Consumer medicine information

Noxicid Caps Heartburn Relief

Esomeprazole

BRAND INFORMATION

Brand name

Noxicid Caps Heartburn Relief

Active ingredient

Esomeprazole

Schedule

S2

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Noxicid Caps Heartburn Relief.

What is in this leaflet

This leaflet answers some of the common questions people ask about NOXICID CAPS HEARTBURN RELIEF. It does not contain all the information that is known about NOXICID CAPS HEARTBURN RELIEF.

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

All medicines have risks and benefits. Your pharmacist or doctor will have weighed the risks of you taking NOXICID CAPS HEARTBURN RELIEF 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 NOXICID CAPS HEARTBURN RELIEF is used for

NOXICID CAPS HEARTBURN RELIEF 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.

How NOXICID CAPS HEARTBURN RELIEF works

NOXICID CAPS HEARTBURN RELIEF is a type of medicine called a proton-pump inhibitor. It works by decreasing the amount of acid made by the stomach, to give relief of symptoms and allow healing to take place. This does not stop food being digested in the normal way.

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

Ask your pharmacist or doctor if you want more information.

There is no evidence that NOXICID CAPS HEARTBURN RELIEF is addictive.

This medicine can be purchased directly from your pharmacy without a doctor’s prescription.

Before you take NOXICID CAPS HEARTBURN RELIEF

When you must not take it

Do not take NOXICID CAPS HEARTBURN RELIEF if you have allergies to:

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

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 NOXICID CAPS HEARTBURN RELIEF if you are also taking atazanavir or cilostazol. Please check with your pharmacist or doctor if you are taking these medicines. These medicines will be affected by NOXICID CAPS HEARTBURN RELIEF.

NOXICID CAPS HEARTBURN RELIEF is not approved for use in children younger than 18 years of age.

Do not take NOXICID CAPS HEARTBURN RELIEF 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

You must 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
  • difficulty swallowing, persistent vomiting or vomiting of blood, blood in stools, unexplained weight loss or some other significant medical conditions
  • have previously taken heartburn/ indigestion medications continuously for 4 or more weeks to control your heartburn
  • recently finished a course of NOXICID CAPS HEARTBURN RELIEF or a similar medicine in the last 2 weeks
  • any other medical conditions
  • been diagnosed with osteoporosis
  • if you have ever had a skin reaction after treatment with a medicine similar to NOXICID CAPS HEARTBURN RELIEF that reduces stomach acid

Ask your pharmacist or doctor before use if you are or may become pregnant. Do not use if you are breastfeeding or wish to start breastfeeding. Ask your pharmacist or doctor about the risks and benefits involved. It is not known if it is safe for you to take NOXICID CAPS HEARTBURN RELIEF while you are pregnant. It may affect your baby.

It is not known if your baby can take in NOXICID CAPS HEARTBURN RELIEF from breast milk if you are breastfeeding.

Taking other medicines

Do not take NOXICID CAPS HEARTBURN RELIEF if you are taking the following medicines:

  • atazanavir and nelfinavir, medicines used to treat Human Immunodeficiency Virus (HIV)
  • cilostazol, a medicine used to treat pain and/or cramping in the lower legs (or arms) due to inadequate blood flow to the muscles
  • warfarin or clopidogrel- medicines used to prevent blood clots
  • methotrexate, a medicine used to treat arthritis and some types of cancer

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 NOXICID CAPS HEARTBURN RELIEF. These include:

  • medicines used to treat fungal infections such as ketoconazole, itraconazole and voriconazole
  • cisapride
  • diazepam, a medicine used to treat anxiety and some other conditions
  • phenytoin, a medicine used to treat epilepsy
  • medicines used to treat depression such as citalopram, clomipramine or imipramine
  • St John’s wort, a herbal remedy used to treat mood disorders
  • medicines used to treat bacterial infections such as clarithromycin and rifampicin
  • warfarin, a medicine used to prevent blood clots
  • medicines for HIV treatment such as atazanavir and nelfinavir
  • digoxin, a medicine used to treat heart conditions
  • tacrolimus and mycophenolate mofetil, medicines used to assist organ transplants
  • erlotinib or related medicines used to treat cancer

These medicines may be affected by NOXICID CAPS HEARTBURN RELIEF 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 and doctor have more information on medicines to be careful with or avoid while taking NOXICID CAPS HEARTBURN RELIEF.

If you have not told your pharmacist or doctor about any of these things, tell them before you take NOXICID CAPS HEARTBURN RELIEF.

How to take NOXICID CAPS HEARTBURN RELIEF

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

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

How to take it

NOXICID CAPS HEARTBURN RELIEF is available as enteric capsules

NOXICID CAPS HEARTBURN RELIEF Enteric capsules

Take one NOXICID CAPS HEARTBURN RELIEF capsule each day.

Swallow NOXICID CAPS HEARTBURN RELIEF enteric capsules whole with a glass of water. Do not crush or chew the capsules.

If the capsules are chewed or crushed, they will not work properly.

Take NOXICID CAPS HEARTBURN RELIEF at about the same time each day.

Keeping a regular time for taking NOXICID CAPS HEARTBURN RELIEF will help to remind you to take it.

NOXICID CAPS HEARTBURN RELIEF is not intended for immediate relief. It may take several days to achieve maximum results.

NOXICID CAPS HEARTBURN RELIEF should 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.

NOXICID CAPS HEARTBURN RELIEF can be taken with food or on an empty stomach.

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

Taking too much (overdose)

Telephone your pharmacist or 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 NOXICID CAPS HEARTBURN RELIEF. Do this even if there are no signs of discomfort or poisoning.

While you are taking NOXICID CAPS HEARTBURN RELIEF

Things you must do

Take NOXICID CAPS HEARTBURN RELIEF exactly as pharmacist or doctor has prescribed.

If you are about to be started on any new medicine, tell your pharmacist, doctor or dentist that you are taking NOXICID CAPS HEARTBURN RELIEF.

Tell all pharmacists, doctors and dentists who are treating you that you are taking NOXICID CAPS HEARTBURN RELIEF.

Tell your pharmacist or doctor if you become pregnant while you are taking NOXICID CAPS HEARTBURN RELIEF.

Tell your doctor if you are not feeling better or your symptoms worsen.

Tell your doctor if your symptoms persist or return within two weeks of completing the course.

If you have suffered from frequent heartburn/indigestion symptoms for some time you should see your doctor.

If you need to have any medical tests while you are taking NOXICID CAPS HEARTBURN RELIEF, tell your doctor It may affect the results of some tests.

Things you must not do

Do not use it to treat any other conditions unless your pharmacist or 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 NOXICID CAPS HEARTBURN RELIEF.

NOXICID CAPS HEARTBURN RELIEF helps most people with reflux disease, but it may have unwanted side effects in a few people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some 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 you pharmacist or 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
  • skin reaction, especially in sun exposed areas, with joint pain
  • muscle twitching or jerking movements
  • irregular (fast or slow) heartbeat
  • loss of consciousness or awareness

These are all rare or very rare side effects. These side effects may require medical attention.

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. These side effects are rare.

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 NOXICID CAPS HEARTBURN RELIEF.

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 NOXICID CAPS HEARTBURN RELIEF
  • you begin to vomit blood or food
  • you pass black (blood-stained) motions.

After taking NOXICID CAPS HEARTBURN RELIEF

Storage

Keep NOXICID CAPS HEARTBURN RELIEF 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 your NOXICID CAPS HEARTBURN RELIEF in the blister pack until it is time to take them. If you take NOXICID CAPS HEARTBURN RELIEF out of the blister it may not keep well.

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

Protect from moisture.

Do not keep NOXICID CAPS HEARTBURN RELIEF or any other medicine in the bathroom or near a sink.

Do not leave NOXICID CAPS HEARTBURN RELIEF in the car or on window sills.

Heat and dampness can destroy some medicines.

Disposal

If your pharmacist or doctor tells you to stop taking NOXICID CAPS HEARTBURN RELIEF or the enteric capsules have passed their expiry date, ask your pharmacist what to do with any enteric capsules you have left over.

Product description

What NOXICID CAPS HEARTBURN RELIEF looks like

NOXICID CAPS HEARTBURN RELIEF Enteric 20mg capsules

White to cream coloured pellets filled in hard gelatin capsule with pink cap and pink body, imprinted with 'Mylan' over 'EM 20' in black ink on cap and body.

Each blister pack contains 14 enteric capsules.

Ingredients

The active ingredient in NOXICID CAPS HEARTBURN RELIEF is esomeprazole (as magnesium). Each NOXICID CAPS HEARTBURN RELIEF contains 20 mg of esomeprazole.

The capsules also contain the following inactive ingredients:

  • Sugar spheres (ARTG PI No: 2535)
  • Sucrose
  • Crospovidone
  • Hyprolose
  • Mannitol
  • Methacrylic acid - ethyl acrylate copolymer (1:1)
  • Triethyl citrate
  • Glyceryl monostearate
  • Polysorbate 80
  • Purified talc
  • Empty Hard Gelatin Capsule Shells Cap & Body – Pink & Pink Size 3 (ARTG PI No:109606)
  • TekPrint SW-9008 Black Ink (ARTG PI No: 2328)
  • Sodium hydroxide

NOXICID CAPS HEARTBURN RELIEF contains traces of sulfites.

Sponsor

NOXICID CAPS HEARTBURN RELIEF is supplied in Australia by:

Alphapharm Pty Ltd trading as Viatris
Level 1, 30 The Bond
30 - 34 Hickson Road
Millers Point NSW 2000
www.viatris.com.au
Phone: 1800 274 276

This leaflet was prepared in March 2023.

Australian registration numbers:

NOXICID CAPS HEARTBURN RELIEF esomeprazole 20 mg (as magnesium) enteric capsules blister pack – AUST R 336014

NOXICID® is a Viatris company trade mark

NOXICID CAPS HEARTBURN RELIEF_cmi\Mar23/00

Published by MIMS May 2023

BRAND INFORMATION

Brand name

Noxicid Caps Heartburn Relief

Active ingredient

Esomeprazole

Schedule

S2

 

1 Name of Medicine

Esomeprazole magnesium.

2 Qualitative and Quantitative Composition

The active ingredient in Noxicid Caps Heartburn Relief is esomeprazole magnesium, a substituted benzimidazole.
The Noxicid Caps Heartburn Relief 20 mg enteric capsules are comprised of enteric coated pellets containing esomeprazole (as magnesium).
Each capsule contains esomeprazole magnesium 22.252 mg (equivalent to esomeprazole 20 mg).

List of excipients with known effect.

Noxicid Caps Heartburn Relief also contains traces of sulfites.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Noxicid Caps Heartburn Relief 20 mg enteric capsule: White to cream coloured pellets filled in hard gelatin capsule with pink cap and pink body, imprinted with 'Mylan' over 'EM 20' in black ink on cap and body.

4 Clinical Particulars

4.1 Therapeutic Indications

Noxicid Caps Heartburn Relief are indicated for:
The symptomatic relief of frequent heartburn and other symptoms of gastro-oesophageal reflux disease (GORD).

4.2 Dose and Method of Administration

Esomeprazole magnesium enteric capsules should be swallowed whole with liquid.
For patients who cannot swallow, the enteric capsules can be opened and pellets mixed in non-carbonated water and administered via a large syringe through a gastric tube. To ensure appropriate dosing and to avoid clogging, the gastric tube should be flushed with non-carbonated water following administration.

Adults.

Relief of heartburn and other symptoms of gastro-oesophageal reflux disease (GORD).
The recommended dose for symptomatic relief of GORD is one Noxicid Caps Heartburn Relief 20 mg capsule once daily for 7-14 days, depending on the severity and persistence of symptoms.
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. If symptom control has not been achieved or relapse has occurred after 14 days treatment with Noxicid Caps Heartburn Relief 20 mg capsule daily, further investigation is recommended. Use for longer than 14 days should only be on medical advice.
Not recommended for use in children and adolescents under 18 years of age.

Elderly.

Dose adjustment is not required in the elderly.

Hepatic impairment.

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 magnesium should not be exceeded (see Section 4.4 Special Warnings and Precautions for Use).

Renal impairment.

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

As with all antisecretory agents, the presence of any alarm symptom (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment with esomeprazole may alleviate symptoms and delay diagnosis.
Patients on long-term treatment (particularly those treated for more than a year) should be kept under regular surveillance.
Patients on on-demand treatment should be instructed to contact their physician if their symptoms change in character. When prescribing esomeprazole for on demand therapy, the implications for interactions with other pharmaceuticals, due to fluctuating plasma concentrations of esomeprazole should be considered (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
When prescribing esomeprazole for eradication of Helicobacter pylori possible drug interactions for all components in the triple therapy should be considered. Clarithromycin is a potent inhibitor of CYP3A4 and hence contraindications and interactions for clarithromycin should be considered when the triple therapy is used in patients concurrently taking other drugs metabolised via CYP3A4 such as cisapride.
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 possibly also Clostridium difficile in hospitalised patients.
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-oesphageal 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.

Acute interstitial nephritis.

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

Osteoporotic fractures.

Some published case controlled and observational studies suggest that proton-pump inhibitor therapy may be associated with an increased risk for osteoporosis-related fractures.
The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.
Patients at risk for developing osteoporosis or osteoporotic fractures are advised to have appropriate clinical monitoring in accordance with current clinical guidelines for these conditions.

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 esomeprazole. The occurrence of SCLE with previous PPI treatment may increase the risk of SCLE with other PPIs.

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.

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 magnesium.

Hypomagnesaemia.

Hypomagnesaemia, 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 hypomagnesaemia 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 hypomagnesaemia (e.g. diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically during PPI treatment.
Hypomagnesaemia may lead to hypocalcaemia and/or hypokalaemia (see Section 4.8 Adverse Effects (Undesirable Effects)).

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.

Noxicid Caps Heartburn Relief is not intended for use in children under the age of 18.

Children 12-18 years.

The pharmacokinetics of esomeprazole were studied in 28 adolescent patients with GORD aged 12 to 18 years, in a single centre study. Patients were randomised to receive esomeprazole 20 mg or 40 mg once daily for 8 days. Mean Cmax and AUC values of esomeprazole were not affected by body weight or age; and more than dose proportional increases in mean Cmax and AUC values were observed between the two dose groups in the study. Overall, esomeprazole pharmacokinetics in adolescent patients aged 12 to 18 years were similar to those observed in adult patients with symptomatic GORD (see Table 1).

Effects on laboratory tests.

Chromogranin A (CgA) increases due to decreased gastric acidity. The increased CgA level may interfere with investigations for neuroendocrine tumours. To avoid this interference the esomeprazole treatment should be temporarily stopped 5-14 days before CgA measurements and that 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 Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Effects of esomeprazole on other drugs), the plasma concentrations of these drugs may be increased and a dose reduction could be needed. This should be considered especially when prescribing esomeprazole for on demand therapy.

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/pharmacodynamics (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 + 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, 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).
Esomeprazole can reduce the absorption of drugs where gastric pH is an important determinant of their bioavailability. Esomeprazole is an enantiomer of omeprazole. Co-administration of omeprazole and mycophenolate mofetil in healthy and transplant patients has been reported to reduce 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 esomeprazole with caution in transplant patients receiving mycophenolate mofetil.

Potential interactions that have been excluded.

Amoxicillin 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 magnesium 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 foetal 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 foetuses 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 magnesium 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 magnesium 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 disorders.

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).
Frequency 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.
See Table 2.

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.

4.9 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 dialysable. 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 on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Noxicid Caps Heartburn Relief (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 plus another, the percentage of GORD patients maintaining an intragastric pH above 4 for at least 8, 12 and 16 hours are tabulated in Table 3.
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 4.

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 enteric capsules. 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 magnesium 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

The inactive ingredients: sugar spheres (ARTG PI No: 2535), crospovidone, hyprolose, mannitol, methacrylic acid-ethyl acrylate copolymer (1:1), triethyl citrate, glycerol monostearate, sodium hydroxide, sucrose, polysorbate 80 and purified talc. The enteric capsules are comprised of the following: empty hard gelatin capsule shells cap and body - Pink and Pink size 3 (ARTG PI No: 109616) and TekPrint SW-9008 Black Ink (ARTG PI No: 2328).

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Noxicid Caps Heartburn Relief enteric capsules: stored below 25°C.

6.5 Nature and Contents of Container

PA/Al/PVC/Al foil blisters, these blister packs comprise 7 and 14 capsules.

Australian Register of Therapeutic Goods (ARTG).

AUST R 336014 - Noxicid Caps Heartburn Relief esomeprazole 20 mg (as magnesium) enteric capsule blister pack.

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 is the S-isomer of omeprazole. It is optically stable in vivo, with negligible conversion to the R-isomer. The chemical name is di-(S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole magnesium salt.

Chemical structure.


CAS number.

CAS registry number: 161973-10-0.

Molecular formula.

C34H36N6O6S2Mg.

Molecular weight.

713.12 (anhydrous).

7 Medicine Schedule (Poisons Standard)

S2 (Pharmacy Medicine).

Summary Table of Changes