Consumer medicine information

Zabep 20

Rabeprazole sodium

BRAND INFORMATION

Brand name

Zabep 20 Tablets

Active ingredient

Rabeprazole sodium

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Zabep 20.

What is in this leaflet

This leaflet answers some common questions about ZABEP 20.

It does not contain all of the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking ZABEP 20 against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, talk to your doctor or pharmacist.

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

What ZABEP 20 is used for

ZABEP 20 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 the throat, also known as heartburn.
  • help stop reflux oesophagitis from coming back or relapsing
  • treat peptic ulcers. Depending on the position of the ulcer it is called a gastric or duodenal 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 amoxicillin) for you. When ZABEP 20 is taken with antibiotics, the combination therapy will kill the Helicobacter pylori and let your ulcer heal.
    The presence of the bacteria Helicobacter pylori may cause the stomach to become inflamed, resulting in pain, nausea and vomiting. When ZABEP 20 is taken with antibiotics, they will help kill Helicobacter pylori and allow the stomach to heal.

ZABEP 20 belongs to a group of medicines called proton pump inhibitors (PPIs). ZABEP 20 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 ZABEP 20 for another reason. Ask your doctor if you have any questions about why ZABEP 20 has been prescribed for you.

ZABEP 20 is available only with a doctor's prescription.

Before you take ZABEP 20

When you must not take it

Do not take ZABEP 20 if you are allergic to medicines containing rabeprazole sodium, or any other proton inhibitors (omeprazole, esomeprazole, lansoprazole, pantoprazole) or any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include skin rash, itching or hives, swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing, wheezing or shortness of breath.

Do not take ZABEP 20 if the expiry date (Exp.) printed on the pack has passed.

Do not take ZABEP 20 if the packaging is torn or shows signs of tampering.

Before you start to take it

Tell your doctor if you are allergic to any other medicines, foods, dyes or preservatives.

Tell your doctor if you are pregnant or plan to become pregnant.

Tell your doctor if you are breastfeeding or wish to breastfeed.

Your doctor will discuss the risks and benefits of taking ZABEP 20 when breastfeeding.

Tell your doctor if you have, or ever have had, liver disease.

If you have not told your doctor about any of the above, tell them before you start taking ZABEP 20.

Taking other medicines

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

Some medicines may be affected by ZABEP 20, or may affect how well it works. These include:

  • 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.

Your doctor can tell you what to do if you are taking any of these medicines.

If you are not sure whether you are taking any of these medicines, check with your doctor or pharmacist.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking ZABEP 20.

How to take ZABEP 20

How much to take

The usual dose is one tablet at the same time each day. For treating Helicobacter pylori infections in combinations with antibiotics (clarithromycin and amoxicillin), the dose is one tablet twice each day, morning and evening.

Your doctor may advise you to take a different dose. This depends on your condition and whether or not you are taking any other medicines.

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

How to take ZABEP 20

Swallow the tablets with a glass of water.

Do not crush or chew the tablets.

They have a special coating, which protects them from the acid in your stomach. If you crush or chew ZABEP 20 tablets, they will not work as well. It does not matter if you take ZABEP 20 with food or on an empty stomach.

If you forget to take ZABEP 20

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 the missed dose as soon as you remember, and then go back to taking your tablets 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, ask your doctor or pharmacist.

How long to take ZABEP 20 for

Keep taking ZABEP 20 for as long as your doctor recommends.

If you take too much ZABEP 20 (overdose)

Immediately telephone your doctor, or the Poisons Information Centre (telephone 13 11 26), or go to Accident and Emergency at the nearest hospital, if you think you or anyone else may have taken too much ZABEP 20. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

While you are taking ZABEP 20

Things you must do

Before starting any new medicine, tell your doctor or pharmacist that you are taking ZABEP 20.

Always swallow ZABEP 20 tablets whole.

Tell all the doctors, dentists and pharmacists who are treating you that you are taking ZABEP 20.

Tell your doctor if you become pregnant while taking ZABEP 20.

If you plan to have surgery, including dental surgery, tell your doctor or dentist that you are taking ZABEP 20.

Things you must not do

Do not use ZABEP 20 to treat any other conditions unless your doctor tells you to.

Do not give ZABEP 20 to anyone else, even if they have the same condition as you.

Do not crush or chew the tablets.

Do not give ZABEP 20 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

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking ZABEP 20.

Like all other medicines, ZABEP 20 may have unwanted side effects in some people. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the 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 notice 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.

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.

Tell your doctor immediately and do not take your next dose of ZABEP 20 if you notice any of the following:

  • signs of allergy such as skin rash, reddening, blister 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 patients. Tell your doctor if you notice anything that is making you feel unwell.

Other problems are more likely to arise from the ulcer itself rather than the treatment.

For these reasons 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.

After using ZABEP 20

Storage

Keep ZABEP 20 where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Keep the tablets in their pack until it is time to take them.

If you take the tablets out of the pack they may not keep well.

Keep your tablets in a cool dry place where the temperature stays below 25°C.

Do not store ZABEP 20 or any other medicine in the bathroom or near a sink.

Do not leave ZABEP 20 in the car or on window sills.

Heat and dampness can destroy some medicines.

Disposal

If your doctor tells you to stop taking ZABEP 20, or your tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

ZABEP 20 - elliptical yellow tablet with no markings.

Each carton of ZABEP 20 contains 30 enteric coated tablets.

Ingredients

The active ingredient in ZABEP 20 is rabeprazole sodium:

Each ZABEP 20 enteric coated tablet contains 20 mg of rabeprazole sodium.

The tablets also contain:

  • povidone
  • hydroxypropyl cellulose
  • magnesium oxide
  • mannitol
  • magnesium stearate
  • ethylcellulose
  • methacrylic acid-ethyl acrylate copolymer (1:1)
  • polysorbate 80
  • sodium lauryl sulphate
  • propylene glycol
  • purified talc
  • iron oxide yellow (E172)
  • titanium dioxide (E171).

The tablets do not contain gluten, lactose, sucrose, tartrazine or any other azo dyes.

Supplier

Alphapharm Pty Limited
(ABN 93 002 359 739)
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
Phone: (02) 9298 3999
www.alphapharm.com.au

Australian registration numbers: ZABEP 20 - AUST R 191867

Date of preparation: May 2015

BRAND INFORMATION

Brand name

Zabep 20 Tablets

Active ingredient

Rabeprazole sodium

Schedule

S4

 

1 Name of Medicine

Rabeprazole sodium.

6.7 Physicochemical Properties

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 sodium is a BCS Class III drug.
The chemical name is (±) 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}- methylsulphinyl]-1H-benzimidazole sodium. Rabeprazole has one chiral centre and is a racemic mixture of two enantiomers. Molecular formula: C18H20N3NaO3S. Molecular weight: 381.43.

Chemical structure.


CAS number.

117976-90-6.

2 Qualitative and Quantitative Composition

Zabep 20 enteric coated tablets contain 20 mg of rabeprazole sodium. The tablets also contain povidone, hydroxypropyl cellulose, magnesium oxide, mannitol, magnesium stearate, ethylcellulose, methacrylic acid - ethyl acrylate copolymer (1:1), polysorbate 80, sodium lauryl sulfate, propylene glycol, iron oxide yellow, titanium dioxide and purified talc. The tablets are gluten free.

3 Pharmaceutical Form

Rabeprazole sodium 20 mg enteric-coated tablet; Yellow, elliptical, biconvex shaped tablet with no markings.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

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 rapidly disappears from both the plasma and gastric mucosa.

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 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, Carcinogenicity).
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.

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 sodium 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 sodium 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 sodium 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 sodium (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 sodium 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 sodium 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 sodium tablets are enteric coated to allow rabeprazole, which is acid labile, to pass through the stomach intact. Absorption is rapid, with peak plasma levels of rabeprazole occurring approximately 3.5 hours after a 20 mg dose. Peak plasma concentrations (Cmax) of rabeprazole 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 is approximately 97% bound to human plasma proteins. After intravenous administration the volume of distribution is 0.34 L/kg.

Metabolism.

Rabeprazole 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.

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.

Geriatrics.

Elimination of rabeprazole 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 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.

In this 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 sodium 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

Zabep 20 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 non-steroidal anti-inflammatory drugs (NSAIDs) usually require treatment with antimicrobial agents in addition to antisecretory drugs whether on first presentation or on recurrence.
Zabep 20 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.

4.3 Contraindications

Zabep 20 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 sodium does not preclude the presence of gastric malignancy, therefore the possibility of malignancy should be excluded prior to commencing treatment with rabeprazole sodium.
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). 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 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 sodium 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, Use in elderly patients; Section 5.2 Pharmacokinetic Properties, Geriatrics.

Paediatric use.

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

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 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 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.

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.

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.

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 sodium.

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 sodium with antacids produces no clinically relevant changes in rabeprazole 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 g.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 B11)
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.
1 Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have not shown evidence of an increased occurrence of fetal damage.
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 body weight gain of the pups.
It is not known whether rabeprazole 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, 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)

Throughout this section, adverse reactions are presented. Adverse reactions are adverse events that were considered to be reasonably associated with the use of rabeprazole based on the comprehensive assessment of the available adverse event information.

Clinical trials.

Rabeprazole sodium 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 sodium 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 sodium.
The adverse events, which may or may not be causally related to rabeprazole sodium, 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, fundic gland polyps (benign).

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.

Post-marketing experience.

In addition to the adverse reactions reported during clinical studies and listed above, the following adverse reactions have been reported during 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 dyscrasias including thrombocytopenia, neutropenia, leukopenia, pancytopenia, agranulocytosis and bicytopenia have been reported rarely. Hypomagnesemia has also 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).

Gastrointestinal disorders.

Frequency not known: withdrawal of long-term PPI therapy can lead to aggravation of acid-related symptoms and may result in rebound acid hypersecretion.

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 sodium tablets should not be chewed or crushed, but should be swallowed whole. Rabeprazole sodium tablets should be taken at the same time each day to facilitate treatment compliance. Rabeprazole sodium 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 sodium 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 sodium 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 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 sodium in combination with antibiotic regimens in patients with renal or hepatic impairment.
Zabep 20 tablets are available in a 20 mg strength only. Should a 10 mg strength be required other rabeprazole sodium tablets are available.

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

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 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.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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.

6.5 Nature and Contents of Container

Aluminium/ aluminium foil blister packs of 30 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

Summary Table of Changes