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Linaclotide: Drug information

Linaclotide: Drug information
(For additional information see "Linaclotide: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Risk of serious dehydration in pediatric patients younger than 2 years:

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.

Brand Names: US
  • Linzess
Brand Names: Canada
  • Constella
Pharmacologic Category
  • Gastrointestinal Agent, Miscellaneous;
  • Guanylate Cyclase-C (GC-C) Agonist
Dosing: Adult
Chronic idiopathic constipation

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

Irritable bowel syndrome with constipation (IBS-C): Oral: 290 mcg once daily.

Opioid-induced constipation

Opioid-induced constipation (alternative agent) (off-label use): Oral: 145 to 290 mcg once daily (Brenner 2020).

Dosing: Kidney Impairment: Adult

No dosage adjustment necessary.

Dosing: Hepatic Impairment: Adult

No dosage adjustment necessary.

Dosing: Older Adult

Refer to adult dosing; use with caution.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Linzess: 72 mcg, 145 mcg, 290 mcg

Generic Equivalent Available: US

No

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Constella: 72 mcg, 145 mcg, 290 mcg

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/202811s017lbl.pdf#page=21, must be dispensed with this medication.

Administration: Adult

Oral: Administer at least 30 minutes before the first meal of the day 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.

Use: Labeled Indications

Chronic idiopathic constipation: Treatment of chronic idiopathic constipation (CIC) in adults

Irritable bowel syndrome with constipation: Treatment of irritable bowel syndrome with constipation (IBS-C) in adults

Use: Off-Label: Adult

Opioid-induced constipation

Medication Safety Issues
Sound-alike/look-alike issues:

LinaCLOtide may be confused with linaGLIPtin.

Pediatric patients: High-risk medication:

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]).

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults with IBS-C or CIC.

>10%: Gastrointestinal: Diarrhea (16% to 22%; severe diarrhea: 2%)

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%), viral gastroenteritis (≤3%), vomiting (<2%)

Nervous system: Headache (4%)

Respiratory: Sinusitis (3%), upper respiratory tract infection (5%)

Frequency not defined: Endocrine & metabolic: Dehydration

Postmarketing:

Gastrointestinal: Hematochezia, nausea, rectal hemorrhage

Hypersensitivity: Anaphylaxis, angioedema

Contraindications

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.

Warnings/Precautions

Concerns related to adverse effects:

• Diarrhea: May cause diarrhea; severe diarrhea associated with dizziness, syncope, hypotension, and electrolyte abnormalities (hypokalemia and hyponatremia) requiring hospitalization or IV fluids has also been reported; consider discontinuation of therapy and rehydration if severe diarrhea occurs. Administration with a high-fat meal may worsen diarrhea.

Metabolism/Transport Effects

None known.

Drug Interactions

There are no known significant interactions.

Pregnancy Considerations

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).

Breastfeeding Considerations

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.

Dietary Considerations

Administer at least 30 minutes before the first meal of the day on an empty stomach. Loose stools and greater stool frequency may occur after administration with a high-fat breakfast.

Monitoring Parameters

IBS-C: Abdominal pain, spontaneous bowel movement quality and frequency

CIC: Frequency of straining during bowel movements; spontaneous bowel movement quality and frequency

Mechanism of Action

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.

Pharmacokinetics

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)

Pricing: US

Capsules (Linzess Oral)

72 mcg (per each): $19.63

145 mcg (per each): $19.63

290 mcg (per each): $19.63

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.

Brand Names: International
  • Constella (AT, BE, CH, CZ, DE, DK, EE, ES, FI, GB, HR, HU, IE, IS, LT, MT, NL, NO, PL, PT, SE, SK);
  • Linzess (BB, HK, JP, MX);
  • Motrax (AR)


For country abbreviations used in Lexicomp (show table)
  1. Brenner DM, Argoff CE, Fox SM, et al. Efficacy and safety of linaclotide for opioid-induced constipation in patients with chronic noncancer pain syndromes from a phase 2 randomized study. Pain. 2020;161(5):1027-1036. doi:10.1097/j.pain.0000000000001754 [PubMed 32310620]
  2. Constella (linaclotide) [product monograph]. Markham, Ontario, Canada: Allergan Inc; July 2022.
  3. Davies A, Leach C, Caponero R, et al. MASCC recommendations on the management of constipation in patients with advanced cancer. Support Care Cancer. 2020;28(1):23-33. doi:10.1007/s00520-019-05016-4 [PubMed 31396746]
  4. Linzess (linaclotide) [prescribing information]. Madison, NJ: Allergan USA Inc; August 2021.
  5. Meyers RS, Thackray J, Matson KL, et al. Key Potentially Inappropriate Drugs in Pediatrics: The KIDs List. J Pediatr Pharmacol Ther. 2020;25(3):175-191. [PubMed 32265601]
  6. Moosavi S, Pimentel M, Wong MS, Rezaie A. Irritable bowel syndrome in pregnancy. Am J Gastroenterol. 2021;116(3):480-490. doi:10.14309/ajg.0000000000001124 [PubMed 33481381]
  7. Müller-Lissner S, Bassotti G, Coffin B, et al. Opioid-induced constipation and bowel dysfunction: a clinical guideline. Pain Med. 2017;18(10):1837-1863. doi:10.1093/pm/pnw255 [PubMed 28034973]
  8. Portenoy RK, Mehta Z, Ahmed E. Prevention and management of side effects in patients receiving opioids for chronic pain. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed June 15, 2021.
  9. Vijayvargiya P, Camilleri M, Vijayvargiya P, Erwin P, Murad MH. Systematic review with meta-analysis: efficacy and safety of treatments for opioid-induced constipation. Aliment Pharmacol Ther. 2020;52(1):37-53. doi:10.1111/apt.15791 [PubMed 32462777]
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