Consumer medicine information

Rabeprazole Sun

Rabeprazole sodium

BRAND INFORMATION

Brand name

Rabeprazole Sun

Active ingredient

Rabeprazole sodium

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Rabeprazole Sun.

What is in this leaflet

This leaflet answers some common questions about RABEPRAZOLE SUN. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

This leaflet was last updated on the date at the end of this leaflet.

More recent information may be available. The latest Consumer Medicine Information is available from https://www.ebs.tga.gov.au/ and may contain important information about the medicine and its use of which you should be aware.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking RABEPRAZOLE SUN against the benefits this medicine is expected to have for you.

If you have any concerns about using RABEPRAZOLE SUN ask your doctor or pharmacist.

Keep this leaflet with your medicine. You may need to read it again.

What RABEPRAZOLE SUN is used for

The name of your medicine is RABEPRAZOLE SUN. It contains the active ingredient rabeprazole sodium.

RABEPRAZOLE SUN belongs to a group of medicines called proton pump inhibitors (PPIS). RABEPRAZOLE SUN works by decreasing the amount of acid the stomach makes, to give relief from the symptoms and allow healing to take place. Your food will still be digested in the normal way.

Gastro-oesophageal reflux disease:

RABEPRAZOLE SUN is used to treat gastro-oesophageal reflux disease (GORD), commonly known as ‘reflux’. . This can be caused by food and acid from the stomach flowing the wrong way (reflux) back up the food pipe, also known as the oesophagus.

Reflux can cause a burning sensation in the chest rising up to the throat, also known as heartburn.

RABEPRAZOLE SUN is also used to help stop reflux oesophagitis from coming back or relapsing.

Peptic Ulcers:

RABEPRAZOLE SUN is used to treat peptic ulcers. Depending on the position of the ulcer it is called a gastric or duodenal ulcer. A gastric ulcer occurs in the stomach. A duodenal ulcer occurs in the duodenum which is the tube leading out of the stomach.

These ulcers can be caused by too much acid being made in the stomach.

Most people who have a peptic ulcer also have a bacteria called Helicobacter pylori in their stomach. Your doctor may also prescribe a course of antibiotics (clarithromycin and amoxycillin) for you. When RABEPRAZOLE SUN is taken with antibiotics, the combination therapy will kill the Helicobacter pylori and let your ulcer heal.

Chronic Gastritis:

The presence of the bacteria Helicobacter pylori may cause the stomach to become inflamed, resulting in pain, nausea and vomiting; all of which are signs of chronic gastritis.

When RABEPRAZOLE SUN tablets are taken with antibiotics, they will help kill Helicobacter pylori and allow the stomach to heal.

Your doctor may have prescribed RABEPRAZOLE SUN for another reason. Ask your doctor if you have any questions about why RABEPRAZOLE SUN has been prescribed for you.

RABEPRAZOLE SUN is only available with a doctor’s prescription.

Before you take RABEPRAZOLE SUN

When you must not take it:

Do not take RABEPRAZOLE SUN if you have an allergy (hypersensitivity) to:

  • rabeprazole sodium
  • any of the ingredients listed at the end of this leaflet
  • other proton pump inhibitors (omeprazole, esomeprazole, lansoprazole, pantoprazole).

Symptoms of an allergic (hypersensitive) reaction may include:

  • rash, itching or hives on the skin
  • shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body

Do not take RABEPRAZOLE SUN if the packaging is torn or shows signs of tampering.

Do not take RABEPRAZOLE SUN after the expiry date (EXP) printed on the pack has passed. If you take RABEPRAZOLE SUN after the expiry date it may not work (as well).

Before you start to take it:

You must tell your doctor if:

  1. you are pregnant or intend to become pregnant.
  2. you are breast-feeding or intend to breast-feed.
It is not known if RABEPRAZOLE SUN passes into breast milk.
  1. you have or have ever had liver disease.

Taking other medicines:

Tell your doctor or pharmacist if you are taking any other medicines, including medicines you can buy without a prescription from a pharmacy, supermarket or health food shop.

Do not take RABEPRAZOLE SUN and tell your doctor or pharmacist if you are taking any of the following:

  • atazanavir, a medicine used (with other antiretrovirals) to treat HIV-1 infection.
  • clopidogrel, an antiplatelet medicine

You should not take RABEPRAZOLE SUN while taking these medicines.

Also tell your doctor or pharmacist if you are taking any of the following:

  • cyclosporin, a medicine used to treat several conditions including prevention of graft rejection following kidney, liver or heart transplantation; severe, active rheumatoid arthritis; severe skin diseases; kidney disease where other treatments have failed.
  • methotrexate, a medicine used to treat some kinds of cancer. It is also used to treat psoriasis (skin disease) and rheumatoid arthritis.
  • digoxin, a medicine used to treat heart problems.
  • ketoconazole, a medicine used to treat fungal infections.
  • Mycophenolate mofetil, a medicine used to prevent organ rejection following kidney, liver or heart transplants.
  • clarithromycin, a medicine used to treat infections.

These medicines may be affected by RABEPRAZOLE SUN or may affect how well RABEPRAZOLE SUN works. Your doctor or pharmacist can tell you what to do if you are taking any other medicines.

If you have not told your doctor or pharmacist about any of the above, tell them before you start taking RABEPRAZOLE SUN.

Your doctor will advise you whether or not to take RABEPRAZOLE SUN or if you need to have your dose adjusted.

How to take RABEPRAZOLE SUN

Follow the directions given to you by your doctor and pharmacist carefully.

They may differ from the information contained in this leaflet.

How much to take:

Adults

The usual dose is one tablet at the same time each day.

The dose of RABEPRAZOLE SUN is usually 20 mg, but may vary from 10 mg to 40 mg per day depending on what condition you are being treated for and how severe it is.

For treating Helicobacter pylori infections in combination with antibiotics (clarithromycin and amoxycillin), the usual dose is one 20 mg tablet twice each day, morning and evening, for 7 days.

Children

RABEPRAZOLE SUN should not be given to children under 18 years of age. Safety and effectiveness of RABEPRAZOLE SUN in children has not been established.

How to take it:

  • RABEPRAZOLE SUN should be swallowed whole, with a glass of water or other liquid.
  • Do NOT crush or chew the tablets. They have a special coating, which protects them from the acid in your stomach. If the coating is broken by chewing, the tablets may not work.
  • It does not matter if you take RABEPRAZOLE SUN with food or on an empty stomach.

Ask your doctor or pharmacist for help if you do not understand the instructions provided with this medicine.

If you forget to take it:

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to. Otherwise, take it as soon as you remember, and then go back to taking it as you would normally.

Do not take a double dose to make up for the dose you missed.

If you are not sure what to do, check with your doctor or pharmacist.

If you have trouble remembering when to take your medicine, ask your pharmacist for some hints.

If you have taken too much (overdose):

Immediately telephone your doctor or the Poisons Information Centre for advice, or go to Accident and Emergency at your nearest hospital. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Poisons Information Centre telephone numbers:

  • Australia: 13 11 26
  • New Zealand: 0800 POISON or 0800 764 766

Keep these telephone numbers handy.

While you are using RABEPRAZOLE SUN

Things you must do:

Use RABEPRAZOLE SUN exactly as your doctor has prescribed.

Always swallow RABEPRAZOLE SUN whole.

Tell your doctor if you become pregnant while you are taking RABEPRAZOLE SUN

Tell your doctor or pharmacist that you are taking RABEPRAZOLE SUN if you are about to start taking a new medicine.

Things you must not do:

Do not use RABEPRAZOLE SUN to treat any other complaint unless your doctor says to.

Do not give this medicine to anyone else, even if they have the same symptoms as you. Do not crush or chew the tablets.

Do not give RABEPRAZOLE SUN to children.

Tell your doctor if you need to have a specific blood test (Chromogranin A) while you are taking RABEPRAZOLE SUN. It may affect the results of this test.

Side Effects

RABEPRAZOLE SUN is usually well tolerated but tell your doctor or pharmacist as soon as possible if you do not feel well while you are using RABEPRAZOLE SUN.

RABEPRAZOLE SUN helps most people with peptic ulcers or reflux disease, but it may have unwanted side effects in a few people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some side effects.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you experience any of the following and they worry you:

  • headache
  • dizziness
  • nausea
  • diarrhoea
  • wind
  • constipation
  • stomach pain
  • vomiting
  • dry mouth
  • muscle weakness, physical weakness or lack of energy
  • runny or blocked nose
  • sore throat and discomfort when swallowing
  • cough
  • chest pain
  • back pain
  • rash
  • itchy rash accompanied by skin eruptions or blisters
  • flu-like symptoms
  • sleeplessness (insomnia)
  • indigestion
  • belching
  • leg cramps
  • swelling of the arms or legs
  • nervousness
  • loss of appetite for food (anorexia)
  • weight gain
  • sweating
  • breast enlargement in men

These side effects are usually mild.

Tell your doctor immediately if you notice any of the following:

  • painful and/or frequent urination (common symptoms of a urinary tract infection)
  • vision or taste disturbance
  • depression
  • feeling dizzy, faint, lightheaded or weak (hypotension)
  • shortness of breath
  • bleeding or bruising more easily than normal
  • signs of frequent infections such as fever, severe chills, sore throat or mouth ulcers.

These are serious side effects. You may need urgent medical attention. Serious side effects are rare.

Tell your doctor immediately and do not take your next dose of RABEPRAZOLE SUN if you experience:

  • signs of allergy such as skin rash, reddening, blisters or itching, swelling of the face, lips or other parts of the body, shortness of breath or wheezing.
  • you pass black (blood-stained) motions
    If you experience symptoms such as severe (watery or bloody) diarrhoea, fever, abdominal pain or tenderness, you may have Clostridium difficile colitis (bowel inflammation).
    Other problems are more likely to arise from the ulcer itself rather than the treatment.

For this reason contact your doctor immediately if you notice any of the following:

  • pain or indigestion
  • you begin to vomit blood or food
  • you pass black (blood-stained) motions

Under rare circumstances supervised by the doctor, proton pump inhibitors (PPIs) might be used for long periods of time.

Low magnesium can occur in some people who take a proton pump inhibitor. Symptoms of low magnesium can include: seizures, dizziness, spasms, cramps or muscle weakness.

Withdrawal of long-term PPI therapy may lead to worsening of acid-related symptoms.

People who take proton pump inhibitor medicines at high doses for a long period of time (1 year or longer) may have an increased risk of fractures of the hip, wrist, or spine.

Proton pump inhibitors may reduce the amount of acid in your stomach. Stomach acid is needed to absorb vitamin B-12 properly. Talk with your doctor or pharmacist about the possibility of vitamin B-12 deficiency if you have been taking a proton pump inhibitor for a long time (i.e. more than 3 years).

Other side effects not listed above may also occur in some people. Tell your doctor if you notice anything making you feel unwell when you are taking, or soon after you have finished taking RABEPRAZOLE SUN.

Ask your doctor or pharmacist if you do not understand anything in this list.

After using RABEPRAZOLE SUN

Storage

Keep your tablets in their blister pack until it is time to take them. If you take them out of the blister they may not keep well.

Keep RABEPRAZOLE SUN in a cool dry place where the temperature is below 25°C. Do not keep RABEPRAZOLE SUN in the refrigerator.

Do not store RABEPRAZOLE SUN, or any other medicine, in the bathroom or near a sink. Do not leave medicines in the car or on window sills. Heat and dampness can destroy some medicines.

Keep your medicines where children cannot reach them. A locked cupboard at least one-and-a-half metres (1.5 m) above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking RABEPRAZOLE SUN, or the tablets have passed their expiry date, ask your pharmacist what to do with any tablets that are left over.

Product description

What it looks like

RABEPRAZOLE SUN 20 mg tablets are yellow, circular-shaped, biconvex, coated tablets imprinted with “RA” on one side and plain on other side. Available in blisters packs of 30 tablets.

Ingredients

Active ingredient

Each tablet of RABEPRAZOLE SUN contains 20 mg of rabeprazole sodium as the active ingredient and a number of inactive ingredients.

The inactive ingredients in RABEPRAZOLE SUN tablets include: mannitol, heavy magnesium oxide, hyprolose, magnesium stearate, ethylcellulose, light magnesium oxide, hypromellose phthalate, diacetylated monoglycerides, purified talc, titanium dioxide, iron oxide yellow and Opacode monogramming ink S-1-1666 Red (ARTG No. 107718).

The tablets do not contain gluten or lactose.

Sponsor

Sun Pharma ANZ Pty. Ltd
12 Waterloo Road
Macquarie Park NSW 2113
Australia

Australian Registration Numbers

RABEPRAZOLE SUN 20 mg tablets: AUST R 228980

This leaflet was prepared in September 2019.

Published by MIMS November 2019

BRAND INFORMATION

Brand name

Rabeprazole Sun

Active ingredient

Rabeprazole sodium

Schedule

S4

 

1 Name of Medicine

Rabeprazole sodium.

6.7 Physicochemical Properties

Molecular formula: C18H20N3NaO3S.
Chemical name: (±) 2-[[[4-(3-Methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole sodium.
Molecular weight: 381.43.
Rabeprazole sodium is a substituted benzimidazole and belongs to the class of proton pump inhibitors. It is very soluble in water, freely soluble in ethanol and insoluble in hexane. Its pKa is 5.
Rabeprazole has one chiral centre and is a racemate of two enantiomers.

Chemical structure.


CAS number.

117976-90-6.

2 Qualitative and Quantitative Composition

Rabeprazole Sun: Each enteric-coated tablets contains 20 mg rabeprazole sodium (equivalent to 18.85 mg rabeprazole).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Rabeprazole Sun 20 mg: Yellow, circular-shaped, biconvex, enteric-coated tablets imprinted with "RA" on one side and plain on other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Anti-secretory activity.

Oral administration of a 20 mg dose of rabeprazole sodium provides rapid and effective reduction of gastric acid secretion. 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 is 69% and 82% respectively, and the duration of inhibition lasts up to 48 hours. The duration of pharmacodynamic action is much longer than the pharmacokinetic half-life (approximately one hour) would predict. This effect is probably due to the prolonged binding of rabeprazole sodium to the parietal H+/K+-ATPase enzyme. 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.
Helicobacter pylori is associated with duodenal and gastric ulcer disease in approximately 95% and 70% of patients respectively. H. pylori is implicated as a major contributing factor in the development of gastritis and ulcers in such patients. Recent evidence also suggests a causative link between H. pylori and gastric carcinoma. H. pylori eradication therapy is appropriate in most patients with duodenal and gastric ulcer where the latter is not caused by nonsteroidal anti-inflammatory drug (NSAID) ingestion (see Section 4.2 Dose and Method of Administration).

Serum gastrin effects.

In clinical studies, patients were treated once daily with 10 or 20 mg rabeprazole sodium for up to 12 months duration. Serum gastrin levels increased during the first 2 to 8 weeks reflecting the inhibitory effects on acid secretion. Gastrin values returned to pre-treatment levels, usually within 1 to 2 weeks after discontinuation of therapy. In a maintenance study, which was subsequently extended up to 5 years duration, serum gastrin levels were only modestly raised in most patients.

Enterochromaffin-like (ECL) cell effects.

Increased serum gastrin secondary to antisecretory agents stimulates proliferation of gastric ECL cells which, over time, may result in ECL cell hyperplasia in rats and mice and gastric carcinoids in rats, especially females (see Section 5.3 Preclinical Safety Data).
In over 400 patients treated with rabeprazole sodium (10 or 20 mg/day) for up to one year, the incidence of ECL cell hyperplasia increased with time and dose, which is consistent with the pharmacological action of the proton pump inhibitor. No patient developed the adenomatoid, dysplastic or neoplastic changes of ECL cells in the gastric mucosa. No patient developed the carcinoid tumours observed in rats.

Mechanism of action.

Rabeprazole sodium suppresses gastric acid secretion by the specific inhibition of the H+/K+- ATPase enzyme (proton pump) at the secretory surface of the gastric parietal cell thereby blocking the final step of acid production. This 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.

Clinical trials.

At the time of registration, more than 3000 patients in the US, Europe and Japan had received rabeprazole sodium in both controlled and uncontrolled clinical studies.
The efficacy of rabeprazole was assessed in nine double-blind, controlled, randomised, parallel group primary efficacy trials in patients with duodenal ulcer, gastric ulcer and gastro-oesophageal reflux disease. Three trials were conducted in each indication, a placebo controlled study and comparative studies with either ranitidine or omeprazole. In all these studies the primary efficacy variable used was ulcer or ulcerative GORD healing rates as determined by endoscopic examination.
A further three clinical trials were conducted to establish efficacy of rabeprazole in the long-term prevention of relapse of gastro-oesophageal reflux disease. Two studies were placebo controlled, whilst the other was actively controlled with omeprazole. In all three studies the primary efficacy variable used was the continued absence of oesophageal erosions or ulcerations as determined by endoscopic examination.

Treatment of erosive or ulcerative gastro-oesophageal reflux disease (GORD).

In the placebo-controlled study, 103 patients were treated for up to eight weeks either with placebo or rabeprazole sodium 10, 20 or 40 mg once daily (od). Rabeprazole was significantly superior to placebo in producing endoscopic healing after four and eight weeks of treatment (p < 0.001).
Rabeprazole sodium 20 mg once daily was also significantly more effective than placebo in terms of symptom relief, providing complete resolution of heartburn frequency, daytime heartburn severity, and decreasing the amount of antacid taken per day after four and eight weeks of treatment.
Rabeprazole sodium 20 mg once daily was statistically superior to ranitidine 150 mg four times per day with respect to the percentage of patients healed at endoscopy and in symptom relief. Rabeprazole sodium was also significantly more effective than ranitidine in terms of providing complete resolution of heartburn frequency, and daytime and night-time heartburn severity; after four and eight weeks of treatment.
In an active-controlled study of 202 patients treated with rabeprazole sodium 20 mg once daily or omeprazole 20 mg once daily for up to eight weeks, rabeprazole sodium was as effective as omeprazole in producing endoscopic healing. The percentages of patients healed at endoscopy at four and eight weeks are given in Table 1.
Rabeprazole sodium 20 mg once daily was also as effective as omeprazole 20 mg once daily in reducing heartburn frequency, in improving daytime and night-time heartburn severity, and in reducing the amount of antacid taken per day.

Prevention of relapse of gastro-oesophageal reflux disease (GORD).

The prevention of relapse in patients with erosive or ulcerative GORD previously healed with gastric anti-secretory therapy was assessed in two U.S. multi-centre, double-blind, placebo-controlled studies of 52 weeks duration. The two studies of identical design randomised 209 and 285 patients respectively, to receive either 10 mg or 20 mg of rabeprazole sodium, or placebo once daily. In both studies rabeprazole sodium was significantly superior to placebo in prevention of relapse of GORD.
In both multicentre trials, rabeprazole sodium 10 mg once daily and 20 mg once daily were significantly more effective than placebo in preventing the recurrence of heartburn frequency (p < 0.001) as well as improving day-time (p < 0.001) and night-time (p ≤ 0.003) heartburn severity.
In the actively controlled European study, 243 patients were treated with a fixed dose of either omeprazole 20 mg once daily, or rabeprazole sodium 10 mg or 20 mg once daily. Treatment with both 10 mg and 20 mg rabeprazole sodium were as effective as omeprazole 20 mg in preventing GORD relapse (p=0.5216 and p=0.8004 respectively). See Table 2.
Rabeprazole sodium 10 mg and 20 mg once daily were also as effective as omeprazole 20 mg once daily in reducing heartburn frequency, and improving daytime and night-time heartburn severity.

Symptomatic gastro-oesophageal reflux disease (GORD).

On-demand treatment was assessed in a European multicentre, double-blind placebo-controlled randomised withdrawal study (n=418) in endoscopically negative patients.
Following an acute open-label phase, patients were randomised to receive rabeprazole sodium 10 mg or placebo taken once daily, when required, over a six month period. Efficacy of rabeprazole sodium 10 mg on-demand, in patients with complete heartburn relief at baseline was primarily evaluated by the unwillingness to continue the trial because of inadequate heartburn control. Overall, the proportion of patients discontinuing due to inadequate heartburn control was significantly higher for placebo (20%) compared to rabeprazole (6%) (p < 0.00001).
Patients were instructed to take study drug until they had experienced a full 24 hours free of heartburn, most patients in the rabeprazole sodium group had maximum episode duration of 4 days or less. In addition, antacid use was about 2-fold higher in the placebo group than in the rabeprazole group (p=0.0011). Treatment failure was associated with an increased antacid consumption.

Treatment of duodenal ulcers.

In a US study (n=100) rabeprazole sodium 20 mg once daily was significantly superior to placebo in producing healing of endoscopically defined duodenal ulcers (p=0.001) after four weeks treatment.
Patients treated for four weeks with rabeprazole sodium 20 mg once daily reported significantly less ulcer pain frequency (p < 0.001). After 7 days treatment with rabeprazole sodium 20 mg once daily, patients reported significantly less daytime (p=0.013) and night-time (p=0.003) ulcer pain severity than patients treated with placebo. This difference continued for the whole study period. Additionally, rabeprazole sodium 20 mg once daily was significantly more effective than placebo in reducing daily antacid use (p < 0.001).
In the ranitidine-controlled trial, 375 patients with endoscopically defined duodenal ulcers were treated with rabeprazole sodium 20 mg once daily or ranitidine 150 mg twice daily for up to four weeks. Rabeprazole sodium 20 mg once daily was significantly more effective than ranitidine 150 mg twice daily at producing complete healing of duodenal ulcers after 2 and 4 weeks (p=0.002 and p=0.017 respectively).
Rabeprazole sodium 20 mg once daily was also significantly more effective than ranitidine 150 mg twice daily in producing complete resolution of ulcer pain frequency (week 2, p=0.006), in alleviating night-time ulcer pain severity (week 2, p=0.044), and in reducing antacid consumption (p=0.037).
In patients with endoscopically defined duodenal ulcers treated for up to four weeks, rabeprazole sodium 20 mg once daily was as effective as omeprazole 20 mg once daily in producing healing of duodenal ulcers. The percentages of patients with endoscopic healing at two and four weeks are shown in Table 3.
Rabeprazole sodium 20 mg once daily was significantly (p=0.038) more effective than omeprazole 20 mg once daily in reducing daytime ulcer pain severity at week 4. In this trial rabeprazole sodium 20 mg once daily also proved to be as effective as omeprazole 20 mg once daily at reducing ulcer pain frequency and night-time ulcer pain.

Treatment of gastric ulcers.

Rabeprazole sodium was found to be significantly (p=0.002) superior to placebo in producing endoscopically defined healing of gastric ulcers after 6 weeks in a placebo-controlled study assessing the effectiveness of rabeprazole sodium 20 mg once daily versus placebo (p < 0.001).
The rates of endoscopic healing of gastric ulcers in patients treated with rabeprazole sodium 20 mg once daily (n=184) and ranitidine 150 mg two times per day (n=180) were found to be equivalent after three and six weeks of treatment.
In a European multicentre study comparing rabeprazole sodium 20 mg (n=113) to omeprazole 20 mg (n=114), the rates of endoscopic healing of gastric ulcers were found to be equivalent with the two treatments at three and six weeks. See Table 4.
Rabeprazole sodium was significantly superior to omeprazole in reducing ulcer pain frequency (week 6, p=0.006), in improving daytime ulcer pain severity (week 3, p=0.023), and in providing complete resolution of night-time ulcer pain severity (week 6, p=0.022).

H. pylori eradication.

In a multicentre, randomised, controlled European study conducted to establish the efficacy of rabeprazole based triple therapy for H. pylori eradication in patients with peptic ulcer disease, the combination: rabeprazole sodium 20 mg twice daily with clarithromycin 500 mg twice daily and amoxycillin 1 g twice daily for a total of 7 days (n = 83), achieved an eradication rate of 94% and a healing rate for duodenal ulcers of 91%.

5.2 Pharmacokinetic Properties

Absorption.

Rabeprazole tablets are enteric-coated to allow rabeprazole sodium, which is acid labile, to pass through the stomach intact. Absorption is rapid, with peak plasma levels of rabeprazole sodium occurring approximately 3.5 hours after a 20 mg dose. Peak plasma concentrations (Cmax) of rabeprazole sodium 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%, largely due 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.

Distribution.

Rabeprazole sodium is approximately 97% bound to human plasma proteins. After intravenous administration the volume of distribution is 0.34 L/kg.

Metabolism.

Rabeprazole sodium is metabolised through the cytochrome P450 (CYP450) hepatic drug metabolism system (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). 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 its presence in plasma is minimal.

Excretion.

Following a single 20 mg 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 also found in the species used in the toxicology studies. The remainder of the dose was recovered in faeces. Total recovery was 99.8%. This suggests low biliary excretion of the metabolites; with bio-transformation and urinary excretion of water soluble metabolites as the primary route of elimination.

Special populations.

Renal disease.

In patients with stable, end-stage, renal failure requiring maintenance haemodialysis (creatinine clearance ≤ 5 mL/min/1.73 m2), the pharmacokinetics of rabeprazole sodium was very similar to that in healthy volunteers.

Hepatic disease.

In a single dose study of 10 patients with chronic mild to moderate compensated cirrhosis of the liver who were administered a 20 mg dose of rabeprazole sodium, AUC0-24 was approximately doubled, the elimination half-life was 2- to 3-fold higher, and total body clearance was decreased to less than half compared to values in healthy men.
In a multiple dose study of 12 patients with mild to moderate hepatic impairment administered 20 mg rabeprazole sodium once daily for eight days, AUC0-∞ and Cmax values increased approximately 30% compared to values in healthy age- and gender-matched subjects. These increases were not statistically significant.
No information exists on rabeprazole disposition in patients with severe hepatic impairment. Please see Section 4.2 Dose and Method of Administration for information on dosage adjustments in patients with hepatic impairment.

Elderly patients.

Elimination of rabeprazole sodium was decreased in the elderly. Following 7 days of daily dosing with 20 mg of rabeprazole sodium, the AUC approximately doubled and the Cmax increased by 60% as compared to young healthy volunteers. However, there was no evidence of rabeprazole sodium accumulation.

5.3 Preclinical Safety Data

Genotoxicity.

Rabeprazole was positive in assays for gene mutations (the AMES test, forward gene mutation tests in Chinese hamster ovary cells (CHO/HGPRT) and mouse lymphoma cells (L5178Y/TK+/-)). Its demethylated-metabolite was also positive in the AMES test. Rabeprazole was negative in assays for chromosomal damage (the in vitro Chinese hamster lung cell chromosome aberration test, the in vivo mouse micronucleus test), and in vitro and ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) tests.

Carcinogenicity.

Note.

In the following section, the relative exposure levels in animals have been calculated using a human dose of 20 mg/day, the maximum recommended rabeprazole sodium dose for the treatment of GORD and active gastro-duodenal ulcers. For H. pylori eradication, the recommended dose of rabeprazole sodium is 40 mg/day (20 mg b.i.d.) for one week; this should be taken into account when reviewing exposure figures.
In an 88/104 week carcinogenicity study in CD-1 mice, rabeprazole at oral doses up to 100 mg/kg/day did not produce any increased tumour occurrence. The highest tested dose produced a systemic exposure to rabeprazole (AUC) of 1.40 microgram.hr/mL which is 1.6 times the human exposure at the recommended dose for GORD (20 mg/day).
In a 104-week carcinogenicity study in SD rats, males were treated with oral doses of 5, 15, 30 and 60 mg/kg/day and females with 5, 15, 30, 60 and 120 mg/kg/day. Rabeprazole produced gastric enterochromaffin-like (ECL) cell hyperplasia in male and female rats and ECL cell carcinoid tumours in female rats at all doses. The lowest dose (5 mg/kg/day) produced a systemic exposure to rabeprazole (AUC) of about 0.1 microgram.hr/mL which is about 0.1 times the human exposure at 20 mg/day. In male rats, no treatment-related tumours were observed at doses up to 60 mg/kg/day producing a rabeprazole plasma exposure (AUC) of about 0.2 microgram.hr/mL (0.2 times the human exposure at 20 mg/day).

4 Clinical Particulars

4.1 Therapeutic Indications

Rabeprazole enteric coated tablets are indicated for:
Treatment and prevention of relapse of gastro-oesophageal reflux disease.
Symptomatic treatment of gastro-oesophageal reflux disease.
Treatment of duodenal ulcers.
Treatment of gastric ulcers.
Patients whose gastric and duodenal ulceration is not associated with ingestion of non-steroidal anti-inflammatory drugs (NSAIDs) usually require treatment with antimicrobial agents in addition to antisecretory drugs whether on first presentation or on recurrence.
Rabeprazole enteric coated tablets are also indicated, in combination with clarithromycin and amoxycillin, for:
Eradication of Helicobacter pylori in patients with peptic ulcer disease or chronic gastritis.
Healing of peptic ulcers in patients with Helicobacter pylori associated ulcers.

4.3 Contraindications

Rabeprazole is contraindicated in patients with known hypersensitivity to rabeprazole sodium, proton pump inhibitors, or any ingredient of this product.

4.4 Special Warnings and Precautions for Use

Symptomatic response to therapy with rabeprazole does not preclude the presence of gastric malignancy, therefore the possibility of malignancy should be excluded prior to commencing treatment with rabeprazole.
Patients using an on-demand regimen for symptomatic GORD should be further reviewed and/or investigated if symptoms persist beyond 6 months.

Acute interstitial nephritis.

Acute interstitial nephritis has been observed in patients taking proton-pump inhibitors (PPIs) including rabeprazole sodium. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue rabeprazole sodium if acute interstitial nephritis develops.

Cyanocobalamin (vitamin B-12) deficiency.

Daily treatment with acid-suppressing medicines over a long period of time (e.g. longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B-12) caused by hypo- or achlorhydria.

Hypomagnesemia.

Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.
For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g. diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and then periodically while treatment continues (see Section 4.8 Adverse Effects (Undesirable Effects)).

Fractures.

Observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, and long-term PPI therapy (a year or longer).

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 such high-doses methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients.

Clostridium difficile.

Treatment with proton pump inhibitors may possibly increase the risk of gastrointestinal infections such as Clostridium difficile.

Subacute cutaneous lupus erythematosus.

Subacute cutaneous lupus erythematosus (SCLE) has been reported with the use of PPIs. 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. The occurrence of SCLE with previous PPI treatment may increase the risk of SCLE with other PPIs.

Fundic gland polyps.

As with other PPIs, long-term use of rabeprazole is associated with an increased risk of fundic gland polyps [see Section 4.8 Adverse Effects (Undesirable Effects)), Post-marketing experience]. Most fundic gland polyps are asymptomatic. Patients with large or ulcerated polyps may be at risk of gastrointestinal bleeding or small intestinal blockage. Use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

Use in hepatic impairment.

No dosage adjustment is necessary for patients with hepatic impairment. While no evidence of significant drug related safety problems was observed in patients with hepatic impairment, it is advised to exercise caution when treatment with rabeprazole is first initiated in patients with severe hepatic dysfunction (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

See Section 4.2 Dose and Method of Administration.

Paediatric use.

See Section 4.2 Dose and Method of Administration.

Effects on laboratory tests.

PPI-induced decreases in gastric acidity may lead to increases in serum chromogranin A (CgA) levels, which may lead to erroneous interpretations of laboratory results in investigations for neuroendocrine tumors. To avoid this interference, temporarily stop rabeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effect of rabeprazole sodium on other drugs - demonstrated interactions.

In vitro studies with human liver microsomes indicated that rabeprazole sodium is metabolised by isoenzymes of CYP450 (CYP2C19 and CYP3A4).
Patients may need to be monitored when the following drugs are taken together with rabeprazole:

Cyclosporin.

In vitro incubations employing human liver microsomes indicated that rabeprazole inhibited cyclosporin metabolism with an IC50 of 62 micromolar, a concentration that is over 50 times higher than the Cmax in healthy volunteers following 14 days dosing with 20 mg rabeprazole sodium. Although in vitro studies may not always be predictive of an in vivo status these findings indicate that no interaction is expected between rabeprazole and cyclosporin.

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.

Digoxin.

A 22% increase in trough digoxin levels was observed in normal subjects given both drugs concomitantly.

Ketoconazole.

A 33% decrease in ketoconazole levels was observed in normal subjects given both drugs concomitantly.

Atazanavir.

Co-administration of atazanavir with other proton pump inhibitors resulted in a substantial reduction in atazanavir exposure. The absorption of atazanavir is pH dependent. Therefore, rabeprazole should not be co-administered with atazanavir.

Mycophenolate mofetil.

Co-administration of proton-pump inhibitors with mycophenolate mofetil in healthy and transplant patients has been reported to reduce the exposure to the active metabolite, mycophenolic acid. This is possibly due to a decrease in mycophenolate mofetil solubility at an increased gastric pH. The clinical relevance of reduced mycophenolic acid exposure on organ rejection has not been established in transplant patients receiving proton-pump inhibitors and mycophenolate mofetil. Use rabeprazole sodium with caution in transplant patients receiving mycophenolate mofetil.

Clopidogrel.

Clopidogrel is metabolised to its active metabolite by CYP2C19. Inhibition of CYP2C19 by rabeprazole would be expected to result in reduced drug levels of the active metabolite of clopidogrel and a reduction in its antiplatelet activity and therefore its clinical efficacy. Concomitant use of rabeprazole with clopidogrel should be discouraged.
Patients may need to be monitored when these drugs are taken together with rabeprazole.

Effect of rabeprazole sodium on other drugs - theoretical interactions.

Rabeprazole sodium produces sustained inhibition of gastric acid secretion. An interaction with compounds whose absorption depends on gastric pH may occur due to the magnitude of acid suppression seen with rabeprazole sodium.

Effect of rabeprazole sodium on other drugs - potential interactions that have been excluded.

Studies in healthy subjects have shown that rabeprazole sodium does not have clinically significant interactions with other drugs metabolised by the CYP450 system. These studies included the drugs warfarin and theophylline (as single oral doses), phenytoin (as a single intravenous dose with supplemental oral dosing), diazepam (as a single intravenous dose) and amoxycillin (as single and multiple oral doses).
Taking rabeprazole with antacids produces no clinically relevant changes in plasma rabeprazole sodium concentrations.
Plasma concentrations of rabeprazole and the active metabolite of clarithromycin are increased by 24% and 50% respectively during concomitant administration. This is considered to be a useful interaction during H. pylori eradication.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Rabeprazole at intravenous doses up to 30 mg/kg/day (plasma AUC of 8.8 microgram.hr/mL, about 10 times the human exposure at 20 mg/day) was found to have no effect on fertility and reproductive performance of male and female rats.
(Category B1)
Teratology studies have been performed in rats at intravenous doses up to 50 mg/kg/day (plasma AUC of 11.8 microgram.hr/mL, about 13 or 6.5 times the human exposure at 20 mg/day and 40 mg/day respectively), and rabbits at intravenous doses up to 30 mg/kg/day (plasma AUC of 7.3 microgram.hr/mL, about 8 or 4 times the human exposure at 20 mg/day and 40 mg/day respectively) and have revealed no evidence of impaired fertility or harm to the foetus due to rabeprazole. There are no adequate and well-controlled studies in pregnant women and post-marketing experience is very limited. Rabeprazole sodium should be used in pregnancy only if the potential benefit justifies the potential risk to the foetus.
Following intravenous administration of 14C-labelled rabeprazole sodium to lactating rats, radioactivity in milk reached levels that were about 2- to 7-fold higher than levels in the blood. Administration of rabeprazole sodium to rats in gestation and during lactation at doses of 400 mg/kg/day (about 195-or 85-times a 20 mg or 40 mg human dose based on mg/m2) resulted in decreases in body weight gain of the pups.
It is not known whether rabeprazole sodium is excreted in human breast milk and there are no studies in lactating women. Since many drugs are excreted in milk and because of the potential for adverse reactions to nursing infants from rabeprazole sodium, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials.

Rabeprazole was generally well tolerated during clinical trials. The observed side effects have generally been mild or moderate and transient in nature. In the majority of cases, the incidence of the adverse events in the rabeprazole treatment group was equal to or less than that observed in the placebo control treatment group.
Only headaches, diarrhoea, abdominal pain, asthenia, flatulence, rash and dry mouth have been associated with the use of rabeprazole.
The adverse events, which may or may not be causally related to rabeprazole, reported in clinical trials are listed below in descending order of frequency.

Common (≥ 1% and < 10%).

Nervous system.

Headache, dizziness.

Gastrointestinal.

Diarrhoea, nausea, abdominal pain, flatulence, vomiting, constipation.

Respiratory.

Rhinitis, pharyngitis, cough.

Musculoskeletal.

Non-specific pain, back pain, myalgia.

Skin.

Rash.

Other.

Asthenia, flu-like syndrome, infection, insomnia, chest pain.

Uncommon (≥ 0.1% and < 1%).

Gastrointestinal.

Dyspepsia, eructation, dry mouth.

Respiratory.

Sinusitis, bronchitis.

Musculoskeletal.

Arthralgia, leg cramps.

Urinary.

Urinary tract infection.

Other.

Fever, nervousness, somnolence, chills, peripheral oedema.

Rare (≥ 0.01% and < 0.1%).

Gastrointestinal.

Anorexia, gastritis, weight gain, stomatitis.

Skin.

Pruritus, sweating.

Special senses.

Vision or taste disturbances.

Haematologic.

Leucocytosis.

Other.

Depression.

Not known.

Gastrointestinal.

Withdrawal of long-term PPI therapy can lead to aggravation of acid-related symptoms and may result in rebound acid hypersecretion.

Post-marketing experience.

Erythema and rarely bullous reactions, urticarial skin eruptions and acute systemic allergic reactions, for example facial swelling, hypotension and dyspnoea have been reported in patients treated with rabeprazole. These usually resolved after discontinuation of therapy.
Erythema multiforme, interstitial nephritis, gynaecomastia, myalgia and potential allergic reactions including anaphylactic reactions have been reported rarely. Blood dyscrasia including thrombocytopenia, neutropenia, leukopenia, pancytopenia, agranulocytosis and bicytopenia have been reported rarely.
There have also been reports of increased hepatic enzymes and serious hepatic dysfunction such as hepatitis and jaundice. Rare reports of hepatic encephalopathy have been received in patients with underlying cirrhosis.
There have been very rare reports of toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome and bullous rashes including subacute cutaneous lupus erythematosus.
There have been post-marketing reports of bone fractures and post-marketing reports of subacute cutaneous lupus erythematosus (SCLE) and fundic gland polyps (see Section 4.4 Special Warnings and Precautions for Use).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Rabeprazole Sun tablets should not be chewed or crushed, but should be swallowed whole. Rabeprazole Sun tablets should be taken at the same time each day to facilitate treatment compliance. Rabeprazole was taken with or without food in the pivotal clinical trials.

Adults.

Treatment of active gastro-oesophageal reflux disease (GORD).

The recommended oral dose for this condition is one 20 mg tablet to be taken once daily for four to eight weeks.

Prevention of relapse of gastro-oesophageal reflux disease (GORD).

The recommended oral dose for preventing relapse of GORD, once healing is achieved, is one 10 mg tablet* to be taken once daily.
If needed this dose should be increased to one 20 mg tablet to be taken once daily.

Symptomatic treatment of gastro-oesophageal reflux disease (GORD).

Treatment should commence at 10 mg once daily* in patients without oesophagitis. If no response, the dose should be increased to 20 mg once daily for four weeks. If symptom control has not been achieved within four weeks, the patient should be further investigated.
Once symptoms have resolved, subsequent symptom control can be achieved using an on-demand regimen of one 10 mg tablet* to be taken once daily, when needed. (See Section 4.4 Special Warnings and Precautions for Use.)

Treatment of active duodenal ulcer and gastric ulcer.

The recommended oral dose for both duodenal ulcer and gastric ulcer is one 20 mg tablet to be taken once daily.
Some patients with duodenal ulcer may respond to one 10 mg tablet* taken once daily.
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 gastric ulcer heal within six weeks. However, again a few patients may require an additional six weeks of therapy to achieve healing.

Eradication of H. pylori.

Patients with gastro-duodenal ulcers or chronic gastritis due to H. pylori infection should be treated with: Rabeprazole Sun 20 mg twice daily + clarithromycin 500 mg twice daily and amoxycillin 1 g twice daily for seven days.
Eradication of H. pylori with this regimen has been shown to result in the healing of duodenal or gastric ulcers without the need for continued ulcer therapy.

Use in children.

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

Use in elderly.

No dosage adjustment is necessary in elderly patients.

Use in patients with renal impairment.

No dosage adjustment is necessary for patients with renal impairment. There are no data on the use of rabeprazole in combination with antibiotic regimens in patients with renal impairment.

Use in patients with hepatic impairment.

Patients with mild to moderate hepatic impairment experience higher exposure to rabeprazole sodium at a given dose than do healthy patients. Caution should be exercised in patients with severe hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use).
There are no data on the use of rabeprazole in combination with antibiotic regimens in patients with hepatic impairment.
* 10 mg rabeprazole sodium enteric-coated tablets are offered by other brands.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.9 Overdose

For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).
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 readily dialysable. As in any case of overdose, treatment should be symptomatic and general supportive measures should be used.

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Mannitol, heavy magnesium oxide, hyprolose, magnesium stearate, ethylcellulose, light magnesium oxide, hypromellose phthalate, diacetylated monoglycerides, purified talc, titanium dioxide, iron oxide yellow and Opacode monogramming ink S-1-1666 Red PI (ARTG No. 107718).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C in the original container. Protect from moisture.

6.5 Nature and Contents of Container

The tablets are supplied in cold form blisters with embedded desiccant.
Available in blisters packs of 7*, 10*, 14*, 28* and 30 tablets.
* Not currently marketed.
The tablets are supplied in cold form blisters with embedded desiccant.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed by taking to your local pharmacy.

Summary Table of Changes