Does Linzess have a role in IBS with constipation?

Linzess is a new drug that received FDA approval by Forest Laboratories for use in irritable bowel syndrome (IBS) with constipation and in chronic idiopathic constipation.  It got my attention because of its biochemistry.

Learning about the mechanism of action of new drugs like Linzess reminds me how much more is understood about the molecular biological level of physiologic function of the human body than when I was in med school.  Linzess is felt to act as a guanylate cyclase-C agonist. An agonist increases the activity of a process, the opposite of an antagonist. Linzess seems to act locally on the surface of the inside of the intestinal lining cells and by activation of guanylate cyclase-C increases levels of intracellular cGMP (cyclic guanosine monophosphate) which results in increased levels of chloride and bicarbonate in the intestinal lumen and speeds up gastrointestinal transit.

Never having heard of guanylate cyclase-C before, I looked and found out that it was initially discovered before I went to med school in 1974-5, but as far as I know this is one of the first clinically important results of this study in medicine.

The FDA approved use of Linzess in IBS with constipation is 290 µg orally once daily, and in chronic idiopathic constipation the approved dose of Linzess is 145 µg orally daily. In both conditions, Linzess is best taken at least 30 minutes prior to first meal of the day. Linzess joins previously FDA approved and Amitiza (lubiprostone) as prescription medications specifically for IBS with constipation and gives us one more option for treatment of this difficult problem.

IBS with constipation is among the more common and refractory conditions seen in gastroenterology and in primary care. Chronic laxative use is common in these patients and can lead to laxative dependence, poor colonic function and even toxic megacolon in severe cases. Osmotic laxatives like milk of magnesia and not observable sugars like lactulose are commonly used. Miralax (polyethylene glycol) has become increasingly popular in recent years but all of these products have limited effectiveness and associated problems.

The efficacy of Linzess in IBS with constipation and in chronic idiopathic constipation is expected to be modest. In the placebo trial, improvement was only 33% for improvement both abdominal pain and constipation versus 21% with placebo or a 12.6% benefit. In constipation, 48% improved with Linzess versus 29% on placebo, a 19% difference.

Diarrhea is the most common side effect of Linzess, occurring in up to 20% or patients. Often the diarrhea begins within the first 2 weeks of treatment.  The diarrhea from Linzess can be severe and the manufacturer recommends that if a person develops diarrhea they should immediately stop the medication and contact their doctor.  Other GI symptoms include abdominal pain, gas and a feeling of fullness or swelling in the abdomen.  Linzess comes with a strict warning that it is not for use in children. In juvenile rats deaths were noted, so Linzess is contraindicated for use in persons under age 18.

It is expected that Linzess will be another expensive medication. Although Forest has not yet set a price, they have intimated that the drug will be priced to be comparable to Amitiza, or in the $260 per month range.  It remains to be seen if it will be more popular than Amitiza, or whether it will be just a niche drug for refractory cases of IBS with constipation and chronic idiopathic constipation.

Edward Pullen is a family physician who blogs at

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