New FDA: Actions: Ironwood Pharmaceuticals' and Forest Laboratories Linzess

NOVEMBER 12, 2012
Monica Holmberg, PharmD, BCPS

Linzess (linaclotide) is approved for treatment of adults with irritable bowel syndrome with constipation or chronic idiopathic constipation.

The FDA has approved Ironwood Pharmaceuticals, Inc’s and Forest Laboratories, Inc’s Linzess (linaclotide) for adult patients with irritable bowel syndrome with constipation (IBS-C) or chronic idiopathic constipation (CIC).1

Patients with IBS-C often report recurrent abdominal pain or discomfort and constipation. Bowel symptoms include hard or lumpy stools in more than 25% of bowel movements and soft or watery stools in less than 25% of bowel movements. IBS-C affects an estimated 13 million Americans. CIC is a functional gastrointestinal disorder in which patients have less than 3 bowel movements per week for at least 3 months. Patients may also describe a sensation of incomplete bowel emptying and hard stools. Up to 35 million Americans are affected by CIC.2

Linzess carries a boxed warning that its use should be avoided in patients younger than 17 years and is contraindicated in patients younger than 6 years.1 Linzess is the first agent in its class to receive FDA approval.2

Pharmacology and Pharmacokinetics

Linzess is a guanylate cyclase-C (GC-C) agonist. Both it and its metabolite bind to GC-C and exert their effect locally on the surface of the intestinal epithelium. When GC-C is activated, both intracellular and extracelluar concentrations of cyclic guanosine monophosphate (cGMP) are increased.

This increase in intracellular cGMP stimulates the secretion of chloride and bicarbonate into the intestinal lumen, resulting in an increase in intestinal fluid and acceleration in transit. Animal models suggest that the increase in extracelluar cGMP is responsible for a decrease in activity of painsensing nerves.

Linzess is metabolized in the gastrointestinal tract to its principal active metabolite. Due to its minimal absorption after oral administration, the systemic availability of Linzess is nearly undetectable. Standard pharmacokinetic parameters such as area under the concentration-time curve, maximum concentration, and half-life cannot be calculated. No dose adjustment is required for hepatic or renal impairment. The impact of age or gender on the pharmacokinetics of Linzess has not been studied.1,2

Dosage and Administration

For the treatment of IBS-C, Linzess should be given as 290 mcg orally once a day. For the treatment of CIC, Linzess should be given as 145 mcg once a day. It should be taken on an empty stomach at least 30 minutes before the first meal of the day. The capsule should be swallowed whole and never broken or chewed.1

Clinical Trials

The safety and effectiveness of Linzess in patients with IBS-C were evaluated in 2 double-blind, placebo-controlled, randomized, multicenter clinical trials. A total of 1604 adult patients were randomized to take either Linzess 290 mcg or a placebo for at least 12 weeks. At the study’s end, the Linzess arm experienced a greater reduction in pain and more complete spontaneous bowel movements than the placebo arm.

The safety and effectiveness of Linzess in patients with CIC was evaluated in 2 double-blind, placebo-controlled, randomized, multi-center clinical trials. A total of 1272 patients were randomized to take Linzess 145 mcg, 290 mcg, or placebo for 12 weeks. Study results demonstrated that patients in the Linzess arms had more spontaneous bowel movements than patients in the placebo arm, but that the 290 mcg dose was no more effective than the 145 mcg dose.1,3

Contraindications, Warnings, and Precautions

Linzess caused deaths in juvenile young mice; as a result, it carries a boxed warning contraindicating its use in patients younger than 6 years. Its use should also be avoided in patients younger than 17 years.

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

Patients using Linzess may experience severe diarrhea. If this occurs, patients should stop Linzess and contact their health care provider immediately. The health care provider should consider dose suspension.

Linzess is Pregnancy Category C. It is not known whether or not it is excreted into human breast milk; caution should be used in women who are nursing.

The most common adverse reactions (≥2%) were diarrhea, abdominal pain, flatulence, and abdominal distention.1

Dr. Holmberg earned her PharmD from the University of Connecticut and completed an ambulatory care residency at the Phoenix VA Healthcare System. Her practice has also included pediatrics and inpatient mental health. She resides in Phoenix, AZ.

1. Linzess complete prescribing information. Accessed September 2012.

2. Ironwood and Forest announce FDA approval of Linzess (linaclotide) for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation. Accessed September 2012.
3. FDA approves Linzess to treat certain cases of irritable bowel syndrome and constipation. Accessed September 2012.

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