RAZOLE Gastro-resistant tablet Ref.[49819] Active ingredients: Rabeprazole

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 Razole.

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 (PPI) or substituted benzimidazoles cannot be excluded.

Patients should be cautioned that Razole should not be chewed or crushed, but should be swallowed whole.

Paediatric population

Rabeprazole sodium gastro-resistant tablets 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 sodium in the treatment of patients with severe hepatic dysfunction the prescriber is advised to exercise caution when treatment with Razole is first initiated in such patients.

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

Treatment with PPIs, including Razole, may possibly increase the risk of gastrointestinal infections such as Salmonella, Campylobacter and Clostridium difficile (see section 5.1).

PPIs, 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 PPIs 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 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 medicines 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 hypoor 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)

PPIs 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 Razole. 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 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 PPI treatment.

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'

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 Razole.

In clinical trials, antacids were used concomitantly with the administration of rabeprazole sodium 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 PPIs. 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.

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.Razole is contraindicated during pregnancy (see section 4.3).

Breast-feeding

It is not known whether rabeprazole sodium is excreted in human breast milk. No studies in breast-feeding women have been performed. Rabeprazole sodium is however excreted in rat mammary secretions. Therefore Razole should not be used during breast-feeding (see section 4.3).

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

Summary of the safety profile

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.

Tabulated list of adverse reactions

The following adverse reactions have been reported from clinical trial and post-marketing experience. Frequencies are defined as: very common (≥1/10), 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).

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 he prescriber is advised to exercise caution when treatment with Razole is first initiated in such patients (see section 4.4).
⁴ See Special warnings and precautions for use (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 HPRA Pharmacovigilance: Website: www.hpra.ie.

Not applicable.