10 mg rabeprazole sodium, equivalent to 9.42 mg rabeprazole.
20 mg rabeprazole sodium, equivalent to 18.85 mg rabeprazole.
Excipients/Inactive Ingredients: D-Mannitol, hydroxypropylcellulose, low substituted hydroxypropylcellulose, carmellose calcium (10 mg only), magnesium stearate, ethylcellulose, magnesium oxide, hypromellose phthalate, glycerol esters of fatty acids, talc, titanium oxide, yellow ferric oxide, carnauba wax.
ATC Code: A02B C04.
Pharmacology: Pharmacodynamics: Mechanism of Action: Rabeprazole sodium belongs to the class of anti-secretory compounds, the substituted benzimidazoles, that do not exhibit anticholinergic or H2 histamine antagonist properties, but suppress gastric acid secretion by the specific inhibition of the H+/K+-ATPase enzyme (the acid or proton pump). The effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus. Animal studies indicate that after administration, rabeprazole sodium rapidly disappears from both the plasma and gastric mucosa. As a weak base, rabeprazole is rapidly absorbed following all doses and is concentrated in the acid environment of the parietal cells. Rabeprazole is converted to the active sulphenamide form through protonation and it subsequently reacts with the available cysteines on the proton pump.
Anti-secretory Activity: After oral administration of a 20mg dose of rabeprazole sodium the onset of the anti-secretory effect occurs within one hour, with the maximum effect occurring within two to four hours. Inhibition of basal and food stimulated acid secretion 23 hours after the first dose of rabeprazole sodium are 69% and 82% respectively and the duration of inhibition lasts up to 48 hours. The inhibitory effect of rabeprazole sodium on acid secretion increases slightly with repeated once-daily dosing, achieving steady state inhibition after three days. When the drug is discontinued, secretory activity normalises over 2 to 3 days.
Serum Gastrin Effects: In clinical studies patients were treated once daily with 10 or 20mg rabeprazole sodium, for up to 43 months duration. Serum gastrin levels increased during the first 2 to 8 weeks reflecting the inhibitory effects on acid secretion and remained stable while treatment was continued. Gastrin values returned to pre-treatment levels, usually within 1 to 2 weeks after discontinuation of therapy.
Human gastric biopsy specimens from the antrum and the fundus from over 500 patients receiving rabeprazole or comparator treatment for up to 8 weeks have not detected changes in ECL cell histology, degree of gastritis, incidence of atrophic gastritis, intestinal metaplasia or distribution of H. pylori infection. In over 250 patients followed for 36 months of continuous therapy, no significant change in findings present at baseline was observed.
Other Effects: Systemic effects of rabeprazole sodium in the CNS, cardiovascular and respiratory systems have not been found to date. Rabeprazole sodium, given in oral doses of 20mg for 2 weeks, had no effect on thyroid function, carbohydrate metabolism, or circulating levels of parathyroid hormone, cortisol, estrogen, testosterone, prolactin, cholecystokinin, secretin, glucagon, follicle stimulating hormone (FSH), luteinizing hormone (LH), renin, aldosterone or somatotrophic hormone.
Studies in healthy subjects have shown that rabeprazole sodium does not have clinically significant interactions with amoxicillin. Rabeprazole does not adversely influence plasma concentrations of amoxicillin or clarithromycin when co-administered for the purpose of eradicating upper gastrointestinal H. pylori infection.
Pharmacokinetics: Absorption: PARIET is an enteric-coated (gastro-resistant) tablet formulation of rabeprazole sodium. This presentation is necessary because rabeprazole is acid-labile. Absorption of rabeprazole therefore begins only after the tablet leaves the stomach. Absorption is rapid, with peak plasma levels of rabeprazole occurring approximately 3.5 hours after a 20mg dose. Peak plasma concentrations (Cmax) of rabeprazole and AUC are linear over the dose range of 10mg to 40mg. Absolute bioavailability of an oral 20mg dose (compared to intravenous administration) is about 52% due in large part to pre-systemic metabolism. Additionally the bioavailability does not appear to increase with repeat administration. In healthy subjects the plasma half-life is approximately one hour (range 0.7 to 1.5 hours), and the total body clearance is estimated to be 283 ± 98 ml/min. There was no clinically relevant interaction with food. Neither food nor the time of day of administration of the treatment affect the absorption of rabeprazole sodium.
Distribution: Rabeprazole is approximately 97% bound to human plasma proteins.
Metabolism and excretion: Rabeprazole sodium, as is the case with other members of the proton pump inhibitor (PPI) class of compounds, is metabolised through the cytochrome P450 (CYP450) hepatic drug metabolising system. In vitro studies with human liver microsomes indicated that rabeprazole sodium is metabolised by isoenzymes of CYP450 (CYP2C19 and CYP3A4). In these studies, at expected human plasma concentrations rabeprazole neither induces nor inhibits CYP3A4; and although in vitro studies may not always be predictive of in vivo status these findings indicate that no interaction is expected between rabeprazole and cyclosporin. In humans the thioether (M1) and carboxylic acid (M6) are the main plasma metabolites with the sulphone (M2), desmethyl-thioether (M4) and mercapturic acid conjugate (M5) minor metabolites observed at lower levels. Only the desmethyl metabolite (M3) has a small amount of anti-secretory activity, but it is not present in plasma.
Following a single 20mg 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 the two metabolites: a mercapturic acid conjugate (M5) and a carboxylic acid (M6), plus two unknown metabolites. The remainder of the dose was recovered in feces.
Gender: Adjusted for body mass and height, there are no significant gender differences in pharmacokinetic parameters following a single 20mg dose of rabeprazole.
Renal dysfunction: In patients with stable, end-stage, renal failure requiring maintenance hemodialysis (creatinine clearance ≤ 5ml/min/1.73m2), the disposition of rabeprazole was very similar to that in healthy volunteers. The AUC and the Cmax in these patients was about 35% lower than the corresponding parameters in healthy volunteers. The mean half-life of rabeprazole was 0.82 hours in healthy volunteers, 0.95 hours in patients during hemodialysis and 3.6 hours post dialysis. The clearance of the drug in patients with renal disease requiring maintenance hemodialysis was approximately twice that in healthy volunteers.
Hepatic dysfunction: Following a single 20mg dose of rabeprazole to patients with chronic mild to moderate hepatic impairment the AUC doubled and there was a 2-3 fold increase in half-life of rabeprazole compared to the healthy volunteers. However, following a 20mg dose daily for 7 days the AUC had increased to only 1.5-fold and the Cmax to only 1.2-fold. The half-life of rabeprazole in patients with hepatic impairment was 12.3 hours compared to 2.1 hours in healthy volunteers. The pharmacodynamic response (gastric pH control) in the two groups was clinically comparable.
Elderly: Elimination of rabeprazole was somewhat decreased in the elderly. Following 7 days of daily dosing with 20mg of rabeprazole sodium, the AUC approximately doubled, the Cmax increased by 60% and t½ increased by approximately 30% as compared to young healthy volunteers. However there was no evidence of rabeprazole accumulation.
CYP2C19 Polymorphism: Following a 20mg daily dose of rabeprazole for 7 days, CYP2C19 slow metabolizers, had AUC and t½ which were approximately 1.9 and 1.6 times the corresponding parameters in extensive metabolizers whilst Cmax had increased by only 40%.
Toxicology: Preclinical Safety Data: Pre-clinical effects were observed only at exposures sufficiently in excess of the maximum human exposure that make concerns for human safety negligible in respect of animal data.
Studies on mutagenicity gave equivocal results. Tests in mouse lymphoma cell line were positive, but in vivo micronucleus and in vivo and in vitro DNA repair tests were negative. Carcinogenicity studies revealed no special hazard for human.
PARIET tablets are indicated for the treatment of: Active duodenal ulcer; active benign gastric ulcer; anastomotic ulcer; erosive or ulcerative gastro-esophageal reflux disease (GERD); gastro-esophageal reflux disease long-term management (GERD maintenance); symptomatic treatment of moderate to very severe gastro-esophageal reflux disease (symptomatic GERD); Zollinger-Ellison syndrome and other pathological hypersecretory conditions; in combination with appropriate antibacterial therapeutic regimens for the eradication of Helicobacter pylori in patients with peptic ulcer disease. (See Dosage & Administration.) Prevention of gastric and duodenal ulcer recurrence associated with low-dose aspirin therapy.
Adults/elderly: Active Duodenal Ulcer, Active Benign Gastric Ulcer and Anastomotic Ulcer: The recommended oral dose is 10mg or 20mg to be taken once daily in the morning.
Most patients with active duodenal ulcer heal within four weeks. However a few patients may require an additional four weeks of therapy to achieve healing. Most patients with active benign gastric ulcer heal within six weeks. However again a few patients may require an additional six weeks of therapy to achieve healing.
Erosive or Ulcerative Gastro-Esophageal Reflux Disease (GERD): The recommended oral dose for this condition is 10mg or 20mg to be taken once daily for four to eight weeks.
Doses of 10 mg or 20 mg twice daily may be administered orally to reflux esophagitis patients for a further 8 weeks when proton pump inhibitor treatment is ineffective. However, a dose of 20 mg twice daily should only be administered to patients with severe mucosa injury.
Gastro-Esophageal Reflux Disease Long-term Management (GERD Maintenance): For long- term management (from data up to 5 years), a maintenance dose of PARIET 10mg or 20mg once daily ca n be used depending upon patient response.
Symptomatic Treatment of Moderate to Very Severe Gastro-Esophageal Reflux Disease (symptomatic GERD): 10mg once daily in patients without esophagitis. If symptom control has not been achieved during four weeks, the patient should be further investigated. Once symptoms have resolved, subsequent symptom control can be achieved using an on-demand regimen taking 10mg once daily when needed.
Zollinger-Ellison Syndrome and other pathological hypersecretory conditions: The dose necessary varies with the individual patient. A starting dose of 60mg daily, and doses of up to 100mg once daily, or 60mg twice daily have been used. Some patients may require divided doses. Dosing should continue for as long as clinically necessary. Some patients with Zollinger-Ellison syndrome have been treated continuously for up to one year.
Eradication of H. pylori: Patients with H. pylori infection should be treated with eradication therapy. The following combination given for 7 days is recommended.
PARIET 20mg twice daily + clarithromycin 500mg twice daily and amoxicillin 1g twice daily.
Prevention of Gastric and Duodenal Ulcer Recurrence Associated with Low-dose Aspirin Therapy: The usual dosage for adults is PARIET 10 mg administered orally once a day. The duration of treatment can be adjusted according to clinical need.
For indications requiring once daily treatment PARIET tablets should be taken in the morning, before eating; and although neither the time of day nor food intake was shown to have any effect on rabeprazole sodium activity, this regimen will facilitate treatment compliance.
Patients should be cautioned that the PARIET tablets should not be chewed or crushed, but should be swallowed whole.
Renal and hepatic impairment: No dosage adjustment is necessary for patients with renal or hepatic impairment.
See Precautions in the treatment of patients with severe hepatic impairment.
Children: Safety and effectiveness of rabeprazole sodium 20 mg for the short-term (up to 8 weeks) treatment of GERD in adolescents 12 years of age and above is supported by a) extrapolation of results from adequate and well-controlled studies that supported the effectiveness of rabeprazole sodium for adults; b) safety and pharmacokinetic studies performed in adolescent patients. The recommended oral dose for adolescents 12 years of age and above is 20 mg once daily for up to 8 weeks.
The safety and effectiveness of rabeprazole sodium for the treatment of GERD in children <12 years of age have not been established. The safety and effectiveness of rabeprazole sodium for other uses have not been established in pediatric patients.
Experience to date with deliberate or accidental overdose is limited. 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 further medical intervention. No specific antidote is known. Rabeprazole sodium is extensively protein bound and is, therefore, not dialysable. As in any case of overdose, treatment should be symptomatic and general supportive measures should be utilised.
PARIET is contra-indicated in patients with known hypersensitivity to rabeprazole sodium, substituted benzimidazoles or to any excipient used in the formulation.
Symptomatic response to therapy with rabeprazole sodium does not preclude the presence of gastric or esophageal malignancy, therefore the possibility of malignancy should be excluded prior to commencing treatment with PARIET.
Patients on long-term treatment (particularly those treated for more than 1 year) should be kept under regular surveillance.
Patients should be cautioned that PARIET tablets should not be chewed or crushed, but should be swallowed whole.
PARIET is not recommended for use in children <12 years of age, as there is no experience of its use in this group.
No evidence of significant drug-related safety problems was seen in a study of patients with mild to moderate hepatic impairment versus normal age and sex-matched controls. However, because there are no clinical data on the use of PARIET in the treatment of patients with severe hepatic dysfunction, the prescriber is advised to exercise caution when treatment with PARIET is first initiated in such patients.
Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.
For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically.
Observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, and long-term PPI therapy (a year or longer).
Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients.
Treatment with proton pump inhibitors may possibly increase the risk of gastrointestinal infections such as Clostridium difficile.
Effects on the Ability to Drive or Operate Machinery: Based on the pharmacodynamic properties and the adverse events profile, it is unlikely that PARIET would cause an impairment of driving performance or compromise the ability to use machinery. If however, alertness is impaired due to somnolence, it is recommended that driving and operating complex machinery be avoided.
Use in Pregnancy: There are no data on the safety of rabeprazole in human pregnancy.
Reproduction studies performed in rats and rabbits have revealed no evidence of impaired fertility or harm to the fetus due to rabeprazole sodium, although low feto-placental transfer occurs in rats.
Use in Lactation: It is not known whether rabeprazole sodium is excreted in human breast milk. No studies in lactating women have been performed. Rabeprazole sodium is however excreted in rat mammary secretions. Therefore PARIET should not be used during breast feeding.
PARIET tablets were generally well tolerated during clinical trials of adult and adolescents. The most commonly reported adverse drug reactions, during controlled clinical trials with rabeprazole were headache, diarrhoea, abdominal pain, asthenia, flatulence, rash and dry mouth. The majority of adverse events experienced during clinical studies were mild or moderate in severity, and transient in nature and consistent between adults and adolescents.
The following adverse events have been reported from clinical trial and post-marketed experience (see table).
Frequencies are defined as: Common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1000) and very rare (<1/10,000).
Click on icon to see table/diagram/image
There have been post-marketing reports of bone fractures (see Precautions).
Rabeprazole sodium produces a profound and long lasting inhibition of gastric acid secretion. An interaction with compounds whose absorption is pH dependent may occur. Co-administration of rabeprazole sodium with ketoconazole or itraconazole may result in a significant decrease in antifungal plasma levels. Therefore individual patients may need to be monitored to determine if a dosage adjustment is necessary when ketoconazole or itraconazole are taken concomitantly with PARIET.
In clinical trials, antacids were used concomitantly with the administration of PARIET and, in a specific drug-drug interaction study, no interaction with liquid antacids was observed.
Co-administration of atazanavir 300 mg/ritonavir 100 mg with omeprazole (40 mg once daily) or atazanavir 400 mg with lansoprazole (60 mg once daily) to healthy volunteers resulted in a substantial reduction in atazanavir exposure. The absorption of atazanavir is pH dependent. Although co-administration with rabeprazole was not studied, similar results are expected with other proton pump inhibitors. Therefore PPIs, including rabeprazole, should not be coadminis-tered with atazanavir.
Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been conducted.
Instructions for Use/Handling: No special requirements.
Incompatibilities: Not applicable.
PARIET should be stored at room temperature not exceeding 25°C and be protected from moisture after unsealing.
Shelf-Life: Shelf life before opening the aluminum pouch: 36 months.
A02BC04 - rabeprazole ; Belongs to the class of proton pump inhibitors. Used in the treatment of peptic ulcer and gastro-oesophageal reflux disease (GERD).
EC tab 10 mg (gastro-resistant, yellow, film-coated, biconvex, with 'E 240' printed in black on one side) x 1 x 14's. 20 mg (gastro-resistant, yellow, film-coated, biconvex with 'E 243' printed in red on one side) x 1 x 14's, 20 x 14's.