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Logo PARIET* 10 mg tablets
PARIET* 20 mg tablets

© J-C 2000        20962A ZA/af/en

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

PARIET* 10 mg tablets
PARIET* 20 mg tablets

COMPOSITION
10 mg: Each enteric-coated delayed release tablet contains 10 mg of rabeprazole sodium, equivalent to 9,42 mg rabeprazole (racemate).
20 mg: Each enteric-coated delayed release tablet contains 20 mg of rabeprazole sodium, equivalent to 18,85 mg rabeprazole (racemate).

PHARMACOLOGICAL CLASSIFICATION
A 11.4.3 Medicines acting on gastro-intestinal tract.

PHARMACOLOGICAL ACTION
Pharmacodynamics:
Mechanism of Action: Rabeprazole sodium belongs to the class of antisecretory compounds, the substituted benzimidazoles, that do not exhibit anticholinergic or H
2 histamine antagonist properties, but suppress gastric acid secretion by the specific inhibition of the H+/K+- ATPase enzyme at the secretory surface of the gastric parietal cell. This enzyme system is regarded as the acid (proton) pump, and therefore rabeprazole sodium is classified as a gastric proton-pump inhibitor blocking the final step of acid production. This 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.
Anti-secretory Activity: After oral administration of a 20 mg 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. This duration of pharmacodyaction is much longer than the pharmacokinetic half life (approximately one hour) would predict. This effect is probably due to the prolonged binding to the parietal H+/K+- ATPase enzyme. 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 20 mg rabeprazole sodium, for up to 24 months duration. Serum gastrin levels increased during the first 2 to 8 weeks reflecting the inhibitory effects on acid secretion. Gastrin values returned to pre-treatment levels, usually within 1 to 2 weeks after discontinuation of therapy.
Pharmacokinetics:
Rabeprazole sodium is acid-labile, and is therefore administered orally as an enteric-coated (gastro-resistant) tablet formulation. Absorption of rabeprazole sodium therefore begins only after the tablet leaves the stomach. Absorption is rapid, with peak plasma levels of rabeprazole sodium occurring approximately 3.5 hours after a 20 mg dose. Peak plasma concentrations (Cmax) of rabeprazole sodium and AUC are linear over the dose range of 10 mg to 40 mg. Absolute bioavailability of an oral 20 mg 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. In patients with chronic hepatic disease, the AUC doubled compared to healthy volunteers, reflecting a decreased first-pass effect, and the plasma half-life increased 2-3 fold.
Rabeprazole sodium is approximately 97% bound to human plasma proteins.
The main plasma metabolites are thioether (M1) and carboxylic acid (M6). Minor metabolites observed at lower levies include sulphone (M2), desmethyl-thioether (M4) and mercapturic acid conjugate (M5). Only the desmethyl metabolite (M3) has a small amount of antisecretory activity, but it is not present in plasma.
Excretion is mainly urinary (90%), with no unchanged drug excreted in the urine. The rest of the metabolites are excreted via the faeces. Total recovery was 99,8% implying a low biliary excretion of the metabolites of rabeprazole sodium.
In patients with stable, end-stage, renal failure requiring maintenance haemodialysis (creatinine clearance <5 mL/min/1.73 m²), the disposition of rabeprazole sodium was very similar to that in healthy volunteers. Elimination of rabeprazole sodium was somewhat decreased in the elderly. Following 7 days of daily dosing with 20 mg of rabeprazole sodium, the AUC approximately doubled, the Cmax increased by 60% as compared to young healthy volunteers. However there was no evidence of rabeprazole sodium accumulation.

INDICATIONS
PARIET tablets are indicated for the treatment of:
- Active duodenal ulcer
- Active benign gastric ulcer
- Symptomatic erosive or ulcerative gastro-oesophageal reflux disease (GORD).
- H. Pylori-positive duodenal ulcers, as part of the eradication programme with appropriate antibiotics.
- Maintenance treatment of healed erosive or ulcerative GORD. Efficacy has not been demonstrated for periods exceeding 12 months.

CONTRA-INDICATIONS
PARIET is contra-indicated in:
- patients with known hypersensitivity to rabeprazole sodium, substituted benzimidazoles or to any excipient used in the formulation.
- Pregnancy and lactation.

DOSAGE AND DIRECTIONS FOR USE .
Adults/elderly:
Active Duodenal Ulcer and Active Benign Gastric Ulcer: 20 mg to be taken once daily in the morning.
Most patients with active duodenal ulcer heal within four weeks. However 2% of patients may require an additional four weeks of therapy to achieve healing.
Some patients with active duodenal ulcer may respond to one 10 mg tablet to be taken once daily in the morning.
Most patients with active benign gastric ulcer heal within six weeks. However 9% of patients, may require an additional six weeks of therapy to achieve healing.
Erosive or Ulcerative Gastro-Oesophageal Reflux Disease (GORD): 20 mg to be taken once daily for four to eight weeks.
Gastro-Oesophageal Reflux Long-term Management (GORD Maintenance): For longterm management up to 12 months, a maintenance dose of PARIET 10 mg or 20 mg once daily can be used. Some patients may respond to a maintenance dose of 10 mg/day.
Eradication of H. Pylori:
PARIET is indicated for H. Pylori-positive duodenal ulcers, as part of the eradication programme with appropriate antibiotics.
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.
PARIET tablets should be used within 3 months of first opening the aluminium pouch container
Renal and hepatic impairment:
No dosage adjustment is necessary for patients with renal or hepatic impairment.
Caution is however advised when PARIET is first initiated in patients with severe hepatic dysfunction, refer "Side-Effects and Special Precautions".
Children:
PARIET is not recommended for use in children, as there is no experience of its use in this group.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
The most common adverse events were headache, diarrhoea and nausea. Other adverse events were rhinitis, abdominal pain, asthenia, flatulence, pharyngitis, vomiting, non-specific pain/back pain, dizziness, flu syndrome, infection, cough, constipation and insomnia. Further less frequent adverse events were rash, myalgia, chest pain, dry mouth, dyspepsia, nervousness, somnolence, bronchitis, sinusitis, chills, eruction, leg cramps, urinary tract infection, arthralgia and fever.
In isolated cases, anorexia, gastritis, weight gain, depression, pruritus, vision or taste disturbances, stomati, sweating and leucocytosis have been observed.
Increased hepatic enzymes have been observed in 2% of patients.
There have been reports of thrombocytopenia, neutropenia and leukopenia.
Bullous eruptions have been reported and other dermatological reactions including erythema have been reported. Treatment should be stopped immediately at the recurrence of skin lesions.
Precautions:
Symptomatic response to therapy with rabeprazole sodium does not preclude the presence of gastric or oesophageal malignancy, therefore the possibility of malignancy should be excluded prior to commencing treatment with PARIET.
Although 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, the prescriber is advised to exercise caution when treatment with PARIET is first initiated in patients with severe hepatic dysfunction.
Interactions:
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. Studies in healthy subjects have shown that rabeprazole sodium does not have clinically significant interactions with other drugs metabolised by the CYP450 system, such as warfarin, phenytoin, theophylline or diazepam.
Rabeprazole sodium produces a profound and long lasting inhibition of gastric acid secretion. An interaction with compounds whose absorption is pH dependent may occur therefore the potential for such interaction was investigated. Co-administration of rabeprazole sodium results in a 33% decrease in ketoconazole levels and a 22% increase in trough digoxin levels in normal subjects. Therefore individual patients may need to be monitored to determine if a dosage adjustment is necessary when such drugs are taken concomitantly with PARIET In clinical trials, antacids were used concomitantly with the administration of PARIET and, in a specific study designed to define this interaction, no interaction with liquid antacids was observed. There was no clinically relevant interaction with food.
In vitro studies with human liver microsomes indicated that rapebrazole sodium is metabolised by isoenzymes of CYP450 (CYP2C19 and CYP3A4). The studies suggest a low interaction potential; however the effect on cyclosporin metabolism is similar to that observed for other proton pump inhibitors.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
No specific antidote is known. Rabeprazole sodium is extensively protein bound and is, therefore, not readily dialysable. Treatment should be supportive and symptomatic.

IDENTIFICATION
10 mg: Pink, film-coated biconvex tablets
20 mg: Light yellow, film-coated biconvex tablets

PRESENTATION
Primary packaging:
Unit dose blister strips (PVC/PVdC/PE laminate/aluminium foil strip) of 7 or 14 or 15 tablets.
Secondary packaging:
Aluminium pouch containing multiples of 7 or 14 or 15 tablet unit dose blister strips and a silica gel desiccant pouch.
Alternative packaging format:
Primary packaging:
Unit dose blister strips (aluminium/aluminium) of 7 or 14 or 15 tablets

STORAGE DIRECTIONS
10 mg: Store the blister strips in the original aluminium pouch container below 25°C.
20 mg: Store below 25°C.
Protect from moisture. Do not store in the refrigerator.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBERS
10 mg: 33/11.4.3/0206
20 mg: 32/11.4.3/0614

NAME AND BUSINESS ADDRESS OF THE APPLICANT
JANSSEN PHARMACEUTICA (PTY) LTD
(Reg. No. 1980/011122/07)
15th Road
Halfway House
1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT
21 July 2000

JANSSEN-CILAG
* TM Eisai Co., Ltd., Tokyo, Japan

Updated on this site: January 2001
Current: June 2003
Source: Community Pharmacy

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