What to do if Constella (linaclotide) causes diarrhea?

Management of Diarrhea Caused by Linaclotide (Constella)

When linaclotide (Constella) causes diarrhea, the first approach should be dose reduction or temporary suspension, followed by rehydration and possible use of antidiarrheal medications if symptoms are severe. 1, 2

Understanding the Mechanism

• Diarrhea is the most common adverse effect of linaclotide, occurring because it is a guanylate cyclase-C agonist that increases intestinal fluid secretion and accelerates gastrointestinal transit 2, 1
• In clinical trials, diarrhea was reported in approximately 20% of patients taking linaclotide, with severe diarrhea occurring in about 2% of patients 1
• Diarrhea typically begins within the first two weeks of treatment 1

Step-by-Step Management Approach

For Mild to Moderate Diarrhea:

1. Dose Adjustment

   • Consider reducing the dose (if using 290 μg, reduce to 145 μg or 72 μg) 1, 3
   • In clinical trials, the lower 72 μg dose showed significantly fewer discontinuations due to diarrhea (2.4%) compared to the 145 μg dose (3.2%) 3

2. Timing of Administration

   • Take linaclotide on an empty stomach at least 30 minutes before the first meal of the day to potentially reduce diarrhea severity 2
   • Consistent daily dosing rather than sporadic use is still recommended for optimal efficacy 4

3. Dietary Modifications

   • Implement a bland diet or BRAT diet (bread, rice, applesauce, toast) 2
   • Ensure adequate hydration and electrolyte replacement 2
   • Avoid lactose-containing products and high-osmolar dietary supplements 2

For Severe or Persistent Diarrhea:

1. Temporary Suspension

   • If severe diarrhea occurs, suspend dosing temporarily 1
   • After symptoms resolve, consider restarting at a lower dose 1, 3

2. Rehydration

   • Ensure proper hydration and electrolyte replacement (oral or intravenous fluids as appropriate) 2
   • Monitor for signs of dehydration, hypotension, or electrolyte abnormalities (hypokalemia and hyponatremia) 1

3. Antidiarrheal Medications

   • For severe cases, consider adding loperamide (initial dose 4 mg followed by 2 mg every 4 hours, not exceeding 16 mg/day) 2
   • If diarrhea persists for more than 24 hours, increase loperamide to 2 mg every 2 hours 2
   • If diarrhea persists for more than 48 hours on high-dose loperamide, consider second-line agents such as octreotide 2

Special Considerations

• Contraindications: Linaclotide is contraindicated in patients less than 2 years of age and in patients with known or suspected mechanical gastrointestinal obstruction 1
• High-Risk Patients: Monitor closely for dehydration in elderly patients or those with comorbidities 1
• Alternative Treatments: If diarrhea remains intolerable despite dose adjustments, consider switching to lubiprostone, which is less likely to cause diarrhea but may cause nausea instead 2

Long-term Management

• In open-label, long-term trials, approximately 29% of patients required dose reduction or suspension due to adverse reactions, primarily diarrhea 1
• Despite this, linaclotide can be maintained for long periods in patients who tolerate it, as there is no evidence of tachyphylaxis 4
• Regular follow-up is important to assess ongoing tolerability and efficacy 4

Common Pitfalls to Avoid

• Abrupt Discontinuation: Rather than completely stopping the medication, first try dose reduction 1, 3
• Inadequate Hydration: Ensure patients understand the importance of maintaining adequate fluid intake 2
• Failure to Warn Patients: Patients should be counseled about the possibility of diarrhea before starting treatment so they can be prepared to manage it 2, 4
• Overlooking Severe Symptoms: Severe diarrhea associated with dizziness, syncope, hypotension, or electrolyte abnormalities requires immediate medical attention 1