OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Prucalopride	179474-81-8	C18-H26-Cl-N3-O3

ANNOTATED BIBLIOGRAPHY

References updated: 25 April 2019

• Zimmerman HJ. Miscellaneous drugs and diagnostic chemicals. In, Zimmerman, HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999: pp. 717-8.

  (Expert review of hepatotoxicity published in 1999; mentions that cisapride, a serotonin type 4 receptor agonist, was reported to lead to one case of liver injury [hepatocellular] during a decade of use).
• Sharkey KA, McNaughton WK. Gastrointestinal motility and water flux, emesis, and biliary and pancreatic disease. In, Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 921-44.

  (Textbook of pharmacology and therapeutics; the serotonin type 4 receptor agonists are used predominantly for treatment of diseases of intestinal motility and irritable bowel syndrome).
• https://www​.accessdata​.fda.gov/drugsatfda_docs​/nda/2018/210166Orig1s000TOC.cfm .

  (FDA Drug Approvals website that has product labels [package inserts], letters of approval and full FDA scientific review of the new drug application for safety and efficacy; mentions that review of 6 studies in more than 3000 treated patients did not raise clinical safety concerns and that there was no evidence of drug induced liver injury).
• Camilleri M, Kerstens R, Rykx A, Vandeplassche L. A placebo-controlled trial of prucalopride for severe chronic constipation. N Engl J Med 2008; 358: 2344-54. [PubMed: 18509121]

  (Among 620 adults with chronic idiopathic constipation treated with prucalopride [2 or 4 mg] vs placebo once daily for 12 weeks, response rates were 31% and 28% vs 12% and adverse events included diarrhea [13.5% and 18.6% vs 5.3%] and nausea [22% vs 8%], but there were no differences in changes in clinical test results among the different treatment groups).
• Camilleri M, Beyens G, Kerstens R, Robinson P, Vandeplassche L. Safety assessment of prucalopride in elderly patients with constipation: a double-blind, placebo-controlled study. Neurogastroenterol Motil 2009; 21: 1256-e117. [PubMed: 19751247]

  (Among 89 elderly nursing home residents treated with prucalopride [0.5, 1 and 2 mg] vs placebo once daily for 28 days, adverse events included diarrhea, abdominal pain but there were “no clinically relevant changes or dose-related effects in the clinical laboratory parameters”).
• Camilleri M, Van Outryve MJ, Beyens G, Kerstens R, Robinson P, Vandeplassche L. Clinical trial: the efficacy of open-label prucalopride treatment in patients with chronic constipation - follow-up of patients from the pivotal studies. Aliment Pharmacol Ther 2010; 32: 1113-23. [PubMed: 21039673]

  (Among 1455 patients with chronic idiopathic constipation enrolled in a continuation trial of prucalopride [2 or 4 mg daily], satisfaction with bowel function remained high [57% to 67%] and adverse events leading to discontinuation included headache, nausea, diarrhea and abdominal pain; no mention of ALT elevations or hepatotoxicity).
• Sloots CE, Rykx A, Cools M, Kerstens R, De Pauw M. Efficacy and safety of prucalopride in patients with chronic noncancer pain suffering from opioid-induced constipation. Dig Dis Sci 2010; 55: 2912-21. [PMC free article: PMC2943574] [PubMed: 20428949]

  (Among 196 patients with opioid induced constipation treated with prucalopride or placebo for 4 weeks, response rates were higher with prucalopride [2 mg 36%, 4 mg 40% vs placebo 23%] and “there were no clinically relevant differences between groups in…laboratory measures”).
• Müller-Lissner S, Rykx A, Kerstens R, Vandeplassche L. A double-blind, placebo-controlled study of prucalopride in elderly patients with chronic constipation. Neurogastroenterol Motil 2010; 22: 991-8. [PubMed: 20529205]

  (Among 300 elderly persons with chronic idiopathic constipation treated with prucalopride [1,2 or 4 mg] vs placebo daily for 4 weeks, clinical responses were more frequent with the higher doses of prucalopride and adverse events were typically headache and gastrointestinal complaints, while there were no clinically significant differences in laboratory assessments).
• Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. [PMC free article: PMC3992250] [PubMed: 20949552]

  (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, but none were attributed to prokinetic agents or the 5-HT4 receptor agonists).
• Ferrajolo C, Capuano A, Verhamme KM, Schuemie M, Rossi F, Stricker BH, Sturkenboom MC. Drug-induced hepatic injury in children: a case/non-case study of suspected adverse drug reactions in VigiBase. Br J Clin Pharmacol 2010; 70: 721-8. [PMC free article: PMC2997312] [PubMed: 21039766]

  (Among 624,673 adverse event reports in children between 2000 and 2006 in the WHO VigiBase, 1% were hepatic, but no prokinetic agent or 5-HT4 receptor agonist was listed among the 41 most commonly implicated agents).
• Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 114: 1419-25. [PubMed: 23419359]

  (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, but none were attributed to prokinetic agents or the 5-HT4 receptor agonists).
• Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol 2014; 13: 231-9. [PubMed: 24552865]

  (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, none of which were attributed to prokinetic agents or 5-HT4 receptor agonists).
• Mugie SM, Korczowski B, Bodi P, Green A, Kerstens R, Ausma J, Ruth M, et al. Prucalopride is no more effective than placebo for children with functional constipation. Gastroenterology 2014; 147: 1285-95. [PubMed: 25239590]

  (Among 213 children with idiopathic constipation treated with prucalopride or placebo for 8 weeks, response rates were similar in both groups [17% vs 18%] as were adverse event rates [70% vs 61%], and changes in clinical chemistry results were minimal and similar in the two groups).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, one case was attributed to metoclopramide, but none to other prokinetic agents).
• Piessevaux H, Corazziari E, Rey E, Simren M, Wiechowska-Kozlowska A, Kerstens R, Cools M, et al. A randomized, double-blind, placebo-controlled trial to evaluate the efficacy, safety, and tolerability of long-term treatment with prucalopride. Neurogastroenterol Motil 2015; 27: 805-15. [PubMed: 25808103]

  (Among 361 adults with chronic idiopathic constipation treated with prucalopride [2 mg daily] vs placebo for 24 weeks, clinical response rates were similar in both groups [25% vs 21%] as were adverse events [42% vs 42%]; there were no hepatic serious adverse events and no mention of ALT elevations or hepatotoxicity).
• Yiannakou Y, Piessevaux H, Bouchoucha M, Schiefke I, Filip R, Gabalec L, Dina I, et al. A randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy, safety, and tolerability of prucalopride in men with chronic constipation. Am J Gastroenterol 2015; 110: 741-8. [PMC free article: PMC4424376] [PubMed: 25869393]

  (Among 374 men with chronic idiopathic constipation treated with prucalopride or placebo, clinical responses were more frequent with prucalopride [38% vs 18%] as were adverse events [42% vs 34%], and mean changes from baseline in clinical laboratory results were “generally small” and were not considered clinically relevant).
• Camilleri M, Piessevaux H, Yiannakou Y, Tack J, Kerstens R, Quigley EM, Ke M, et al. Efficacy and safety of prucalopride in chronic constipation: an integrated analysis of six randomized, controlled clinical trials. Dig Dis Sci 2016; 61: 2357-72. [PMC free article: PMC4943977] [PubMed: 27056037]

  (Pooled analysis of 7 placebo controlled trials of prucalopride in chronic idiopathic constipation identified 2484 patients among whom response rates were higher with prucalopride [28% vs 13%] and adverse events [mean duration of exposure=87 days] more frequent with prucalopride [63% vs 53%], but were mostly mild and none were fatal, while rates of abnormalities of laboratory tests were low and similar in both groups).