RABELIX

(Rabeprazole Sodium Delayed-Release 20mg Tablets)

DESCRIPTION

The active ingredient in RABELIX Delayed-Release Tablets is rabeprazole sodium, a substituted benzimidazole that inhibits gastric acid secretion. Rabeprazole sodium is a white to slightly yellowish-white solid. It is very soluble in water and methanol,freely soluble in ethanol, chloroform and ethyl acetate and insoluble in ether and n-hexane. The stability of rabeprazole sodium is a function of pH; it is rapidly degraded in acid media, and is more stable under alkaline conditions. RABELIX is available for oral administration as delayed-release, enteric-coated tablets containing 20 mg of rabeprazole Sodium

CLINICAL PHARMACOLOGY

Pharmacokinetics and Metabolism

RABELIX delayed-release tablets are enteric-coated to allow rabeprazole sodium, which is acid, labile, to pass through the stomach relatively intact. After oral administration of 20 mg RABELIX, peak plasma concentrations (Cmax) of rabeprazole occur over a range of 2.0 to 5.0 hours (Tmax). The rabeprazole Cmax and AUC are linear over an oral dose range of 10 mg to 40 mg. There is no appreciable accumulation when doses of 10 mg to 40 mg are administered every 24 hours; the pharmacokinetics of rabeprazole is not altered by multiple dosing. The plasma half-life ranges from 1 to 2 hours.

Absorption :

Following oral administration of 20 mg, rabeprazole is absorbed and can be detected in plasma by 1 hour. Absolute bioavailability for a 20 mg oral tablet of rabeprazole (compared to intravenous administration) is approximately 52%. The effects of food on the absorption of rabeprazole have not been evaluated.

Distribution :

Rabeprazole is 96.3% bound to human plasma proteins.

Metabolism :

Rabeprazole is extensively metabolized. The thioether and sulphone are the primary metabolites measured in human plasma. These metabolites were not observed to have significant antisecretory activity. In vitro studies have demonstrated that rabeprazole is primarily metabolized in the liver by cytochromes P450 3A (sulphone metabolite) and 2C19 (desmethyl rabeprazole). The thioether metabolite is formed by reduction of rabeprazole.

Elimination :

Following a single 20 mg oral dose of 14C-labeled rabeprazole, approximately 90% of the drug was eliminated in the urine, primarily as thioether carboxylic acid; its glucuronide, and mercapturic acid metabolites. The remainder of the dose was recovered in the feces. Total recovery of radioactivity was 99.8%. No unchanged rabeprazole was recovered in the urine or feces.

Special Populations

Geriatric :

In 20 healthy elderly subjects administered 20 mg rabeprazole once daily for seven days, AUC values approximately doubled and the Cmax increased by 60% compared to values in a parallel younger control group. There was no evidence of drug accumulation after once daily administration.

Pediatric :

The pharmacokinetics of rabeprazole in pediatric patients under the age of 18 years has not been studied.

Renal Disease :

In 10 patients with stable end-stage renal disease requiring maintenance hemodialysis (creatinine clearance < 5 mL/min/1.73 m2), no clinically significant differences were observed in the pharmacokinetics of rabeprazole after a single 20 mg oral dose when compared to 10 healthy volunteers.

Hepatic Disease :

In a single dose study of 10 patients with chronic mild to moderate compensated cirrhosis of the liver who were administered a 20 mg dose of rabeprazole, AUC0-24 was approximately doubled, the elimination half-life was 2-to 3-fold higher, and total body clearance was decreased to less than half compared to values in healthy men.

In a multiple dose study of 12 patients with mild to moderate hepatic impairment administered 20 mg rabeprazole once daily for eight days, AUC0-¥ and Cmax values increased approximately 20% compared to values in healthy age-and gender-matched subjects. These increases were not statistically significant. No information exists on rabeprazole disposition in patients with severe hepatic impairment.

PHARMACODYNAMICS

Mechanism of Action

Rabeprazole belongs to a class of antisecretory compounds (substituted benzimidazole proton-pump inhibitors) that do not exhibit anticholinergic or histamine H2-receptor antagonist properties, but suppress gastric acid secretion by inhibiting the gastric H+, K+ATPase at the secretory surface of the gastric parietal cell. Because this enzyme is regarded as the acid (proton) pump within the parietal cell, rabeprazole has been characterized as a gastric proton-pump inhibitor. Rabeprazole blocks the final step of gastric acid secretion. In gastric parietal cells, rabeprazole is protonated, accumulates, and is transformed to an active sulfenamide. When studied in vitro, rabeprazole is chemically activated at pH 1.2 with a half-life of 78 seconds. It inhibits acid transport in porcine gastric vesicles with a half-life of 90 seconds.

Antisecretory Activity

The anti-secretory effect begins within one hour after oral administration of 20 mg RABELIX. The median inhibitory effect of RABELIX on 24-hour gastric acidity is 88% of maximal after the first dose. RABELIX 20 mg inhibits basal and peptone meal-stimulated acid secretion versus placebo by 86% and 95%, respectively, and increases the percent of a 24-hour period that the gastric pH>3 from 10% to 65% (see table below). This relatively prolonged pharmacodynamic action compared to the short pharmacokinetic half-life (1-2 hours) reflects the sustained inactivation of the H+, K+ATPase.

INDICATIONS AND USAGE

Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD)

RABELIX is indicated for short-term (4 to 8 weeks) treatment in the healing and symptomatic relief of erosive or ulcerative gastroesophageal reflux disease (GERD). For those patients who have not healed after 8 weeks of treatment, an additional 8 –week course of RABELIX may be considered.

Maintenance of Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD)

RABELIX is indicated for maintaining healing and reduction in relapse rates of heartburn symptoms in patients with erosive or ulcerative gastroesophageal reflux disease (GERD maintenance).

Healing of Duodenal Ulcers

RABELIX is indicated for short-term (up to four weeks) treatment in the healing and symptomatic relief of duodenal ulcers. Most patients heal within four weeks.

Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome.

RABELIX is indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison Syndrome.

CONTRAINDICATIONS

Rabeprazole is contraindicated in patients with known hypersensitivity to rabeprazole, substituted benzimidazoles or to any component of the formula tion.

PRECAUTIONS

General

Symptomatic response to therapy with rabeprazole does not preclude the presence of gastric malignancy. Patients with healed GERD were treated for up to 40 months with rabeprazole and monitored with serial gastric biopsies. Patients without H. pylori infection (221 of 326 patients) had no clinically important pathologic changes in the gastric mucosa. Patients with H. pylori infection at baseline (105 of 326 patients) had mild or moderate inflammation in the gastric body or mild inflammation in the gastric antrum. Patients with mild grades of infection or inflammation in the gastric body tended to change to moderate, whereas those graded moderate at baseline tended to remain stable. Patients with mild grades of infection or inflammation in the gastric antrum tended to remain stable. At baseline, 8% of patients had atrophy of glands in the gastric body and 15% had atrophy in the gastric antrum.

At endpoint, 15% of patients had atrophy of glands in the gastric body and 11% had atrophy in the gastric antrum. Approximately 4% of patients had intestinal metaplasia at some point during follow-up, but no consistent changes were seen.

Information for Patients

Patients should be cautioned that RABELIX delayed-release tablets should be swallowed whole. The tablets should not be chewed, crushed, or split.

Drug Interactions

Rabeprazole is metabolized by the cytochrome P450 (CYP450) drug metabolizing enzyme system. Studies in healthy subjects have shown that rabeprazole does not have clinically significant interactions with other drugs metabolized by the CYP450 system, such as warfarin and theophylline given as single oral doses, diazepam as a single intravenous dose, and phenytoin given as a single intravenous dose (with supplemental oral dosing). In vitro incubations employing human liver microsomes indicated that rabeprazole inhibited cyclosporin metabolism with an IC50 of 62 micromolar, a concentration that is over 50 times higher than the Cmax in healthy volunteers following 14 days of dosing with 20 mg of rabeprazole. This degree of inhibition is similar to that by omeprazole at equivalent concentrations. Rabeprazole produces sustained inhibition of gastric acid secretion. An interaction with compounds which are dependent on gastric pH for absorption may occur due to the magnitude of acid suppression observed with rabeprazole. For example, in normal subjects, co-administration of rabeprazole 20 mg QD resulted in an approximately 30% decrease in the bioavailability of ketoconazole and increases in the AUC and Cmax for digoxin of 19% and 29%, respectively. Therefore, patients may need to be monitored when such drugs are taken concomitantly with rabeprazole. Co-administration of rabeprazole and antacids produced no clinically relevant changes in plasma rabeprazole concentrations.

Pregnancy

Teratogenic Effects. Pregnancy Category B: RABELIX should be used during pregnancy only if clearly needed.

Pediatric Use

The safety and effectiveness of rabeprazole in pediatric patients have not been established.

ADVERSE REACTIONS

Worldwide in general, rabeprazole treatment has been well-tolerated in both short-term and long-term trials. The adverse events rates were generally similar between the 10 and 20 mg doses.

DOSAGE AND ADMINISTRATION

Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD)

The recommended adult oral dose is one RABELIX 20 mg delayed-release tablet to be taken once daily for four to eightweeks. For those patients who have not healed after 8 weeks of treatment, an additional 8-week course of ACIPHEX may be considered.

Maintenance of Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD Maintenance)

The recommended adult oral dose is one RABELIX 20 mg delayed-release tablet to be taken once daily.

Healing of Duodenal Ulcers

The recommended adult oral dose is one RABELIX 20 mg delayed-release tablet to be taken once daily after the morning meal for a period up to four weeks. Most patients with duodenal ulcer heal within four weeks. A few patients may require additional therapy to achieve healing.

Treatment of Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome

The dosage of RABELIX in patients with pathologic hypersecretory conditions varies with the individual patient. The recommended adult oral starting dose is 60 mg once a day. Doses should be adjusted to individual patient needs and should continue for as long as clinically indicated. Some patients may require divided doses. Doses up to 100 mg QD and 60 mg BID have been administered. Some patients with Zollinger-Ellison syndrome have been treated continuously with RABELIX for up to one year. No dosage adjustment is necessary in elderly patients, in patients with renal disease or in patients with mild to moderate hepatic impairment. Administration of rabeprazole to patients with mild to moderate liver impairment resulted in increased exposure and decreased elimination. Due to the lack of clinical data on rabeprazole in patients with severe hepatic impairment, caution should be exercised in those patients.

RABELIX tablets should be swallowed whole. The tablets should not be chewed, crushed, or split.