SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 5 ADVERSE REACTIONS 6 DRUG INTERACTIONS 9 DOSAGE AND ADMINISTRATION 10 OVERDOSAGE 11 ACTION AND CLINICAL PHARMACOLOGY 11 STORAGE AND STABILITY 16 DOSAGE FORMS, COMPOSITION AND PACKAGING 16
PHARMACEUTICAL INFORMATION 17 COMPARATIVE BIOAVAILABILITY 18 CLINICAL TRIALS 20 DETAILED PHARMACOLOGY 27 MICROBIOLOGY 31 TOXICOLOGY 32 REFERENCES 38
Pr
NOVO-RABEPRAZOLE EC
rabeprazole sodium 10 and 20 mg Enteric-Coated Tablets H+, K+ -ATPase Inhibitor
Note: When used in combination with amoxicillin and clarithromycin, the Product Monographs for
those agents must be consulted and followed.
| Route of Administration | Dosage Form/ Strength | Clinically Relevant Nonmedicinal Ingredients |
| Oral | Tablet 10 mg, 20 mg | lactose For a complete listing see Dosage Forms, Composition and Packaging Section |
NOVO-RABEPRAZOLE EC (rabeprazole sodium) is indicated for: treatment of conditions where a reduction of gastric acid secretion is required, such as:
Symptomatic relief and healing of erosive or ulcerative gastroesophageal reflux disease (GERD).
Long-term maintenance of healing of erosive or ulcerative gastroesophageal reflux disease (GERD).
Treatment of symptoms (i.e. heartburn and regurgitation) in symptomatic gastroesophageal reflux disease (GERD), also called non-erosive reflux disease (NERD).
Symptomatic relief and healing of duodenal ulcers.
Symptomatic relief and healing of gastric ulcers.
Long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome.
Eradication of H. pylori associated with duodenal ulcer disease (active or history within the past 5 years). Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence. Clinical trials using combinations of rabeprazole with appropriate antibiotics, have indicated that such combinations are successful in eradicating H. pylori. Presented below in Table 1.1 are the data from a U.S. multicentre study (Study 604) comparing rabeprazole, amoxicillin, and clarithromycin (RAC) for 3, 7 or 10 days versus omeprazole, amoxicillin and clarithromycin (OAC) for 10 days. In a European multicentre study (Study 603), RAC was compared to OAC for 7 days.
Table 1.1: H. pylori eradication+ rates with rabeprazole or omeprazole plus amoxicillin and clarithromycin in patients with duodenal ulcer disease
| Proton Pump Inhibitor in Treatment | Treatment Time | % of Patients Cured [95% Confidence Interval of the difference RAC-OAC] (Number of Patients) | ||
| Per-Protocol ++ | Intent-to-Treat ++ | |||
| Study 604 North America | Rabeprazole | 3 days | 30% [-61%,-43%] (n=167) | 27% [-55%, -37%] (n=187) |
| Rabeprazole | 7 days | 84% * [-5%, +11%] (n=166) | 77% * [-4%, +12%] (n=194) | |
| Rabeprazole | 10 days | 86% * [-3%, +12%] (n=171) | 78% * [-4%, +13%] (n=196) | |
| Omeprazole | 10 days | 82% (n=179) | 73% (n=206) | |
| Study 603 Europe | Rabeprazole | 7 days | 94% [-0.7%, +20%] (n=65) | 84% [+0.5, +24.5] (n=83) |
| Omeprazole | 7 days | 84% (n=63) | 72% (n=85) | |
+ In study 604, H.Pylori eradication was assessed at 6 weeks but not more than 10 weeks by 13C-UBT. In study 603, successful eradication of
H.Pylori was defined as a negative 13C-UBT at week 5 and week 13 post treatment assessments.
++ Patients were included in the analysis if they had H.Pylori infection documented at baseline, defined as a positive 13C-UBT plus rapid urease test or culture and were not protocol violators. Patients who dropped out of the study due to an adverse event related to the study drug were included in the evaluable analysis as failures of therapy.
++ Patients were included in the analysis if they had documented H.Pylori infection at baseline defined as a positive 13C-UBT plus rapid urease test or culture, and took at least one dose of study medication.
* Equivalent to OAC; two-sided 95% confidence interval on the difference between regimens is within [-15%,+15%]
Geriatrics: WARNlNGS AND PRECAUTlONS - Special Populations
See
Pediatrics (< 18 years of age):
The safety and efficacy of rabeprazole have not been established in children under the age of 18 years.
Patients who are hypersensitive to rabeprazole, substituted benzimidazoles or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph;
Amoxicillin is contraindicated in patients with a known hypersensitivity to any penicillin. (Please refer to the amoxicillin Product Monograph before prescribing);
Clarithromycin is contraindicated in patients with known hypersensitivity to clarithromycin, erythromycin or other macrolide antibacterial agents. Clarithromycin is also contraindicated in patients receiving concurrent therapy with astemizole, terfenadine, cisapride or pimozide. (Please refer to the clarithromycin tablets Product Monograph before prescribing).
When gastric ulcer is suspected, the possibility of malignancy should be excluded before therapy with NOVO-RABEPRAZOLE EC is instituted, as treatment with rabeprazole may alleviate symptoms and delay diagnosis.
General
Symptomatic response to therapy with NOVO-RABEPRAZOLE EC (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. Increases 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 INR and prothrombin time. As demonstrated with other PPI's, prolonged use may impair the aborption of protein-bound Vitamin B12 and may contribute to the development of Vitamin B12 deficiency.
Information for Patients
NOVO-RABEPRAZOLE EC tablets can be taken with or without meals. Patients should be advised that NOVO-RABEPRAZOLE EC tablets should be swallowed whole, not chewed or crushed.
Hepatic/Biliary/Pancreatic
For patients with severe liver disease, dosage adjustment should be considered.
Renal
No dosage adjustment is necessary in patients with renal insufficiency.
Special Populations
: The safety of rabeprazole sodium treatment in pregnancy has not been established. NOVO-RABEPRAZOLE EC tablets should not be administered to pregnant women unless the expected benefits outweigh the potential risks to the fetus.
: It is not known whether rabeprazole is excreted in human milk. NOVO- RABEPRAZOLE EC tablets should not be given to nursing mothers unless the expected benefits outweigh the potential risks to the infant.
The safety and efficacy of rabeprazole have not been established in children under the age of 18 years.
: 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 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 specific 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 | ||
| 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
angina pectoris, arrhythmia, bradycardia, bundle branch block,
System:
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
diabetes mellitus, hyperthyroidism, hypothyroidism.
System
:
Hemic and
anemia, ecchymosis, hypochromic anemia, lymphadenopathy.
Lymphatic System:
Metabolic and Nutritional Disorders:
dehydration, edema, face edema, gout, iron deficiency anemia, liver
fatty deposit, peripheral edema, thirst, weight gain, weight loss.
Musculoskeletal
arthritis, arthrosis, bone pain, bursitis, joint disorder, leg cramps,
System
: 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
apnea, asthma, carcinoma of lung, dyspnea, epistaxis, hiccup,
System
: hyperventilation, hypoventilation, hypoxia, laryngitis, lung disorder, pneumonia, pulmonary embolus, respiratory disorder, voice alteration.
Skin and
acne, alopecia, contact dermatitis, dry skin, fungal dermatitis, herpes
Appendages
: 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
breast enlargement, breast neoplasm, breast pain, cystitis, dysmenorrhea,
System
: dysuria, hematuria, 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.
Combination Treatment with Amoxicillin and Clarithromycin
In clinical trials using combination therapy with rabeprazole plus amoxicillin and clarithromycin (RAC), no adverse events unique to this drug combination were observed. In the U. S. multicentre Study 604, the most frequently reported drug-related adverse events for patients who received the triple therapy for 7 or 10 days were diarrhea (8% and 7%) and taste perversion (6% and 10%), respectively. In the European multicentre Study 603, the most frequently occurring adverse events were diarrhea (13%) and taste perversion (14%) in patients receiving RAC therapy for 7 days. No clinically significant laboratory abnormalities particular to the drug combinations were observed. When rabeprazole sodium is used in combination with amoxicillin and clarithromycin, the Product Monographs for those agents must be consulted and followed.
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.
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 increased INR and prothrombin time in patients receiving proton pump inhibitors, including rabeprazole, and warfarin concomitantly. Increases 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 with Clarithromycin
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).
Drug-Food Interactions
Taking rabeprazole with food or antacids produced no clinically relevant changes in plasma rabeprazole concentrations.
Recommended Dose and Dosage Adjustment
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 Ulcerative 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).
Symptomatic Relief and Healing of Duodenal Ulcers
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.
Symptomatic Relief and Healing of Gastric Ulcers
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.
Eradication of H. pylori Associated with Duodenal Ulcer Disease - Triple Therapy:
| Rabeprazole Sodium | 20 mg | Twice Daily for 7 Days |
| Amoxicillin | 1000 mg | Twice Daily for 7 Days |
| Clarithromycin | 500 mg | Twice Daily for 7 Days |
All three medications should be taken twice daily with the morning and evening meals. In patients who fail therapy, susceptibility testing should be done. If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be instituted.
Long-term Treatment of Pathological Hypersecretory 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.
Administration
NOVO-RABEPRAZOLE EC tablets can be taken with meals or on an empty stomach. NOVO- RABEPRAZOLE EC tablets are enteric-coated and therefore should be swallowed whole with a beverage (not chewed or crushed).
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.
NOVO-RABEPRAZOLE EC (rabeprazole sodium) is an antisecretory compound (substituted benzimidazole proton pump inhibitor) that suppresses 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 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.
Pharmacodynamics
Antisecretory Activity
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+-ATPase.
Table 1.3: Gastric Acid Parameters - Rabeprazole sodium versus Placebo After 7 Days of Once-Daily Dosing
| 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)
The ability of rabeprazole sodium to cause a dose-related decrease in mean intragastric acidity is illustrated in Table 1.4.
Table 1.4: Mean AUC Acidity for Three Rabeprazole sodium Doses versus Placebo
| Rabeprazole Sodium (mg QD) | ||||
| Parameter | 10 | 20 | 40 | Placebo |
| Mean AUC 0-24 acidity (mmol *hr/L) | 156 * | 131 * | 86 * | 678 |
(p<0.001 versus placebo)
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
| Parameter | Rabeprazole Sodium 20 mg QD | Omeprazole 20 mg QD | Placebo | |||
| 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 | 3.21 | 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 |
No inferential statistics conducted for this parameter.
*
(p<0.001) versus placebo
#
(p<0.001) versus omeprazole 20 mg QD
+
(p<0.05) versus omeprazole 20 mg QD
(1) Gastric pH was measured every hour over a 24-hour period
Effects on Esophageal Acid Exposure
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.
Effects on Serum Gastrin
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 tablets.
Effects on Enterochromaffin-like (ECL) Cells
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/m2) basis in patients given the recommended 20 mg/day (12.3 mg/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 findings 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.
Endocrine Effects
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 b-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.
Other Effects
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.
Microbiology
Rabeprazole sodium, amoxicillin and clarithromycin triple therapy has been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections as described in the INDICATIONS AND CLINICAL USE section and in Product Monograph Part II: CLINICAL TRIALS.
Pharmacokinetics
Rabeprazole Sodium tablets are enteric-coated. 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.
: Rabeprazole is 96.3% bound to human plasma proteins.
: 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.
In vitro
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.
Special Populations and Conditions
: 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).
: See
section above
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/1.73 m2), the pharmacokinetics of rabeprazole (rabeprazole sodium 20 mg oral dose) were comparable to those in 10 healthy volunteers. Combination Therapy with Antimicrobials: Sixteen healthy volunteers were given 20 mg rabeprazole sodium, 1000 mg amoxicillin, 500 mg clarithromycin, or the combination of all 3 rabeprazole, amoxicillin, and clarithromycin (RAC) in a four-way crossover study. Each of the four treatments was administered for 7 days with single doses administered on days 1 and 7 and twice daily on days 2-6. The AUC and Cmax for clarithromycin and amoxicillin were similar during combined treatment compared to monotherapy. The rabeprazole AUC and Cmax increased by 11% and 34%, respectively, and the 14-hydroxyclarithromycin (active metabolite of clarithromycin) AUC and Cmax increased by 42% and 46%, respectively, during the combined treatment compared to values obtained during monotherapy. This increase in exposure to rabeprazole and 14- hydroxyclarithromycin is not considered to be clinically significant. In an open-label, randomized, four-period crossover study in 20 healthy Japanese volunteers, 16 extensive metabolizers (EM) and four poor metabolizers (PM) of CYP2C19 genotype were given 20 mg rabeprazole, 400 mg clarithromycin, 750 mg amoxicillin, or the combination of rabeprazole, amoxicillin and clarithromycin. Each of the treatments consisted of a single oral administration under fasting conditions on days 1 and 7, and twice daily administration on days 2 to 6. As illustrated in Table 1.6, in the EM and PM subjects, an interaction was observed for clarithromycin, 14-hydroxyclarithromycin, and rabeprazole which resulted in a higher Cmax and AUC0-12 during the combination treatment compared to monotherapy. For the amoxicillin treatment, no interaction was observed in the PM subjects, and only a very slight increase in Cmax, in EM subjects, was observed in the combination treatment when compared to monotherapy.
Table 1.6: Percent (%) Increase in Pharmacokinetic Parameters (Cmax and AUC0-12) for Extensive Metabolizers (EM) and Poor Metabolizers (PM) During Combination Therapy+ vs. Monotherapy++
| Parmacokinetic Parameter | Active Substance | ||||
| rabeprazole | clarithromycin | clarithromycin M-5 metabolite (14-hydroxyclarithromycin) | amoxicillin | ||
| % Increase C max (ug/mL) | EM * | 38% | 11% | 45% | 11% |
| PM * | 22% | 24% | 67% | No interaction | |
| % Increase AUC 0-12 (ug.h/mL) | EM | 32% | 11% | 46% | No interaction |
| PM | 35% | 24% | 73% | No interaction | |
+
Test treatment (combination therapy) consisted of clarithromycin 400 mg + amoxicillin 750 mg + rabeprazole 20 mg
++
Reference treatments (monotherapy): A: clarithromycin 400 mg; B: amoxicillin 750 mg; C: rabeprazole 20 mg
* EM = Extensive Metabolizer; PM = Poor Metabolizer.
Store at room temperature (15 to 30degC) protected from moisture.
NOVO-RABEPRAZOLE EC 10 or 20 mg is supplied as enteric-coated tablets.
: Pink, round tablets, imprinted in black ink with "N" on one side and with "10" on the other side, available in bottles of 100 and unit dose blister packages of 30.
: Yellow, round tablets, imprinted in black ink with "93" over "64" on one side, available in bottles of 100 and unit dose blister packages of 30.
Composition
Each tablet contains: Medicinal ingredient: 10 or 20 mg of rabeprazole sodium. Non-medicinal ingredients: anatase titanium dioxide, antifoam, hydroxypropyl cellulose, hypromellose 15 cP, hydroxypropyl methylcellulose, hypromellose phthalate, iron oxide red, iron oxide yellow, iron oxide black, lactose monohydrate, lecithin (soya), low- substituted hydroxypropyl cellulose, magnesium oxide, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, shellac glaze, stearic acid, titanium dioxide, triethyl citrate.