RABEPAGI®10

Composition: Each tablet contains:
Rabeprazole sodium . . . . . . . . . . . . . . . .10 mg
Presentation:
Box of 3 blisters x 10 enteric film-coated tablets.
Indications:
Active duodenal ulcer.
Active benign gastric ulcer.
Symptomatic erosive or ulcerative gastro-oesophageal reflux disease (GORD).
Zollinger-Ellison syndrome.
Benign gastric and duodenal ulcers: Combination with appropriate antibiotic therapy for Helicobacter pylori (H. pylori) eradication.

Additional information

Dosage and administration

Adults/ elderly:
Active duodenal ulcer: 20mg once daily, for 4 weeks. If the ulcer is not fully healed, an additional four weeks may be administered.
Active benign gastric ulcer: 20mg once daily, for 6 weeks. A further 6 weeks of treatment may be needed in patients whose ulcers have not fully healed.
Symptomatic erosive or ulcerative gastro-oesophageal reflux disease (GORD): 20mg once daily, for 4 – 8 weeks.
Gastro-oesophageal reflux disease long-term management (GORD Maintenance): For long-term management, a maintenance dose of rabeprazole sodium 10mg or 20mg once daily can be used depending upon patient response.
Symptomatic treatment of gastro-oesophageal reflux disease without esophagitis: The recommended dose is 10mg once daily for 4 weeks, then 10mg once daily when needed. If symptom control has not been achieved during four weeks, the patient should be further investigated.
Zollinger-Ellison syndrome: The recommended starting dose is 60mg once daily. The dose may be titrated upwards to 100mg once daily or 60mg twice daily based on individual patient needs. Treatment should continue for as long as clinically indicated.
Benign gastric and duodenal ulcers associated with Helicobacter pylori (H. pylori) infection:
The combination of the following drugs is recommended for 7 days, taken in the morning and evening: Rabeprazole 20mg twice daily, clarithromycin 500mg twice daily, and amoxicillin 1g twice daily.
Patients with liver failure, renal impairment: No dose adjustment is required.
Administration:
Rabepagi tablet is taken in the morning before a meal. It should be swallowed whole, not be chewed or crushed.

Contraindications

Hypersensitivity to rabeprazole, benzimidazole derivatives or any excipient of the drug.
Rabeprazole sodium is not recommended for use in children because safety and effectiveness of rabeprazole in children has not been established (There are no adequate and well-controlled studies with rabeprazole in children).
Pregnant or breastfeeding women.

Warnings and precautions for use

The possibility of malignancy should be excluded prior to commencing treatment with rabeprazole sodium for patients with gastric ulcer since rabeprazole can mask the symptoms and interfere with the diagnosis.
Patients with hepatic disorders:
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.
Treatment with proton pump inhibitors (PPI) may possibly increase the risk of gastrointestinal infections such as Salmonella, Campylobacter and Clostridium difficile.
A risk of cross-hypersensitivity reactions with other PPI cannot be excluded.
Hematopoietic disorders: There have been post-marketing reports of haematopoietic disorders (thrombocytopenia and neutropenia). In most cases, the cause can not be determined, these disorders are uncomplicated and disappear when rabeprazole is discontinued.
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. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.
Interaction with warfarin: Steady state interactions of rabeprazole and warfarin have not been adequately evaluated in patients. There have been reports of increased INR and prothrombin time in patients receiving proton pump inhibitor and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients receiving concomitantly proton pump inhibitor and warfarin may need to be monitored for increases in INR and prothrombin time.
Acute interstitial nephritis: Acute interstitial nephritis has been observed in patients receiving proton pump inhibitors (PPI) including rabeprazole. Acute interstitial nephritis can occur at any time during PPI treatment and is usually due to hypersensitivity reactions. Discontinue use of rabeprazole if acute interstitial nephritis develops.
Bone fractures: Several published observational studies in adults have shown that PPI therapy may increase the risk of osteoporosis-related fractures of the hip, wrist or spine. The risk of fracture was increased in patients taking high doses, i.e, multiple daily doses, and long-term PPI therapy (1 year or longer). Patients should be given the lowest dose and the shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be treated according to established treatment guidelines.
Vitamin B12 deficiency: Daily treatment with any acid suppressant for a long time (e.g. longer than 3 years) can lead to malabsorption of cyanocobalamin (vitamin B12) due to hypo- or achlorhydria. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed in patients treated with rabeprazole.
Hypomagnesaemia: The symptomatic and asymptomatic magnesium deficiency rarely occurs in patients treated with PPIs for at least three months, and in most cases after a year of therapy. Serious manifestations including tetany, arrhythmias, and seizures can occur. 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.
Concomitant use of rabeprazole with methotrexate: Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose) 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.
This medicinal product contains tartrazine (E 102) that may cause allergic-type reactions.

Recommendation for pregnancy and breastfeeding

Pregnancy:
Rabeprazole is contraindicated during pregnancy since there are no data on the safety of rabeprazole in human pregnancy.
Lactation:
It is not known whether rabeprazole sodium is excreted in human breast milk. No studies in lactating women have been performed. Therefore, rabeprazole should not be used during breast feeding.

Effects on ability to drive and use machines

Patients who drive or operate machinery should use rabeprazole with caution because it may cause headache, dizziness, drowsiness.

Interactions, incompatibilities of medicine

Co-administration of rabeprazole sodium with ketoconazole or itraconazole may reduce absorption of ketoconazole or itraconazole. Therefore, patients may need to be monitored when such drugs are taken concomitantly with rabeprazole to adjust the dosage appropriately.
Co-administration of rabeprazole with erlotinib, nelfinavir, delavirdin, posaconazole should be avoided.
Rabeprazole may reduce the concentrations/effects of atazanavir, clopidogrel, dabigatran, etexilat, dasatinib, erlotinib, indinavir, iron salts, itraconazole, ketoconazole, mesalamine, mycophenolate, nelfinavir.
Rabeprazole may increase the concentration/effect of substances metabolized by CYP2C19 and CYP2C8 (high risk level) methotrexate, saquinavir, voriconazole.
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.

Undesirable effects (ADRs)

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-marketing experience.
Common, ADR > 1/100
Infections and infestations: Infection.
Psychiatric disorders: Insomnia.
Nervous system disorders: Headache, dizziness.
Respiratory, thoracic and mediastinal disorders: Cough, pharyngitis, rhinitis.
Gastrointestinal disorders: Diarrhoea, vomiting, nausea, abdominal pain, constipation, flatulence.
Musculoskeletal, connective tissue and bone disorders: Non-specific pain, back pain.
General disorders: Asthenia, flu-like syndrome.
Uncommon, 1/1000 < ADR < 1/100
Psychiatric disorders: Anxiety, restlessness.
Nervous system disorders: Drowsiness.
Respiratory, thoracic and mediastinal disorders: Bronchitis, sinusitis.
Gastrointestinal disorders: Dyspepsia, dry mouth, eructation.
Skin and subcutaneous tissue disorders: Rash, erythema.
Musculoskeletal, connective tissue and bone disorders: Myalgia, leg cramps, arthralgia, fracture of the hip, wrist or spine.
Renal and urinary disorders: Urinary tract infection.
General disorders: Chest pain, chills, pyrexia.
Investigations: Increased hepatic enzymes.
Rare, 1/10, 000 < ADR < 1/1, 000
Psychiatric disorders: Depression.
Blood and the lymphatic system disorders: Neutropenia, leucopenia, thrombocytopenia, leucocytosis.
Immune system disorders: Hypersensitivity (e.g. facial swelling, hypotension and dyspnoea).
Metabolism and nutrition disorders: Anorexia.
Eye disorders: Visual disturbance.
Gastrointestinal disorders: Gastritis, stomatitis, taste disturbance.
Hepato-biliary disorders: Hepatitis, jaundice, hepatic encephalopathy.
Skin and subcutaneous tissue disorders: Pruritus, sweating, bullous reactions.
Renal and urinary disorders: Interstitial nephritis.
Others: Weight increased.
Very rare, ADR < 1/10, 000
Skin and subcutaneous tissue disorders: Erythema multiforme, toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS).
Not known:
Psychiatric disorders: Confusion.
Metabolism and nutrition disorders: Hyponatremia, hypomagnesaemia.
Vascular disorders: Peripheral oedema.
Skin and subcutaneous tissue disorders: Subacute cutaneous lupus erythematosus.
Reproductive system and breast disorders: Gynaecomastia.
Guidelines for ADR management:
Stop using rabeprazole if signs of an allergic reaction occur.

Overdose and management

Symptoms:
Up to date, there has been no experience with deliberate or unintentional rabeprazole overdose. The maximum established exposure has not exceeded 60mg twice daily, or 160mg once daily. Effects are generally minimal, representative of the known adverse event profile and reversible without further medical intervention.
Management:
No specific antidote is known.
Rabeprazole 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.

Pharmacodynamic properties

Rabeprazole is a benzimidazole derivative, which acts as a proton pump inhibitor.
Rabeprazole is effective against both basal and stimulated acid secretion, does not exhibit anticholinergic or histamine H2-receptor antagonist properties, but suppress gastric acid secretion by the inhibition of the H+/K+-ATPase enzyme at the secretory surface of the gastric parietal cell. This enzyme is regarded as the acid (proton) pump within the parietal cell, and therefore rabeprazole sodium is classified as a gastric proton-pump inhibitor. Rabeprazole binds to the parietal H+/K+-ATPase enzyme and blocks the final step of acid production. In gastric parietal cell, rabeprazole is protonated and transformed to an active sulphenamide, which binds to cysteines of proton pump to inactivate this enzyme.

Pharmacokinetic properties

Absorption is rapid, with peak plasma levels of rabeprazole occurring approximately 3.5 hours after administration. Oral bioavailability is about 52% due to hepatic first-pass metabolism and are not significantly altered after the administration of single and multiple doses.
Rabeprazole is about 97% bound to plasma proteins.
Rabeprazole is extensively metabolised in the liver by cytochrome P450 isoenzymes (CYP2C19 and CYP3A4) to the thioether, thioether carboxylic acid, sulfone, and desmethylthioether.
The plasma half-life is about 1 hour and increases two to three-fold in patients with hepatic impairment, 1.6 times in CYP2C19 slow metabolisers and by 30 per cent in the elderly.
The metabolites are mainly excreted in the urine (about 90%), the remainder is recovered in feces.

Storage conditions, shelf-life, quality specification of the medicine

Storage conditions: Protect from humidity and light, below 30 degrees C.
Shelf – life: 24 months from the manufacture date.
Quality specification: In house specification.