Brand name: Linzess
Drug class: GI Drugs, Miscellaneous
- Guanylate Cyclase-C Agonists
Chemical name: Cyclic (1-6),(2-10),(5-13)-tris(disulfide) l-cysteinyl-l-cysteinyl-l-α-glutamyl-l-tyrosyl-l-cysteinyl-l-cysteinyl-l-asparaginyl-l-prolyl-l-alanyl-l-cysteinyl-l-threonylglycyl-l-cysteinyl-l-tyrosine
Molecular formula: C₅₉H₇₉N₁₅O₂₁S₆
CAS number: 851199-59-2

Medically reviewed by Drugs.com on Jun 30, 2023. Written by ASHP.

Introduction

Guanylate cyclase-C (GC-C) agonist; stimulates secretion of chloride and bicarbonate into intestinal lumen, which increases intestinal fluid and accelerates intestinal transit.

Uses for Linaclotide

Irritable Bowel Syndrome with Constipation

Symptomatic treatment of irritable bowel syndrome (IBS) with constipation in adults.

Chronic Idiopathic Constipation

Symptomatic treatment of chronic idiopathic constipation in adults.

Linaclotide Dosage and Administration

Administration

Oral Administration

Administer orally on an empty stomach, at least 30 minutes prior to first meal of the day. (See Food under Pharmacokinetics.)

Swallow capsules whole.

If patient cannot swallow whole capsule, open capsule and sprinkle contents (beads) on applesauce and administer orally or disperse capsule contents in water and administer orally or via a nasogastric or gastrostomy tube. Use these mixtures immediately; do not store for later use. Administration in other soft foods or liquids not studied.

Do not crush or chew capsules or capsule contents.

If a dose is missed, do not double the dose. Administer the next dose at the regularly scheduled time.

Oral Administration in Applesauce

Sprinkle entire contents of a capsule onto one teaspoonful of room-temperature applesauce. Administer entire mixture immediately.

Oral Administration of Capsule Contents Dispersed in Water

Add entire contents of a capsule to a cup containing approximately 30 mL of room-temperature bottled water, swirl gently for ≥20 seconds, then administer immediately.

Disperse any beads remaining in the cup in an additional 30 mL of water, swirl gently for ≥20 seconds, then administer immediately.

Linaclotide is coated on the surface of the beads and will dissolve off the beads into the water. Manufacturer states that consumption of all the beads is not necessary to deliver a complete dose.

Administration via Nasogastric or Gastrostomy Tube

Add entire contents of a capsule to a cup containing 30 mL of room-temperature bottled water, swirl gently for ≥20 seconds, then draw up entire contents into an appropriately sized catheter-tipped syringe and administer into the nasogastric or gastrostomy tube rapidly (10 mL per 10 seconds) using steady pressure.

Disperse any beads remaining in the cup in an additional 30 mL of water and repeat the process. Then flush the nasogastric or gastrostomy tube with ≥10 mL of water.

Linaclotide is coated on the surface of the beads and will dissolve off the beads into the water. Manufacturer states that administration of all the beads is not necessary to deliver a complete dose.

Dosage

Adults

Irritable Bowel Syndrome with Constipation

Oral

290 mcg once daily.

Chronic Idiopathic Constipation

Oral

145 mcg once daily.

72 mcg once daily may be used based on individual presentation or tolerability.

Higher dosage (290 mcg daily) not associated with additional clinical benefit.

Special Populations

Hepatic Impairment

No dosage adjustments needed.

Renal Impairment

No dosage adjustments needed.

Geriatric Patients

No specific dosage recommendations.

Related/similar drugs

dicyclomine, MiraLAX, lactulose, docusate, Colace, bisacodyl, Linzess

Cautions for Linaclotide

Contraindications

• Infants and children <6 years of age. (See Pediatric Use under Cautions.)

• Known or suspected mechanical GI obstruction.

Warnings/Precautions

Warnings

Pediatric Risk

Lethality reported in neonatal mice. Contraindicated in infants and children <6 years of age; avoid use in children and adolescents 6 to <18 years of age. (See Pediatric Use under Cautions.)

Other Warnings and Precautions

Diarrhea

Diarrhea may occur, generally within first 2 weeks of therapy.

Severe diarrhea reported in 2% of patients receiving linaclotide 145 or 290 mcg daily and in <1% of those receiving 72 mcg daily. Severe diarrhea that was associated with dizziness, syncope, hypotension, and electrolyte abnormalities (hypokalemia and hyponatremia) and required hospitalization or IV fluids has been reported.

Interrupt linaclotide and rehydrate patient if severe diarrhea develops.

Specific Populations

Pregnancy

Not expected to result in fetal exposure if administered to pregnant women; however, available data on use in pregnant women are insufficient to inform fetal risk.

No evidence of adverse embryofetal developmental effects in studies in rats and rabbits, but severe maternal toxicity and associated effects on fetal morphology observed in studies in mice at dosages much higher than recommended human dosages. No developmental abnormalities and no effects on growth, learning and memory, or fertility observed in the offspring of exposed rats.

Limited systemic exposure to linaclotide achieved in these animal species. Do not directly compare animal and human doses for evaluating relative exposure.

Lactation

Not known whether linaclotide distributes into human milk, affects human milk production, or affects breast-fed infant.

Not known whether the negligible systemic absorption observed in adults will result in clinically important exposure in breast-fed infants. Potential for serious adverse effects if exposure occurs. Consider benefits of breast-feeding and importance of the drug to the woman; also consider any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition. (See Pediatric Use under Cautions.)

Pediatric Use

Contraindicated in infants and children <6 years of age; avoid use in children and adolescents 6 to <18 years of age. Safety and efficacy in pediatric patients <18 years of age not established, and deaths reported within 24 hours of administration in neonatal mice (age approximately equivalent to human age of 0–28 days).

In neonatal mice, linaclotide 10 mcg/kg daily caused deaths on postnatal day 7; deaths were due to dehydration resulting from increased fluid secretion into the intestine as a consequence of GC-C stimulation. Tolerability to linaclotide increased with age in juvenile mice, but deaths also reported after single doses of 100 or 600 mcg/kg in mice 2 or 3 weeks of age, respectively.

Because of increased intestinal expression of GC-C, infants and children <6 years of age may be at a greater risk of developing diarrhea and its potentially serious consequences compared with individuals ≥6 years of age. Although no deaths observed in older juvenile mice, avoid use of linaclotide in children and adolescents 6 to <18 years of age because of deaths reported in neonatal mice and lack of safety and efficacy data in pediatric patients.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults. Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and/or drug therapy.

Hepatic Impairment

Not studied, but hepatic impairment not expected to affect metabolism or clearance.

Renal Impairment

Not studied, but renal impairment not expected to affect clearance.

Common Adverse Effects

Diarrhea, abdominal pain, flatulence, abdominal distension, viral gastroenteritis, headache, upper respiratory tract infection, sinusitis.

Drug Interactions

Does not interact with CYP isoenzymes in vitro.

Does not interact with common efflux and uptake transporters, including P-glycoprotein (P-gp), in vitro.

No formal drug interaction studies to date. However, systemic exposure to linaclotide and its active metabolite is negligible after oral administration. Interactions mediated by CYP enzymes or common transporters not expected. (See Pharmacokinetics.)

Linaclotide Pharmacokinetics

Absorption

Bioavailability

Minimally absorbed; negligible systemic bioavailability following oral administration.

Food

Administration immediately after a high-fat breakfast resulted in looser stools and higher stool frequency.

Plasma Concentrations

At recommended dosages, plasma concentrations are below measurable levels.

Distribution

Extent

Not expected to be distributed to tissues to any clinically relevant extent.

Elimination

Metabolism

Metabolized by carboxypeptidase A in GI tract; parent drug and active metabolite are proteolytically degraded in intestinal lumen to smaller peptides and amino acids.

Elimination Route

3–5% of orally administered dose excreted in feces as active peptide, mainly as active metabolite.

Special Populations

Hepatic impairment: Not studied; not expected to affect metabolism or clearance.

Renal impairment: Not studied; not expected to affect clearance.

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15–30°C).

Keep in original container, tightly closed and protected from moisture. Do not remove desiccant from container. Do not subdivide or repackage.

Actions

• Binds to GC-C receptor on luminal surface of intestinal epithelium. Stimulation of GC-C causes increased concentrations of cyclic guanosine monophosphate (cGMP), which activates the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel leading to secretion of chloride and bicarbonate into intestinal lumen; results in increased intestinal fluid and accelerated intestinal transit.

• Changes stool consistency and increases stool frequency.

• In animals, causes decreased visceral hyperalgesia and abdominal pain; effect thought to be mediated by activation of GC-C. Mechanism(s) of abdominal pain relief in patients with IBS with constipation not fully elucidated.

Advice to Patients

• Importance of reading patient information (medication guide) provided by the manufacturer.

• Potential for severe diarrhea and dehydration if accidentally ingested by a child, especially a child <6 years of age. Importance of keeping linaclotide out of reach of children and of properly disposing of any unused drug. (See Pediatric Use under Cautions.)

• Diarrhea or abdominal pain may occur; importance of discontinuing linaclotide and notifying clinician if diarrhea becomes severe or if unusual or severe abdominal pain occurs, especially if associated with hematochezia or melena.

• Importance of taking linaclotide once daily on an empty stomach. Swallow capsule whole; do not crush or chew capsules or capsule contents. Importance of advising patient of alternative forms of administration if patient is unable to swallow whole capsule.

• Importance of storing linaclotide in the original container, protected from moisture; do not remove desiccant from container and do not repackage.

• If a dose is missed, omit the missed dose and take the next dose at the regularly scheduled time. Do not take 2 doses at the same time.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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