Pariet

1. Name Of The Medicinal Product

PARIET® 10mg.

PARIET® 20mg.

2. Qualitative And Quantitative Composition

One tablet contains:

9.42 mg rabeprazole as 10mg rabeprazole sodium

18.85 mg rabeprazole as 20mg rabeprazole sodium

3. Pharmaceutical Form

Gastro-resistant tablets.

4. Clinical Particulars

4.1 Therapeutic 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).

• Gastro-Oesophageal Reflux Disease Long-term Management (GORD Maintenance)

• In combination with appropriate antibacterial therapeutic regimens for the eradication of Helicobacter pylori in patients with peptic ulcer disease. See section 4.2

4.2 Posology And Method Of Administration

Adults/elderly:

Active Duodenal Ulcer and Active Benign Gastric Ulcer: The recommended oral dose for both active duodenal ulcer and active benign gastric ulcer is 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-Oesophageal Reflux Disease(GORD): The recommended oral dose for this condition is 20mg to be taken once daily for four to eight weeks.

Gastro-Oesophageal Reflux Disease Long-term Management (GORD Maintenance): For long-term management, a maintenance dose of PARIET 20 mg or 10 mg once daily can be used depending upon patient response.

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 amoxycillin 1g twice daily.

For indications requiring once daily treatmentPARIET 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 section 4.4 Special Warnings and Precautions for Use of PARIET in the treatment of patients with severe hepatic impairment.

Children:

PARIET is not recommended for use in children, as there is no experience of its use in this group.

4.3 Contraindications

PARIET is contra-indicated in patients with known hypersensitivity to rabeprazole sodium, substituted benzimidazoles or to any excipient used in the formulation. PARIET is contra-indicated in pregnancy and during breast feeding.

4.4 Special Warnings And Precautions For Use

Symptomatic response to therapy with rabeprazole sodium does not preclude the presence of gastric or oesophagealmalignancy, 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 a 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, 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.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

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 the drugs studied including warfarin, phenytoin, theophylline or diazepam metabolised by the CYP450 system.

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. Rabeprazole does not adversely influence plasma concentrations of amoxycillin or clarithromycin when co-administered for the purpose of eradicating upper gastro-intestinal H. pylori infection.

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 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.

4.6 Pregnancy And Lactation

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 foetus due to rabeprazole sodium, although low foeto-placental transfer occurs in rats. PARIET is contraindicated during pregnancy.

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.

4.7 Effects On Ability To Drive And Use Machines

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.

4.8 Undesirable Effects

PARIET tablets were generally well tolerated during clinical trials. The observed undesirable effects have generally been mild/moderate and transient in nature.

In clinical trials the most common adverse events (incidence . Further less frequent adverse events (incidence

In isolated cases, anorexia, gastritis, weight gain, depression, pruritus, vision or taste disturbances, stomatitis, sweating, leucocytosis have been observed.

However, only headaches, diarrhoea, abdominal pain, asthenia, flatulence, rash, and dry mouth have been associated with the use of PARIET tablets.

Post-marketing experience:

Erythema and rarely bullous reactions have been reported in patients treated with Pariet which have usually resolved after discontinuation of therapy.

Thrombocytopenia, neutropenia and leucopenia have been reported rarely.

There have been reports of increased hepatic enzymes

4.9 Overdose

There is no experience to date with deliberate overdose. Dosages of up to 80mg/day have been well tolerated. No specific antidote is known. Rabeprazole sodium is extensively protein bound and is, therefore, not readily dialysable. As in any case of overdose, treatment should be symptomatic and general supportive measures should be utilised.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC code: A02B C04

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 36months 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, oestrogen, testosterone, prolactin, cholecystokinin, secretin, glucagon, follicle stimulating hormone (FSH), luteinising hormone (LH), renin, aldosterone or somatotrophic hormone.

5.2 Pharmacokinetic Properties

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 (C_max) 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. 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: 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 faeces.

Gender: Adjusted for body mass and height, there are no significant gender differences in pharmacokinetic parameters following a single 20 mg dose of rabeprazole.

Renal dysfunction:In patients with stable, end-stage, renal failure requiring maintenance haemodialysis (creatinine clearance ²), the disposition of rabeprazole was very similar to that in healthy volunteers. The AUC and the C_max 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 haemodialysis and 3.6 hours post dialysis. The clearance of the drug in patients with renal disease requiring maintenance haemodialysis was approximately twice that in healthy volunteers.

Hepatic dysfunction: Following a single 20 mg 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 20 mg dose daily for 7 days the AUC had increased to only 1.5-fold and the C_max 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 C_max 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 metabolisers, had AUC and t½ which were approximately 1.9 and 1.6 times the corresponding parameters in extensive metabolisers whilst Cmax had increased by only 40%.

5.3 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 humans.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Mannitol, magnesium oxide, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, magnesium stearate, ethylcellulose, hypromellose phthalate, diacetylated monoglycerides, talc, titanium dioxide (E171), yellow iron oxide (E172) (20mg only), red iron oxide (E172) (10mg only),

carnauba wax and ink ((shellac food grade (E904), red iron oxide (E172), soya lecithin (E322), antifoam DC1510 - 20mg tablets); and (pharmaceutical glaze black iron oxide (E172), propylene glycol, medicinal antifoam A - 10mg tablets)).

6.2 Incompatibilities

None.

6.3 Shelf Life

Shelf-life before opening the aluminium pouch - 24 months.

After first opening the aluminium pouch - 3 months

6.4 Special Precautions For Storage

Do not store above 25°C. Do not refrigerate

After opening, store in the original package aluminium pouch

Do not store above 25°C. Do not refrigerate.

6.5 Nature And Contents Of Container

Primary packaging:

• Unit dose blister strips (PVC/PVdC/PE-5ply 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.

Tertiary packaging:

• Cardboard carton containing aluminium pouch(es) and leaflet.

Pack sizes: 7, 14, 15, 28, 30, 56, 75, 120 tablets

Alternative packaging Format 20 mg tablets only:

Primary packaging:

• Unit dose blister strips (aluminium/aluminium) of 7 or 14 or 15 tablets

• Secondary packaging:

Cardboard carton containing multiples of 7 or 14 or 15 tablet unit dose blister strips and leaflet.

Pack sizes: 7, 14, 15, 28, 30, 56, 75, 120 tablets

6.6 Special Precautions For Disposal And Other Handling

No specified instruction needed.

7. Marketing Authorisation Holder

Eisai Ltd., Hammersmith International Centre,

3 Shortlands, London W6 8EE, United Kingdom.

8. Marketing Authorisation Number(S)

PL 10555/0010 (10mg tablets)

PL 10555/0008 (20mg tablets)

9. Date Of First Authorisation/Renewal Of The Authorisation

8 May 1998.

10. Date Of Revision Of The Text

29 September 2000