Consumer medicine information

RABEPRAZOLE GA TABLETS

Rabeprazole sodium

BRAND INFORMATION

Brand name

Rabeprazole-GA

Active ingredient

Rabeprazole sodium

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using RABEPRAZOLE GA TABLETS.

What is in this leaflet

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

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

If you have any concerns about using Rabeprazole-GA ask your doctor or pharmacist.

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

What Rabeprazole-GA is used for

The name of your medicine is Rabeprazole-GA. It contains the active ingredient Rabeprazole-GA.

Reflux Oesophagitis:
Rabeprazole-GA is used to treat reflux oesophagitis or reflux disease. 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-GA is also used to help stop reflux oesophagitis from coming back or relapsing.

Peptic Ulcers:
Rabeprazole-GA 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-GA 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.

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

How Rabeprazole-GA works

Rabeprazole-GA belongs to a group of medicines called proton pump inhibitors (PPIs). Rabeprazole-GA 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.

Your doctor may have prescribed Rabeprazole-GA for another reason. Ask your doctor if you have any questions about why Rabeprazole-GA has been prescribed for you.

Rabeprazole-GA is only available with a doctor’s prescription.

Before you take Rabeprazole-GA

When you must not take it:

Do not take Rabeprazole-GA if you have an allergy 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 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-GA if:

  • the packaging is torn or shows signs of tampering.
  • the expiry date (month and year) printed on the pack has passed. If you take Rabeprazole-GA after the expiry date it may not work.

Before you start to take it:

You must tell your doctor if:

  • you are pregnant or intend to become pregnant.
  • you are breast-feeding or intend to breast-feed. It is not known if Rabeprazole-GA passes into breast milk.
  • 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.

In particular, tell your doctor or pharmacist if you are taking any of the following:

  • digoxin, a medicine used to treat heart problems.
  • ketoconazole, a medicine used to treat fungal infections.
  • Atazanavir, a medicine used (with other antiretrovirals) to treat HIV-1 infection.

These medicines may be affected by Rabeprazole-GA or may affect how well Rabeprazole-GA 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-GA.

Your doctor will advise you whether or not to take Rabeprazole-GA or if you need to have your dose adjusted.

Taking Rabeprazole-GA

How much to take:

Adults
The usual dose is one tablet at the same time each day. For treating Helicobacter pylori infections in combination with antibiotics (clarithromycin and amoxycillin), the dose is one tablet twice each day, morning and evening.
The dose of Rabeprazole-GA tablets 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.

Children
Rabeprazole-GA should not be given to children.

How to take it:

  • Rabeprazole-GA 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-GA 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 you forget to take your tablet take it as soon as you remember, and then continue to take it as you would normally.

However, if it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

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-GA

Things you must do:

  • Use Rabeprazole-GA exactly as your doctor has prescribed.
  • Always swallow Rabeprazole-GA tablets whole.
  • Tell your doctor if you become pregnant while you are taking Rabeprazole-GA

Tell your doctor or pharmacist that you are taking Rabeprazole-GA if you are about to start taking a new medicine.

Things you must not do:

  • Do not use Rabeprazole-GA 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-GA to children.

Things that may help your condition

Some self help measures suggested below may help your condition. Talk to your doctor or pharmacist for more information about these measures.

  • Alcohol - your doctor may advise you to limit your alcohol intake.
  • Aspirin and many other medicines used to treat arthritis/period pain/headaches - these medicines may irritate the stomach and may make your condition worse. Your doctor or pharmacist may suggest other medicines you can take.
  • Caffeine - your doctor may advise you to limit the number of drinks which contain caffeine, such as coffee, tea, cocoa and cola drinks, because they contain ingredients that may irritate your stomach.
  • Eating habits - eat smaller, more frequent meals. Eat slowly and chew your food carefully. Try not to rush at meal times.
  • Smoking - your doctor may advise you to stop smoking or at least cut down.
  • Weight - your doctor may suggest losing some weight to help your condition.

Side Effects

Rabeprazole-GA is usually well tolerated but tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Rabeprazole-GA.

Rabeprazole-GA 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
  • diarrhoea
  • constipation
  • stomach pain
  • muscle weakness
  • flatulence
  • dry mouth
  • breast enlargement in men
  • itchy rash accompanied by skin eruption

These side effects are usually mild.

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

  • 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-GA 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.

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-GA.

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.

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

After using Rabeprazole-GA

Storage

Rabeprazole-GA tablets may be packaged in either a clear blister strip in an aluminium pouch with a desiccant sachet, or in a double-sided aluminium blister strip.

Rabeprazole-GA tablets packaged in the clear blister strips should be kept in the original aluminium pouch with the desiccant after opening. Any remaining Rabeprazole-GA tablets should be discarded 1 month after the aluminium foil pouch is opened.

Do not take Rabeprazole-GA tablets out of the blister pack until it is time to take them. If you take them out of the blister they may not keep well.

Keep Rabeprazole-GA tablets in a cool dry place where the temperature is below 25°C. Do not keep Rabeprazole-GA in the refrigerator.

Do not store Rabeprazole-GA, 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-GA tablets, or the tablets have passed their expiry date, ask your pharmacist what to do with any tablets that are left over.

Product Description

What Rabeprazole-GA looks like:

Rabeprazole-GA 10 mg tablets are red biconvex enteric coated tablets, plain on both sides.

Rabeprazole-GA 10 mg tablets are supplied in blister packs of 28 tablets.

Ingredients

Each Rabeprazole-GA tablet contains 10 mg of Rabeprazole sodium as the active ingredient.

Each tablet also contains the following other ingredients:

  • Magnesium oxide,
  • mannitol,
  • sodium starch glycollate,
  • povidone (K-30) magnesium stearate,
  • ethylcellulose,
  • diethyl phthalate,
  • hypromellose phthalate,
  • titanium dioxide,
  • purified talc,
  • iron oxide red.

The tablets do not contain lactose or gluten.

Sponsor

This leaflet was prepared in October 2013.

Published by MIMS December 2013

BRAND INFORMATION

Brand name

Rabeprazole-GA

Active ingredient

Rabeprazole sodium

Schedule

S4

 

Name of the medicine

Rabeprazole sodium.

Excipients.

Heavy magnesium oxide, mannitol, sodium starch glycollate, povidone, magnesium stearate, ethyl cellulose, diethyl phthalate, hydroxypropylcellulose, hypromellose phthalate, titanium dioxide, purified talc. The 10 mg tablet also contains iron oxide red, and the 20 mg tablet contains iron oxide yellow.

Description

Chemical name: (±) 2-[{4-(3-methoxypropoxy)- 3-methylpyridin-2-yl}- methylsulphinyl]-1H- benzimidazole sodium. Molecular formula: C18H20N3NaO3S. MW: 381.43. CAS: 117976-89-3 (rabeprazole); 117976-90-6 (rabeprazole sodium). Rabeprazole sodium is a substituted benzimidazole and belongs to the class of proton pump inhibitors. Its solubility in water is pH dependent, being very soluble in water at pH 9 to 11, and only slightly soluble in water at pH 8. It is very soluble in methanol, freely soluble in dichloromethane and practically insoluble in hexane. Rabeprazole has one chiral centre and is a racemate of two enantiomers.

Pharmacology

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.

Pharmacodynamics.

Antisecretory activity.

Oral administration of a 20 mg dose of rabeprazole sodium provides rapid and effective reduction of gastric acid secretion. The onset of the antisecretory 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 Dosage and 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 pretreatment 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 Carcinogenicity, mutagenicity and impairment of fertility).
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.

Pharmacokinetics.

Absorption.

Rabeprazole-GA 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 presystemic 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 Interactions with Other Medicines). 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 antisecretory activity, but its presence in plasma is minimal.

Elimination and 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 biotransformation and urinary excretion of water soluble metabolites as the primary route of elimination.

Renal disease.

In patients with stable, endstage, 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, 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 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 the Dosage and Administration section for information on dosage adjustments in patients with hepatic impairment.

Geriatrics.

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.

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 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 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 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 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 20 mg once daily or omeprazole 20 mg once daily for up to eight weeks, rabeprazole 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 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 antisecretory therapy was assessed in two U.S. multicentre, 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, or placebo once daily. In both studies rabeprazole was significantly superior to placebo in prevention of relapse of GORD.
In both multicentre trials, rabeprazole 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 10 mg or 20 mg once daily. Treatment with both 10 mg and 20 mg rabeprazole were as effective as omeprazole 20 mg in preventing GORD relapse (p = 0.5216 and p = 0.8004 respectively). See Table 2.
Rabeprazole 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 10 mg or placebo taken once daily, when required, over a six month period. Efficacy of rabeprazole 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 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 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 20 mg once daily reported significantly less ulcer pain frequency (p < 0.001). After 7 days treatment with rabeprazole 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 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 20 mg once daily or ranitidine 150 mg twice daily for up to four weeks. Rabeprazole 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 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 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 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 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 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 20 mg once daily versus placebo (p < 0.001).
The rates of endoscopic healing of gastric ulcers in patients treated with rabeprazole 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 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 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 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%.

Indications

Rabeprazole-GA is 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 nonsteroidal anti-inflammatory drugs (NSAIDs) usually require treatment with antimicrobial agents in addition to antisecretory drugs whether on first presentation or on recurrence.
Rabeprazole-GA is 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.

Contraindications

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

Precautions

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

Use in patients with 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-GA is first initiated in patients with severe hepatic dysfunction (see Dosage and Administration).

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 Adverse Effects).

Carcinogenicity, mutagenicity and impairment of fertility.

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 dose for the treatment of GORD and active gastroduodenal ulcers. For H. pylori eradication, the recommended dose of rabeprazole 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).
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.
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.

Use in pregnancy.

(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 postmarketing experience is very limited. Rabeprazole sodium should be used in pregnancy only if the potential benefit justifies the potential risk to the foetus.

Use in lactation.

Following intravenous administration of 14C-labelled rabeprazole to lactating rats, radioactivity in milk reached levels that were about 2 to 7-fold higher than levels in the blood. Administration of rabeprazole 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 bodyweight 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.

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).

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. 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.

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.

Coadministration of atazanavir with other proton pump inhibitors resulted in a substantial reduction in atazanavir exposure. The absorption of atazanavir is pH dependent. Therefore, Rabeprazole-GA should not be coadministered with atazanavir.
Patients may need to be monitored when these drugs are taken together with Rabeprazole-GA.

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.

Adverse Effects

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.

Nonspecific 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.

Pruritis, sweating.

Special senses.

Vision or taste disturbances.

Haematologic.

Leucocytosis.

Other.

Depression.

Postmarketing 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. Hypomagnesemia and 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.

Dosage and Administration

Rabeprazole-GA tablets should not be chewed or crushed, but should be swallowed whole. Rabeprazole-GA 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 Precautions).

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 gastroduodenal ulcers or chronic gastritis due to H. pylori infection should be treated with: Rabeprazole-GA 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-GA is not recommended for use in children as there is no experience of its use in this group.

Use in elderly patients.

No dosage adjustment is necessary in elderly patients.

Use in patients with hepatic or renal impairment.

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

Overdosage

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.

Presentation

Tablets (biconvex, enteric coated, blank on both sides), 10 mg (≡ rabeprazole 9.42 mg, pink): 28's; 20 mg (≡ rabeprazole 18.85 mg, light yellow): 30's* (aluminium/ aluminium blister pack).
*Not currently marketed in Australia.

Storage

Rabeprazole-GA tablets should be stored below 25°C. Do not refrigerate or freeze.

Poison Schedule

S4.