Ramep™ is 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)

• Symptomatic treatment of moderate to very severe gastro-oesophageal reflux disease (symptomatic

GORD)

• Zollinger-Ellison Syndrome

• In combination with appropriate antibacterial therapeutic regimens for the eradication of

Helicobacter pylori in patients with peptic ulcer disease. See section 4.2.

Posology

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 20 mg 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 20 mg 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 Ramep™ 20 mg or 10 mg once daily can be

used depending upon patient response.

Symptomatic treatment of moderate to very severe gastro-oesophageal reflux disease (symptomatic

GORD): 10 mg once daily in patients without oesophagitis. 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 10 mg once daily

when needed.

Zollinger-Ellison Syndrome: The recommended adult starting dose is 60 mg once a day. The dose

may be titrated upwards to 120 mg/day based on individual patient needs. Single daily doses up to

100 mg/day may be given. 120 mg dose may require divided doses, 60 mg twice daily. Treatment

should continue for as long as clinically indicated.

Eradication of H. pylori: Patients with H. pylori infection should be treated with eradication therapy.

The following combination given for 7 days is recommended.

Ramep™ 20 mg twice daily + clarithromycin 500 mg twice daily and amoxicillin

1 g twice daily.

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 Ramep™ in the

treatment of patients with severe hepatic impairment.

Paediatric population

Ramep™ is not recommended for use in children, as there is no experience of its

use in this group.

Method of administration

For indications requiring once daily treatment Ramep™ 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 Ramep™ tablets should not be chewed or

crushed, but should be swallowed whole.

4.4 Special warnings and precautions for use

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 Ramep™.

Patients on long-term treatment (particularly those treated for more than a year) should be kept under

regular surveillance.

A risk of cross-hypersensitivity reactions with other proton pump inhibitor or substituted

benzimidazoles cannot be excluded.

Patients should be cautioned that Ramep™ tablets should not be chewed or

crushed, but should be swallowed whole.

There have been post marketing reports of blood dyscrasias (thrombocytopaenia and neutropaenia). In

the majority of cases where an alternative aetiology cannot be identified, the events were

uncomplicated and resolved on discontinuation of rabeprazole.

Hepatic enzyme abnormalities have been seen in clinical trials and have also been reported since

market authorization. In the majority of cases where an alternative aetiology cannot be identified, the

events were uncomplicated and resolved on discontinuation of rabeprazole. No evidence of significant

medicinal product 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 Ramep™ in the treatment of patients with severe

hepatic dysfunction the prescriber is advised to exercise caution when treatment with Ramep™

 is first initiated in such patients.

Co-administration of atazanavir with Ramep™ is not recommended (see section

4.5).

Treatment with proton pump inhibitors, including Ramep™, may possibly

increase the risk of gastrointestinal infections such as Salmonella, Campylobacter and Clostridium

difficile (see section 5.1).

Proton pump inhibitors, especially if used in high doses and over long durations (>1 year), may

modestly increase the risk of hip, wrist and spine fracture, predominantly in the elderly or in presence

of other recognised risk factors. Observational studies suggest that proton pump inhibitors may

increase the overall risk of fracture by 10–40%. Some of this increase may be due to other risk

factors. Patients at risk of osteoporosis should receive care according to current clinical guidelines

and they should have an adequate intake of vitamin D and calcium.

Hypomagnesaemia

Severe hypomagnesaemia has been reported in patients treated with proton pump inhibitors (PPIs)

like rabeprazole sodium for at least three months, and in most cases for a year. Serious manifestations

of hypomagnesaemia such as fatigue, tetany, delirium, convulsions, dizziness and ventricular

arrhythmia can occur but may begin insidiously and be overlooked. In most affected patients,

hypomagnesaemia improved after magnesium replacement and discontinuation of the PPI.

For patients expected to be on prolonged treatment or who take PPIs with medicinal products or drugs

that may cause hypomagnesaemia (e.g. diuretics), health care professionals should consider

measuring magnesium levels before starting PPI treatment and periodically during treatment.

Concomitant use of Rabeprazole with Methotrexate

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.

Influence on vitamin B12 absorption

Rabeprazole sodium, as all acid-blocking medicines, may reduce the absorption of vitamin B12

(cyanocobalamin) due to hypo- or a- chlorhydria. This should be considered in patients with reduced

body stores or risk factors for reduced vitamin B12 absorption on long-term therapy or if respective

clinical symptoms are observed.

Subacute cutaneous lupus erythematosus (SCLE)

Proton pump inhibitors are associated with very infrequent cases of SCLE. If lesions occur, especially

in sun-exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical

help promptly and the health care professional should consider stopping Ramep™.

SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other

proton pump inhibitors.

Interference with laboratory tests

Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours.

To avoid this interference, Ramep™ treatment should be stopped for at least 5

days before CgA measurements (see section 5.1). If CgA and gastrin levels have not returned to

reference range after initial measurement, measurements should be repeated 14 days after cessation of

proton pump inhibitor treatment.

Paediatric population

 Ramep™ is not recommended for use in children, as there is no experience of its

use in this group.

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

Ramep™.

In clinical trials, antacids were used concomitantly with the administration of rabeprazole 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 not studied,

similar results are expected with other proton pump inhibitors. Therefore PPIs, including rabeprazole,

should not be co-administered with atazanavir (see section 4.4).

Methotrexate

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 medicinal product interaction studies of methotrexate with

PPIs have been conducted.

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. Ramep™

is contraindicated during pregnancy.

Breast-feeding

It is not known whether rabeprazole sodium is excreted in human breast milk. No studies in breastfeeding

women have been performed. Rabeprazole sodium is however excreted in rat mammary

secretions. Therefore Ramep™ must not be used during breast-feeding.

Based on the pharmacodynamic properties and the adverse events profile, it is unlikely that

Ramep™ 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.

The most commonly reported adverse 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.

The following adverse events have been reported from clinical trial and post-marketing experience.

Frequencies are defined as: common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare

(≥1/10,000, <1/1,000) and very rare (< 1/10,000). Not known (cannot be estimated from the available

data).

Infections and infestations

Common: infection

Blood and the lymphatic system disorders

Rare: neutropenia, leucopenia, thrombocytopenia, leucocytosis

Immune system disorders

Rare: hypersensitivity1,2

Metabolism and nutrition disorders

Rare: anorexia

Not known: hyponatraemia, hypomagnesaemia (see section 4.4).

Psychiatric disorders

Common: insomnia

Uncommon: nervousness

Rare: depression

Not known: Confusion

Nervous system disorders

Common: headache, dizziness

Uncommon: somnolence

Eye disorders

Rare: visual disturbance

Vascular disorders

Not known: peripheral oedema

Respiratory, thoracic and mediastinal disorders:

Common: cough, pharyngitis, rhinitis

Uncommon: bronchitis, sinusitis

Gastrointestinal disorders

Common: diarrhoea, vomiting, nausea, abdominal pain, constipation, flatulence, fundic gland polyps

(benign)

Uncommon: dyspepsia, dry mouth, eructation

Rare: gastritis, stomatitis, taste disturbance

Not known: microscopic colitis

Hepatobiliary disorders

Rare: hepatitis, jaundice, hepatic encephalopathy3

Skin and subcutaneous tissue disorders

Uncommon: rash, erythema2

Rare: pruritus, sweating, bullous reactions2

Very rare: erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)

Not known: Subacute cutaneous lupus erythematosus (see section 4.4)

Musculoskeletal, connective tissue and bone disorders

Common: non-specific pain, back pain

Uncommon: myalgia, leg cramps, arthralgia, fracture of the hip, wrist or spine (see section 4.4).

Renal and urinary disorders

Uncommon: urinary tract infection

Rare: interstitial nephritis

Reproductive system and breast disorders

Not known: gynaecomastia

General disorders and administration site conditions:

Common: asthenia, influenza like illness

Uncommon: chest pain, chills, pyrexia

Investigations:

Uncommon: increased hepatic enzymes3

Rare: weight increased

1 Includes facial swelling, hypotension and dyspnoea

2 Erythema, bullous reactions and hypersensitivity reactions have usually resolved after

discontinuation of therapy.

3 Rare reports of hepatic encephalopathy have been received in patients with underlying cirrhosis. In

treatment of patients with severe hepatic dysfunction the prescriber is advised to exercise caution

when treatment with [Ramep™] is first initiated in such patients (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare

professionals are asked to report any suspected adverse reactions via the national reporting system

listed in Appendix V.

To reports any side effect(s):

   Saudi Arabia:

      Other GCC States:

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

dialyzable. As in any case of overdose, treatment should be symptomatic and general supportive

measures should be utilised.

Pharmacotherapeutic group: Alimentary tract and metabolism, drugs for peptic ulcer and gastro

oesophageal reflux disease (GORD), proton pump inhibitors, 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 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. 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 medicinal product is discontinued, secretory activity

normalises over 2 to 3 days.

Decreased gastric acidity due to any means, including proton pump inhibitors such as rabeprazole,

increases counts of bacteria normally present in the gastrointestinal tract. Treatment with proton

pump inhibitors, including Ramep™, may possibly increase the risk of

gastrointestinal infections such as Salmonella, Campylobacter and Clostridium difficile.

Serum Gastrin Effects

In clinical studies patients were treated once daily with 10 or 20 mg 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 20 mg 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.

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.

During treatment with antisecretory medicinal products, serum gastrin increases in response to the

decreased acid secretion. Also CgA increases due to decreased gastric acidity. The increased CgA

level may interfere with investigations for neuroendocrine tumours.

Available published evidence suggests that proton pump inhibitors should be discontinued between 5

days and 2 weeks prior to CgA measurements. This is to allow CgA levels that might be spuriously

elevated following PPI treatment to return to reference range.

Absorption

Ramep™ 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 20 mg dose. Peak plasma concentrations

(Cmax) of rabeprazole 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. 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.

Biotransformation and elimination

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 cyclosporine. 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 20 mg 14C labelled oral dose of rabeprazole sodium, no unchanged medicinal

product 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 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 haemodialysis and 3.6 hours post dialysis. The clearance of

the medicinal product 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 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 20 mg 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 20 mg 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%.

Non-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.

Tablet core:

Calcium hydoxide

Mannitol

Low-substituted hydroxypropyl cellulose

Sodium stearyl fumarate

Coating 1

Hypromellose

Talc

Gastro-resistant coating 2(10mg)

Hypromellose phthalate

Dibutyl sebacate

Yellow ferric oxide (E172)

Red ferric oxide (E172)

Titanium dioxide (E171)

Gastro-resistant coating 2(20mg)

Hypromellose phthalate

Dibutyl sebacate

Yellow ferric oxide (E172)

Titanium dioxide (E171)

Not applicable

Do not store above 30°C. Store in the original package in order to protect from moisture.

Al/Al blister with a desiccant:

AT/H/0260/01-02

5, 7, 10, 14, 15, 20, 25, 28, 30, 37, 50, 56, 60, 75, 90, 98, 100 and 120 gastro-resistant tablets

AT/H/0261/01-02

7, 10, 14, 20, 28, 30, 56, 60 and 98 gastro-resistant tablets

AT/H/0262/01-02

7, 10, 14, 15, 20, 28, 30, 37, 56, 60, 75, 98 and 120 gastro-resistant tablets

Not all pack sizes may be marketed.

No special precautions.