Source: Health Products Regulatory Authority (IE) Revision Year: 2021 Publisher: Rowa Pharmaceuticals Limited, Newtown, Bantry, Co. Cork, Ireland
Pharmacotherapeutic group: Alimentary tract and metabolism, Drugs for peptic ulcer and gastro-oesophageal reflux disease (GORD), proton pump inhibitors
ATC code: A02BC04
Rabeprazole sodium belongs to the class of anti-secretory compounds, the substituted benzimidazoles, that do not exhibit anticholinergic or H2-histamine-antagonist properties, but suppress gastric acid secretion by the specific inhibition of H+/K+ -ATPase enzyme (the acid or proton pump). The effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus. Animal studies indicate that after administration, rabeprazole sodium rapidly disappear from both plasma and the gastric mucosa. As a weak base, rabeprazole is rapidly absorbed following all doses and is concentrated in the acid environment of parietal cells. Rabeprazole is converted to the active sulphenamide form through protonation, and subsequently reacts with the available cysteines on the proton pump.
After oral administration of a 20mg dose of rabeprazole sodium the onset of the anti-secretory effect occurs within one hour, with the maximum effect occurring within two to four hours. Inhibition of basal and food-stimulated acid secretion 23 hours after the first dose of rabeprazole sodium are 69% and 82% respectively and inhibition lasts up to 48 hours. The inhibitory effect of rabeprazole sodium on acid secretion increases slightly with repeated once-daily dosing, achieving steady-state inhibition after three days. When the drug is discontinued, secretory activity normalises over 2 to 3 days.
Decreased gastric acidity due to any means, including PPIs such as rabeprazole, increases counts of bacteria normally present in the gastrointestinal tract. Treatment with PPI may possibly increase the risk of gastrointestinal infections such as Salmonella, Campylobacter and Clostridium difficile.
In clinical studies patients were treated once daily with 10 mg or 20 mg rabeprazole sodium, for up to 43 months. Serum gastrin levels increased during the first 2 to 8 weeks reflecting the inhibitory effects on acid secretion and remained stable while treatment was continued. Gastrin values returned to pre-treatment levels, usually 1 to 2 weeks after discontinuation of therapy.
Human gastric biopsy specimens from the antrum and the fundus from over 500 patients receiving rabeprazole or comparator treatment for up to 8 weeks have not detected changes in ECL cell histology, degree of gastritis, incidence of atrophic gastritis, intestinal metaplasia or distribution of H. pylori infection. In over 250 patients followed for 36 months of continuous therapy, no significant change in findings present at baseline was observed.
Systemic effects of rabeprazole sodium in the CNS, cardiovascular and respiratory systems have not been found to date. Rabeprazole sodium, given in oral doses of 20-mg for 2 weeks, had no effect on thyroid function, carbohydrate metabolism or circulating levels of parathyroid hormone, cortisol, oestrogen, testosterone, prolactin, cholecystokinin, secretin, glucagon, follicle stimulating hormone (FSH), luteinising hormone (LH), renin, aldosterone or somatotropic hormone.
Studies in healthy volunteers have shown that rabeprazole sodium does not have clinically significant interactions with amoxicillin. Rabeprazole does not adversely influence plasma concentrations of amoxicillin or clarithromycin when co-administered for the purpose of eradicating upper gastrointestinal H. pylori infection. During treatment with antisecretory medicinal products, serum gastrin increases in response to the decreased acid secretion. Also CgA increases due to decreased gastric acidity. The increased CgA level may interfere with investigations for neuroendocrine tumours.
Available published evidence suggests that PPIs should be discontinued between 5 days and 2 weeks prior to CgA measurements. This is to allow CgA levels that might be spuriously elevated following PPI treatment to return to reference range.
The European Medicines Agency has deferred the obligation to submit the results of studies with the reference medicinal product containing rabeprazole sodium in one or more subsets of the paediatric population in the treatment Gastro-Oesophageal Reflux Disease (see section 4.2 for information on paediatric use).
The European Medicines Agency has waived the obligation to submit the results of studies with the reference medicinal product containing rabeprazole sodium in all subsets of the paediatric population in the treatment of Zollinger-Ellison syndrome, duodenal ulcer and gastric ulcer (see section 4.2 for information on paediatric use).
Razolegastro-resistant tablets are an enteric-coated (gastro-resistant) tablet formulation of rabeprazole sodium. This presentation is necessary because rabeprazole is acid-labile. Absorption of rabeprazole therefore begins after the tablet leaves the stomach. Absorption is rapid with peak plasma levels of rabeprazole occurring approximately 3.5 hours after a 20-mg dose. Peak plasma concentrations (Cmax) of rabeprazole and AUC are linear over a dose range of 10 mg to 40 mg. Absolute bioavailability of an oral 20-mg dose (compared to intravenous administration) is about 52% due to in large part to pre-systemic metabolism. Additionally the bioavailability does not appear to increase with repeat administration. In healthy subjects the plasma half-life is approximately one hour (from 0.7 to 1.5 hours), and the total body clearance is estimated to be 283 ± 98 ml/min. There was no clinically relevant interaction with food. Neither food nor the time of day of administration of the treatment affect the absorption of rabeprazole sodium.
Rabeprazole is approximately 97% bound to human plasma proteins.
Rabeprazole sodium, as is the case with other members of the of proton pump inhibitors, is metabolised through the cytochrome P450 (CYP450) hepatic drug metabolising system. In vitro studies with human liver microsomes indicated that rabeprazole sodium is metabolised by isoenzymes of CYP450 (CYP2C19 and CYP3A4). In these studies, at expected human plasma concentrations rabeprazole neither induces nor inhibits CYP3A4; and although in vitro studies may not always be predictive of in vivo status these findings indicate that no interaction is expected between rabeprazole and cyclosporin. In humans, thioether (M1) and carboxylic acid (M6) are the main plasma metabolites with the sulphone (M2), desmethyl-thioether (M4) and mercapturic acid conjugate (M5) minor metabolite observed at lower levels. Only the desmethyl metabolite (M3) has a small amount of anti-secretory activity, but it is not present in plasma.
Following a single 20-mg 14C labelled oral dose of rabeprazole sodium, no unchanged drug was excreted in urine. Approximately 90% of the dose was eliminated in urine mainly as the two metabolites: a mercapturic acid conjugate (M5) and carboxylic acid (M6), plus two unknown metabolites. The remainder of the dose was recovered in faeces.
Adjusted for body mass and height, there are no significant gender difference in pharmacokinetic parameters following a single 20-mg dose of rabeprazole.
In patients with stable, end-stage, renal failure requiring haemodialysis (creatinine clearance ≤5 ml/min/1.73 m²), the metabolism and elimination of rabeprazole was very similar to that in healthy volunteers. AUC and Cmax in these patients was about 35% lower than in corresponding parameters in healthy volunteers. The mean half-life for rabeprazole was 0.82 hour in healthy volunteers, 0.95 hours in patients during haemodialysis and 3.6 hours post-dialysis. The clearance of the drug in patients with renal disease requiring maintenance haemodialysis was approximately twice that in healthy volunteers.
Following a single 20-mg dose of rabeprazole to patients with chronic mild to moderate hepatic impairment the AUC doubled and there was a 2-3-fold increase in halflife of rabeprazole compared to healthy volunteers. However, following a 20-mg daily dose for 7 days the AUC had increased by only 1.5-fold and Cmax by only 1.2-fold. The half-life of rabeprazole in patients with hepatic impairment was 12.3 hours compared to 2.1 hours in healthy volunteers. The pharmacodynamic response (gastric pH control) in the two groups was clinically comparable.
Elimination of rabeprazole was somewhat lower in the elderly. Following 7 days of daily dosing with 20-mg of rabeprazole sodium, the AUC approximately doubled, the Cmax increased by 60% and half-life increased by approximately 30% as compared to young healthy volunteers. However, there was no evidence of rabeprazole accumulation.
Following a 20-mg daily dose of rabeprazole for 7 days, CYP2C19 slow metabolisers, had the AUC and t½ which were approximately 1.9 and 1.6 times the corresponding parameters in extensive metabolisers whilst Cmax had increased by only 40%.
Non-clinical effects were observed only at exposures sufficiently in excess of the maximum human exposure that make concerns for human safety negligible in respect to animal data.
Studies on mutagenicity gave equivocal results. Tests in mouse lymphoma cell lines were positive, but in vivo micronucleolus and in vivo and in vitro DNA repair tests were negative. Carcinogenicity studies revealed no special hazard for humans.
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