Linaclotide is a guanylate cyclase-C agonist indicated in adults for the treatment of:

• Irritable bowel syndrome with constipation (IBS-C)
• Chronic idiopathic constipation (CIC)

Linaclotide is an orally administered, peptide agonist of guanylate cyclase 2C used for the treatment of irritable bowel syndrome. Chemically, it is a heterodetic cyclic peptide and consists of fourteen amino acids.

Pharmacodynamics: Taking Linaclotide immediately after a high-fat breakfast resulted in looser stools and a higher stool frequency compared with taking it in the fasted state. In clinical trials, Linaclotide was administered on an empty stomach, at least 30 minutes before breakfast.

Pharmacokinetics: Linaclotide is minimally absorbed with negligible systemic availability following oral administration. Concentrations of Linaclotide and its active metabolite in plasma are below the limit of quantification after oral doses of 145 mcg or 290 mcg were administered. Therefore, standard pharmacokinetic parameters such as the area under the curve (AUC), maximum concentration (Cmax), and half-life (t½) cannot be calculated.

Given that Linaclotide plasma concentrations following recommended oral doses are not measurable, Linaclotide is not expected to be distributed to tissues to any clinically relevant extent.

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.

Active peptide recovery in the stool samples of fed and fasted healthy subjects following administration of Linaclotide 290 mcg once daily for seven days averaged about 5% (fasted) and about 3% (fed), and all of it as the active metabolite.

Irritable Bowel Syndrome with Constipation (IBS-C): The recommended dosage of Linaclotide is 290 mcg capsule orally once daily.

Chronic Idiopathic Constipation (CIC): The recommended dosage of Linaclotide is 145 mcg capsules orally once daily. A dosage of 72 mcg capsule once daily may be used based on individual presentation or tolerability.

No drug-drug interaction studies have been conducted with Linaclotide. Systemic exposures of the drug and active metabolite are negligible following oral administration. Linaclotide does not interact with the cytochrome P450 enzyme system based on the results of in vitro studies. In addition, Linaclotide does not interact with common efflux and uptake transporters (including the efflux transporter P-glycoprotein). Based on these in vitro data, no drug-drug interactions through modulation of CYP enzymes or common transporters are anticipated.

Linaclotide is contraindicated in:

• Patients less than 6 years of age due to the risk of serious dehydration
• Patients with known or suspected mechanical gastrointestinal obstruction

Adverse reactions: Diarrhea, abdominal pain, flatulence, upper respiratory infection (URI), headache, viral gastroenteritis, sinusitis, abdominal distension, severe diarrhea, dyspepsia, fecal incontinence, gastroesophageal reflux disease (GERD), vomiting, fatigue.

Side effects: Diarrhea, stomach/abdominal pain or discomfort, gas, bloating, heartburn, vomiting, headache, cold symptoms such as stuffy nose, sneezing or sinus pain, swelling, or a feeling of fullness or pressure in the abdomen (distention).

Pregnancy Category C. Linaclotide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is unknown whether it is distributed in breast milk; however, Linaclotide and its active metabolite are not measurable in plasma following administration of the recommended clinical doses.

Risk of Serious Dehydration in Pediatric Patients: Linaclotide is contraindicated in patients less than 6 years of age. The safety and effectiveness of Linaclotide in patients less than 18 years of age have not been established. In neonatal mice (human age equivalent of approximately 0 to 28 days), Linaclotide increased fluid secretion as a consequence of GC-C agonism, resulting in mortality within the first 24 hours due to dehydration. Due to increased intestinal expression of GC-C, patients less than 6 years of age may be more likely than patients 6 years of age and older to develop severe diarrhea and its potentially serious consequences.

Avoid the use of Linaclotide in pediatric patients 6 years to less than 18 years of age. Although there were no deaths in older juvenile mice, given the deaths in young juvenile mice and the lack of clinical safety and efficacy data in pediatric patients, avoid the use of Linaclotide in pediatric patients 6 years to less than 18 years of age.

Diarrhea: It was the most common adverse reaction of Linaclotide-treated patients in the pooled IBS-C and CIC double-blind placebo-controlled trials. The incidence of diarrhea was similar between the IBS-C and CIC populations. Severe diarrhea was reported in 2% of 145 mcg and 290 mcg Linaclotide-treated patients, and in less than 1% of 72 mcg Linaclotide-treated CIC patients.

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 Linaclotide. If severe diarrhea occurs, suspend dosing and rehydrate the patient.

Single Linaclotide doses of 2897 mcg were administered to 22 healthy subjects; the safety profile in these subjects was consistent with that in the overall Linaclotide-treated population, with diarrhea being the most commonly reported adverse reaction.

Other laxative preparations

Store between 2°-8°C in a frost-free place. Keep away from light. Keep out of the reach of children.