Product News: Linzess for Irritable Bowel Syndrome with Constipation

Linzess (linaclotide capsules) was approved in August 2012 by the FDA as a once-daily treatment for adult men and women suffering from irritable bowel syndrome with constipation (IBS-C) or chronic idiopathic constipation (CIC). It is estimated that IBS affects 13-35 million Americans. Symptoms associated with this condition include abdominal pain and constipation.

According to Ironwood Pharmaceuticals, Inc, and Forest Laboratories, Inc, linaclotide is “a first-in-class guanylate cyclase-C (GC-C) agonist and acts locally in the intestine with minimal systemic exposure.” It has been shown to reduce intestinal pain and accelerate gastrointestinal transit.

Pharmacology and Pharmacokinetics

The full prescribing information for Linzess notes that linaclotide “is a guanylate cyclase-C (GC-C) agonist. Both linaclotide and its active metabolite bind to GCC and act locally on the luminal surface of the intestinal epithelium. Activation of GC-C results in an increase in both intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP). Elevation in intracellular cGMP stimulates secretion of chloride and bicarbonate into the intestinal lumen, mainly through activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel, resulting in increased intestinal fluid and accelerated transit.”

Linzess has been shown to change stool consistency as measured by the Bristol Stool Form Scale (BSFS) and increase stool frequency.

Linzess is “minimally absorbed with low systemic availability following oral administration,” and is minimally distributed to body tissues. Linaclotide is “metabolized within the gastrointestinal tract to its principal, active metabolite by loss of the terminal tyrosine moiety. Both linaclotide and the metabolite are proteolytically degraded within the intestinal lumen to smaller peptides and naturally occurring amino acids.”

Although this medication has not been studies in patients with hepatic or renal impairment, because linaclotide and its metabolite are metabolized within the gastrointestinal tract, renal and/or hepatic impairment are not expected.

Dosage and Administration

Linzess is taken orally once daily, on an empty stomach, at least 30 minutes prior to the first meal of the day. Recommended doses are 290 mcg (for IBS‐C patients) and 145 mcg (for CIC patients).

The medication should be swallowed whole. The 145 mcg dose is white to off-white opaque with gray imprint “FL 145;” the 290 mcg dose is white to off-white opaque with gray imprint “FL 290.”

Clinical Trials

In placebo-controlled Phase III clinical trials of more than 2,800 adults, Linzess was shown to “significantly reduce abdominal pain in IBS-C patients and significantly increase bowel movement frequency in both IBS-C patients and CIC patients. Improvements were reported in the first week of treatment and maintained throughout the treatment period. When a subset of Linzess-treated patients in the trials were switched to placebo, they reported their symptoms returned toward pretreatment levels within one week, while placebo-treated patients switched to Linzess reported symptom improvements.”

Contraindications, Warnings, and Precautions

Linzess is contraindicated in pediatric patients up to 6 years of age. Use should be avoided in pediatric patients 6 through 17 years of age.

Linzess is also contraindicated in patients with known or suspected mechanical gastrointestinal obstruction.

The most common adverse reaction reported by patients treated with Linzess during clinical trials was diarrhea, with severe diarrhea reported by 2% of patients.

Other adverse events reported during clinical trials include abdominal pain, flatulence, headache, viral gastroenteritis, and abdominal distension.