Rabeprazole

Rabeprazole is an inhibitor of the gastric proton pump. It causes dose-dependent inhibition of acid secretion.

In 8-week studies, among patients with gastro-oesophageal reflux disease (GORD), rabeprazole 20 mg/day or 10mg twice daily was as effective as omeprazole and superior to ranitidine in the healing of GORD. Symptom relief with rabeprazole was superior to that provided by placebo and ranitidine and similar to omeprazole. In long-term trials rabeprazole 10 mg/day was similar to omeprazole 20 mg/day in a 2-year study and superior to placebo in 1-year studies, in both the maintenance of healing and prevention of symptoms in patients with healed GORD.

In nonerosive GORD, 4-week studies have shown rabeprazole to be more effective than placebo in relieving heartburn and various other gastrointestinal symptoms. Data among patients with Barrett’s oesophagus suggest rabeprazole 20 mg/day may be more effective than placebo in maintaining healing of associated oesophagitis after 1 year of treatment.

One-week triple Helicobacter pylori eradication therapy with rabeprazole plus clarithromycin and amoxicillin achieved eradication rates of ≥85%. Rabeprazole is as effective as omeprazole and lansoprazole when included as part of a triple-therapy regimen for the eradication of H. pylori. Eradication rates of >90% were achieved when rabeprazole 20 to 40 mg/day was included as part of a quadruple eradication regimen.

As monotherapy for peptic ulcer healing and symptom relief, 4- to 8-week studies have shown rabeprazole 10 to 40 mg/day to be superior to placebo and ranitidine and have similar efficacy to omeprazole. Preliminary 1-year data among 16 patients with Zollinger-Ellison syndrome suggest rabeprazole 60 to 120 mg/day can resolve and prevent the recurrence of symptoms and endoscopic lesions associated with this condition.

In clinical trials of up to 2 years’ duration the tolerability of rabeprazole is similar to that of placebo, ranitidine and omeprazole. Common adverse events assigned to rabeprazole have been diarrhoea, headache, rhinitis, nausea, pharyngitis and abdominal pain. Histological changes and increases in serum gastrin levels were unremarkable and typical of proton pump inhibitors. No dosage adjustment is necessary in renal and mild to moderate hepatic impairment.

Conclusion: Rabeprazole is a well tolerated proton pump inhibitor. It has proven efficacy in healing, symptom relief and prevention of relapse of peptic ulcers and GORD and can form part of effective H. pylori eradication regimens. It is an important alternative to H₂ antagonists and an additional treatment option to other proton pump inhibitors in the management of acid-related disorders.

Rabeprazole inhibits the gastric parietal cell proton pump (H⁺/K⁺-ATPase), dose-dependently reducing basal and peptone-stimulated acid secretion with 20 mg/day providing the optimum antisecretory effect.

In healthy volunteers, rabeprazole had a similar or faster onset of action than omeprazole and pantoprazole. In addition, rabeprazole had a greater antisecretory effect over a 24-hour period than esomeprazole, omeprazole, lansoprazole and pantoprazole. Rabeprazole had a duration of action of ≥24 hours. Among patients with gastro-oesophageal reflux disease (GORD) rabeprazole is as effective as omeprazole and more effective than placebo in normalising 24-hour oesophageal acid exposure.

Rabeprazole produces dose-dependent increases in gastrin levels which are directly related to increases in pH and has no effect on endocrine function.

Unlike omeprazole and lansoprazole, multiple-dose studies in volunteers have shown the effect of rabeprazole on intragastric pH to be unaffected by cytochrome P450 (CYP) 2C19 genotype status.

Rabeprazole is dose-dependently absorbed after oral administration and is extensively metabolised primarily via nonenzymatic metabolism with minor contributions from CYP 3A and 2C19 pathways. Rabeprazole is extensively distributed in a variety of tissues including gastric mucosa and 96% bound to plasma proteins. No significant accumulation occurs during repeated administration, and 90% of a dose is excreted in the urine as its thioether carboxylic acid metabolite and its glucuronide and mercapturic acid metabolites. The elimination half-life of rabeprazole is ≈1 to 2 hours. Other than pH-dependent interactions with digoxin and ketoconazole, rabeprazole has no clinically significant drug interactions. Administration of food slows the rate but does not affect the extent of absorption.

Well designed trials have compared the efficacy of rabeprazole 10 and 20 mg/day with placebo or omeprazole 20 mg/day in maintaining healing and symptom relief in patients following healing of grades 2 to 4 GORD. One study demonstrated no difference in relapse rates between rabeprazole 10 mg/day and omeprazole 20 mg/day regimens after 1 year of treatment. In addition, the probability of remaining healed at 2 years was 100% for patients treated with omeprazole 20 mg/day or rabeprazole 10 mg/day versus 97.5% for those treated with rabeprazole 20 mg/day. There were no significant differences in symptom frequency or severity between regimens after 2 years of treatment. In addition, 1-year placebo-controlled studies report rabeprazole (10 and 20 mg/day) to be superior to placebo in both maintenance of healing and the reduction of the rate and severity of symptoms in patients with healed GORD.

In patients with nonerosive GORD, two 4-week, well controlled studies have shown rabeprazole 10 and 20 mg/day to be more effective than placebo in relieving heartburn and various other gastrointestinal symptoms. Onset of treatment benefit was seen from the first day of treatment. Rabeprazole was significantly better than placebo in reducing daytime and night-time heartburn symptoms and in a further trial in reducing the mean gastro-oesophageal symptom assessment distress scale score within a 4-week period.

In a nonblind, 1-year study among patients with Barrett’s oesophagus, rabeprazole 20 mg/day was significantly more effective than placebo in maintaining healing of associated erosive GORD at all time points. At week 52, 90% of patients treated with rabeprazole 20 mg/day remained healed versus 47% in the placebo group.

Duodenal Ulcer and Gastric Ulcer. In randomised trials, as part of triple therapy, rabeprazole 20 to 40 mg/day has been shown to be an effective part of a H. pylori eradication triple-therapy regimen. When combined with twice daily clarithromycin 500mg and either metronidazole 400mg or amoxicillin 1g eradication rates of ≥90% can be achieved. In three large, randomised studies, rabeprazole as part of a 7-day triple-therapy eradication regimen was as effective as omeprazole or lansoprazole. In a well designed study rabeprazole 20mg twice daily was compared with omeprazole 20mg twice daily in addition to clarithromycin 500mg twice daily and amoxicillin 1g twice daily. Intention-to-treat analysis revealed eradication rates of 84% for rabeprazole-treated patients versus 69% for omeprazole-treated patients (no p-value reported). In a nonblind study, eradication rates with lansoprazole 30mg twice daily, rabeprazole 20mg and 10mg twice daily in addition to amoxicillin 500mg three times a day and clarithromycin 200mg twice daily were 82.7, 85.6 and 87%, respectively.

Preliminary data from a small, noncomparative 1-year study indicate that rabeprazole in dosages of up to 120 mg/day can resolve, and prevent the recurrence of symptoms and endoscopic lesions associated with Zollinger-Ellison syndrome.

Rabeprazole has been well tolerated in short- and long-term studies of up to 2 years in duration when administered in doses of up to 120 mg/day for the treatment of acid-related disorders. In over 1700 patients only headache (2.4%) was reported more often than with placebo. The most common adverse events reported in clinical trials were headache, diarrhoea, rhinitis, nausea, pharyngitis and abdominal pain. Flatulence occurred significantly more frequently in omeprazole-treated patients and less frequently in ranitidine-treated patients than in rabeprazole-treated patients in three well designed comparative studies. No other significant differences occurred between treatment groups.

Serum gastrin changes that are consistent with proton pump inhibitor pharmacology have been reported in well designed trials, in patients receiving rabeprazole. No trial reported mean values at endpoint that were outside the normal range. In controlled clinical trials 3/1456 patients treated with rabeprazole and 2/237 patients treated with placebo developed treatment-emergent abnormalities in AST, ALT or both.

Scoring of enterochromaffin-like cells in biopsies taken prospectively from patients in studies of up to 2 years in duration demonstrate some hyperplastic changes, but no evidence of adenomatoid, dysplastic or neoplastic changes.

In the treatment and relapse prevention of GORD, US studies using decision analysis models have shown rabeprazole to be more cost effective than omeprazole, lansoprazole and ranitidine; however, no study was performed alongside a prospective clinical trial. In analyses from a third-party perspective, a 1-year relapse prevention study reported treatment with rabeprazole resulted in an average cost-effectiveness ratio of $US1637 per occurrence prevented, compared with $US2439 for lansoprazole and $US1968 for omeprazole. The incremental cost per patient, relative to rabeprazole, was $US257 for lansoprazole and $US185 for omeprazole. In the treatment of GORD, the incremental cost-effectiveness ratio was $US313 when rabeprazole was compared with ranitidine. For ranitidine and rabeprazole to be equally cost effective, the 8-week system response rate with ranitidine therapy would have had to increase from 28 to 72%.

Rabeprazole is licensed world wide for use in acid-related disorders; however, it is not licensed in the US for the treatment of gastric ulcer or as part of a H. pylori eradication regimen. The usual oral dosage for the treatment of duodenal ulcers, gastric ulcers and GORD is 20 mg/day for 4 to 8 weeks with a further course given if needed. The dosage can be reduced to 10 to 20 mg/day for maintenance therapy. In Europe rabeprazole 10 mg/day is licensed for the treatment of non-erosive GORD. In H. pylori eradication regimens the licensed oral dosage is 20mg twice daily as part of a 7-day triple-therapy regimen. Dosages for Zollinger-Ellison syndrome, in the US, are up to 60mg twice daily.

The dosage of rabeprazole need not be adjusted in the elderly or in those with renal and mild-to-moderate hepatic impairment. As with other proton pump inhibitors coadministration of rabeprazole with digoxin and ketoconazole should be treated with caution.