What is the recommended dosing and administration of Linzess (linaclotide) for an adult with irritable bowel syndrome with constipation or chronic idiopathic constipation, and what are the major side effects and contraindications?

Linzess (Linaclotide) Dosing and Clinical Management

Recommended Dosing

For irritable bowel syndrome with constipation (IBS-C) in adults, use 290 mcg orally once daily; for chronic idiopathic constipation (CIC) in adults, use 145 mcg once daily, with 72 mcg once daily as an alternative based on tolerability concerns. 1

Dosing by Indication

• IBS-C: 290 mcg once daily 2, 1
• CIC: 145 mcg once daily (standard) or 72 mcg once daily (alternative for tolerability) 3, 4, 1
• Functional constipation (pediatric 6-17 years): 72 mcg once daily 1

The 290 mcg dose approved for IBS-C can also be considered for CIC patients, recognizing that these conditions overlap and are often indistinguishable in clinical practice 3

Administration Instructions

Linzess must be taken on an empty stomach at least 30 minutes before the first meal of the day, as taking it with food significantly reduces efficacy. 3, 4, 1

Key Administration Points

• Take at approximately the same time each day 1
• Do not crush or chew the capsule or capsule contents 1
• If a dose is missed, take the next dose at the regular time—never take 2 doses at the same time 3
• For patients with difficulty swallowing, capsules can be opened and administered with applesauce or water (see full prescribing information) 1

Major Side Effects

Diarrhea is the most common and clinically significant adverse effect, occurring in 16.3% of IBS-C patients (compared to 2.3% with placebo) and leading to discontinuation in approximately 3.4-5.7% of cases. 2, 3, 5

Adverse Event Profile

• Diarrhea: 16.3% in IBS-C patients vs 2.3% placebo 2
• Discontinuation due to diarrhea: 3.4% vs 0.2% placebo (RR 14.94) 2
• Other common effects (≥2%): abdominal pain, flatulence, abdominal distension 1
• No serious adverse events or deaths due to diarrhea were reported in clinical trials 2

Management of Diarrhea

• If severe diarrhea occurs, suspend dosing and rehydrate the patient 1
• Consider dose reduction if diarrhea is problematic 4
• Most common reasons for discontinuation over the first year are loss of efficacy and insurance coverage barriers, not adverse events 3, 4

Absolute Contraindications

Linzess is absolutely contraindicated in two populations:

1. Patients less than 2 years of age (BLACK BOX WARNING: risk of serious dehydration; linaclotide caused deaths due to dehydration in neonatal mice) 1
2. Patients with known or suspected mechanical gastrointestinal obstruction 3, 1

Clinical Efficacy Evidence

The American Gastroenterological Association provides a strong recommendation with HIGH certainty evidence for linaclotide in IBS-C 2

IBS-C Efficacy (290 mcg dose)

• FDA composite endpoint met: 34.0% vs 18.8% placebo (RR 0.81) across 4 RCTs with 2,612 patients 2
• Abdominal pain improvement: RR 0.83 compared to placebo 2
• Complete spontaneous bowel movements (CSBMs): RR 0.86 compared to placebo 2
• Network meta-analysis ranked linaclotide first in efficacy among secretagogues for IBS-C 2

CIC Efficacy

• Increases CSBMs per week by 1.37 compared to placebo 4
• Increases spontaneous bowel movements by 1.97 per week compared to placebo 4
• Improves stool consistency by 1.25 on Bristol Stool Scale 4
• Triples responder rates compared to placebo (RR 3.14) 4

Treatment Algorithm Position

Linaclotide is recommended as a second-line agent after failure of over-the-counter laxatives for both IBS-C and CIC. 4

Clinical Decision-Making

• Start with OTC laxatives as first-line therapy 4
• Add or switch to linaclotide for inadequate response to OTC agents 4
• Consider linaclotide particularly for patients with concurrent abdominal symptoms (bloating, discomfort, pain) 4
• When diarrhea avoidance is the priority, consider plecanatide instead (4.3% diarrhea rate vs 16.3% with linaclotide) 5
• When maximizing efficacy is the priority, linaclotide 290 mcg is ranked first among secretagogues 5

Special Populations and Considerations

• Elderly patients (≥65 years): Efficacy appears similar to general population, though sample sizes were limited 4
• Patients on diuretics or medications affecting sodium balance: May be at higher risk of hyponatremia 4
• Duration of treatment: Clinical trials evaluated 12 weeks, but the FDA label does not provide a limit on treatment duration 4

Mechanism of Action

Linaclotide is a 14-amino acid peptide guanylate cyclase-C agonist that stimulates GC-C receptors on enterocytes, resulting in intestinal chloride and bicarbonate secretion, increased luminal fluid, accelerated gastrointestinal transit, and inhibition of colonic nociceptors in animal models 2, 4