Rabeprazole is a proton pump inhibitor (PPI) and a potent inhibitor of gastric acidity used in the therapy of gastroesophageal reflux and peptic ulcer disease. Rabeprazole therapy is associated with a low rate of transient and asymptomatic serum aminotransferase elevations and is a rare cause of clinically apparent liver injury.
Rabeprazole (ra bep' ra zole), like other PPIs, binds to and inactivates the H+/K+-ATPase of gastric parietal cells, causing inhibition of the proton pump that transports H+ into the gastric lumen, the final common step in gastric acid production. Rabeprazole is a prodrug and is converted to the active form in the acidic secretory canaliculi of parietal cells. Because the inhibition is irreversible, acid secretion is suppressed for 24 to 48 hours, until new proton pump molecules have been synthesized and transported to the cell membrane. Rabeprazole was the third PPI approved for use in the United States (1999) and is widely used in the therapy of acid-peptic disease, including duodenal and gastric ulcer disease and gastroesophageal reflux. Rabeprazole is available in delayed release tablets of 20 mg in generic forms and under the brand name Aciphex. The typical dose for duodenal ulcer disease is 20 mg once daily for 4 to 8 weeks, with similar doses for long term maintenance therapy. Twice daily doses are used for more severe cases of gastrointestinal reflux and peptic ulcer disease, and doses of up to 120 mg daily for Zollinger-Ellison syndrome. Rabeprazole is very well tolerated. Side effects are uncommon and usually mild; they may include nausea, vomiting, abdominal discomfort, constipation, diarrhea, flatulence, skin rash, headaches and dizziness.
Despite its wide use, rabeprazole has only rarely been associated with hepatic injury. In large scale, long term trials of rabeprazole, serum ALT elevations occurred in less than 1% of patients and at rates similar to those with placebo or comparator drugs. In large case series of drug induced liver injury, rabeprazole has accounted for few instances of symptomatic acute liver injury. Only a few cases of clinically apparent liver disease due to rabeprazole have been published and the characteristics of the injury have not been well defined, but appear to be similar to the features of hepatic injury associated with other proton pump inibitors. Clinically apparent liver injury due to proton pump inhibitors typically arises within the first 4 weeks of treatment with symptoms of jaundice, nausea and fatigue and a hepatocellular or mixed pattern of serum enzyme elevations. Recovery is typically rapid upon withdrawal of the agent. Rash, fever and eosinophilia are rare, as is autoantibody formation. Instances of recurrence on rechallenge have been reported.
Mechanism of Injury
The acute onset and rapid recurrence of hepatic injury with proton pump inhibitors suggests a hypersensitivity reaction, but may merely reflect altered metabolism or acute toxicity of a metabolic byproduct. Rabeprazole is metabolized predominantly by the CYP 2C19 microsomal drug-metabolizing enzyme and may interfere with clearance of other agents metabolized in a similar fashion.
Outcome and Management
The mild and asymptomatic elevations in serum aminotransferase that have been observed during rabeprazole therapy are usually transient and may resolve even without dose modification. Clinically apparent liver injury due to rabeprazole is rare, but calls for prompt withdrawal of the agent. Cases of acute liver failure due to proton pump inhibitor use have been described, but not specifically with rabeprazole. Recurrence of acute liver injury on rechallenge after an initial episode of clinically apparent liver injury with rabeprazole has been reported. There is no information about cross reactivity among the various PPIs after rabeprazole hepatotoxicity, but the PPIs all share a benzimidazole structure, and caution should be used in attempting to reintroduce another PPI after clinically apparent PPI associated hepatic injury.
REPRESENTATIVE TRADE NAMES
Rabeprazole – Generic, Aciphex®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 10 January 2014
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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. PubMed Citation (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).
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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 Citation (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. PubMed Citation (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. PubMed Citation (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. PubMed Citation (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 Citation (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).
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