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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:

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

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

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 (Significant): Considerations
Diarrhea

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)

Adverse Reactions

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.

>10%: Gastrointestinal: Diarrhea (16% to 22%; severe diarrhea: 2%) (table 1)

Linaclotide: Adverse Reaction: Diarrhea

Drug (Linaclotide)

Placebo

Dose

Indication

Number of Patients (Linaclotide)

Number of Patients (Placebo)

22%

7%

145 mcg once daily

Chronic idiopathic constipation

411

401

19%

7%

72 mcg once daily

Chronic idiopathic constipation

411

401

16%

5%

145 mcg once daily

Chronic idiopathic constipation

430

423

20%

3%

290 mcg once daily

Irritable bowel syndrome with constipation

807

798

Severe: 2%

Severe: 1%

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%), 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; pediatric patients <6 years of age.

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 (Adult Data Unless Noted)

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): $20.61

145 mcg (per each): $20.61

290 mcg (per each): $20.61

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 code abbreviations (show table)
  1. Baaleman DF, Gupta S, Benninga MA, et al. The use of linaclotide in children with functional constipation or irritable bowel syndrome: a retrospective chart review. Paediatr Drugs. 2021;23(3):307-314. doi:10.1007/s40272-021-00444-4 [PubMed 33876403]
  2. 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]
  3. Chang L, Sultan S, Lembo A, Verne GN, Smalley W, Heidelbaugh JJ. AGA clinical practice guideline on the pharmacological management of irritable bowel syndrome with constipation. Gastroenterology. 2022;163(1):118-136. doi:10.1053/j.gastro.2022.04.016 [PubMed 35738724]
  4. Chey WD, Lembo AJ, Lavins BJ, et al. Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety. Am J Gastroenterol. 2012;107(11):1702-1712. doi:10.1038/ajg.2012.254 [PubMed 22986437]
  5. Constella (linaclotide) [product monograph]. St-Laurent, Quebec, Canada: AbbVie Corporation; October 2022.
  6. Corsetti M, Tack J. Linaclotide: a new drug for the treatment of chronic constipation and irritable bowel syndrome with constipation. United European Gastroenterol J. 2013;1(1):7-20. doi:10.1177/2050640612474446 [PubMed 24917937]
  7. 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]
  8. Johnston JM, Kurtz CB, Macdougall JE, et al. Linaclotide improves abdominal pain and bowel habits in a phase IIb study of patients with irritable bowel syndrome with constipation. Gastroenterology. 2010;139(6):1877-1886.e2. doi:10.1053/j.gastro.2010.08.041 [PubMed 20801122]
  9. Lacy BE, Pimentel M, Brenner DM, et al. ACG clinical guideline: management of irritable bowel syndrome. Am J Gastroenterol. 2021;116(1):17-44. doi:10.14309/ajg.0000000000001036 [PubMed 33315591]
  10. Linzess (linaclotide) [prescribing information]. Madison, NJ: Allergan USA Inc; August 2021.
  11. Love BL, Johnson A, Smith LS. Linaclotide: a novel agent for chronic constipation and irritable bowel syndrome. Am J Health Syst Pharm. 2014;71(13):1081-1091. doi:10.2146/ajhp130575 [PubMed 24939497]
  12. 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. doi:10.5863/1551-6776-25.3.175 [PubMed 32265601]
  13. 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]
  14. 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]
  15. Nee JW, Johnston JM, Shea EP, et al. Safety and tolerability of linaclotide for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation: pooled phase 3 analysis. Expert Rev Gastroenterol Hepatol. 2019;13(4):397-406. doi:10.1080/17474124.2019.1575203 [PubMed 30791771]
  16. 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.
  17. Rao S, Lembo AJ, Shiff SJ, et al. A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol. 2012;107(11):1714-1724. doi:10.1038/ajg.2012.255 [PubMed 22986440]
  18. Rey E, Mearin F, Alcedo J, et al. Optimizing the use of linaclotide in patients with constipation-predominant irritable bowel syndrome: an expert consensus report. Adv Ther. 2017;34(3):587-598. doi:10.1007/s12325-016-0473-8 [PubMed 28083815]
  19. Schoenfeld P, Lacy BE, Chey WD, et al. Low-dose linaclotide (72 μg) for chronic idiopathic constipation: a 12-week, randomized, double-blind, placebo-controlled trial. Am J Gastroenterol. 2018;113(1):105-114. doi:10.1038/ajg.2017.230 [PubMed 29091082]
  20. Serrano-Falcón B, Delgado-Aros S, Mearin F, et al. Clinical response to linaclotide at week 4 predicts sustained response in irritable bowel syndrome with constipation and improvements in digestive and extra-digestive symptoms. Therap Adv Gastroenterol. 2019;12:1756284819857358. doi:10.1177/1756284819857358 [PubMed 31428193]
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