Version May 2024
Linaclotide is contraindicated in pediatric patients younger than 2 years; in nonclinical studies in neonatal mice, administration of a single, clinically relevant adult oral dose of linaclotide caused deaths due to dehydration.
Chronic idiopathic constipation (CIC): Oral: 145 mcg once daily; 72 mcg once daily may be used based on patient presentation or tolerability.
Irritable bowel syndrome with constipation:
Note: Reserve for patients with persistent constipation despite osmotic laxative use (Ref).
Oral: 290 mcg once daily; dose may be reduced to 145 mcg once daily if patient develops diarrhea (typically occurs within 2 weeks). Symptoms of abdominal pain and bowel function generally improve by day 7 (Ref); some experts will allow up to an 8- to 12-week trial before considering alternative therapy (Ref).
Opioid-induced constipation (alternative agent) (off-label use): Oral: 145 to 290 mcg once daily (Ref).
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function: No dosage adjustment necessary for any degree of kidney impairment (systemic absorption limited) (Ref).
Hemodialysis, intermittent (thrice weekly): Unlikely to be dialyzed: No supplemental dose or dosage adjustment necessary (systemic absorption limited) (Ref).
Peritoneal dialysis: Unlikely to be dialyzed: No dosage adjustment necessary (systemic absorption limited) (Ref).
CRRT: No dosage adjustment necessary (systemic absorption limited) (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary (systemic absorption limited) (Ref).
No dosage adjustment necessary.
Refer to adult dosing; use with caution.
(For additional information see "Linaclotide: Pediatric drug information")
Functional constipation: Children ≥6 years and Adolescents <18 years: Oral: 72 mcg once daily.
Children ≥6 years and Adolescents <18 years: Oral: No dosage adjustment necessary.
Children ≥6 years and Adolescents <18 years: Oral: No dosage adjustment necessary.
Diarrhea is the most commonly reported adverse reaction with linaclotide, leading to dose reduction, treatment interruption, and/or discontinuation of therapy (Ref). Diarrhea was a patient-reported outcome in published experiences (Ref) and was not explicitly defined, but most frequently described as mild to moderate in severity (Ref).
Mechanism: Dose-related; related to the pharmacologic action (activation of receptors in the intestines causing the release of chloride, bicarbonate, and fluid, which decreases intraluminal transit time) (Ref).
Onset: Varied; typically occurs within the first 1 to 2 weeks of therapy (Ref).
Risk factors:
• Dose; occurred more frequently at higher doses in dose-finding studies and in postmarketing published experiences (Ref)
• Concurrent use of laxatives; especially at treatment initiation (Ref)
• Ethnicity (Caucasian) (Ref)
• Older age (≥65 years) (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults with irritable bowel syndrome with constipation or chronic idiopathic constipation unless otherwise indicated.
>10%: Gastrointestinal: Diarrhea (children and adolescents: 4% [severe diarrhea: <1%]; adults: 16% to 22% [severe diarrhea: 2%]) (table 1)
|
Drug (Linaclotide) |
Placebo |
Population |
Dose |
Indication |
Number of Patients (Linaclotide) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
4% |
2% |
Children and adolescents |
72 mcg once daily |
Functional constipation |
164 |
164 |
|
Severe: <1% |
Severe: 0% |
Children and adolescents |
72 mcg once daily |
Functional constipation |
164 |
164 |
|
22% |
7% |
Adults |
145 mcg once daily |
Chronic idiopathic constipation |
411 |
401 |
|
19% |
7% |
Adults |
72 mcg once daily |
Chronic idiopathic constipation |
411 |
401 |
|
16% |
5% |
Adults |
145 mcg once daily |
Chronic idiopathic constipation |
430 |
423 |
|
20% |
3% |
Adults |
290 mcg once daily |
Irritable bowel syndrome with constipation |
807 |
798 |
|
Severe: 2% |
Severe: 1% |
Adults |
290 mcg once daily |
Irritable bowel syndrome with constipation |
807 |
798 |
1% to 10%:
Gastrointestinal: Abdominal distension (2% to 3%), abdominal pain (7%), bowel urgency (<2%), dyspepsia (<2%), fecal incontinence (<2%), flatulence (4% to 6%), gastroesophageal reflux disease (<2%), nausea (children and adolescents: 1%), viral gastroenteritis (≤3%), vomiting (<2%)
Nervous system: Headache (4%)
Respiratory: Sinusitis (3%), upper respiratory tract infection (5%)
<1%:
Endocrine & metabolic: Dehydration (children and adolescents)
Gastrointestinal: Abdominal distress (children and adolescents)
Postmarketing:
Gastrointestinal: Hematochezia, rectal hemorrhage
Hypersensitivity: Anaphylaxis, angioedema
Pediatric patients <2 years of age; mechanical gastrointestinal obstruction (known or suspected).
Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to linaclotide or any component of the formulation; pediatric patients <6 years of age.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Linzess: 72 mcg, 145 mcg, 290 mcg
No
Capsules (Linzess Oral)
72 mcg (per each): $21.64
145 mcg (per each): $21.64
290 mcg (per each): $21.64
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Constella: 72 mcg, 145 mcg, 290 mcg
Oral: Administer at least 30 minutes before a meal on an empty stomach; loose stools and greater stool frequency may occur after administration with a high-fat breakfast. Swallow capsule whole; do not break, crush, or chew capsules or capsule contents.
For patients with swallowing difficulties, capsules may be opened and administered orally either in applesauce or with water or administered with water via a nasogastric or gastric feeding tube. Mixing beads from capsules in other soft foods or in other liquids has not been tested.
Administration in applesauce: Open capsule and sprinkle entire contents (beads) onto 1 teaspoonful (5 mL) of room temperature applesauce. Swallow entire contents immediately; do not chew the beads. Do not store mixture for future use.
Administration in water: Open capsule and sprinkle entire contents (beads) into a cup with ~30 mL of room temperature bottled water. Gently swirl for at least 20 seconds and swallow immediately; add another 30 mL of water to any remaining beads in cup, swirl for at least 20 seconds, and swallow immediately. Do not store the water-bead mixture for future use. Note: The drug is coated on surface of beads and will dissolve off the beads in water; beads will remain visible and will not dissolve; therefore, it is not necessary to consume all the beads to deliver complete dose.
Administration via nasogastric or gastric feeding tube: Open capsule and empty entire contents (beads) into a clean container with 30 mL of room temperature bottled water. Gently swirl for at least 20 seconds; draw up bead and water mixture with catheter syringe and apply rapid and steady pressure (10 mL per 10 seconds) to dispense the bead-water mixture into the tube; add another 30 mL of water to any remaining beads and repeat process. Flush nasogastric/gastric tube with at least 10 mL of water after administration. Note: Not necessary to flush all the beads through tube to deliver complete dose.
Oral: Administer at least 30 minutes before a meal; administer at the same time each day. Swallow capsule whole; do not break, crush, or chew capsules or capsule contents.
For patients with swallowing difficulties:
Administration in applesauce: Oral: Open capsule and sprinkle entire contents (beads) onto 5 mL (1 teaspoonful) of room temperature applesauce. Swallow entire contents immediately; do not chew the beads. Do not store mixture for future use. Mixing beads from capsules in other soft foods has not been tested.
Administration in water: Oral: Open capsule and sprinkle entire contents (beads) into a cup with ~30 mL of room temperature bottled water. Gently swirl for at least 20 seconds and then swallow mixture immediately; add another 30 mL of water to any remaining beads in cup, swirl for at least 20 seconds, and swallow immediately. Do not store the water-bead mixture for future use. Mixing beads from capsules in other liquids has not been tested. Note: The drug is coated on surface of beads and will dissolve off the beads in water; beads will remain visible and will not dissolve; therefore, it is not necessary to consume all the beads to deliver complete dose.
For administration via NG or gastric feeding tube: Open capsule and empty entire contents (beads) into a clean container with 30 mL of room temperature bottled water. Gently swirl for at least 20 seconds; draw up bead and water mixture with catheter syringe and apply rapid and steady pressure (10 mL per 10 seconds) to dispense the bead-water mixture into the tube; add another 30 mL of water to any remaining beads and repeat process. Flush NG/gastric tube with at least 10 mL of water after administration. Note: Not necessary to flush all the beads through tube to deliver complete dose.
Missed dose: If a dose is missed, skip the missed dose and administer next dose at regular time; do not double doses.
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/202811s021lbl.pdf#page=23, must be dispensed with this medication.
Chronic idiopathic constipation: Treatment of chronic idiopathic constipation in adults.
Functional constipation: Treatment of functional constipation in pediatric patients 6 to 17 years of age.
Irritable bowel syndrome with constipation: Treatment of irritable bowel syndrome with constipation in adults.
Opioid-induced constipation
LinaCLOtide may be confused with linaGLIPtin.
KIDs List: Linaclotide, when used in pediatric patients <6 years of age, is identified on the Key Potentially Inappropriate Drugs in Pediatrics (KIDs) list and should be avoided due to risk of death from dehydration (weak recommendation; very low quality of evidence) (PPA [Meyers 2020]).
None known.
There are no known significant interactions.
Linaclotide and its metabolite are not measurable in plasma when used at recommended doses. Maternal use is not expected to result in fetal exposure; however, until information specific to use in pregnancy becomes available, agents other than linaclotide may be preferred (Moosavi 2021).
Linaclotide is not present in breast milk.
Linaclotide was administered to breastfeeding patients in oral doses of 72 mcg, 145 mcg, or 290 mcg once daily for 3 days. Linaclotide and its metabolite were below the limits of quantification in all samples obtained over 24 hours. According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.
Administer at least 30 minutes before a meal on an empty stomach. Loose stools and greater stool frequency may occur after administration with a high-fat breakfast.
Signs and symptoms of diarrhea or dehydration, including dizziness, syncope, hypotension, or electrolyte abnormalities (hypokalemia and hyponatremia).
IBS-C: Abdominal pain, spontaneous bowel movement quality and frequency.
CIC: Frequency of straining during bowel movements; spontaneous bowel movement quality and frequency.
Pediatric patients 6 to <18 years: Functional constipation: Stool output, signs/symptoms of dehydration (particularly severe: dizziness, hypotension, electrolyte abnormalities [potassium, sodium]).
Linaclotide and its active metabolite bind and agonize guanylate cyclase-C on the luminal surface of intestinal epithelium. Intracellular and extracellular cyclic guanosine monophosphate (cGMP) concentrations are subsequently increased resulting in chloride and bicarbonate secretion into the intestinal lumen. Intestinal fluid increases and GI transit is accelerated. Increased extracellular cGMP may decrease visceral pain by reducing pain-sensing nerve activity.
Absorption: Minimal systemic availability; plasma concentrations are not measurable when used at recommended doses.
Distribution: Minimal tissue distribution is expected given immeasurable plasma concentrations when used at recommended doses.
Metabolism: Metabolized within GI tract to active metabolite; parent drug and metabolite undergo proteolytic degradation within the intestinal lumen to smaller peptides and amino acids
Excretion: Primarily feces (3% to 5%; as the active metabolite)
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