] Centers for Medicare & Medicaid Services. Medicare drug price negotiation program: Selected drugs for initial price applicability year 2027. January 2025. https://www.cms.gov/files/document/factsheet-medicare-negotiation-selected-drug-list-ipay-2027.pdf. Accessed August 4, 2025.

[5] Public Citizen. Comments to CMS regarding selected drugs for price negotiations (round 2). March 1, 2025. https://www.citizen.org/article/comments-to-cms-regarding-selected-drugs-for-price-negotiation-round-2/. Accessed August 4, 2025.

[6] A bacterial enterotoxin derivative with a laxative action, nothing more. Prescrire Int. 2014;23(155):285-288.

[7] Linaclotide (LINZESS) for constipation. Med Lett Drugs Ther. 2012;54(1403):91-92.

[8] Fukudo S, Miwa H, Nakajima A, et al. High-dose linaclotide is effective and safe in patients with chronic constipation: A phase III randomized, double-blind, placebo-controlled study with a long-term open-label extension study in Japan. Neurogastroenterol Motil. 2019;31(1):e13487.

[9] National Institute for Health and Care Management. Irritable bowel syndrome in adults: diagnosis and management. Updated April 4, 2017. https://www.nice.org.uk/guidance/cg61/resources/irritable-bowel-syndrome-in-adults-diagnosis-and-management-pdf-975562917829. Accessed August 4, 2025.

[10] Food and Drug Administration. Division director summary review for LINZESS (linaclotide) NDA 202811. August 2012. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202811Orig1s000SumR.pdf. Accessed August 4, 2025.

[11] AbbVie. Label: linaclotide (LINZESS). June 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/202811s021lbl.pdf. Accessed August 4, 2025.

[12] Food and Drug Administration. Clinical review for LINZESS (linaclotide) NDA 202811. July 2012. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202811Orig1s000MedR.pdf. Accessed August 4, 2025.

[13] Sindic A. Current understanding of guanylin peptides actions. ISRN Nephrol. 2013(April 17): 813648.

[14] National Institute for Health and Care Management. Irritable bowel syndrome in adults: diagnosis and management. Updated April 4, 2017. https://www.nice.org.uk/guidance/cg61/resources/irritable-bowel-syndrome-in-adults-diagnosis-and-management-pdf-975562917829. Accessed August 4, 2025.