OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Rabeprazole	117976-90-6	C18-H21-N3-O3-S.Na

ANNOTATED BIBLIOGRAPHY

References updated: 15 April 2019

• Zimmerman HJ. Proton pump inhibitors. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 720-1.

  (Expert review of hepatotoxicity published in 1999 states that aminotransferase elevations occur in ~1% of PPI treated patients, but only 1 case of acute liver injury has been reported with omeprazole, none with the more recently released lansoprazole and pantoprazole).
• Sharkey KA, McNaughton WK. Pharmacotherapy of gastric acidity, peptic ulcers, and gastroesophageal reflux 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).
• Arnold R. Safety of proton pump inhibitors--an overview. Aliment Pharmacol Ther 1994; 8 Suppl 1: 65-70. [PubMed: 8180297]

  (Side effects of PPIs are uncommon and no more frequent than with cimetidine and ranitidine; "Omeprazole had no clinically relevant effects of laboratory values including...liver function").
• Reilly JP. Safety profile of the proton-pump inhibitors. Am J Health Syst Pharm 1999; 56 (23 Suppl 4): S11-7. [PubMed: 10597119]

  (Review of side effects of proton pump inhibitors, including long term tolerance).
• Martin RM, Dunn NR, Freemantle S, Shakir S. The rates of common adverse events reported during treatment with proton pump inhibitors used in general practice in England: cohort studies. Br J Clin Pharmacol 2000; 50: 366-72. [PMC free article: PMC2014999] [PubMed: 11012560]

  (Prescription event monitoring of common side effects of omeprazole, lansoprazole and pantoprazole from the UK found low rates of diarrhea [0.18-0.39/1000 days], abdominal pain [0.17-.21], nausea [0.16-0.22] and headache [0.10-0.17]; no analysis of liver toxicities).
• Johnstone D, Berger C, Fleckman P. Acute fulminant hepatitis after treatment with rabeprazole and terbinafine. Arch Intern Med 2001; 161: 1677-8. [PubMed: 11434801]

  (46 year old developed jaundice 4 weeks after starting terbinafine, rabeprazole and citalopram [bilirubin 1.2, ALT >3000 U/L], biopsy showing submassive necrosis, resolving in 2 months; authors suggest that rabeprazole rather than terbinafine was the cause).
• Andrade RJ, Lucena MI. Acute fulminant hepatitis after treatment with rabeprazole and terbinafine: is rabeprazole the culprit? Arch Intern Med 2002; 162: 360-1. [PubMed: 11822934]

  (Letter in response to Johnstone [2001] argues that terbinafine rather than rabeprazole was the cause of the hepatotoxicity).
• Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug-induced liver injury in the United States. Liver Transpl 2004; 10: 1018-23. [PubMed: 15390328]

  (Among ~50,000 liver transplants reported to UNOS between 1990 and 2002, 270 [0.5%] were done for drug induced acute liver failure, but none were attributed to an H2 blocker or proton pump inhibitor).
• de Abajo FJ, Montero D, Madurga M, García Rodríguez LA. Acute and clinically relevant drug-induced liver injury: a population based case-control study. Br J Clin Pharmacol 2004; 58: 71-80. [PMC free article: PMC1884531] [PubMed: 15206996]

  (Analysis of General Practice Research Database from UK on 1.6 million persons from 1994-2000 found 128 cases of drug induced liver injury [2.4/100,000 person years]; 3 cases were attributed to cimetidine for an odds ratio of 2.0 compared to controls [n=5000], which was not statistically significant; rabeprazole was not discussed).
• Sabaté M, Ibáñez L, Pérez E, Vidal X, Buti M, Xiol X, Mas A. Fulminant drug-induced hepatic failure leading to death or liver transplantation in Sweden. Scand J Gastroenterol 2005; 40: 1095-101. [PubMed: 16165719]

  (Survey of all cases of DILI with fatal outcome from Swedish Adverse Drug Reporting system from 1966-2002; 103 cases were identified and judged as highly probable, probable or possible; 1 case was attributed to ranitidine, 1 to omeprazole, but none to other antiulcer agents).
• Salgueiro E, Rubio T, Hidalgo A, Manso G. Safety profile of proton pump inhibitors according to the spontaneous reports of suspected adverse reactions. Int J Clin Pharmacol Ther 2006; 44: 548-56. [PubMed: 17176621]

  (Analysis of PPI related reports to Spanish Pharmacovigilance Database during 2004 found 58 reports of liver injury from omeprazole [n=36], lansoprazole [7], pantoprazole [12], rabeprazole [2] and esomeprazole [1], correlating somewhat with relative number of prescriptions; 82% were taking other medications; most resolved uneventually).
• Sabaté M, Ibáñez L, Pérez E, Vidal X, Buti M, Xiol X, Mas A, et al. Risk of acute liver injury associated with the use of drugs: a multicentre population survey. Aliment Pharmacol Ther 2007; 25:1401-9. [PubMed: 17539979]

  (Population based survey of 126 cases of acute liver injury due to drugs between 1993-1999 in Spain; 8 were attributed to ranitidine alone [incidence 5.1/100,000 person-years] and 5 to omeprazole alone [2.1/100,000]).
• Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. [PMC free article: PMC3654244] [PubMed: 18955056]

  (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, 2 were attributed to ranitidine, none to cimetidine or the proton pump inhibitors).
• 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]

  (World wide pharmacovigilance database contained 9036 hepatic adverse drug reactions in children, but no antiulcer medication was listed in the top 40 causes).
• 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 no case was linked to an antiulcer medication).
• Aktaş B, Başar Ö, Altinbaş A, Ekiz F, Yüksel O. Rabeprazole-induced acute cholestatic liver injury. Turk J Gastroenterol 2012; 23: 309-10. [PubMed: 22798130]

  (46 year old man developed jaundice one week after starting rabeprazole [bilirubin 8.3 mg/dL, ALT 374 U/L, Alk P 470 U/L], with resolution within 15 days of stopping and recurrence of jaundice within 3 days of restarting).
• 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; 144: 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 rabeprazole, despite it being among the 10 most prescribed medications in Iceland).
• 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 rabeprazole or other proton pump inhibitors).
• 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.e7. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 3 [0.3%] were attributed to proton pump inhibitors [omeprazole, esomeprazole and lansoprazole], but none to rabeprazole).
• Tsai CF, Chen MH, Wang YP, Chu CJ, Huang YH, Lin HC, Hou MC, et al. Proton pump inhibitors increase risk for hepatic encephalopathy in patients With cirrhosis in a population study. Gastroenterology 2017; 152: 134-41. [PubMed: 27639806]

  (Analysis of the Taiwan National Health Insurance database found a higher rate of proton pump inhibitor use among patients with cirrhosis who developed hepatic encephalopathy [38%: 445 of 1166] compared to a matched group with cirrhosis who did not [rate not provided]; the relative risk was raised for all agents except for rabeprazole).
• Weersink RA, Bouma M, Burger DM, Drenth JPH, Froukje Harkes-Idzinga S, Hunfeld NGM, Metselaar HJ, et al. Safe use of proton pump inhibitors in patients with cirrhosis. Br J Clin Pharmacol 2018; 84: 1806-20. [PMC free article: PMC6046475] [PubMed: 29688583]

  (Systematic review of 69 publications in the literature suggested that doses of proton pump inhibitors should be reduced in patients with cirrhosis and only esomeprazole used in those with Child Pugh Class C cirrhosis, plasma levels of rabeprazole being elevated in patients with cirrhosis, 2-fold with Child Pugh class A, 3-fold with class B and 5-fold with class C).