Consumer medicine information

Chemists' Own Heartburn Relief Esomeprazole Tablets

Esomeprazole

BRAND INFORMATION

Brand name

Chemists' Own Heartburn Relief Esomeprazole

Active ingredient

Esomeprazole

Schedule

S2

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Chemists' Own Heartburn Relief Esomeprazole Tablets.

What is in this leaflet

This leaflet answers some of the common questions people ask about CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS.

It does not contain all the information that is known about CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS.

It does not take the place of talking to your pharmacist or doctor.

All medicines have risks and benefits. Your pharmacist will have weighed the risks of you taking CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS against the benefits they expect it will have for you.

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

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

What CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS is used for

CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS is used for the relief of frequent heartburn and stomach acid complaints due to gastro-oesophageal reflux disease (GORD). This can be caused by "washing back" (reflux) of food and acid from the stomach into the food pipe (oesophagus).

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

Frequent heartburn is when you have heartburn for two or more times a week. Heartburn that occurs frequently is a typical symptom of GORD.

Who should use CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS

CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS is recommended for adults 18 years of age and over, who suffer from frequent heartburn at least 2 times a week.

CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS is not the right medicine for you if you suffer heartburn only occasionally (one episode of heartburn a week or less), or if you want immediate relief of heartburn.

How CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS works

CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS is a type of medicine called a proton-pump inhibitor. It works by decreasing the amount of acid made by the stomach. This gives relief of symptoms and also allows healing to take place. This does not stop food being digested in the normal way.

CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS is available only from your pharmacist. It can be purchased directly from your local pharmacy without a doctor's prescription.

There is no evidence that this medicine is addictive.

Before you take CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS

When you must not take it

Do not take CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS if you have allergies to:

  • esomeprazole or any ingredient listed at the end of this leaflet
  • any medicines containing a proton-pump inhibitor such as omeprazole, lansoprazole, pantoprazole and rabeprazole

Some of the symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.

Do not take CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS if you are also taking atazanavir or cilostazol (see Taking other medicines). Please check with your pharmacist or doctor if you are taking these medicines. These medicines will be affected by CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS.

CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS is not recommended for children and adolescents under 18 years of age.

Do not take CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS after the use by (expiry) date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

Before you start to take it

Tell your pharmacist or doctor if you have:

  • allergies to any other medicines, foods, dyes or preservatives
  • any problems with your liver
  • severe kidney problems
  • any other medical conditions
  • difficulty swallowing, persistent vomiting or vomiting blood, blood in the stools or unexplained weight loss
  • taken other medication for indigestion or heartburn continuously for four or more weeks in order to control your symptoms
  • recently finished a course of CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS or similar medicine within the last two weeks

Do not take CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS if you are pregnant or breastfeeding unless your doctor says so. Ask your doctor about the risks and benefits involved. It is not known if it is safe for you to take this medicine while you are pregnant. It may affect your baby.

It is not known if this medicine passes into breast milk if you are breastfeeding.

Taking other medicines

Do not take CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS if you are taking the following medicines:

  • atazanavir, a medicine used to treat Human Immunodeficiency Virus (HIV)
  • cilostazol, a medicine used to treat muscle pain or cramping caused by reduced blood circulation in the lower legs (intermittent claudication).

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

Some medicines may interfere with CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS.

These include:

  • ketoconazole, itraconazole and voriconazole, medicines used to treat fungal infections
  • diazepam, a medicine used to treat anxiety and some other conditions
  • phenytoin, a medicine used to treat epilepsy or fits
  • citalopram, clomipramine and imipramine, medicines used to treat depression
  • St John's wort, a herbal remedy used to treat mood disorders
  • clarithromycin and rifampicin, medicines used to treat bacterial infections
  • warfarin and clopidogrel, medicines used to prevent blood clots
  • nelfinavir or medicines for HIV treatment
  • digoxin, a medicine used to treat heart conditions
  • methotrexate, a medicine used to treat arthritis and some types of cancer
  • tacrolimus, a medicine used to assist in organ transplants
  • erlotinib or related medicines used to treat cancer

These medicines may be affected by CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS or may affect how well it works. You may need different amounts of your medicine or you may need to take different medicines.

Your pharmacist or doctor can tell you what to do if you are taking any other medicines.

Your pharmacist or doctor have more information on medicines to be careful with or avoid while taking this medicine.

If you have not told your pharmacist or doctor about any of these things, tell them before you take CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS.

How to take CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS

Follow all directions given to you by your pharmacist or doctor carefully. These instructions may differ from the information contained in this leaflet.

If you do not understand the directions on the label, ask your pharmacist or doctor for help.

How much to take

Take one CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS 20 mg tablet each day.

How to take it

Swallow the tablets whole with a glass of water.

Do not crush or chew the tablets. If the tablets are chewed or crushed they will not work properly.

If you have difficulty swallowing the tablets:

  1. Place the tablet in half a glass of non-carbonated water. Mineral water or other liquids are not suitable.
  2. Gently mix the tablet and water by stirring, taking care not to crush the tablet.
  3. Stir until the tablet dissolves into little pellets.
  4. Drink the liquid with the pellets immediately, or within 30 minutes. Do not chew the pellets.
  5. Rinse the glass with half a glass of water and drink.

When to take it

Take CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS at about the same time each day.

This medicine can be taken with food or on an empty stomach.

How long to take it

CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETSshould be taken for at least 7 days, and up to 14 days. You should not take it for more than 14 days unless directed by a doctor.

Tell your pharmacist or doctor if you do not feel better while taking this medicine. If your symptoms persist or recur within two weeks of completing the course, consult a doctor. Your doctor may recommend further examination.

If you forget to take it

If you forget to take a dose, take it as soon as you remember, and then go back to taking it as you would normally.

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 that you missed.

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

Taking too much (overdose)

Telephone your doctor or the Poisons Information Centre (13 11 26) or go to Accident and Emergency at your nearest hospital immediately if you think that you or anyone else may have taken too many CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS.

Do this even if there are no signs of discomfort or poisoning.

While you are taking CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS

Things you must do

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are taking CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS.

Tell all doctors, dentists and pharmacists who are treating you that you are taking this medicine.

If you become pregnant while you are taking CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS, tell your doctor or pharmacist immediately.

If you need to have any medical tests while you are taking CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS, tell your doctor that you are taking this medicine. It may affect the results of some tests.

Things you must not do

Do not take this medicine to treat any other complaints unless your doctor tells you to.

Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

Side effects

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

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 of the side effects.

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

Tell your pharmacist or doctor if you notice any of the following and they worry you:

  • nausea or vomiting
  • constipation
  • diarrhoea
  • headache
  • wind
  • stomach pain
  • skin rash, itchy skin
  • dizziness
  • dry mouth

These side effects are usually mild.

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

  • blurred vision
  • mood changes, confusion or depression
  • muscle pain or weakness, joint pain
  • increase in breast size (males)
  • increased sweating
  • changes in sleep patterns
  • fever
  • increased bruising
  • "pins and needles"
  • hair loss
  • tremor
  • blood in the urine

These side effects may require medical attention.

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

If you notice any of the following happen, tell your pharmacist or doctor immediately or go to Accident and Emergency at the nearest hospital:

  • shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • severe skin reaction which may include rash, itching, redness, blistering or peeling of the skin
  • signs of liver inflammation including yellowing of the skin or eyes, feeling generally unwell, nausea, vomiting, loss of appetite

These are very serious side effects. You may need urgent medical treatment or hospitalisation.

Occasionally, this medicine may be associated with changes in your liver or blood, which may require your doctor to do certain blood tests.

Tell your pharmacist or doctor if you think you have any of these effects or notice anything else that is making you feel unwell. Some people may get other side effects while taking this medicine.

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

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

  • pain or indigestion during treatment with this medicine
  • you begin to vomit blood or food
  • you pass black (blood-stained) motions

Heat and dampness can destroy some medicines.

After taking it

Storage

Keep your CHEMISTS ’OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS in the blister pack until it is time to take them. If you take this medicine out of the blister pack it will not keep well.

Keep it in a cool, dry place where the temperature stays below 25°C.

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

Do not leave it in the car or on a window sill.

Keep it where young children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

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

Product description

What this medicine looks like

CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS

20 mg are light pink, oblong, biconvex, film coated tablets debossed with ‘20’ on one side and ‘CE’ on the other side.

Ingredients

Each tablet contains 20 mg esomeprazole (as esomeprazole magnesium)

The enteric coated tablets also contain:

  • Microcrystalline cellulose
  • Iron oxide red
  • Povidone
  • Pregelatinised maize starch
  • Silicon dioxide
  • Lactose
  • Hyprolose
  • Crospovidone
  • Confectioner’s sugar (sucrose and maize starch)
  • Magnesium oxide light
  • Purified talc
  • Macrogol 6000
  • Methacrylic acid - ethyl acrylate copolymer (1:1)
  • Glyceryl monostearate
  • Macrogol 400
  • Polysorbate 80
  • Hypromellose phthalate
  • Acetone
  • Non-pareil seeds 40-50 (ARTG 108808)
  • OPADRY complete film coating system 03B84893 PINK (ARTG 108603)

CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS are available in blister packs of 7 and 14 tablets. CHEMISTS’ OWN HEARTBURN RELIEF ESOMEPRAZOLE TABLETS contains lactose. The tablets are gluten free.

Supplier

Arrow Pharma Pty Ltd
15-17 Chapel Street
Cremorne, VIC 3121
Australia

Australian registration numbers: AUST R 252676

This leaflet was prepared in September 2021.

Published by MIMS October 2021

BRAND INFORMATION

Brand name

Chemists' Own Heartburn Relief Esomeprazole

Active ingredient

Esomeprazole

Schedule

S2

 

1 Name of Medicine

The name of the medicine is esomeprazole magnesium, a substituted benzimidazole.

2 Qualitative and Quantitative Composition

Each tablet of Chemists' Own Heartburn Relief Esomeprazole contains 20 mg esomeprazole (as esomeprazole magnesium) as enteric-coated pellets.

Excipients with known effect.

Lactose monohydrate and sucrose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Dosage form: Enteric coated tablet.

Chemists' Own Heartburn Relief Esomeprazole Tablets 20 mg.

Light pink, oblong, biconvex, film coated tablets debossed with '20' on one side and 'CE' on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Chemists' Own Heartburn Relief Esomeprazole Tablets is indicated for the symptomatic relief of frequent heartburn, acid regurgitation and other symptoms associated with gastro-oesophageal reflux disease (GORD).

4.2 Dose and Method of Administration

Chemists' Own Heartburn Relief Esomeprazole Tablets should be swallowed whole with liquid. The tablets should not be chewed or crushed.
If required, the tablets can also be dispersed in half a glass of non-carbonated water (mineral water is not suitable). No other liquids should be used. Stir until the tablets disintegrate and drink the liquid with the pellets immediately or within 30 minutes. Rinse the glass with half a glass of water and drink. The pellets must not be chewed or crushed.

Symptomatic gastro-oesophageal reflux disease (GORD).

Adults.

The recommended dose for the relief of heartburn and other symptoms of GORD is one Chemists' Own Heartburn Relief Esomeprazole Tablets 20 mg once daily for at least 7 days, and up to 14 days. Patients should be referred to their doctor if symptoms persist or worsen while taking this course, or if symptoms persist or recur within two weeks of completing the course. Further investigation is recommended. Use for longer than 14 days should only be on medical advice.

Children and adolescents less than 18 years.

Not recommended for use in children and adolescents below 18 years of age.

Geriatrics.

Dose adjustment is not required in the elderly.

Hepatic insufficiency.

Dose adjustment is not required in patients with mild to moderate liver impairment (Child Pugh A and B). For patients with severe liver impairment (Child Pugh C), a maximum dose of 20 mg esomeprazole should not be exceeded (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment).

Renal insufficiency.

Dosage adjustment is not required in patients with impaired renal function. Due to limited experience in patients with severe renal insufficiency such patients should be treated with caution.

4.3 Contraindications

Known hypersensitivity to esomeprazole, substituted benzimidazoles or any other constituents of the formulation.
Esomeprazole like other proton pump inhibitors should not be administered with atazanavir (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Effects of esomeprazole on other drugs).
Esomeprazole, an inhibitor of CYP2C19, is contraindicated in patients taking cilostazol.

4.4 Special Warnings and Precautions for Use

Patients should be referred to their doctor for review if:
They have significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melaena; and when gastric ulcer is suspected or present, as treatment with esomeprazole may alleviate symptoms and delay diagnosis. In these cases, malignancy should be excluded.
They are being treated for gastro-oesophageal reflux (heartburn) or gastro-oesophageal reflux disease (GORD) and symptoms persist for more than 14 days.
Their symptoms persist or recur within two weeks of completing a course of esomeprazole.
They have any other significant medical conditions.
They are an adolescent or child under the age of 18 years.
Decreased gastric acidity due to any means including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and, in hospitalised patients, possibly also Clostridium difficile.

Special patient populations.

CYP2C19 enzyme.

Approximately 3% of the population lack a functional CYP2C19 enzyme and are called poor metabolisers. In these individuals the metabolism of esomeprazole is most likely catalysed by CYP3A4. After repeated once-daily administration of 40 mg esomeprazole, the mean area under the plasma concentration-time curve was approximately 100% higher in poor metabolisers than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean plasma concentrations were increased by about 60%. These findings have no implications for the dosage of esomeprazole.
In case of clopidogrel, a prodrug which is transformed into its active metabolite via CYP2C19, the plasma concentrations of the active metabolite may be decreased (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Gender.

Following a single dose of 40 mg esomeprazole the mean area under the plasma concentration-time curve is approximately 30% higher in females than in males. No gender difference is seen after repeated once-daily administration. These findings have no implications for the dosage of esomeprazole.

Use in hepatic impairment.

The metabolism of esomeprazole in patients with mild to moderate liver dysfunction (Child Pugh A or B) may be impaired, however no dose adjustment is required. The metabolic rate is decreased in patients with severe liver dysfunction (Child Pugh C) resulting in a doubling of the area under the plasma concentration-time curve for esomeprazole. Therefore, a maximum of 20 mg should not be exceeded in patients with severe dysfunction. Esomeprazole or its major metabolites do not show any tendency to accumulate with once daily dosing (see Section 4.2 Dose and Method of Administration).

Use in renal impairment.

No studies have been performed in patients with decreased renal function. Since the kidney is responsible for the excretion of the metabolites of esomeprazole but not for the elimination of the parent compound, the metabolism of esomeprazole is not expected to be changed in patients with impaired renal function.

Use in the elderly.

The metabolism of esomeprazole is not significantly changed in elderly subjects (71-80 years).

Paediatric use.

Not recommended for use in children and adolescents below 18 years of age.

Effects on laboratory tests.

Chromogranin A (CgA) increases due to decreased gastric acidity. The increased CgA level may interfere with investigations for neuroendocrine tumours. Literature reports indicate that proton pump inhibitor treatment should be stopped 5 to 14 days before CgA measurement. Measurements should be repeated if levels have not normalised by this time.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Esomeprazole is metabolised via the CYP2C19 and CYP3A4 isoforms of the hepatic cytochrome P-450 system and may be expected to interact with the pharmacokinetics of other drugs metabolised by this system.
Esomeprazole inhibits CYP2C19, the major esomeprazole metabolising enzyme. Thus, when esomeprazole is combined with drugs metabolised by CYP2C19 (see Effects of esomeprazole on other drugs), the plasma concentrations of these drugs may be increased and a dose reduction could be needed.

Other drugs that affect esomeprazole.

Clarithromycin.

Concomitant administration of esomeprazole and a CYP3A4 inhibitor, clarithromycin (500 mg bid), resulted in a doubling of the exposure (AUC) to esomeprazole. Dose adjustment of esomeprazole is not required.
Concomitant administration of esomeprazole and a combined inhibitor of CYP2C19 and CYP3A4, such as voriconazole, may result in more than doubling of the esomeprazole exposure. However, dose adjustment of esomeprazole, with normal dosage, is not required.
CYP3A4 is a less important pathway than CYP2C19. However, inhibitors of CYP3A4 other than clarithromycin (e.g. ketoconazole, itraconazole, erythromycin etc.) may also reduce esomeprazole clearance, although this is unlikely to be of any clinical significance.
Drugs known to induce CYP2C19 or CYP3A4 or both (such as rifampicin and St. John's wort) may lead to decreased esomeprazole serum levels by increasing the esomeprazole metabolism.

Effects of esomeprazole on other drugs.

Cisapride.

In healthy volunteers, concomitant administration of esomeprazole 40 mg resulted in a 32% increase in area under the plasma concentration-time curve (AUC) and a 31% prolongation of elimination half-life (t½) but no significant increase in peak plasma levels of cisapride. The slightly prolonged QTc interval observed after administration of cisapride alone, was not further prolonged when cisapride was given in combination with esomeprazole (see Section 4.4 Special Warnings and Precautions for Use).

Cilostazol.

Omeprazole as well as esomeprazole act as inhibitors of CYP2C19. Omeprazole, given in doses of 40 mg to healthy subjects in a cross-over study, increased Cmax and AUC for cilostazol by 18% and 26% respectively, and one of its active metabolites by 29% and 69% respectively (see Section 4.3 Contraindications).

Citalopram, clomipramine and imipramine.

Because the plasma concentrations of these drugs may be increased by the concomitant administration of esomeprazole a dose reduction could be needed.

Clopidogrel.

Results from studies in healthy subjects have shown a pharmacokinetic/pharmacodynamic (PK/PD) interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and esomeprazole (40 mg p.o. daily) resulting in decreased exposure to the active metabolite of clopidogrel by an average of 40%, and resulting in decreased maximum inhibition of (ADP induced) platelet aggregation by an average of 14%. Based on these data, concomitant use of esomeprazole and clopidogrel should be avoided.
When clopidogrel was given together with a fixed dose combination of esomeprazole 20 mg + ASA 81 mg compared to clopidogrel alone in a study in healthy subjects there was a decreased exposure by almost 40% of the active metabolite of clopidogrel. However, the maximum levels of inhibition of (ADP induced) platelet aggregation in these subjects were similar in the clopidogrel and the clopidogrel + the combined (esomeprazole + ASA) product groups.
There are both observational and clinical studies on the clinical implications of a PK/PD interaction (with proton pump inhibitors, including omeprazole) investigating the number of major cardiovascular events when clopidogrel and proton pump inhibitors are given concomitantly.

Diazepam.

Concomitant administration of 30 mg esomeprazole to healthy volunteers resulted in 45% decrease in clearance of the CYP2C19 substrate diazepam. This interaction is unlikely to be of clinical relevance.

NSAID drugs.

Studies evaluating concomitant administration of esomeprazole and either naproxen (non-selective NSAID) or rofecoxib (COX-2 selective NSAID) did not identify any clinically relevant interactions in young healthy Caucasian volunteers.

Phenytoin.

Concomitant administration of 40 mg esomeprazole resulted in a 13% increase in trough plasma levels of phenytoin in epileptic patients. Dose adjustment was not required in this study. It is recommended to monitor the plasma concentrations of phenytoin when treatment with esomeprazole is introduced or withdrawn.

Warfarin.

Concomitant administration of 40 mg esomeprazole to warfarin-treated patients showed that, despite a slight elevation in the trough plasma concentration of the less potent R-isomer of warfarin, the coagulation times were within the accepted range. However, from post-marketing use cases of elevated INR of clinical significance have been reported during concomitant treatment with warfarin. Close monitoring is recommended when initiating and ending treatment with warfarin or other coumarin derivatives.

Tacrolimus.

Concomitant administration of esomeprazole has been reported to increase the serum levels of tacrolimus.

Methotrexate.

When given together with proton pump inhibitors, methotrexate levels have been reported to increase in some patients. In high-dose methotrexate administration a temporary withdrawal of esomeprazole may need to be considered.

Antiretroviral drugs.

Concomitant administration with esomeprazole and atazanavir is contraindicated.
Omeprazole has been reported to interact with some antiretroviral drugs. The clinical importance and the mechanisms behind these reported interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviral drug. Other possible interaction mechanisms are via CYP2C19. For some antiretroviral drugs, such as atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole and concomitant administration is not recommended. For other antiretroviral drugs, such as saquinavir, increased serum levels have been reported. There are also some antiretroviral drugs for which unchanged serum levels have been reported when given with omeprazole. Due to the similar pharmacodynamic effects and pharmacokinetic properties of omeprazole and esomeprazole, concomitant administration with esomeprazole and antiretroviral drugs such as nelfinavir is not recommended.

Medicinal products with pH dependent absorption.

The decreased intragastric acidity during treatment with esomeprazole and other PPIs, might increase or decrease the absorption of drugs if the mechanism of absorption is influenced by gastric acidity. In common with the use of other inhibitors of acid secretion or antacids, the absorption of drugs such as ketoconazole, itraconazole and erlotinib can decrease and the absorption of drugs such as digoxin can increase during treatment with esomeprazole. Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (up to 30% in two out of ten subjects).

Potential interactions that have been excluded.

Amoxycillin or quinidine.

Esomeprazole has been shown to have no clinically relevant effects on the pharmacokinetics of amoxicillin or quinidine.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

A fertility study has not been conducted on esomeprazole. However, there was no evidence that omeprazole impaired fertility in the rat at an estimated exposure (plasma AUC) of 1-2.5 times the maximum clinical exposure for adults.
(Category B3)
For esomeprazole limited clinical data on exposed pregnancies are available. Esomeprazole should only be given to pregnant women if its use is considered essential.
Esomeprazole was not teratogenic in rats or rabbits at oral doses up to 800 and 250 micromol/kg.day, respectively [corresponding to respective exposures (plasma AUC) of about 6-10 times and 0.04 times the anticipated clinical value in adults]. However, in rabbits, esomeprazole was associated with reduced fetal weights and an increased incidence of minor skeletal anomalies, although these effects were most probably related to the maternal toxicity of esomeprazole in this species. No effects on the fetuses were observed in the rat teratology study, in which an adequate systemic exposure to esomeprazole was achieved.
It is not known if esomeprazole or its metabolites appear in human breast milk. No studies in lactating women have been performed. Therefore, esomeprazole should not be used during breast feeding.

4.7 Effects on Ability to Drive and Use Machines

Esomeprazole is not likely to affect the ability to drive or use machines.

4.8 Adverse Effects (Undesirable Effects)

Esomeprazole is well tolerated.

Clinical trials and post-marketing data.

The following adverse reactions have been identified or suspected in the clinical trials programme and/or from post-marketing experience for esomeprazole. None was found to be dose-related.
Adverse reactions within each body system are listed in descending order of frequency (Very common: ≥ 10%; common: ≥ 1% and < 10%; uncommon: ≥ 0.1% and < 1%; rare: ≥ 0.01% and < 0.1%; very rare: < 0.01%). These include the following:

Blood and lymphatic system disorders.

Rare: leukopenia, thrombocytopenia.
Very rare: agranulocytosis, pancytopenia.

Immune system disorders.

Rare: hypersensitivity reactions e.g. angioedema and anaphylactic reaction/shock.

Metabolism and nutrition disorders.

Uncommon: peripheral oedema.
Rare: hyponatraemia.
Very rare: hypomagnesaemia; severe hypomagnesaemia may result in hypocalcaemia. Hypomagnesaemia may also result in hypokalaemia.

Psychiatric disorders.

Uncommon: insomnia.
Rare: agitation, confusion, depression.
Very rare: aggression, hallucination.

Nervous system disorders.

Common: headache.
Uncommon: dizziness, paraesthesia, somnolence.
Rare: taste disturbance.

Eye disturbances.

Rare: blurred vision.

Ear and labyrinth disorders.

Uncommon: vertigo.

Respiratory, thoracic, mediastinal disorders.

Rare: bronchospasm.

Gastrointestinal.

Common: abdominal pain, diarrhoea, flatulence, nausea/vomiting, constipation.
Uncommon: dry mouth.
Rare: stomatitis, gastrointestinal candidiasis.
Very rare: microscopic colitis.
Frequency not known: Withdrawal of long-term PPI therapy can lead to aggravation of acid-related symptoms and may result in rebound acid hypersecretion.

Hepatobiliary disorders.

Uncommon: increased liver enzymes.
Rare: hepatitis with or without jaundice.
Very rare: hepatic failure, hepatic encephalopathy.

Skin and subcutaneous tissue disorders.

Uncommon: dermatitis, pruritus, urticaria, rash.
Rare: alopecia, photosensitivity.
Very rare: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), acute generalised exanthematous pustulosis (AGEP), drug rash with eosinophilia and systemic symptoms (DRESS).
Not known: subacute cutaneous lupus erythematosus (SCLE).

Musculoskeletal, connective tissue and bone disorders.

Rare: arthralgia, myalgia.
Very rare: muscular weakness.

Renal and urinary disorders.

Very rare: interstitial nephritis.

Reproductive system and breast disorders.

Very rare: gynaecomastia.

General disorders and administration site conditions.

Rare: malaise, hyperhidrosis.

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. Health care professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

The symptoms described in connection with deliberate esomeprazole overdose are transient. The symptoms described in connection with 280 mg were gastrointestinal symptoms and weakness. Single doses of 80 mg esomeprazole were uneventful. No specific antidote is known. Esomeprazole is extensively protein bound and is therefore not readily dialyzable. As in any case of overdose, treatment should be symptomatic and general supportive measures should be utilised.
For information on the management of overdose, contact the Poisons Information Centre 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Esomeprazole is a proton pump inhibitor. Esomeprazole is the S-isomer of omeprazole. It is optically stable in vivo, with negligible conversion to the R-isomer.

Mechanism of action.

Esomeprazole magnesium reversibly reduces gastric acid secretion by specifically inhibiting the gastric enzyme H+, K+-ATPase proton pump in the parietal cell. Both the R- and S-isomer of omeprazole have similar pharmacodynamic activity. In humans, acid control with esomeprazole is dose dependent and is significantly greater, more sustained and less variable compared to that obtained with equal doses of omeprazole.
Esomeprazole is a weak base and is concentrated and converted to the active form in the highly acidic environment of the secretory canaliculi of the parietal cell, where it inhibits the enzyme H+, K+-ATPase (the acid pump) and inhibits both basal and stimulated acid secretion.

Effect on gastric acid secretion.

After oral dosing with esomeprazole 20 mg and 40 mg the onset of effect occurs within one hour. After repeated administration with 20 mg esomeprazole once daily for five days, mean peak acid output after pentagastrin stimulation is decreased 90% when measured 6-7 hours after dosing on day five.
After five days of oral dosing with 20 mg and 40 mg of esomeprazole, intragastric pH above 4 was maintained for a mean time of 13 hours and 17 hours, respectively over 24 hours in symptomatic GORD patients. The corresponding time for omeprazole 20 mg of 10 hours was significantly shorter. In this study, the percentage of GORD patients maintaining an intragastric pH above 4 for at least 8, 12 and 16 hours are tabulated (see Table 1).
In vivo results demonstrate that acid control with esomeprazole is dose dependent and that it is significantly greater, more sustained and less variable compared to an equal dose of the racemate.
Using AUC as a surrogate parameter for plasma concentration, a relationship between inhibition of acid secretion and exposure has been shown.
A 6-way crossover study was conducted to investigate the dose response relationship assessed by intragastric pH monitoring after repeated once daily oral doses of 20, 40 and 80 mg of esomeprazole and 20, 40 and 80 mg of pantoprazole in symptomatic GORD patients. Results are provided in Table 2.

Other effects related to acid inhibition.

During treatment with antisecretory agents serum gastrin increases in response to decreased acid secretion. An increased number of ECL cells possibly related to the increased serum gastrin levels, have been observed in some patients during long term treatment with esomeprazole. During long-term treatment with antisecretory drugs gastric glandular cysts have been reported to occur. These changes are a physiological consequence of pronounced inhibition of acid secretion, are benign and appear reversible.

Clinical trials.

Symptomatic treatment of GORD in patients with normal endoscopy.

At the time of registration, five randomised, double-blind controlled clinical trials (n=3,362) were evaluated to assess the efficacy of esomeprazole in the complete resolution of heartburn at 4 weeks comparing esomeprazole 20 mg or 40 mg with omeprazole 20 mg or placebo. Study B7 was a dose-finding study, two studies compared esomeprazole 40 mg and omeprazole 20 mg (B8 and B9), and two compared esomeprazole 20 mg, 40 mg and placebo (B16 and B17).
There were no apparent differences in any of the studies between population subsets based on gender, age, race or H. pylori status in the proportion of patients with complete resolution of heartburn by treatment. The proportion of patients with complete resolution of heartburn at 4 weeks in studies B7, B8 and B9 (n=2,645), independent of treatment, was approximately 60%. There was no statistically significant difference between any of the treatment groups with regard to complete resolution of heartburn at 2 weeks or 4 weeks.
In studies B16 and B17 the proportion of patients (n=717) with complete resolution of heartburn at 4 weeks was significantly higher for esomeprazole 20 mg and 40 mg compared to placebo.

5.2 Pharmacokinetic Properties

Absorption.

Esomeprazole is acid labile and is administered orally as enteric coated pellets in tablets. The enteric coating film, protecting the esomeprazole magnesium, dissolves at a pH above 5.5. Hence esomeprazole magnesium is not released until the pellets are emptied into the duodenum.
Once esomeprazole magnesium dissolves in this near neutral environment, the esomeprazole ion transforms to its neutral form and is absorbed as such. In vivo conversion to the R-isomer is negligible. Absorption is rapid with peak plasma levels of esomeprazole occurring approximately 1 to 2 hours after the dose. The absolute bioavailability is 50% after a single dose of 20 mg and increases to 68% after repeated once-daily administration.
Food intake both delays and decreases the absorption of esomeprazole although this has no significant influence on the effect of esomeprazole on intragastric acidity.

Distribution.

The apparent volume of distribution at steady state in healthy subjects is approximately 0.22 L/kg body weight. Esomeprazole is 97% protein bound.

Metabolism.

Esomeprazole is completely metabolised by the cytochrome P450 system (CYP450). The intrinsic clearance of esomeprazole (S-isomer) is one third of that of the R-isomer, resulting in a higher AUC with less inter-individual variation compared to the racemate. The major part of the metabolism of esomeprazole is dependent on the polymorphic CYP2C19, responsible for the formation of the hydroxy- and desmethyl metabolites of esomeprazole. The remaining part is dependent on another specific isoform, CYP3A4, responsible for the formation of esomeprazole sulphone, the main metabolite in plasma.
The parameters below reflect mainly the pharmacokinetics in individuals with a functional CYP2C19 enzyme, extensive metabolisers.
Total plasma clearance is about 17 L/h after a single dose and about 9 L/h after repeated administration. The plasma elimination half-life is about 1.3 hours after repeated once-daily dosing. The area under the plasma concentration-time curve increases with repeated administration of esomeprazole. This increase is dose-dependent and results in a non-linear dose-AUC relationship after repeated administration. This time- and dose-dependency is due to a decrease of first pass metabolism and systemic clearance probably caused by an inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulphone metabolite. Esomeprazole is completely eliminated from plasma between doses with no tendency for accumulation during once-daily administration.

Excretion.

The major metabolites of esomeprazole have no effect on gastric acid secretion. Almost 80% of an oral dose of esomeprazole is excreted as metabolites in the urine, the remainder in the faeces. Less than 1% of the parent drug is found in urine.

5.3 Preclinical Safety Data

Genotoxicity.

Esomeprazole was negative in a bacterial gene mutation assay. In clastogenicity tests, esomeprazole was positive (as was omeprazole) in an in vitro chromosome aberration test in human lymphocytes. However, two in vivo tests (a mouse micronucleus test and an in vivo chromosome aberration test in rat bone marrow) in the presence of long and high systemic exposure to esomeprazole, showed that esomeprazole was not clastogenic under in vivo conditions. Exposure levels in man are well below those at which clastogenic effects occurred in vitro.

Carcinogenicity.

Preclinical bridging studies between the enantiomer esomeprazole and the racemate (omeprazole) showed that these compounds are pharmacologically and toxicologically similar at equivalent systemic exposure. Thus, the extensive preclinical database for omeprazole is also relevant for the safety assessment of esomeprazole.
No carcinogenicity studies have been conducted on esomeprazole. However, omeprazole (the racemate) produced enterochromaffin-like (ECL) cell hyperplasia and gastric carcinoids in rats. In a 104-week study in rats, carcinoids were observed at doses (on a mg/m2 basis) which ranged from 0.4 to 30-fold the maximum clinical dose for adults. However, a no-effect dose level was not determined in female rats. A similar effect was not observed in a 78-week mouse carcinogenicity study with omeprazole. These gastric effects in the rat are believed to be the result of sustained, pronounced hypergastrinaemia secondary to reduced production of gastric acid. Similar effects are elicited by other proton pump inhibitors, H2-receptor antagonists and by partial fundectomy.

6 Pharmaceutical Particulars

6.1 List of Excipients

Non-pareil seeds 40-50 (ARTG 108808), hyprolose, crospovidone, sucrose and maize starch, magnesium oxide light, purified talc, macrogol 6000, methacrylic acid - ethyl acrylate copolymer (1:1), glyceryl monostearate, macrogol 400, polysorbate 80, hypromellose phthalate, acetone, microcrystalline cellulose, iron oxide red, povidone, pregelatinised maize starch, silicon dioxide, lactose and OPADRY complete film coating system 03B84893 Pink (ARTG 108603).

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

Available in Al/Al blister packs of 7 and 14 tablets.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Esomeprazole magnesium is an off-white to slight coloured powder, soluble in N,N-Dimethyl formamide.

Chemical structure.


Chemical name: di-(S)-5-methoxy-2-[[(4- methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole magnesium salt.
Molecular Formula: C34H36N6O6S2Mg. Molecular Weight: 713.12.

CAS number.

[161973-10-0].

7 Medicine Schedule (Poisons Standard)

S3 (Pharmacist Only Medicine).

Summary Table of Changes