6111 Royalmount Ave., Suite 100 Montreal, Quebec H4P 2T4 www.pharmascience.com Date of Revision: May 26, 2008 Submission Control No: 110891

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 5 DRUG INTERACTIONS 8 DOSAGE AND ADMINISTRATION 9 OVERDOSAGE 10 ACTION AND CLINICAL PHARMACOLOGY 10 STORAGE AND STABILITY 15 DOSAGE FORMS, COMPOSITION AND PACKAGING 15

PART II: SCIENTIFIC INFORMATION 16

PHARMACEUTICAL INFORMATION 16 CLINICAL TRIALS 16 DETAILED PHARMACOLOGY 26 TOXICOLOGY 29 REFERENCES 35

PART III: CONSUMER INFORMATION. 38

pms-RABEPRAZOLE EC

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

When gastric ulcer is suspected, the possibility of malignancy should be excluded before therapy with rabeprazole is instituted, as treatment with rabeprazole may alleviate symptoms and delay diagnosis.

Symptomatic response to therapy with rabeprazole sodium does not preclude the presence of gastric malignancy. Steady state interactions of rabeprazole and warfarin have not been adequately evaluated in patients. There have been reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including rabeprazole, and warfarin concomitantly. Increase in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with a proton pump inhibitor and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time. As demonstrated with other PPI's, prolonged use may impair the absorption of protein-bound Vitamin B12 and may contribute to the development of Vitamin B12 deficiency.

pms-RABEPRAZOLE EC tablets can be taken with or without meals. Patients should be advised that pms-RABEPRAZOLE EC tablets should be swallowed whole, not chewed or crushed.

Pregnant Women:

The safety of rabeprazole sodium treatment in pregnancy has not been established. pms-RABEPRAZOLE EC tablets should not be administered to pregnant women unless the expected benefits outweigh the potential risks to the fetus.

Nursing Women:

It is not known whether rabeprazole is excreted in human milk. pms- RABEPRAZOLE EC tablets should not be given to nursing mothers unless the expected benefits outweigh the potential risks to the infant.

Pediatrics 18 years of age):

The safety and efficacy of rabeprazole have not been established in children under the age of 18 years.

Geriatrics:

Ulcer healing rates in elderly patients are similar to those in younger patients. Adverse events and laboratory test abnormalities in elderly patients occurred at rates similar to those in younger patients. No dose adjustment is required in elderly patients.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Worldwide, over 3,094 patients have been treated with rabeprazole sodium in Phase II-III clinical trials involving various dosages and durations of treatment. In general, rabeprazole treatment has been well tolerated in both short-term and long-term trials.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very speck conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Incidence in North American and European Clinical Trials

The following adverse events were reported by the treating physicians to have a possible or probable relationship to drug in at least 1% of patients treated with rabeprazole sodium compared to patients who received placebo:

Table 1.2: Incidence of Possibly- or Probably-Related Adverse Events in Short-Term and Long-Term Controlled North American and European Studies

	Rabeprazole sodium n=1746 (%)	Placebo n=388 (%)
Body as a Whole	2.8	2.8
Headache	2.8	2.8
Digestive System
Diarrhea	2.6	2.3

Less Common Clinical Trial Adverse Drug Reactions (<1%)

In short- and long-term studies, the following adverse events were reported in <1% of the patients treated with rabeprazole sodium without regard to causality:

Body as a whole:

enlarged abdomen, abscess, ascites, carcinoma, substernal chest pain, asthenia, allergic reaction, fever, chills, cellulitis, cyst, hangover effect, hernia, injection site hemorrhage, injection site pain, injection site reaction, malaise, moniliasis, mucous membrane disorder, neck pain, neck rigidity, neoplasm, overdose, pelvic pain, photosensitivity, suicide attempt.

Cardiovascular System:

angina pectoris, arrhythmia, bradycardia, bundle branch block, cardiovascular disorder, coronary artery disorder, abnormal electrocardiogram, embolus, hypertension, increased capillary fragility, migraine, myocardial infarction, palpitation, sinus bradycardia, supraventricular tachycardia, syncope, tachycardia, thrombophlebitis, thrombosis, varicose vein, vascular disorder, ventricular extrasystoles, QTc prolongation, ventricular tachycardia.

Digestive System:

abdominal pain, abnormal stools, anorexia, bloody diarrhea, cholangitis, cholecystitis, cholelithiasis, cirrhosis of liver, colitis, constipation, diarrhea, duodenal ulcer, duodenitis, dry mouth, dyspepsia, dysphagia, esophageal stenosis, esophagitis, eructation, flatulence, gastritis, gastrointestinal hemorrhage, gastroenteritis, gastrointestinal carcinoma, gingivitis, glossitis, hepatic encephalopathy, hepatitis, hepatoma, increased appetite, melena, mouth ulceration, nausea and vomiting, pancreas disorder, pancreatitis, periodontal abscess, proctitis, rectal disorder, rectal hemorrhage, salivary gland enlargement, stomach ulcer, stomatitis, tooth caries, tooth disorder, ulcer ileum, ulcerative colitis, ulcerative stomatitis.

Endocrine System:

diabetes mellitus, hyperthyroidism, hypothyroidism.

Hemic and Lymphatic System:

anemia, ecchymosis, hypochromic anemia, lymphadenopathy.

Metabolic and Nutritional Disorders:

dehydration, edema, face edema, gout, iron deficiency anemia, liver fatty deposit, peripheral edema, thirst, weight gain, weight loss.

Musculoskeletal System:

arthritis, arthrosis, bone pain, bursitis, joint disorder, leg cramps, myalgia, rheumatoid arthritis, tendon disorder.

Nervous System:

abnormal dreams, acute brain syndrome, addiction, agitation, amnesia, anxiety, cerebral hemorrhage, confusion, convulsion, dementia, depression, dizziness, extrapyramidal syndrome, hyperkinesia, hypertonia, insomnia, libido decreased, nervousness, neuralgia, neuropathy, paresthesia, sleep disorder, somnolence, tremor, twitching, vasodilatation, vertigo.

Respiratory System

apnea, asthma, carcinoma of lung, dyspnea, epistaxis, hiccup, hyperventilation, hypoventilation, hypoxia, laryngitis, lung disorder, pneumonia, pulmonary embolus, respiratory disorder, voice alteration.

Skin and Appendages:

acne, alopecia, contact dermatitis, dry skin, fungal dermatitis, herpes simplex, herpes zoster, nail disorder, pruritus, psoriasis, rash, seborrhea, benign skin neoplasm, skin carcinoma, skin discoloration, skin hypertrophy, skin melanoma, skin nodule, sweating, urticaria.

Special Senses:

abnormal vision, amblyopia, blepharitis, blurry vision, cataract, conjunctivitis, corneal opacity, deafness, diplopia, dry eyes, ear disorder, ear pain, eye disorder, eye hemorrhage, eye pain, glaucoma, lacrimation disorder, otitis externa, otitis media, retinal degeneration, retinal disorder, strabismus, taste perversion, tinnitus, vestibular disorder, vitreous disorder.

Urogenital System:

breast enlargement, breast neoplasm, breast pain, cystitis, dysmenorrhea, dysuria, hernaturia, impotence, kidney calculus, leukorrhea, mastitis, menorrhagia, menstrual disorder, metrorrhagia, orchitis, polycystic kidney, polyuria, prostatic disorder, urinary frequency, urinary incontinence, urinary tract disorder, uterine hemorrhage, vaginal hemorrhage, vaginitis.

Monitoring and Laboratory Tests

An extensive evaluation of laboratory analyses has not revealed any significant and/or clinically relevant changes during rabeprazole sodium treatment. The following changes in laboratory parameters were reported as adverse events: abnormal platelets, albuminuria, increased creatine phosphokinase, abnormal erythrocytes, hypercholesteremia, hyperglycemia, hyperlipemia, hypokalemia, hyponatremia, leukocytosis, leukorrhea, abnormal liver function tests, prostatic specific antigen increase, urine abnormality, abnormal WBC. In controlled clinical studies, 3/1456 (0.2%) patients treated with rabeprazole and 2/237 (0.8%) patients treated with placebo developed treatment-emergent abnormalities (which were either new on study or present at study entry with an increase of 1.25 x baseline value) in SGOT (AST), SGPT (ALT), or both. None of the three rabeprazole patients experienced chills, fever, right upper quadrant pain, nausea or jaundice.

Post-Market Adverse Drug Reactions

Additional adverse events reported from worldwide marketing experience with rabeprazole sodium are: sudden death, coma and hyperammonemia, jaundice, rhabdomyolysis, disorientation and delirium, anaphylaxis, angioedema, bullous and other drug eruptions of the skin, interstitial pneumonia, TSH elevations, myalgia and arthralgia. In most instances, the relationship to rabeprazole sodium was unclear. There have also been rare reports of increased hepatic enzymes and rare reports of hepatitis. Rare reports of hepatic encephalopathy have been received in patients with underlying cirrhosis. In addition, agranulocytosis, hemolytic anemia, leukopenia, pancytopenia, thrombocytopenia, neutropenia and acute systemic allergic reactions (facial swelling, hypotension, dyspnea) have been reported. There have been very rare reports of interstitial nephritis, gynecomastia, erythema multiforme, toxic epidermal necrolysis and Stevens-Johnson syndrome

DRUG INTERACTIONS

Rabeprazole is metabolized by the cytochrome P450 (CYP450) drug metabolizing 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, phenytoin, theophylline or diazepam. Steady state interactions of rabeprazole and other drugs metabolized by this enzyme system have not been studied in patients. Studies with rabeprazole in humans reveal no inhibition or activation of the CYP450 system of the liver. There have been reports of increases INR and prothrombin time in patients receiving prothrombin time inhibitors, including rabeprazole and warfarin concomitantly. Increase in INR and prothrombin time may lead to abnormal bleeding and even death. In vitro incubations employing human liver microsomes indicated that the degree of inhibition of cyclosporin metabolism by rabeprazole and omeprazole is similar at equivalent concentrations. Rabeprazole produces sustained inhibition of gastric acid secretion. An interaction with compounds whose absorption depends on gastric pH may occur due to the magnitude of acid suppression seen with rabeprazole: consequently, the co-administration of ketoconazole and rabeprazole decreases the absorption of ketoconazole, thereby decreasing plasma levels, whereas the concomitant use of digoxin results in an increase in digoxin plasma levels. Therefore, patients may need to be monitored when such drugs are taken concomitantly with rabeprazole.

Combination therapy consisting of rabeprazole, amoxicillin and Clarithromycin resulted in increases in plasma levels of rabeprazole and 14-hydroxyclarithromycin. (See ACTION AND CLINICAL PHARMACOLOGY, Special populations and conditions, Combination therapy with antimicrobials.

Taking rabeprazole with food or antacids produced no clinically relevant changes in plasma rabeprazole concentrations.

DOSAGE AND ADMINISTRATION

Symptomatic Relief and Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD) The recommended adult oral dose is 20 mg once daily. In most patients, healing occurs in four weeks. For patients not healed after this initial course, an additional four weeks of treatment is recommended. Symptom relief is usually rapid. If symptom relief is not achieved after four weeks, further investigation is recommended (see INDICATIONS AND CLINICAL USE).

Long-term Maintenance of Healing of Erosive or UIcerative Gastroesophageal Reflux Disease (GERD Maintenance) 10 mg once daily has been demonstrated to be effective versus placebo in the maintenance of healing of GERD. The maximum recommended adult oral dose is 20 mg once daily (see INDICATIONS AND CLINICAL USE).

Treatment of Symptoms (i.e. Heartburn and Regurgitation) of Symptomatic Gastroesophageal Reflux Disease (GERD) or Non-Erosive Reflux Disease (NERD) The recommended adult oral dose is 10 mg once daily to a maximum of 20 mg once daily in patients with NERD. If symptom control is not achieved after four weeks, further investigation is recommended (see INDICATIONS AND CLINICAL USE).

The recommended adult oral dose is 20 mg once daily for up to four weeks (see INDICATIONS AND CLINICAL USE). Most patients with duodenal ulcer heal within four weeks but a few patients may require additional therapy to achieve healing. Symptom relief is usually rapid with improvement achieved after two weeks for most patients.

The recommended adult oral dose is 20 mg once daily for up to six weeks (see INDICATIONS AND CLINICAL USE). Most patients with gastric ulcer heal within six weeks, but a few patients may require additional therapy to achieve healing. Symptom relief is usually rapid with improvement achieved after three weeks for most patients.

Long-term Treatment of Pathological Hvpersecretory Conditions Including Zollinger-Ellison Syndrome The rabeprazole sodium dosage 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 rabeprazole sodium tablets for up to one year. No dosage adjustment is necessary in patients with renal insufficiency or in elderly patients. For patients with severe liver disease, dosage adjustment should be considered.

pms-RABEPRAZOLE EC tablets can be taken with meals or on an empty stomach. pms- RABEPRAZOLE EC tablets are enteric-coated and therefore should be swallowed whole with a beverage (not chewed or crushed).

OVERDOSAGE

Because strategies for the management of overdose are continually evolving, it is advisable to contact a Poison Control Centre to determine the latest recommendations for the management of an overdose of any drug.

There has been no experience with large overdoses of rabeprazole although seven reports of accidental overdosage with rabeprazole have been received. The maximum established exposure has not exceeded 60 mg twice daily or 160 mg once daily. Effects are generally minimal, representative of the known adverse event profile, and reversible without any further medical intervention. No specific antidote for rabeprazole is known; in the event of overdosage, treatment should be symptomatic and supportive. Rabeprazole is extensively protein-bound and is not readily dialyzable.

ACTION AND CLINICAL PHARMACOLOGY

Rabeprazole sodium is an antisecretory compound (substituted benzimidazole proton pump inhibitor) that suppresses gastric acid secretion by inhibiting the gastric H+, Kam-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 sodium has been characterized as a gastric proton pump inhibitor. Rabeprazole sodium blocks the final step of gastric acid secretion and produces dose-related sustained inhibition of both basal and stimulated gastric acid secretion.

The antisecretory effect begins within one hour after oral administration of rabeprazole sodium tablets (20 mg), and reaches its maximum within two to four hours. The median inhibitory effect of rabeprazole sodium on 24-hour gastric acidity is 88% of maximal after the first dose and the inhibition of acid secretion increases with repeated once-daily dosing to steady-state within seven days. Rabeprazole sodium 20 mg, versus placebo, inhibits basal and pentagastrin- induced acid secretion by 86% and 95%, respectively. At this dosage, it also increases the percentage of time (from 10% to 65%) within a 24-hour period that the gastric pH>3 (see Table 1.3). This relatively prolonged pharmacodynamic action compared to the short pharmacokinetic half-life (approximately one hour) reflects the sustained inactivation of the H+, K F-ATPase.

Table 1.3: Gastric Acid Parameters - rabeprazole sodium versus Placebo After 7 Days of Once-Daily Dosing

The ability of rabeprazole sodium to cause a dose-related decrease in mean intragastric acidity is illustrated in Table 1.4.

The decrease in gastric acidity and the increase in gastric pH observed with 20 mg rabeprazole sodium were compared to the same parameters with 20 mg omeprazole and placebo, as illustrated in Table 1.5.

Table 1.5: Gastric Acid Parameters - rabeprazole sodium versus Omeprazole and Placebo on Day 1 and Day 8 of Multiple Once-Daily Dosing

In patients with gastroesophageal reflux disease (GERD) and moderate to severe esophageal acid exposure, rabeprazole sodium doses of 20 or 40 mg/day normalized 24-hour esophageal acid exposure. After seven days' treatment, the percentage of time that the esophageal pH <4 was 5.1% at the 20 mg dose and 2.0% at the 40 mg dose, from baselines of 24.7% and 23.7%, respectively. Normalization of 24-hour intraesophageal acid exposure was correlated to gastric pH >4 for at least 35% of the 24-hour period; this level was achieved in 90% of subjects receiving a 20 mg rabeprazole sodium dose and in 100% of subjects receiving a 40 mg rabeprazole sodium dose. With rabeprazole sodium doses of 20 or 40 mg/day, effects on gastric and esophageal pH were significant and substantial after one day of treatment and more pronounced after seven days of treatment.

In patients given daily doses of rabeprazole sodium tablets for up to eight weeks to treat ulcerative or erosive esophagitis and in patients treated for up to 52 weeks to prevent recurrence of disease, there was a dose-related increase in the median fasting gastrin level. The group median values stayed within the normal range. These data are indicative of dose- dependent inhibition on gastric acid secretion by rabeprazole sodium.

Increased serum gastrin secondary to antisecretory agents stimulates proliferation of gastric ECL cells which, over time, may result in ECL cell hyperplasia in laboratory rats and mice and gastric carcinoids in laboratory rats. During life-time exposure of rats with doses of rabeprazole up to 120 mg/kg/day [60 times the exposure on a body surface (mg/rn2) basis in patients given the recommended 20 mg/day (12.3 rng/m2) dose], ECL cell hyperplasia was observed in both male and female rats, while gastric carcinoids were observed in female Sprague Dawley rats only. ECL cell hyperplasia was observed with rabeprazole in both male and female rats and mice. Human gastric biopsy specimens from the antrum and the fundus from 330 patients receiving rabeprazole treatment for up to 8 weeks detected no consistent pattern of changes in ECL cell histology. Histological fmdings from 61 patients receiving rabeprazole also showed no consistent pattern of changes in degree of gastritis. No chronic atrophic gastritis was found in these patients either at baseline or endpoint assessment. There was no consistent change in the incidence of intestinal metaplasia or distribution of H. pylori infection. In over 400 patients undergoing rabeprazole sodium treatment (10 or 20 mg/day) for up to one year, the incidence of ECL cell hyperplasia was low and comparable to that observed with omeprazole (20 mg/day); no patient demonstrated the adenomatoid changes or carcinoid tumour as observed in rats.

Studies in humans for up to one year have revealed no clinically significant effects on the endocrine system. In healthy male volunteers treated with rabeprazole sodium tablets for 13 days, no clinically relevant changes have been detected in the following endocrine parameters examined: 17 P-estradiol, thyroid-stimulating hormone, tri-iodothyronine, thyroxine, thyroxine-binding protein, parathyroid hormone, insulin, glucagon, renin, aldosterone, follicle-stimulating hormone, luteotrophic hormone, prolactin, somatotrophic hormone, dehydroepiandrosterone, cortisol-binding globulin, urinary 6b-hydroxycortisol, and testosterone.

In humans treated with rabeprazole sodium for up to one year, no systemic effects have been observed on the central nervous system, lymphoid, hematopoietic, renal, hepatic, cardiovascular, ocular, or respiratory systems.

With rabeprazole sodium enteric-coated tablets, absorption is rapid following ingestion. After oral administration of 20 mg rabeprazole sodium, peak plasma concentrations (Cmax) are reached at an average of 1.6 - 5.0 hours; bioavailability compared to intravenous administration is 52%. Rabeprazole does not accumulate and its pharmacokinetics are not altered by multiple dosing. The plasma half-life is approximately one hour. Absorption: Following oral administration, rabeprazole is rapidly absorbed and can be detected in plasma as early as 0.5 hours. The rabeprazole Cmax and AUC are linear with doses from 10 mg to 40 mg. Taking rabeprazole sodium tablets with food does not alter Cmax or AUC relative to the fasting state; the Tmax is increased by 1.7 hours. Antacids do not significantly affect the absorption of rabeprazole sodium. Administration of rabeprazole sodium with a high fat meal may delay its absorption by approximately 4 hours or longer; however, the Cmax and the extent of absorption (AUC) are not altered.

Distribution: .

Metabolism:

In humans the thioether and carboxylic acid are the main plasma metabolites. These metabolites were not observed to have significant antisecretory activity. The sulphone, desmethyl-thioether and mercapturic acid conjugate minor metabolites were observed at lower

levels. Only the desmethyl metabolite has a small amount of antisecretory activity, but it is not present in plasma.

studies have demonstrated that rabeprazole is metabolized primarily by non-enzymatic reduction to form the thioether metabolite. Rabeprazole is also metabolized in the liver by cytochromes P450 3A (CYP3A), to a sulphone metabolite, and cytochrome P450 2C19 (CYP2C19), to desmethyl rabeprazole. CYP2C19 exhibits a known genetic polymorphism due to its deficiency in some sub-populations (e.g. 3 to 5% of Caucasians and 17 to 20% of Asians). Rabeprazole metabolism is slow in these sub-populations; therefore, they are referred to as poor metabolizers of the drug.

Excretion: Following a single 20 mg 14C-labelled oral dose of rabeprazole sodium, no unchanged drug was excreted in the urine. Approximately 90% of the dose was eliminated in urine mainly as two metabolites: a mercapturic acid conjugate and a carboxylic acid; there are also two unknowns. The remainder of the dose was recovered in feces.

Pediatrics:

The pharmacokinetic profile of rabeprazole sodium in adolescents and children under the age of 18 years has not been studied.

Geriatrics: In 20 healthy elderly subjects given a 20 mg rabeprazole sodium dose once daily for seven days, AUC doubled and the Cmax increased by 60% compared to measurements in a parallel younger control group. There was no evidence of drug accumulation (see WARNINGS AND PRECAUTIONS).

Race: See Metabolism

Hepatic Insufficiency: In two studies, in which 23 patients with varying degrees of chronic compensated hepatic cirrhosis were given a 20 mg rabeprazole sodium dose, the AUC of rabeprazole approximately doubled and the Cmax increased by 50% compared to measurements in healthy age-and sex-matched subjects. Renal Insufficiency: In 10 patients with stable end-stage renal failure requiring maintenance hemodialysis (creatinine clearance < 5 ml./min/l.73 m2), the pharmacokinetics of rabeprazole (rabeprazole sodium 20 mg oral dose) were comparable to those in 10 healthy volunteers.

STORAGE AND STABILITY

DOSAGE FORMS, COMPOSITION AND PACKAGING:

pms-RABEPRAZOLE EC (rabeprazole sodium) 10 or 20 mg is supplied as enteric-coated tablets. The pink, round, 10 mg biconvex coated tablets imprinted with "RB10", are available in HDPE bottles of 100 tablets and 500 tablets; and in Blisters of 10 tablets format. The yellow, round, 20 mg biconvex coated tablets imprinted with "RB20", are available in HDPE Bottle of 100 tablets and 500 tablets; and in blisters of 10 tablets format.

Each tablet contains: Medicinal ingredient: 10 or 20 mg of Rabeprazole sodium. Both 10 mg tablets and 20 mg tablets contain the following non-medicinal ingredients: Hydroxypropyl cellulose, Hydroxypropyl methylcellulose, Manitol, Magnesium oxide, Magnesium stearate, Methacrylic acid, Polyethylene glycol, Shellac glaze, Sodium lauryl sulfate, Talc, Titanium dioxide, Triethyl citrate and Zein. The 10 mg tablets also contain Antifoam, Hypromellose, Industrial methylated spirit, Iron oxide black, Iron oxide red and Lecithin (soya). The 20 mg tablets also contain Ammonium Hydroxide, FD&C red /allura red AC aluminum lake, Propylene Glycol and Yellow iron oxide.

PHARMACEUTICAL INFORMATION

Drug Substance

Common name: Rabeprazole Sodium Chemical name: 2-[[[4-(3-methoxypropoxy)-3-methyl-2- pyridinyl]methyi]sulflnyl]-benzimidazole as a racemate Molecular formula and molecular mass: C18H2ON3NaO3S, 381.43 Structural formula: Physicochemical properties: 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 n-octyl alcohol/water partition coefficient is 214.

CLINICAL TRIALS

Study results

In a U.S. multicentre, double-blind, placebo-controlled study, 103 patients were treated for up to eight weeks with placebo, 10 mg, 20 mg or 40 mg rabeprazole sodium QD. For this and all studies of GERD healing, only patients with GERD symptoms and at least grade 2 esophagitis (modified Hetzel-Dent grading scale) were eligible for entry. Endoscopic healing was defined as grade 0 or 1. Each active dose was significantly superior to placebo in producing endoscopic healing after four and eight weeks of treatment. The percentage of patients with endoscopic healing with 20 mg rabeprazole sodium dosing and placebo are presented in Table 2.1.

Table 2.1: Healing of Erosive or Ulcerative Gastroesophageal Reflex Disease (GERD) Percentage of Patients Healed

A 20 mg rabeprazole sodium dose QD was also significantly more effective than placebo in providing complete resolution of heartburn frequency (p=0.003), in providing complete resolution of daytime heartburn severity (p=0.036), and in decreasing the amount of antacid taken per day (p<0.001). In a U.S. multicentre, double-blind, active-controlled study of 338 patients, rabeprazole sodium was statistically superior to ranitidine with respect to the percentage of patients healed at endoscopy after four and eight weeks of treatment (see Table 2.2)

Table 2.2: Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD) Percentage of Patients Healed

A 20 mg rabeprazole sodium dose QD was also significantly more effective than ranitidine 150 mg QID in providing complete resolution of heartburn frequency (p<0.001) and daytime (p=0.025) and nighttime (p=0.002) heartburn severity. In an international, double-blind, active-controlled study of 202 patients treated with a 20 mg rabeprazole sodium dose QD or 20 mg omeprazole QD for up to eight weeks, rabeprazole sodium was comparable to omeprazole in producing endoscopic healing. The percentage of patients healed at endoscopy at four and eight weeks are given in Table 2.3.

Table 2.3: Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD) Percentage of Patients Healed

Additionally, a 20 mg rabeprazole sodium dose QD was as effective as omeprazole 20 mg in reducing heartburn frequency, improving daytime and nighttime heartburn severity, and reducing the amount of antacid taken per day.

Long-term Maintenance of Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD Maintenance) The long-term maintenance of healing in patients with erosive or ulcerative GERD previously healed with gastric antisecretory therapy was assessed in two U.S. multicentre, double-blind, placebo-controlled studies of 52 weeks' duration. Two studies of identical design randomized 209 and 288 patients, respectively, to receive either a 10 mg or 20 mg of rabeprazole sodium dose QD or placebo. In both studies, rabeprazole sodium was significantly superior to placebo in the maintenance of GERD healing. Table 2.4 gives results from a combined analysis of the two studies for the percentages of patients with endoscopically maintained healing.

Table 2.4: Long-term Maintenance of Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD Maintenance) - Percentage of Patients in Endoscopic Remission

In both multicentre trials, rabeprazole sodium 20 mg QD was significantly more effective than placebo in preventing recurrence of heartburn frequency (p<0.001) as well as daytime (p<0.001) and nighttime (p<_0.003) heartburn severity.

Two U.S. multicentre, double-blind, placebo-controlled studies were conducted in 316 patients with daytime and nighttime heartburn. Patients reported 5 or more periods of moderate to very severe heartburn during the placebo treatment phase the week prior to randomization. Patients were confirmed by endoscopy to have no esophageal erosions. Patients enrolled did not have a history of esophagitis. Patients entering the trial were required, at a minimum, not to have taken any proton pump inhibitor (PPI) within the 14 days before study entry, allowing time for the development of mucosal evidence of disease in those patients with true esophagitis. From the combined data from these two studies, there was a significantly greater (p<0.001) proportion of heartburn-free periods for the rabeprazole 10 mg group (53%) and the rabeprazole 20 mg group (49%) when compared to placebo (25%) over the 4-week treatment duration. The rabeprazole 10 and 20 mg groups also significantly reduced daily antacid consumption versus placebo over 4 weeks (p<0.001)_ Results on the proportion of subjects with complete heartburn relief and satisfactory relief of heartburn from the two pivotal clinical trials are summarized in Tables 2.5 and 2.6 below.

Table 2.5: Complete Relief of Heartburn and Satisfactory Relief of Heartburn Frequency from Study RABUSA-2

Table 2.6: Complete Relief of Heartburn and Satisfactory Relief of Heartburn Frequency from Study RABUSA-3

The mean decreases from baseline in average daytime and nighttime heartburn scores were significantly greater for rabeprazole 20 mg as compared to placebo at week 4. Graphical displays depicting the daily mean daytime and nighttime scores are provided in Figures 1 to 4. Figure 1: Mean Daytime heartburn scores RAB-USA-2

Heartburn Scores: 0 = None, 1 = Slight, 2 = Moderate, 3 = Severe, 4 = Very Severe

In a U.S. double-blind, multicentre study assessing the effectiveness of 20 mg and 40 mg rabeprazole sodium dosages QD versus placebo for healing endoscopically defined duodenal ulcers, 100 patients were treated for up to four weeks. Rabeprazole sodium was significantly superior to placebo in producing healing of duodenal ulcers. The percentages of patients with endoscopic healing are presented in Table 2.7.

Patients treated with a rabeprazole sodium dosage of 20 mg QD reported significantly less ulcer pain frequency (p<0.001) and significantly less daytime (p=0.002) and nighttime (p=0.001) ulcer pain severity than patients treated with placebo. Additionally, rabeprazole sodium 20 mg QD was significantly more effective than placebo in reducing daily antacid use (p<0.001). In a U.S. multicentre, double-blind, active-controlled trial, 376 patients with endoscopically defined duodenal ulcers were treated with a 20 mg rabeprazole sodium dose QD or ranitidine 150 mg BID for up to four weeks. The percentages of patients with endoscopic healing at two and four weeks are presented in Table 2.8.

Additionally, rabeprazole sodium 20 mg QD was significantly more effective than ranitidine 150 mg BID in producing complete resolution of ulcer pain frequency (week 2, p=0.006), in alleviating nighttime ulcer pain severity (week 2, p=0.044), and in reducing antacid consumption (p=0.037). An international double-blind, active-controlled trial was conducted in 205 patients comparing 20 mg rabeprazole sodium QD with 20 mg omeprazole QD. In patients with endoscopically defined duodenal ulcers treated for up to four weeks, rabeprazole sodium was comparable to omeprazole in producing healing of duodenal ulcers. The percentages of patients with endoscopic healing at two and four weeks are presented in Table 2.9.

Additionally, rabeprazole sodium 20 mg QD was significantly (p=0.038) more effective than omeprazole 20 mg in reducing daytime ulcer pain severity at week four.

In a U.S. double-blind, multicentre study assessing the effectiveness of a 20 mg and 40 mg rabeprazole sodium dosage QD versus placebo for healing endoscopically defined gastric ulcers, 94 patients were treated for up to six weeks. Rabeprazole sodium was significantly superior to placebo in producing healing of gastric ulcers. The percentages of patients with endoscopic healing at three and six weeks are presented in Table 2.10.

Patients treated with a 20 mg rabeprazole sodium dose QD for six weeks also required significantly fewer daily antacid doses than did patients treated with placebo (p=0.039). In two active-controlled trials of rabeprazole sodium, one conducted in the U.S. versus ranitidine 150 mg BID and one conducted in Europe versus omeprazole 20 mg, the rates of endoscopic healing of gastric ulcers were the same with the two treatments at three weeks and at six weeks. In the European study comparing a rabeprazole sodium 20 mg dose QD to omeprazole 20 mg, rabeprazole sodium was significantly superior in reducing ulcer pain frequency (week 6, p=0.006), in improving daytime ulcer pain severity (week 3, p=0.023), and in providing complete resolution of nighttime ulcer pain severity (week 6, p=0.022).

Treatment of Pathological Hvpersecretory Conditions Including Zollinger-Ellison Syndrome

Twelve patients with idiopathic gastric hypersecretion or Zollinger-Ellison syndrome have

been treated successfully with rabeprazole sodium doses from 20 to 120 mg for up to 12 months. Rabeprazole sodium treatment produced satisfactory inhibition of gastric acid secretion in all patients and complete resolution of signs and symptoms of acid-peptic disease where present. Rabeprazole sodium treatment also prevented recurrence of gastric hypersecretion and manifestations of acid-peptic disease in all patients. The high doses of rabeprazole sodium used to treat this small cohort of patients with gastric hypersecretion were not associated with drug-related adverse effects.

Comparative Bioavailability Studies

The objective of this study was to evaluate and compare the relative bioavailability and therefore the bioequivalence of two formulations of Rabeprazole tablets after a single oral dose administration under fed conditions. The study was a single center, randomized, single dose, blinded, crossover design planned for 40 healthy male subjects.

The objective of this study was to evaluate and compare the relative bioavailability and therefore the bioequivalence of two formulations of Rabeprazole tablets after a single oral dose administration under fasting conditions. The study was a single center, randomized, single dose, blinded, crossover design planned for 24 healthy male subjects.

DETAILED PHARMACOLOGY

Rabeprazole sodium was shown to be a potent inhibitor of gastric acid secretion under basal and histamine-stimulated conditions in rats and dogs. The inhibitory effect of rabeprazole sodium on gastric acid secretion was more marked under hyperacidic conditions than on basal acid secretion. The ED50 values for rabeprazole sodium on gastric acid secretion are summarized in Table 2.11, below.

Table 2.11: Rabeprazole Sodium ED50 Value for the Inhibition of Gastric Acid Secretion

Rabeprazole sodium was shown to have s significant anti-ulcer effects in several ulcerogenic models: HCl-ethanol-induced ulcers, water-immersion restraint stress-induced ulcers, cold-restraint stress-induced ulcers, or cysteamine-induced duodenal ulcers, acetic acid-induced ulcers, and Shay ulcers in rats. The available ED50 values for rabeprazole sodium on the anti-ulcer activity are summarized in Table 2.12.

Similar potency was observed for rabeprazole sodium on gastric acid secretion inhibition, except in the severe ulcer model induced with hydrochloric acid and ethanol.

In conscious dogs with indwelling gastric fistulas, the duration of the antisecretory action following a single intraduodenal dose of rabeprazole sodium or omeprazole after histamine challenges or pentagastrin challenges appeared to be dose-related and was longer in omeprazoletreated animals than rabeprazole sodium-treated animals within 24 hours. The inhibitory effect on gastric acid secretion was not cumulative when either drug was used and there was no measurable drug effect three days after discontinuation of rabeprazole sodium as reflected by plasma gastrin levels.

The desmethyl (M-3) and the thioether (M-1) metabolites of rabeprazole sodium were both shown to inhibit histamine-stimulated gastric acid secretion in dogs with indwelling gastric fistulas but these activities were less potent than rabeprazole sodium. A series of studies was conducted to determine the effects of rabeprazole sodium on H+, K+- ATPase activity. Using three experimental systems, the mechanism(s) by which gastric acid secretion returned to normal levels following irreversible inhibition of the proton pump (H+, K+-ATPase) by rabeprazole sodium was investigated. New synthesis of H+, K+-ATPase and the dissociation of the enzyme-inhibitor complex by endogenous extracellular GSH are suggested as contributing to the reversal of the antisecretory activity in dogs.

Rabeprazole sodium had no inhibitory effect on lesion healing or collagen regeneration in ethanol-HCI-induced ulcers in rats, whereas histamine H2-receptor antagonists (cimetidine and famotidine) had inhibitory effects on lesion healing and collagen synthesis.

Rabeprazole sodium had no significant effect on gastric emptying or intestinal transit in mice at doses of 1, 3, 10 or 30 mg/kg. No clear or significant effects on gastric or duodenal motility were observed after rabeprazole sodium was administered (i.d. ), at 50 mg/kg. At 100 mg/kg (i.d. ), rabeprazole sodium reduced gastric motility for 40 to 60 minutes, and a dose of 200 mg/kg (i.d.) rabeprazole sodium reduced gastric motility for up to 90 minutes. Rabeprazole sodium had no significant effect on biliary or pancreatic secretion in anesthetized rats.

Rabeprazole sodium is unstable in acidic media and undergoes pH-dependent decomposition especially rapidly below pH 4-5. When administered orally in an unbuffered solution, rabeprazole sodium is absorbed rapidly by the mouse, rat, rabbit and dog, but its bioavailability is low at gastric pH. Protection against gastric acid either by oral administration in sodium bicarbonate buffer (rodents and dog), by pretreatment with aqueous sodium bicarbonate (rat, dog), restricted feeding regimen (rat, dog), or by delivery directly (rat), or indirectly as enteric-coated tablets (dog, long-term studies) into the duodenum, increased rabeprazole sodium bioavailability. By contrast, pretreatment with pentagastrin (i.m. ), which stimulates gastric acid secretion, significantly lowered canine Cmax and AUC values for orally administered rabeprazole sodium.

The R(+) and S(-) enantiomers of rabeprazole sodium exhibited stereochemically related pharmacokinetic differences when administered individually either p.o. (1.5 mg/kg, in water) or i.v. (1.5 mg/kg, in saline) to the Beagle dog. The same differences were seen after co- administration of the RS-(") racemate, both p.o. and i.v. (3 mg/kg). With similar apparent volumes of distribution, the systemic clearance, Cltot of R(+)-rabeprazole sodium was approximately half that of S(-)-rabeprazole sodium, and the ratio both of plasma half-lives and AUC values after i.v. administration was approximately 2.0. The shorter half-life and greater clearance of the S(-) enantiomer is probably due to more rapid metabolism, as evidenced by much higher plasma concentrations of the sulphone metabolite M-2 after S(-)-rabeprazole sodium administration. There was little or no interconversion between enantiomers in vivo. In the rat, co-administration of both enantiomers of rabeprazole sodium as the RS (") racemate (40 mg/kg, i.v.) produced pharmacokinetic results comparable to those when R(+)-rabeprazole sodium and S(-)-rabeprazole sodium were administered separately (20 mg/kg, i.v. ). The R/S ratios for AUC value, total clearance, and volume of distribution were, respectively, 1.34, 0.67, and 0.62. Plasma half-lives for R(+)- and S(-)-rabeprazole sodium were comparable and the principal plasma metabolites were the achiral thioether (M-1) and desmethyl thioether (M-3). The greater volume of distribution for the S(-) enantiomer is consistent with lower protein binding relative to R(+)-rabeprazole sodium.

Protein Binding and Erythrocyte Penetration Species-specific differences in protein binding of racemic rabeprazole and its individual enantiomers were seen in human, rat and Beagle dog plasma in vitro. There was no difference in the binding of the individual enantiomers in human and dog plasma , but the S(-) isomer was significantly less protein bound than the R (+) form in rat plasma. Ex vivo, protein binding of radioactivity after oral administration of 14C-rabeprazole sodium was lower in the dog and rat, and decreased as a function of time post-dose, reflecting weaker binding of metabolites present to a greater extent than rabeprazole sodium in vivo. In vitro, 14C- rabeprazole penetrated erythrocytes rapidly and to a much smaller extent, in human and canine blood than in rat blood.

Distribution of radioactivity into tissues was determined after oral administration of 14C- E3810 , 10 mg/kg, to the Beagle dog. With the exception of the thyroid and pigmented ocular structure (ciliary body > iris>> choroid body), tissue depletion of radioactivity paralleled that in plasma and had fallen to <0.2 mg-equiv/g by Day 28. In another study, tissue distribution was similar after p.o. and i.v. administration and radioactivity in excess of that in plasma persisted in thyroid, choroid, and to a lesser extent, in lens and retina 8 days post dose. Radioactivity in gastric mucosa 0.5 hours after i.v. administration was two times higher than in plasma. Pretreatment with pentagastrin resulted in higher levels of radioactivity in gastric mucosa in the dog. High intracellular radioactivity was localized in the 105,000 x g pellet of gastric mucosal cell homogenates, the locus for intracellular binding of E3810 (H+K+-ATPase). After intraduodenal administration of 14C-rabeprazole to the rat, 20 mg/kg, plasma and tissue clearance was rapid except for hematocytes, thyroid, spleen, adrenals and liver, in which drug-related materials persisted at levels in excess of that in plasma nine days post-dose. Tissue distribution profiles of rabeprazole-related substances were investigated by administering 20 mg/kg of 14C-rabeprazole intraduodenally to male rats. Identification of metabolites in tissues revealed that M-5 and M-6 (the mercapturic acid and carboxylic acid analogs, respectively) were the major metabolites in all tissues except the stomach where M-l (the thioether of E3810) predominated. One hour after i.v. administration of a 5 mg/kg dose of 14C-rabeprazole to SD rats, the highest levels of 14C was observed in the gastric mucosa, followed by descending order by glandular stomach, kidney, bladder, liver, hematocytes, small intestine and thyroid. The highest levels of 14C-rabeprazole after 168 hours were found in hematocytes. Similar patterns of tissue distribution of radioactivity, depletion kinetics, and metabolic profile of 14C-E3810 were observed after single intraduodenal (20 mg/kg) and 14-day repeated oral (10 mg/kg/day) dosing. Following a single oral dose of 14C-rabeprazole, 20 mg/kg, to pregnant rats on Days 12 and 19 of gestation, the highest concentrations of radioactivity in the tissues of dams (excluding the gastrointestinal tract), were found in the liver and kidney. By 24 hours post-dose, the radioactivity in all tissues, except stomach and thyroid, has declined. No substantial accumulation of 14C-rabeprazole (0.01% to 1.16% of administered dose) was observed in fetal tissues after administration of '4C-rabeprazole to pregnant rats on Days 12 or 19 of gestation. Significant levels of radioactivity (two- to seven-fold higher levels than in blood) were observed in milk (obtained from the stomach of neonates) after the oral administration of 14C-rabeprazole to lactating females on the 14th day after delivery.

TOXICOLOGY

Single-dose toxicity studies of rabeprazole and its metabolites, synthetic by-products, degradation products, and enantiomers were conducted in mice, rats and/or dogs (see Table 2.15). The oral LD50 in mice and rats was >= 1000 mg/kg; the intravenous LD50 in mice and rats was >=150 mg/kg. CIinical signs consisted of laboured breathing, prostration, salivation, mydriasis, convulsions, and death. In dogs, the oral lethal dose was > 2000 mg/kg. Clinical signs at oral doses of 400 and 2000 mg/kg included watery diarrhea, tonic convulsions, emesis, salivation, and prostration. There was no delayed toxicity in these acute studies.

Table 2.15: List of Acute (Single-Dose) Toxicity Studies
Species/ Strain (Status)	Number/ Gender/ Group	Route of Admin./ Vehicle	Dose	Duration	LD 50 or NOEL
M	F
Mouse/ICR (Oral route: fasted 19 - 22 hrs prior to dosing; i. v. route: ad libitum feeding	5 per sex per group	p.o. (gavage)/ purified water i.v. / physiological saline	Male: 629, 786, 983, 1229, 1536, 1920, and 2400 mg/kg Female: 629, 786, 983, 1229, 1536, 1920, 2400 and 3000 mg/kg Male: 131, 164, 205, 256, and 320 mg/kg Female: 164, 205, 229, 256, and 320 mg/kg	Single dose	1206 220	1012 237
Rat/Slc: SD (oral route: fasted 17 - 24 hrs prior to dosing; i.v. route: ad libitum feeding)	5 per sex per group	p.o. (gavage)/ purified water i.v./ physiological saline	Male: 819, 1024, 1280, 1431, 1600, and 2000 mg/kg Female: 655, 819, 1024, 1280, 1600, and 2000 mg/kg Male: 98, 123, 154, 172, and 192 mg/kg Female: 98, 123, 154, 192, 240, and 300 mg/kg	Single dose	1447 157	1322 152
Rat SIc:SD (ad libitum feeding)	5 per sex per group	i.v.INaOH and physiological saline	0, 50, 100, and 200 mg (S-) E3810 /kg 50, 100, and 200 mg (R+) E3810 /kg	Single dose	Not Determined	Not Determined
Rat/Sic: SD (animals were fasted over night)	5 per sex per group	Degradation Products I and II and Impurity P .O. (gavage) Metabolite i.v./ 0.5 methylcellulose solution	Degradation Prod. I : 0, 500, and 1500 mg/kg Degradation Prod. II: 50, 150, and 500 mg/kg Impurity: 500 and 1500 mg/kg Metabolite: 0, 10, 30 mg/kg (male and female), 100 mg/kg (male only)	Single dose	Not Determined	Not Determined
Dog/Beagle (ad libitum feeding)	1 per sex per group	p.o (gavage)/ purified water	80, 400, and 2000 mg/kg	Single dose	> 2000	> 2000

Long-term toxicity of rabeprazole sodium was studied in mice, rats and dogs after oral and intravenous administration. Mice received oral doses of 2-400 mg/kg for up to 104 weeks. Rats received oral doses ranging from 1-300 mg/kg for up to 13 weeks and intravenous doses 1-75 mg/kg up to four weeks. Dogs received oral doses 0.1-30 mg/kg up to one year and intravenous doses 1-25 mg/kg up to 14 days.

In mice, signs of toxicity (most evident in male mice) at 400 mg/kg included torpor, ataxia, hypopnea, bradypnea, and prostration. These signs resolved within 30 minutes. Increases in stomach and/or liver weight, thickening of the gastric glandular mucosa and/or hyperplastic gastropathy were observed at doses of 25, 100 and 400 mg/kg. It was concluded that oral doses up to 200 mg/kg (dose reduced to 100 mg/kg at week 41) for 88 weeks in males and 104 weeks in females did not provide any evidence of an oncogenic potential. A number of changes in the stomach that were attributable to the pharmacological activity of rabeprazole sodium were seen in animals treated with 200 mg/kg (dose reduced to 100 mg/kg at week 41).

In the rat, rabeprazole sodium was well tolerated in all dose groups (5, 15, 30, 60 and 120 [females only]) when administered by gavage for six months, as morphologic changes were slight in magnitude and were not associated with alterations in growth, morbidity or mortality. Drug-related changes were detected in the kidney, thymus, stomach and/or thyroid at doses > 15 mg/kg. No effects were observed at 5 mg/kg. In a 52-week study of rats administered doses of 1, 5 and 25 mg/kg by gavage, the gastric changes observed in the treated animals were attributable to the expected pharmacological effects and not toxicological changes, and the NOAEL was 5 mg/kg. Intravenous administration of rabeprazole sodium in the rat at doses of 75 mg/kg for 14 days showed clinical signs such as hypoactivity, salivation, prone position, and flushing of the nose, but these signs disappeared after one hour of administration. Thymus weight was decreased and liver weight was increased.

Rabeprazole sodium had no effect on liver, kidney, heart, or lung at doses up to and including 30 mg/kg given by oral administration. Because of the smaller thymus weights observed in females treated with 30 mg/kg, the NOEL was 10 mg/kg. Rabeprazole sodium (0.1, 0.3, or 1.0 mg/kg) and omeprazole (0.3, 1.0, or 3.0 mg/kg) were given orally to male and female dogs for 13 weeks followed by a 13-week recovery period. Expected pharmacologic responses (elevated gastrin levels and gastric changes) were observed with both proton pump inhibitors. Gastric changes were reversible at 0.3 mg/kg with both compounds and no gastric lesions were detected at 0.1 mg/kg of rabeprazole sodium. Effects were not observed in other organ systems with either compound. In a one-year followed by a two-month reversibility phase study, soft and watery stools and emesis were among the observations made in dogs treated with 8 or 25 mg/kg rabeprazole sodium. Changes in clinical chemistry parameters included increases in cholesterol and triglycerides, and decreases in chloride and total protein. Serum gastrin levels, gross and histopathologic changes in stomach included increases in stomach weight, gastric mucosal and nonmucosal mass, and ECL hypertrophy and for hyperplasia were observed in the rabeprazole- treated groups. The maximum tolerated dose was 8 mg/kg and the NOEL was 2 mg/kg. In a 52 week study, a number of changes were observed in the stomach of dogs treated with for 1 or 5 mg/kg of rabeprazole sodium. These changes included increased stomach weight, thickening of the gastric mucosa, chief cell cytoplasmic atrophy, foci of cellular and chromogranin positive cell hypertrophy, and elevated gastrin levels. These changes, considered to be the result of a prolonged pharmacological effect and not a toxic effect of rabeprazole sodium, were completely or partially reversed at the end of the recovery period. In a 52-week study, over a dose range of 0.2 to 5 mg/kg, no change in ECL cell populations was evaluated. In a 14-day study in the dog, rabeprazole was administered intravenously at doses of 1, 5, and 25 mg/kg. The lowest dose tested (1 mg/kg) was judged to be a no-effect-dose level for toxicity for rabeprazole in this study. At daily doses of 5 mg/kg, treatment-related findings included vomiting and stool changes and histopathologic changes in the thyroid and the stomach.

In repeat-dose studies of up to one year in duration in rats and dogs and a three-month study in mice, trophic changes in the gastric mucosa were expected based on experience and the published literature of the H2 receptor antagonists and other proton pump inhibitors (Abe-1990, Ekman-1985, Hakanson-1986&1992, Atkinson-1990, Tuch-1992, Betton-1988, Creutzfeldt- 1986, Poynter-1985&1991, Havu-1986&1990, Polak-1988). Gastric changes, stimulated by chronic and sustained acid suppression, were manifested by hypergastrinemia, ECL-cell hypertrophy, hyperplasia, and neoplasia (female rats only), chief cell eosinophilia, and fluidic mucosal thickening in rats. Gastric changes were observed at low doses in these studies: 1 mg/kg-rat, 0.3 mg/kg-dog, 25 mg/kg-mouse. Increases in gastrin levels and trophic effects on the gastric mucosa were not observed at 0.2 mg/kg in a 52-week dog study. A four-week study in antrectromized rats treated with 40 mg/kg rabeprazole sodium revealed no increased levels of gastrin and no ECL cell hyperplasia indicating that chronic stimulation of G cells and gastrin release is critical in the pathogenesis of hypergastrinemia and trophic gastric lesions. Reversibility of non-neoplastic changes was demonstrated in several studies in rats, mice and dogs. In mice diffuse neuroendocrine cell hyperplasia was fully restored and hyperplastic gastropathy was partially reversed after 13 or 26 weeks of recovery period.

Because the oral bioavailability of rabeprazole sodium is low in rats and rabbits (less than 5%), rabeprazole was administered intravenously in the reproduction studies to maximize systemic exposure. Male and female fertility (+2 generations), embryo-fetal development (EFD) and perinatal/postnataI (+2 generations) studies, and effects on leuteinizing hormone (LH) and testosterone (T) were completed. In the fertility study (0, 1, 6, 30 mg/kg), no effects were observed on male or female fertility or on growth, development, or reproductive performance of the Fl generation. At maternally toxic doses (25 and 50 mg/kg) in the rat EFD study, incomplete ossification of the parietal and/or occipital bones was observed. There were no other effects on viability, weight or morphology. At maternally toxic doses (30 mg/kg) in the rabbit EFD study, decreased fetal weight and delayed ossification of the proximal tibial epiphysis was observed. There were no other effects on fetal viability or morphology. Adequate absorption of rabeprazole was demonstrated in the rabbit during the organogenesis period. In the perinatal/postnatal study in rats (0, 1, 6, 30 mg/kg), maternal toxicity was noted at 30 mg/kg, but this did not affect general reproductive performance or nursing of the dams. No effects on fetal development, parturition, lactation, postnatal growth and offspring development, or offspring reproductive performance were observed in this study. Lansoprazole-induced Leydig cell tumours in the rat testes is related to an imbalance of LH regulation (Atkinson-1990). Rabeprazole does not cause Leydig cell tumours or perturbations of the LH/T axis.

Rabeprazole was not genotoxic in the in vitro test for chromosome aberration in CHL/IU cells, the in vivo mouse micronucleus test, and the in vivo/ex vivo and in vitro unscheduled DNA synthesis assays in rat hepatocytes. The CHO/HGPRT forward gene mutation assay: There was no evidence of induced mutation by treatment with rabeprazole at concentrations ranging from 10 to 40 mg/mL in the activated test. A weak response for mutagenicity was observed at concentrations ranging from 90 to110 mg/mL in the absence of metabolic activation. However, this response was not reproducible. Treatment with either EMS or 3MC resulted in induction of HGPRT mutants. It was concluded that rabeprazole was not mutagenic in HGPRT' Chinese hamster ovary cells. Ames tests: Positive and negative results were observed. Positive results were seen with the carboxylic acid metabolite (M6) of rabeprazole which were attributable to contaminants originating from the reverse-phase chromatography column used for purifying M6. The L5178Y TK mouse lymphoma assay: Rabeprazole was negative for inducing mutations in L5178Y TK+/- cells when testing in the absence metabolic activation, but was weakly positive when tested at concentrations of 25 and 30 ug/mL in the presence of metabolic activation.

In a two-year carcinogenicity study in Fischer rats on a restricted feeding regime, ECL cell hyperplasia was observed but no gastric carcinoids were identified at doses up to 20 mg/kg/day (about 10 times the exposure on a body surface [mg/m2] basis for patients given the recommended 20 mg/day [12.3 mg/m2] dose). A second two-year carcinogenicity study was conducted in Sprague-Dawley rats on an ad libitum feeding regime given oral doses of rabeprazole at 5, 15, 30 and 60 mg/kg/day for males and 5, 15, 30, 60 and 120 mg/kg/day for females (about 2-60 times the exposure on a body surface [mg/m2] basis for patients given the recommended 20 mg/day [12.3 mg/m2] dose). AIthough ECL cell hyperplasia was observed in both male and female rats and mice in the carcinogenicity studies, rabeprazole produced dose-related gastric carcinoids only in female Sprague-Dawley rats at doses >=5 mg/kg. Rabeprazole was not observed to induce tumours in any other tissue. In a two-year mouse carcinogenicity study, no drug-induced tumours were identified at doses up to 100 mg/kg/day (24 times exposure on a body surface [mg/m2] basis for patients given the recommended 20 mg/day [12.3 mg/m2] dose). In a 28-week mouse carcinogenicity study, a group of male and female p53(+/-) C57BL/6 mice were administered rabeprazole daily by oral gavage at levels of 0 (vehicle control), 20, 60 or 200 mg/kg/day. A positive control group received a dose level of 400 mg/kg/day of p-cresidine daily by oral gavage in the same manner. Treatment-related non-neoplastic changes were described in the report as mucosal hyperplasia of the glandular stomach. These changes were attributable to pharmacologic effects of rabeprazole. There was no evidence of carcinogenic effect by rabeprazole treatment in the stomach. A small number of neoplasms (malignant lymphoma) were observed in the study. The incidence of malignant lymphoma was 1/20 in mid-dose males; 1/20 in each of low-, mid- and high-dose group females (or 5%). Four female mice treated with rabeprazole died, three of them with malignant lymphoma. There was no dose response and the incidence of these neoplasms was not higher than expected based on the testing facility historical control data, or from data published by Storer, RD, et al.19 (that reported a historical incidence of malignant lymphoma in p53(+/-) C57BL/6 mice of 1.7-5.7% for males and 1.8-8% for females). The positive control group showed the expected tumor response, which is the development of mostly transitional cell carcinoma in the urinary bladder, thereby validating the study. The study was valid for detecting carcinogenic potential.

REFERENCES

Inhibitions of acid secretion by E3810 and omeprazole, and their reversal by glutathione. Biochem Pharmacol 1991; 42(2):321-8. Ishizaki T, Chiba K, Manabe K, Koyama E, Hayashi M, Yasuda S, et al. Comparison of the interaction potential of a new proton pump inhibitor, E3810, versus omeprazole with diazepam in extensive and poor metabolizers of S-mephenytoin 4'-hydroxylation. Clin Pharmacol Ther 1995; 58(2):155-64. Matsumoto N, Murakami Y, Komatsu H; Toga K, Yamazaki M, Kawamoto T, et al. Effect of proton pump inhibitor, E3810 on intragastric pH. Proceedings of the Japanese Sac of Gastric Secretion Research 1991; 23:1-5. Miner P Jr., On W, Filippone J, Jokubaitis L Sloan S. Rabeprazole in nonerosive gastroesophageal reflux disease: A randomized placebo-controlled trial. Am J Gastroenterol 2002; 97(6):1332-1339. Miyazaki Y, Imamura I, Yasunaga Y, Shinomura M, Fukui H, Wada H, et al. Effects of potent acid secretion inhibitors on gastrin secretion and histamine metabolism in the gastric mucosa. A study with the proton pump inhibitor E3810. Bulletin of Symposium of Gastric Secretion 1992; 24:93-6. Morii M, Takata H, Fujisaki H, Takeguchi N. The potency of substituted benzimidazoles such as _ E3810, omeprazole, Ro 18-5364 to inhibit gastric H+, K+-ATPase is correlated with the rate of acid-activation of the inhibitor. Biochem Pharmacol 1990; 39:661-7. Morii M, Takeguchi N. Different biochemical modes of action of two irreversible W, K+-ATPase inhibitors, omeprazole and E3810. JBiol Chem 1993; 268(29):21553-9. Noguchi M, Nakanowatari J, Tanabe Y, Tagaya 0, Aoi T, Yamatsu K, et al. E3810 toxicity study in Beagle dogs after repeated oral administration for 13 weeks followed by a 5 week recovery period. GI Research 1993; 1(5 suppl. ):527-56 (59- 88). 14.Ohnishi A, Yasuda S, Ogawa T, Tomono Y, Hasegawa J, Morishita N. Results of phase I studies of E3810, a new proton pump inhibitor in healthy male volunteers. Single and multiple dose study. GI Research 1993; 1(5):199-207. Ohnishi A, Yasuda S, Ogawa T, Tomono Y, Hasegawa J, Morishita N. E3810 phase I clinical trial results - single and repeated administrations. GI Research 1993; 1(5):667-75. Okada F, Osumi I, Kawaguchi T, Yamatsu K, Igarashi T. Fetal organogenesis study in rabbits treated intravenously with E3810. GI Research 1993; 1 (5 suppl. ): 647-54 (179-86). Osumi I , Goto M, Okada F, Matsubara Y, Yamatsu K, Igarashi T. Fetal organogenesis study in rats treated orally with E3810. GI Research 1993; 1 (5 suppl. ): 615-32 (147-64). Shmizu M, Uto K, Kobayashi Y, Yamashita Y, Kato M, Shinoda A, et al. Perinatal and postnatal toxicity study of E3810 in rats after intravenous administration. GI Research 1993; 1 (5 suppl. ): 633-46 (165-77). Storer RD, French JE, Haseman J, Jajian G, LeGrand EK, et al. p53+1- Hemizygous knockout mouse: Overview of available data. Toxicologic Pathology 2001; 29 (Suppl. ): 30-50. Williams MP, Sercombe J, Hamilton MI, Pounder RE. A placebo-controlled trial to assess the effects of 8 days of dosing with rabeprazole versus omeprazole on 24-h intragastric acidity and plasma gastrin concentrations in young healthy male subjects. Aliment Pharmacol Ther 1998; 12:1079-1089. Yasuda S, Horai Y, Tomono Y, Nakai H, Yamato C, Manabe K, et al. Comparison of the kinetic disposition and metabolism of E3810, a new proton pump inhibitor, and omeprazole in relation to S-mephytoin 4-hydroxylation status. Clin Pharmacol Ther 1995; 58(2):143-54. Yasuda S, Ohnishi A, Ogawa T, Tomono Y, Hasegawa J, Nakai H, et al. Pharmacokinetic properties of E3810, a new proton pump inhibitor, in healthy male volunteers. Int J Clin Pharmacol Ther 1994; 32:466-73. A double-blind, placebo-controlled trial of rabeprazole tablets, 20 mg once daily, in the treatment of subjects without erosive esophagitis and who have symptoms of chronic gastroesophageal reflux disease (GERD). Janssen Research Foundation, Data on File, 2001. PARIET(r) enteric coated tablets Product Monograph (Janssen-Ortho Inc.), Revision date: January 26, 2005, Control No: 094301 Comparative Bioequivalence studies of pms-RABEPRAZOLE EC DR 20 mg tablets: Data on file at Pharmascience Inc. IMPORTANT: PLEASE READ

This leaflet is part III of a three-part "Product Monograph" published when pms-Rabeprazole EC was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about pms-RABEPRAZOLE EC Contact your doctor or pharmacist if you have any questions about the drug.

Read this leaflet carefully. It contains general information about pms-RABEPRAZOLE EC tablets that you should know in addition to the specific advice from your doctor or pharmacist. It is important for you to carefully follow your doctor's instructions regarding how and when to take pms-RABEPRAZOLE EC tablets.

relief and healing of stomach ulcers; healing of gastroesophageal reflux disease (GERD) and relief of its symptoms such as burning sensation rising from the chest towards the neck (heartburn) and the flow of bitter/sour juice into the mouth (regurgitation);

treatment of symptoms (i.e. heartburn and regurgitation) of non- erosive reflux disease (NERD);

pms-RABEPRAZOLE EC tablets may also be used in rare conditions like "Zollinger-Ellison syndrome," where the stomach produces Iarge amounts of acid.

pms-RABEPRAZOLE EC tablets work by reducing the amount of acid made in your stomach.

Each pms-RABEPRAZOLE EC tablet contains rabeprazole sodium as the medicinal ingredient.

Both 10 mg tablets and 20 mg tablets contain the following non- medicinal ingredients: Hydroxypropyl cellulose, Hydroxypropyl

Methacrylic acid, Polyethylene glycol, Shellac glaze, Sodium lauryl sulfate, Talc, Titanium dioxide, Triethyl citrate and Zein.

The 10 mg tablets also contain Antifoam, Hypromellose, Industrial methylated spirit, Iron oxide black, Iron oxide red and Lecithin (soya).

The 20 mg tablets also contain Ammonium Hydroxide, FD&C red /allura red AC aluminum lake, Propylene Glycol and Yellow iron oxide.

Drugs that may interact with pms- RABEPRAZOLE EC include: Ketoconazole, digoxin, warfarin

Your doctor has recommended you take pms-RABEPRAZOLE EC tablets for a specific number of weeks. Keep taking your pms- RABEPRAZOLE EC tablets, as recommended by your doctor, until you have finished all your tablets. Do not stop even when you start to feel better. If you stop taking pms-RABEPRAZOLE EC tablets too soon, your symptoms may return.

pms-RABEPRAZOLE EC tablets may be taken with or without meals and should be swallowed whole with a beverage, not chewed or crushed.

healing occurs in four weeks. If not healed, your doctor may recommend an additional four weeks of treatment.

If you have reflux symptoms without esophagitis, such as heartburn and regurgitation:

maximum of 20 mg once daily in patients without esophagitis_ If symptom control is not achieved after four weeks, your doctor may recommend further investigation.

The recommended dose is 20 mg once daily for up to four weeks. Your doctor may decide to continue treatment to ensure healing depending on your condition_

Your doctor may decide to continue treatment to ensure healing depending on your condition.

In the unlikely event of an overdose contact your doctor or Poison Control Centre immediately.

If you forget to take one dose of pms-RABEPRAZOLE EC medication, take a tablet as soon as you remember, unless it is

at all. Never double-up on a dose to make up for the one you have missed, just go back to your regular schedule.

Like any medication, pms-RABEPRAZOLE EC tablets may cause side effects in some people. When side effects have been reported, they have been generally mild and did not last a long time. Headache and diarrhea are the most common side effects; less often rash, itchiness and dizziness can occur. If any of these become troublesome, consult your doctor. If you experience any unusual or unexpected symptoms while using pms-RABEPRAZOLE EC tablets, consult your doctor.

This is not a complete list of side effects. For any unexpected effects while taking pms-RABEPRAZOLE EC, contact your doctor or pharmacist.

Keep your tablets stored at room temperature (15deg to 30degC) and protected from moisture. They should be kept in a safe place, where children cannot reach them.

To monitor drug safety, Health Canada through the Canada Vigilance Program collects information on serious and unexpected side effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Canada Vigilance:

NOTE: Should you require information related to the management of the side effect, please contact your health care provider before notifying Canada Vigilance. The Canada Vigilance Program does not provide medical advice.

This information is intended to alert you to which situations you should call your doctor about. Other situations which cannot be

should stop you from calling your doctor with any questions or concerns you have about using pms-RABEPRAZOLE EC tablets.

This document plus the full product monograph, prepared for health professionals can be obtained by contacting the sponsor, Pharmascience Inc., at 1-888-550-6060.

Route of Administration	Dosage Form / Strength	Clinically Relevant Nonmedicinal Ingredients
oral	Tablets / 10 mg & 20 mg	None For a complete listing see Dosage Forms, Composition and Packaging section.

Parameter	Rabeprazole sodium (20 mg QD)	Placebo
Basal Acid Output (mmol/hr)	0.4 *	2.8
Stimulated Acid Output (mmoL(hr)	0.6 *	13.3
% Time Gastric pH>3	65 *	10
*(p<0.01 versus placebo)

	Rabeprazole sodium (mg QD)
Parameter	10	20	40	Placebo
Mean AUC 0 -24 acidity (mmol.hr/L)	156 *	131 *	86 *	678

Parameter	Rabeprazole sodium 20 mg QD		Omeprazole 20 mg QD		Place	bo
Parameter	Day 1	Day 8	Day 1	Day 8	Day 1	Day 8
Mean AUC 0 24 Acidity	340.8 *#	176.9 * +	577.1 *	271.2 *	925.5	862.4
Median trough pH (23-hr) 1	3.77	3.51	1.43	3 . 2 1	1.27	1.38
% Time Gastric pH>3 (1)	54.6 *#	68.7 * +	36.7 *	59.4 *	19.1	21.7
% Time Gastric pH>4 (1)	44.1 *#	60.3 * +	24.7 *	51.4 *	7.6	11.0

Week	20 mg Rabeprazole sodium QD	Placebo
4	N=25 56% *	N=26 0%
8	84% *	I2%

Week	Rabeprazole sodium 20 mg QD	Ranitidine 150 mg QID
	N=169	N=169
4	59% *	36%
8	87% *	66%

	PLACEBO n (%) +	Rabeprazole 10 mg QD n (%)+	Rabeprazole 20 mg QD n (%)+
Intent-To-Treat (ITT) population	N=68	N=64	N=67
Per-Protocol (PP) population	N=61	N=59	N=58
Complete Heartburn Relief	0 (0.0)	12 (18.8)	12 (17.9)
Double-blind Week 2	0 (0.0)	12 (18.8)	12 (17.9)
Double-blind Week 4	2 (2.9)	17 (26.6)	17 (25.4)
Satisfactory Heartburn Relief	12 (17.6)	40 (62.5)	29 (43.3)
Double-blind Week 2	12 (17.6)	40 (62.5)	29 (43.3)
Double-blind Week 4	19 (27.9)	33 (51.6)	34 (50.7)

	PLACEBO n (%) t	Rabeprazole 20 mg QD n (%) t
Intent-To-Treat (ITT) population	N=58	N=59
Per-Protocol (PP) population	N=45	N=45
Complete Heartburn Relief Double-blind Week 2 Double-blind Week 4	2 (3,4) 2 (3.4)	13 (22.0) 17 (28.8)
Satisfactory Heartburn Relief Double-blind Week 2 Double-blind Week 4	15 (25.9) 12 (20.7)	33 (55.9) 30 (50.8)

Week	Rabeprazole sodium 20 mg QD	Ranitidine 150 mg BID
2	N=188 40% *	N=188 26%

Rabeprazole (1 x 20 mg EC tablet) From measured data uncorrected for potency Geometric Mean Arithmetic Mean (CV %)
Parameter	Test *	Reference +	% Ratio of Geometric Means +	Confidence Interval (90%) +
AUC T	609.53	628.01	97.06	90.32 - 104.30
(ng *h/mL)	679.11 (49.2)	685.21 (48.4)	97.06	90.32 - 104.30
AUC I	660.38	672.48	98.20	91.89 - 104.94
(ng *h/mL)	719.41 (46.8)	724.15 (47.0)	98.20	91.89 - 104.94
C max	407.95	414.54	98.41	86.41 - 112.08
(ng/mL)	446.15 (38.2)	445.40 (39.8)	98.41	86.41 - 112.08
T ma SS	6.50	7.00
(h)	(3.53 - 20.00)	(3.00 - 17.00)
T EUR (h)	1.40 (70.7)	1.45 (88.9)

Species	Model	Acid Secretion	ED 50 (mg/kg)
rat	pylorus ligated	basal	3.4
rat	pylorus ligated	basal	ca. 3
rat	pylorus ligated	histamine-stimulated	ca. 1
rat	acute gastric fistula	histamine-stimulated	ca. 1.4
dog	chronic gastric fistula	histamine-stimulated	0.06

Species	Ulcerogenesis Model	ED 50 (mg/kg)
Rat	HC1-ethanol-induced	ca. 17
Rat	water-immersion restraint stress-induced	ca. 3.9
Rat	cold-restraint stress ulcer	ca. 3.5

Week	Rabeprazole sodium 20 mg QD	Omeprazole 20 mg QD
4	N=100 81%	N=102 81%

Week	Rabeprazole sodium 20 mg QD	Placebo
	N=34	N=33
2	44%	21%
4	79% *	39%
* p l . 0 0 1 vs placebo

Week	Rabeprazole sodium 20 mg QD	Omeprazole 20 mg QD
2	N=102 69%	N=103 61%
4	98%	93%

Week	Rabeprazole sodium 20 mg QD	Placebo
3	N=32 32%	N=31 29%
6	90% *	39%

PHARMASCIENCE INC.