drug, secretory activity returns to normal after 2 to 3 days.

Effects on Serum Gastrin: In clinical studies patients were treated with a dose of Rabeprazole 10 or 20 mg once daily for a period of up to 43 months of treatment. Serum gastrin increased during the first 2 to 8 weeks reflecting the inhibitory effect on acid secretion and remained stable during treatment.

Serum gastrin levels returned to pre-treatment, usually within the first or second week after discontinuing it.

In biopsies of gastric antrum and fundus of more than 500 patients who received Rabeprazole or other drug of the group for a period of up to 8 weeks, there were no changes in the histology of Enterochromaffin-like (ECL) Cells, grade of gastritis, incidence of atrophic gastritis, intestinal metaplasia or infection distribution by H. Pylori. In over 250 patients followed for 36 months of continuous treatment, there were no significant changes from baseline.

Other effects: No systemic effects of Rabeprazole were found in the central nervous system, the cardiovascular system and the respiratory system.

Rabeprazole in doses of 20 mg orally for 2 weeks, had no effects on thyroid function, metabolism of carbohydrates, or serum levels of parathyroid hormone, cortisol, estrogen, testosterone, prolactin, cholecystokinin, secretin, glucagon, follicle stimulating hormone (FSH), luteinizing hormone (LH), renin, aldosterone or somatotrophic hormone.

Studies in healthy individuals have shown that Rabeprazole does not have clinically significant interactions with amoxicillin or clarithromycin when administered together for the eradication of H. pylori from the upper gastrointestinal tract.

Pharmacokinetics

Absorption: Rabec® is a Rabeprazole sodium gastro-resistant coated tablet.

This formulation is necessary because Rabeprazole is acid labile. Rabeprazole absorption begins after the tablet leaves the stomach. The absorption is rapid with a plasma peak at about 3.5 hours after a dose of 20mg. The rabeprazole Cmax and AUC (Area under the curve) have a linear behavior within a dose range of 10 to 40 mg. The absolute bioavailability of an oral dose of 20 mg (compared to intravenous administration) is approximately 52% due in large part to its presystemic metabolism.

Bioavailability does not appear to increase with repeated administration. In healthy individuals the plasma half-life is of approximately 1 hour (range 0.7 to 1.5 hours.), and the clearance is about 283 ± 98 ml / min. Neither food nor time of day of administration has shown to affect the absorption of Rabeprazole sodium.

Distribution: Rabeprazole is 97% bound to plasma proteins. Metabolism and Elimination: Rabeprazole is metabolized by cytochrome

P450. In vitro studies using human liver microsomes indicated that Rabeprazole sodium is metabolized by CYP2C19 and CYP3A4 isozymes. It was found in these studies that rabeprazole does not induce or inhibit CYP3A4. While in vitro studies do not predict the in vivo response, these findings indicate that an interaction between Rabeprazole and cyclosporine is not to be expected. In humans, thioether (M1) and carboxylic acid (M6) are the main metabolites. Only the desmethyl metabolite (M3) has a mild

antisecretory activity, but it is not found in plasma.

Following a single 20 mg dose of 14C-labeled Rabeprazole, there was no urinary excretion of unchanged drug. Approximately 90% of the dose was excreted in urine mainly as carboxylic acid (M6) and mercapturic acid (M5) metabolites, along with other metabolites. The rest of the dose is eliminated through feces.

Features in special patient groups Gender: After adjusting for body mass index and height, there are no

significant gender differences in pharmacokinetic parameters after a single dose of rabeprazole 20 mg.

Renal impairment: In patients with renal failure requiring dialysis (with creatinine clearance ≤ 5 ml/min/1.73m2), the disposition of rabeprazole was similar to that found in healthy individuals. The AUC (Area under the curve) and Cmax (maximum concentration) in these patients was 35% lower than in healthy volunteers. The half-life was 0.82 hours in healthy volunteers, 0.95 hours during hemodialysis and 3.6 hours post dialysis. The clearance of the drug in patients requiring hemodialysis was approximately twice that found in healthy volunteers. Hepatic impairment: Following administration of a single dose of 20 mg of Rabeprazole to patients with chronic mild to moderate hepatic impairment, the AUC and Cmax, doubled and half-life increased 2 to 3 times compared to

healthy volunteers. However, after a daily dose of 20 mg for 7 days, the AUC increased 1.5 fold and Cmax 1.2-fold. The half-life of Rabeprazole in patients with liver failure was 12.3 hours compared with 2.1 hours in healthy volunteers. Pharmacodynamics’ response in both groups (Control of gastric pH) was clinically comparable. Elderly: The elimination of Rabeprazole was diminished in this age group. After 7 days of administration of a daily dose of 20 mg of Rabeprazole sodium, the AUC was almost doubled, Cmax increased by 60% and half-life increased approximately 30% compared to young healthy volunteers. But

there was no evidence of accumulation of rabeprazole. CYP2C19 polymorphism: After a daily dose of 20 mg for 7 days, poor

metabolizers had an AUC and half-life 1.9 and 1.6 times respectively higher than the parameters for faster metabolizers, while the Cmax increased only 40%.

DOSAGE AND ADMINISTRATION

Rabec® tablets should be swallowed whole. The tablets should not be chewed, or split.

Treatment of active duodenal ulcer and active benign gastric ulcer

The recommended dose for the treatment of both active duodenal ulcer and of active benign gastric ulcer is 20 mg once daily in the morning.

Most active duodenal ulcer patients achieve resolution of symptoms within four weeks of treatment. However, some patients may require four weeks of treatment more to achieve healing. The majority of patients with active benign gastric ulcer resolve their symptoms within six weeks of treatment.

However, some patients may also require an additional six weeks of treatment to achieve healing.

Treatment of erosive or ulcerative gastroesophageal reflux disease (GERD)

The recommended dose for this disease is 20 mg once daily for four to eight weeks.

Maintenance in Treatment of erosive or ulcerative GERD

For long-term management, a maintenance dose of Rabec® 20 mg or 10 mg once daily may be given taking into account the patient's response.

Treatment of symptomatic moderate to severe GERD

The recommended dose for patients without esophagitis is 10 mg once daily. In case of failure to achieve control of symptoms after 4 weeks of treatment, the patient should be studied. Once symptoms have cleared, a subsequent

symptom control may be achieved using an on demand regimen of 10 mg once daily as needed.

Zollinger – Ellison syndrome

The recommended starting dose for adults is 60 mg once daily. The dose may be titrated, reaching up to 120 mg / day according to individual patient needs. A single daily dose of up to 100 mg / day may be administered. It may be necessary to separate daily doses of 120 mg in two doses of 60 mg. The treatment should be continued according to clinical indication.

Eradication of Helicobacter Pylori

Patients infected with H. Pylori should be treated with eradication therapy. We recommend the administration of the following combinations for 7 days. Rabec® 20 mg twice daily + clarithromycin 500 mg twice daily + amoxicillin 1g twice daily.