4.1. Therapeutic indications

Rabeprazole sodium 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)

- 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.

4.2. Posology and method of administration

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 longterm management, a maintenance dose of Rabeprazole sodium 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.

Rabeprazole sodium 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 Rabeprazole sodium in the treatment of patients with severe hepatic impairment.

Paediatric population

Rabeprazole sodium 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 Rabeprazole sodium 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 Rabeprazole sodium tablets should not be chewed or crushed, but should be swallowed whole.

4.3. Contraindications

Hypersensitivity to the active substance, substituted benzimidazoles or to any of the excipients listed in section 6.1

Pregnancy and lactation.

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 Rabeprazole sodium.

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 substituted benzimidazoles cannot be excluded.

Patients should be cautioned that Rabeprazole sodium tablets should not be chewed or crushed, but should be swallowed whole.

Paediatric population

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

There have been post marketing reports of blood dyscrasias (thrombocytopenia and neutropenia). 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 authorisation. 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 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 rabeprazole in the treatment of patients with severe hepatic dysfunction the prescriber is advised to exercise caution when treatment with Rabeprazole sodium is first initiated in such patients.

Co-administration of atazanavir with Rabeprazole sodium is not recommended (see section 4.5).

Treatment with proton pump inhibitors, including Rabeprazole sodium, may possibly increase the risk of gastrointestinal infections such as Salmonella, Campylobacter and Clostridium difficile (see section 5.1).

Severe hypomagnesaemia has been reported in patients treated with PPIs like rabeprazole 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 they 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 digoxin 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.

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.

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 Rabeprazole sodium. 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, Rabeprazole sodium 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.

4.5. Interaction with other medicinal products and other forms of interaction

Rabeprazole sodium produces a profound and long lasting inhibition of gastric acid secretion. An interaction with compounds whose absorption is pH dependent may occur. Coadministration 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 Rabeprazole sodium.

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 drug interaction studies of methotrexate with PPIs have been conducted.

4.6. Fertility, 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. Rabeprazole sodium is contraindicated during pregnancy.

Breast-feeding

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 Rabeprazole sodium 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 Rabeprazole sodium 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

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.

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

Frequencies are defined as:

- Common (≥ 1/100 to < 1/10)

- Uncommon (≥ 1/1,000 to < 1/100)

- Rare (≥ 1/10,000 to < 1/1,000)

- Very rare (< 1/10,000)

- Not known (cannot be estimated from the available data)

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System Organ Class

Common

Uncommon

Rare

Very rare

Not known

Infections and infestations

infection

Blood and lymphatic system disorders

neutropenia, leucopenia, thrombocytopenia, leucocytosis

Immune system disorders

hypersensitivity1,2

Metabolism and nutrition disorders

anorexia

hyponatremia, hypomagnesaemia (see section 4.4)

Psychiatric disorders

insomnia

nervousness

depression

confusion

Nervous system disorders

headache, dizziness

somnolence

Eye disorders

visual disturbance

Vascular disorders

peripheral oedema

Respiratory, thoracic and mediastinal disorders

cough, pharyngitis, rhinitis

bronchitis, sinusitis

Gastrointestinal disorders

diarrhoea, vomiting, nausea, abdominal pain, constipation, flatulence, fundic gland polyps (benign)

dyspepsia, dry mouth, eructation

gastritis, stomatitis, taste disturbance

microscopic colitis

Hepato-biliary disorders

hepatitis, jaundice, hepatic encephalopathy3

Skin and subcutaneous tissue disorders

rash, erythema2

pruritus, sweating, bullous reactions2

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

Subacute cutaneous lupus erythematosus (see section 4.4)

Musculoskeletal, connective tissue and bone disorders

non-specific pain, back pain

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

Renal and urinary disorders

urinary tract infection

interstitial nephritis

Reproductive system and breast disorders

gynaecomastia

General disorders and administration site conditions

asthenia, influenza like illness

chest pain, chills, pyrexia

Investigations

increased hepatic enzymes3

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 Rabeprazole sodium 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:Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.

4.9. Overdose

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.