Consumer medicine information

APO-Omeprazole

Omeprazole

BRAND INFORMATION

Brand name

APO-Omeprazole

Active ingredient

Omeprazole

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Omeprazole.

What is in this leaflet

Read this leaflet carefully before taking your medicine. This leaflet answers some common questions about omeprazole. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the last page. More recent information on this medicine may be available.

Ask your doctor or pharmacist:

  • if there is anything you do not understand in this leaflet,
  • if you are worried about taking your medicine, or
  • to obtain the most up-to-date information.

You can also download the most up to date leaflet from www.apotex.com.au.

All medicines have risks and benefits. Your doctor has weighed the risks of you using this medicine against the benefits they expect it will have for you.

Pharmaceutical companies cannot give you medical advice or an individual diagnosis.

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

What this medicine is used for

The name of your medicine is APO-Omeprazole. It contains the active ingredient omeprazole.

It is used to treat:

  • Reflux Oesophagitis
    Omeprazole is used to treat the symptoms of reflux oesophagitis or reflux disease. 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.
    Omeprazole is also used to help stop reflux oesophagitis coming back or relapsing.
  • Peptic Ulcers
    Omeprazole is used to treat peptic ulcers. Depending on the position of the ulcer it is called a gastric or duodenal ulcer. A gastric ulcer occurs in the stomach. A duodenal ulcer occurs in the duodenum, which is the tube leading out from the stomach.
    These ulcers can be caused by too much acid being made in the stomach.
    Omeprazole is also used to help stop peptic or duodenal ulcers coming back.
  • Peptic Ulcers Associated with Helicobacter pylori Infection
    Helicobacter pylori is a bacteria that often occurs in the stomach together with peptic ulcers.
    When omeprazole is taken together with an antibiotic, they work together to kill the bacteria and let your ulcer heal. You may need further treatment with antibiotics.
  • Peptic Ulcers Associated with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
    Some peptic ulcers are caused by taking medicines called non-steroidal anti-inflammatory drugs (NSAIDs), a type of medicine used to treat pain, swelling or inflammation, including arthritis and joint pain.
    Omeprazole is used to treat and help to prevent ulcers developing, which are associated with long-term use of NSAIDs.
  • Zollinger-Ellison Syndrome
    Omeprazole is also used to treat a rare condition called Zollinger-Ellison syndrome, where the stomach produces large amounts of acid, much more than in ulcers or reflux disease.

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

This medicine is available only with a doctor's prescription.

How it works

Omeprazole belongs to a group of medicines called proton-pump inhibitors.

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.

There is no evidence that this medicine is addictive.

Use in children

This medicine should not be used in children.

Before you take this medicine

When you must not take it

Do not take Omeprazole if you have an allergy to:

  • omeprazole or any ingredient listed at the end of this leaflet
  • any medicine containing a proton-pump inhibitor

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.

Do not take Omeprazole if you are also taking cilostazol. Please check with your doctor or pharmacist if you are taking cilostazol. This medicine will be affected by Omeprazole.

Do not take Omeprazole 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.

If you are not sure whether you should take this medicine, talk to your doctor.

Before you start to take it

You must tell your doctor if you have:

  • allergies to any other medicines, foods, dyes or preservatives
  • any problems with your liver
  • any other medical conditions
  • been diagnosed with osteoporosis
  • if you have ever had a skin reaction after treatment with a medicine similar to Omeprazole that reduces stomach acid

Do not take Omeprazole 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 Omeprazole while you are pregnant. It may affect your baby.

It is not known if your baby can take in Omeprazole from breast milk if you are breastfeeding.

Taking other medicines

Do not take Omeprazole if you are taking the following medicine:

  • cilostazol - a medicine used to treat intermittent claudication

Tell your 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 Omeprazole tablets. These include:

  • phenytoin - a medicine used to treat epilepsy or fits
  • warfarin and clopidogrel - medicines used to prevent blood clots
  • digoxin - a medicine used to treat heart conditions
  • diazepam - a medicine used to treat anxiety and some other conditions
  • St John's wort - a herbal remedy used to treat mood disorders
  • ketoconazole, itraconazole, voriconazole - medicines used to treat fungal infection
  • clarithromycin or rifampicin - medicines used to treat infections
  • atazanavir and nelfinavir - medicines used to treat viral infections such as HIV
  • tacrolimus and mycophenolate mofetil - medicines used to assist in organ transplants
  • methotrexate - a medicine used to treat arthritis and some types of cancer
  • erlotinib or related medicines used to treat cancer

These medicines may be affected by Omeprazole or may affect how well it works. You may need different amounts of your medicine or you may need to take different medicines. Your doctor can tell you what to do if you are taking any other medicines.

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

If you have not told your doctor about any of these things, tell them before you take Omeprazole.

How to take this medicine

Follow carefully all directions given to you by your doctor or pharmacist. Their instructions may be different to the information in this leaflet.

How much to take

Your doctor or pharmacist will tell you how much of this medicine you should take.

The usual dose is 20 mg once a day. The dose may vary from 10 mg to 40 mg a day depending on what condition you are being treated for and how severe it is. This may also depend whether you are taking any other medicines.

Do not stop taking your medicine or change your dosage without first checking with your doctor.

When to take it

Take this medicine at the same time each day. Taking it at the same time each day will have the best effect and will also help you remember when to take it.

It does not matter if you take it before, with or after food.

How long to take it for

In most patients, omeprazole relieves symptoms rapidly and healing is usually complete within 4 weeks. Continue taking your medicine for as long as your doctor tells you.

Make sure you have enough to last over weekends and holidays.

If you forget to take it

If it is almost time to take your next dose, skip the missed dose and take your next dose at the usual time. Otherwise take it as soon as you remember and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for missed doses. This may increase the chance of you experiencing side effects.

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

If you take too much (overdose)

If you think that you or anyone else may have taken too much of this medicine, immediately telephone your doctor or the Poisons Information Centre (Tel: 13 11 26 in Australia) for advice. Alternatively go to the Accident and Emergency Department at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking this medicine

Things you must do

Take Omeprazole exactly as your doctor has prescribed.

If you are about to start any new medicine, remind your doctor and pharmacist that you are taking Omeprazole.

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

Tell your doctor if you become pregnant while you are taking Omeprazole.

Tell your doctor if your symptoms return. Although Omeprazole can heal ulcers successfully, it may not prevent them recurring at a later date.

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

Things you must not do

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

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

Do not stop taking your medicine or change the dosage without checking with your doctor. If you stop taking it suddenly or change the dose, your condition may worsen or you may have unwanted side effects.

Possible side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking omeprazole or if you have any questions or concerns.

Do not be alarmed by the following lists of side effects. You may not experience any of them. All medicines can have side effects. Sometimes they are serious but most of the time they are not.

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

This list includes the more common side effects. Mostly, these are mild:

  • constipation
  • nausea/vomiting
  • flatulence (wind)
  • stomach pain
  • diarrhoea
  • headache
  • skin rash, itchy skin
  • dizziness
  • dry or sore mouth

Tell your doctor as soon as possible if you notice any of the following.

These may be serious side effects. You may need medical attention. Most of these side effects are rare.

  • muscle pain, joint pain or weakness
  • "pins and needles" (tingling or numbness) in the hands and feet
  • changes in sleep patterns
  • increased sweating
  • hair loss
  • tremor
  • mood changes, confusion or depression
  • increase in breast size (males)
  • fever, vomiting and abdominal cramps accompanied by diarrhoea with or without blood or mucous
  • increased bruising, or bleeding more easily
  • disturbance in hearing.
  • Blurred vision

If you experience any of the following, stop taking your medicine and contact your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

These are very serious side effects and are usually very rare. You may need urgent medical attention or hospitalisation.

  • swelling of the face, lips, mouth, tongue or throat, which may cause difficulty in breathing
  • shortness of breath or difficulty in breathing
  • skin reaction, which may include rash, itching, redness, blistering or peeling of the skin
  • swelling of feet, hands and ankles
  • ulcers, blisters of bleeding of the lips, eyes, mouth, nose and genitals
  • blood in urine
  • signs of liver inflammation including yellowing of the skin or eyes, generally feeling unwell, nausea, vomiting, loss of appetite
  • skin reaction, especially in sun-exposed areas, with joint pain

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

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

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may occur in some people. Other problems are more likely to arise from the ulcer itself rather than the treatment.

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

  • pain or indigestion that occurs during treatment with Omeprazole
  • you begin to vomit blood or food
  • you pass black (blood-stained) Motions

Tell your doctor if your reflux symptoms return

Storage and disposal

Storage

Keep your medicine in its original packaging until it is time to take it. If you take your medicine out of its original packaging it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 25°C. Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep this medicine 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.

Disposal

If your doctor or pharmacist tells you to stop taking this medicine or it has passed its expiry date, your pharmacist can dispose of the remaining medicine safely.

Product description

What APO-Omeprazole looks like

20 mg omeprazole is a red brown, oblong, enteric coated tablet.

Ingredients

Each tablet contains 20 mg of omeprazole as the active ingredient.

It also contains the following inactive ingredients:

  • ascorbyl palmitate
  • microcrystalline cellulose
  • crospovidone
  • magnesium stearate
  • povidone
  • lactose monohydrate
  • hypromellose phthalate
  • triacetin
  • purified talc
  • iron oxide red
  • iron oxide black

This medicine is gluten-free, sucrose-free, tartrazine-free and free of other azo dyes.

APO-Omeprazole is available in:

Blister packs and bottles of 30 tablets.

Not all pack types may be available.

Australian Registration Numbers

APO-Omeprazole 20 mg tablet (blister pack): AUST R 243812.

APO-Omeprazole 20 mg tablet (bottles): AUST R 243813.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

APO and APOTEX are registered trade marks of Apotex Inc.

This leaflet was last updated in August 2020

Published by MIMS October 2020

BRAND INFORMATION

Brand name

APO-Omeprazole

Active ingredient

Omeprazole

Schedule

S4

 

1 Name of Medicine

Omeprazole.

2 Qualitative and Quantitative Composition

Each enteric-coated tablet contains 20 mg omeprazole as the active ingredient.

Excipients with known effect.

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

3 Pharmaceutical Form

Red brown, oblong, enteric-coated tablet.

4 Clinical Particulars

4.1 Therapeutic Indications

Gastroesophageal reflux disease (GORD).

Symptomatic GORD.

The relief of heartburn and other symptoms associated with GORD.

Erosive oesophagitis.

The treatment and prevention of relapse.

Peptic ulcers.

The treatment of duodenal and gastric ulcer.
Combination therapy for the treatment of peptic ulcer disease associated with Helicobacter pylori infection.
The treatment of gastric and duodenal ulcers and erosions associated with nonsteroidal anti-inflammatory drugs.
The prevention of gastric and duodenal ulcers and erosions associated with nonsteroidal anti-inflammatory drugs in patients assessed as being at high risk of gastroduodenal ulcer or complications of gastroduodenal ulcer.
Long-term prevention of relapse in gastric and duodenal ulceration, in patients proven to be Helicobacter pylori negative, or in whom eradication is inappropriate, e.g. the elderly, or ineffective.

Zollinger-Ellison syndrome.

The treatment of Zollinger-Ellison syndrome.

4.2 Dose and Method of Administration

APO-Omeprazole enteric coated tablets are intended for oral administration. They must be swallowed whole (not broken or chewed) with liquid.

Dosage.

APO-Omeprazole is only available as 20 mg enteric coated tablet which must not be broken.
For 10 mg dosing, another brand of omeprazole with a 10 mg dose strength should be used.

Symptomatic GORD.

Recommended dose for symptom relief.

Omeprazole 10-20 mg once daily for a maximum of 4 weeks.
In most patients symptom relief is rapid. If symptom control has not been achieved after 4 weeks treatment with omeprazole 20 mg daily, further investigation is recommended.

Erosive oesophagitis.

Recommended healing dosage.

Omeprazole 20 mg once daily for 4-8 weeks.
In most patients, symptomatic relief is rapid and healing is usually complete within 4 weeks. For those patients not fully healed on endoscopic examination during initial treatment, endoscopic healing usually occurs during a further 4 weeks treatment period.
In patients with ulcerative reflux oesophagitis refractory to treatment, omeprazole 40 mg once daily usually produces healing within 8 weeks.

Maintenance therapy.

It is recommended that, after healing, maintenance therapy be commenced, omeprazole 10 mg once daily. If needed, this dose should be increased to omeprazole 20 mg once daily.

Peptic ulcer disease associated with Helicobacter pylori infection.

Patients whose gastric or duodenal ulceration is not associated with ingestion of NSAIDs require treatment with antimicrobial agents, in addition to antisecretory drugs, whether on first presentation or on recurrence. Omeprazole administered at a dose of 40 mg once daily or 20 mg twice daily in association with the following combinations has been found to achieve eradication rates of approximately 90%:
amoxycillin 500 mg and metronidazole 400 mg both 3 times a day, for 2 weeks; or
amoxycillin 1 g and clarithromycin 500 mg both twice a day, for 1 week; or
clarithromycin 250 mg and metronidazole 400 mg twice a day, for 1 week.
Patients should be retreated if there is a return of symptoms and H. pylori infection. In this situation, possible resistance of the organism to the antimicrobial agents should be considered when deciding on the combination to be used.
To ensure healing in patients with active peptic ulcer disease, see further dosage recommendations for duodenal and gastric ulcer.

Duodenal ulcer.

Recommended healing dosage.

Omeprazole 20 mg once daily for 4-8 weeks.
In most patients, symptomatic relief is rapid and healing is usually complete within 4 weeks.
For those patients not fully healed during initial treatment, healing usually occurs during a further 4 weeks treatment period.
In duodenal ulcer patients refractory to treatment, omeprazole 40 mg once daily usually produces healing within 4-8 weeks.

Maintenance therapy.

For the long-term prevention of relapse in patients with duodenal ulcer who are proven to be H. pylori negative and whose ulceration had not been associated with NSAIDs, the recommended dose is omeprazole 10-20 mg daily.
For NSAID associated duodenal ulcers, see NSAID associated gastric or duodenal ulcers or erosions.

Gastric ulcer.

Recommended healing dosage.

Omeprazole 20 mg once daily for 4-8 weeks.
In most patients, symptomatic relief is rapid and healing is usually complete within 4 weeks.
For those patients not fully healed during initial treatment, healing usually occurs during a further 4 weeks treatment period.
In gastric ulcer patients refractory to treatment, omeprazole 40 mg once daily usually produces healing within 8 weeks.

Maintenance therapy.

For the long-term prevention of relapse in patients with gastric ulcer who are proven to be H. pylori negative and whose ulceration had not been associated with NSAIDs, the recommended dose is omeprazole 20 mg daily.
For NSAID associated duodenal ulcers, see NSAID associated gastric or duodenal ulcers or erosions.

NSAID associated gastric or duodenal ulcers or erosions.

In patients with or without continued NSAID treatment, the recommended dose is omeprazole 20-40 mg daily. Symptom resolution is rapid and healing occurs within 4 weeks in most patients.
For those patients not fully healed after the initial course, healing usually occurs during a further 4 weeks treatment period.
For the prevention of NSAID associated gastric or duodenal ulcers or erosions and dyspeptic symptoms, the recommended dose is omeprazole 20 mg once daily.

Zollinger-Ellison syndrome.

Recommended initial dose.

Omeprazole 60 mg once daily.
The dosage should be adjusted individually and treatment continued for as long as is clinically indicated. More than 90% of patients with severe disease and inadequate response to other therapies have been effectively controlled on doses of 20-120 mg daily. When doses exceed 80 mg orally daily, the dose should be divided and given twice daily.

Use in the elderly.

No dosage adjustment of omeprazole is necessary in the elderly.

Hepatic impairment.

The rate of plasma elimination of omeprazole and its metabolites is decreased in patients with liver cirrhosis. However, no accumulation has been observed during the use of the recommended dose of omeprazole 20 mg daily and no adjustment to the normal dosage regime is required (see Section 4.4 Special Warnings and Precautions for Use).

Renal impairment.

The systemic bioavailability of omeprazole is not significantly altered in patients with reduced renal function and no dosage adjustment is required.

4.3 Contraindications

Hypersensitivity to omeprazole, substituted benzimidazoles or any other ingredient.
Omeprazole, an inhibitor of CYP2C19, is contraindicated in patients taking cilostazol.

4.4 Special Warnings and Precautions for Use

Acute interstitial nephritis.

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

Antimicrobial resistance.

The development of antimicrobial resistance may have an adverse effect on eradication regimens. The clinical impact of this resistance on H. pylori has not been comprehensively studied.

Concomitant therapy with clopidogrel.

Results from studies in healthy subjects have shown a pharmacokinetic/ pharmacodynamic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and omeprazole (80 mg p.o. daily, i.e. four times the recommended dose), resulting in decreased exposure to the active metabolite of clopidogrel by an average of 46% and resulting in decreased maximum inhibition of (ADP-induced) platelet aggregation by an average of 16%. Based on these data, concomitant use of omeprazole and clopidogrel should be avoided (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Cyanocobalamin (vitamin B12) 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 B12) caused by hypo- or achlorhydria.

Effects of acid inhibition.

Decreased gastric acidity due to any means including proton pump inhibitors increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with acid reducing drugs may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and, in hospitalised patients, possibly also Clostridium difficile.

Subacute cutaneous lupus erythematosus.

Subacute cutaneous lupus erythematosus (SCLE) has been reported with the use of PPIs. If lesions occur, especially in sun-exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical help promptly and the health care professional should consider stopping APO-Omeprazole. The occurrence of SCLE with previous PPI treatment may increase the risk of SCLE with other PPIs.

Use in hepatic impairment.

Patients with impaired liver function show a markedly increased bioavailability, a reduced total plasma clearance, and up to a 4-fold prolongation of the elimination half-life. However, urinary recovery over 96 hours remains unchanged, indicating no accumulation of omeprazole or its metabolites. The normal dose of omeprazole 20 mg daily may be used in patients with severe liver disease (see Section 4.2 Dose and Method of Administration).

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.

Special patient populations - CYP2C19 enzyme.

Approximately 3% of the Caucasian population and 15-20% of the Asian population lack a functional CYP2C19 enzyme and are called poor metabolisers. In these individuals the metabolism of omeprazole is most likely catalysed by CYP3A4. After repeated once-daily administration of 20 mg omeprazole, the mean AUC was 5 to 10 times higher in poor metabolisers than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations were also 3 to 5 times higher. The implications of these findings need to be addressed from clinical perspective.

Undiagnosed malignancy.

As with all anti-secretory agents, the presence of any alarm symptom (e.g. significant unintentional weight loss, recurring vomiting, dysphagia, hematemesis or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment with omeprazole may alleviate symptoms and delay diagnosis.

Use in the elderly.

See Section 4.2 Dose and Method of Administration.

Paediatric use.

No data available.

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 omeprazole treatment should be temporarily stopped five days before CgA measurements.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Absorption.

Medicinal products with pH dependent absorption.

The decreased intragastric acidity during treatment with omeprazole and other PPIs, might increase or decrease the absorption of drugs if the mechanism of absorption is influenced by gastric acidity.
Omeprazole produces a profound and sustained inhibition of gastric acid secretion. The absorption of compounds whose absorption depends on gastric pH, e.g. ketoconazole, itraconazole, erlotinib etc., may decrease and the absorption of drugs such as digoxin can increase during treatment with omeprazole. 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).
Co-administration of omeprazole in healthy subjects and in transplant patients receiving mycophenolate mofetil 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 omeprazole and mycophenolate mofetil. Use omeprazole with caution in transplant patients receiving mycophenolate mofetil.

Metabolism.

Cytochrome P450 effects.

Omeprazole is mainly metabolised via the hepatic cytochrome P450 system (CYP2C19) and may be expected to interact with the metabolism of other drugs metabolised by this enzyme.

Effects of omeprazole on other drugs.

Diazepam.

Following dosing with omeprazole 40 mg once daily, the clearance of diazepam was decreased by 54% and the mean elimination half-life of diazepam was increased by 130%, with a consequent significant increase in plasma diazepam concentrations. For omeprazole 20 mg, the clearance of diazepam was decreased by approximately 25% in the majority of the population, while no change was detected in poor metabolisers. Consideration should be given to a reduction in diazepam dosage when omeprazole enteric coated tablets are co-prescribed.

Phenytoin.

Omeprazole 40 mg daily for seven days reduced plasma clearance of intravenous phenytoin by 15-20% and increased the elimination half-life by 27%. Monitoring of patients receiving phenytoin is recommended and a reduction of the phenytoin dose may be necessary. In a study that administered omeprazole 20 mg to epileptic patients, steady-state plasma levels of phenytoin were unchanged during omeprazole treatment.

Warfarin.

Concomitant administration of omeprazole 20 mg to patients on continuous treatment with warfarin caused a slight though statistically significant increase in the plasma concentration of the R-enantiomer of warfarin. Plasma concentrations of the more potent S-enantiomer were not affected and no change in warfarin's anticoagulant activity was observed.
In patients receiving warfarin or other vitamin K antagonists, monitoring of INR is recommended and a reduction of the warfarin (or other vitamin K antagonist) dose may be necessary.

Cilostazol.

Omeprazole 40 mg daily for 7 days 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).

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 omeprazole may need to be considered.

Antiretroviral drugs.

Concomitant administration with omeprazole and drugs such as atazanavir and nelfinavir is not recommended.
Omeprazole has been reported to interact with some antiretroviral drugs. The clinical importance and the mechanisms behind these 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. For other antiretroviral drugs, such as saquinavir, elevated serum levels have been reported. There are also some antiretroviral drugs of which unchanged serum levels have been reported when given with omeprazole.

Clopidogrel.

Studies in healthy subjects have shown a pharmacokinetic/ pharmacodynamic (PK/PD) interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and omeprazole (80 mg p.o daily, i.e. four times the recommended dose), resulting in a decreased exposure of the active metabolite of clopidogrel by an average of 46% and resulting in decreased maximum inhibition of (ADP induced) platelet aggregation by an average of 16%. Based on these data, concomitant use of omeprazole and clopidogrel should be avoided.
When clopidogrel was given together with a fixed-dose combination of esomeprazole 20 mg and aspirin 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 + aspirin) 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.

Tacrolimus.

Concomitant administration of omeprazole and tacrolimus may increase the serum levels of tacrolimus.

Potential interactions that have been excluded.

Results from a range of in vivo interaction studies with omeprazole versus other drugs indicate that omeprazole 20-40 mg, given repeatedly, has no influence on any other relevant isoforms of CYP, as shown by the lack of metabolic interaction with substrates for CYP1A2 (caffeine, phenacetin, theophylline), CYP2C9 (S-warfarin, piroxicam, diclofenac, naproxen), CYP2D6 (metoprolol, propranolol), CYP2E1 (ethanol), and CYP3A (cyclosporin, lignocaine, quinidine, oestradiol).

Effects of other drugs on omeprazole.

Drugs known to induce CYP2C19 or CYP3A4 or both (such as rifampicin and St John's wort) may lead to decreased omeprazole serum levels by increasing the rate of metabolism of omeprazole.
Drugs known to inhibit CYP2C19 or CYP3A4 or both (such as clarithromycin or voriconazole) may lead to increased omeprazole serum levels by decreasing the rate of metabolism of omeprazole.

Clarithromycin.

Plasma concentrations of omeprazole are increased during concomitant administration.

Voriconazole.

Concomitant administration of omeprazole and the CYP2C19 and CYP3A4 inhibitor, voriconazole, resulted in more than doubling of the omeprazole exposure.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There was no evidence of an adverse effect on fertility following administration of omeprazole to male and female rats at doses up to 320 mg/kg/day orally (16-fold anticipated exposure at the clinical oral dose of 40 mg/day, based on plasma AUC) and 100 mg/kg/day intravenously (14-fold anticipated exposure at the clinical intravenous dose of 40 mg/day, based on plasma AUC). Oral administration to male rats prior to mating and to female rats prior to and throughout gestation at 7-fold clinical exposure was associated with embryofoetal toxicity.
(Category B3)
Results from three prospective epidemiological studies indicate that whilst there was no increase in the overall malformation rates compared with controls, the data indicated a potentially higher rate of cardiac defects in the omeprazole group.
There was no evidence of teratogenicity following administration of omeprazole to pregnant rats and rabbits during the period of organogenesis. Doses in rats were associated with systemic exposures of up to 16- and 14-fold (oral and intravenous administration, respectively) the anticipated exposure at the clinical dose of 40 mg/day (based on plasma AUC). Studies in rats did not demonstrate embryotoxicity apart from increased locomotor activity in prenatally exposed offspring at systemic exposures approximating clinical exposure, based on plasma AUC.
In rabbits, oral doses were associated with systemic exposure less than clinical exposure (plasma AUC) and intravenous doses were up to 13-fold the 40 mg/day clinical dose (on a mg/m2 basis). Embryofoetal toxicity and maternotoxicity occurred at doses associated with less than clinical exposures.
Omeprazole and its metabolites are excreted in milk in rats but it is not known if this occurs in humans. In rats, reduced offspring postpartum growth rate was observed following administration of omeprazole during late gestation and throughout lactation at oral doses of 138 mg/kg/day and above (7-fold anticipated exposure at the clinical dose of 40 mg/day, based on plasma AUC) and intravenous doses of 3.2 mg/kg/day and above (less than clinical exposure).
It is recommended that omeprazole not be used in breastfeeding mothers.

4.7 Effects on Ability to Drive and Use Machines

No effects have been observed.

4.8 Adverse Effects (Undesirable Effects)

Omeprazole enteric coated tablets are well tolerated. Most adverse reactions have been mild and transient and there has been no consistent relationship with treatment.
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 disorders.

Rare: leukopenia, thrombocytopenia, agranulocytosis, pancytopenia.

Immune system disorders.

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

Metabolism and nutrition disorders.

Rare: hyponatraemia.
Very rare: weight increase, hypomagnesaemia and hypokalaemia (reported in children); severe hypomagnesaemia may result in hypocalcaemia. Hypomagnesaemia may also result in hypokalaemia.

Psychiatric disorders.

Uncommon: insomnia.
Rare: agitation, aggression, reversible mental confusion, depression, hallucinations.

Nervous system disorders.

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

Eye disorders.

Rare: blurred vision.

Ear and labyrinth disorders.

Uncommon: vertigo.

Respiratory, thoracic and mediastinal disorders.

Rare: bronchospasm.
Very rare: dyspnoea.

Gastrointestinal disorders.

Common: diarrhoea, constipation, abdominal pain, nausea/ vomiting, flatulence.
Rare: stomatitis, gastrointestinal candidiasis, dry mouth, microscopic colitis.
Very rare: dyspepsia, haemorrhagic necrotic gastritis (reported in children).
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: encephalopathy in patients with pre-existing liver disease, hepatitis with or without jaundice, hepatic failure.

Skin and subcutaneous tissue disorders.

Uncommon: rash, urticaria, pruritus, dermatitis.
Rare: photosensitivity, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), alopecia.
Not known: subacute cutaneous lupus erythematosus (SCLE).

Musculoskeletal, connective tissue and bone disorders.

Rare: arthralgia, muscular weakness, myalgia.

Renal and urinary disorders.

Rare: interstitial nephritis.
Very rare: impaired renal function, including nephrosis.

Reproductive system and breast disorders.

Rare: gynaecomastia.
Very rare: impotence (although causality has not been established).

General disorders and administration site conditions.

Uncommon: malaise.
Rare: increased sweating, peripheral oedema.

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 and contact Apotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

Rare reports have been received of overdosage with omeprazole. In the literature doses of up to 560 mg have been described and occasional reports have been received when single oral doses have reached up to omeprazole 2,400 mg (120 times the usual recommended clinical dose). Nausea, vomiting, dizziness, abdominal pain, diarrhoea and headache have been reported from overdosage with omeprazole.
Also apathy, depression and confusion have been described in single cases. The symptoms described in connection to omeprazole overdosage have been transient, and no serious clinical outcome due to omeprazole has been reported.
The rate of elimination was unchanged (first order kinetics) with increased doses and no specific treatment has been needed.
In suspected cases of overdosage treatment should be supportive and symptomatic.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Omeprazole reversibly reduces gastric acid secretion by specifically inhibiting the gastric enzyme H+, K+-ATPase, the proton pump, in the acid environment of the intracellular canaliculi within the parietal cell. This effect of omeprazole on the final step of the gastric acid formation process is dose dependent and effectively inhibits both basal acid secretion and stimulated acid secretion, irrespective of the stimulus to acid production.
Omeprazole has no effect on acetylcholine or histamine receptors. No clinically significant pharmacodynamic effects, other than those explained by the effect on acid secretion, have been observed.

Effect on gastric acid secretion.

Oral dosing with omeprazole 20 mg once daily provides rapid and effective reduction of gastric acid secretion. After a single dose the onset of antisecretory effect occurs within 1 hour and is maximal within 2 hours. With repeated once daily dosing the maximum effect is usually achieved within 4 days of commencing treatment.
A mean decrease of approximately 80% in 24 hour intragastric acidity is maintained in duodenal ulcer patients treated with an oral dose of omeprazole 20 mg. Omeprazole produces a mean decrease in peak pentagastrin stimulated acid output of approximately 70% 24 hours after dosing. When the drug is discontinued, secretory activities return to approximately 50% of maximum after 24 hours and gradually return to normal over 3-5 days.

Peptic ulcer disease associated with Helicobacter pylori.

Helicobacter pylori (H. pylori) is associated with duodenal and gastric ulcer disease in about 95% and 70% of patients, respectively. H. pylori is the major factor in the development of gastritis and ulcers in such patients. Recent evidence also suggests a causative link between H. pylori and gastric carcinoma. An attempt to eradicate H. pylori is appropriate therapy in most patients with duodenal and gastric ulcer where the latter is not caused by nonsteroidal anti-inflammatory drug (NSAID) ingestion (see Section 4.2 Dose and Method of Administration).
In vitro testing has shown that omeprazole has an MIC90 (minimum inhibitory concentration) of 25 microgram/mL against H. pylori. However, in vivo it only suppresses the organism without eradicating it. The combination of omeprazole and antimicrobial agents results in eradication of the organism in vivo, despite the fact that antimicrobial agents administered singly have also proved ineffective in eradicating H. pylori. The mechanism of the synergy between omeprazole and antimicrobial agents in eradicating H. pylori is not completely understood. Optimal eradication rates are achieved when omeprazole is combined with two antimicrobial agents.
Eradication of H. pylori is associated with reduced peptic ulcer recurrence.

Other effects related to acid inhibition.

During long-term treatment gastric glandular cysts have been reported in a somewhat increased frequency. These changes are benign and appear to be reversible.
In some patients, fasting serum gastrin levels have been noted to rise 2 to 4-fold during treatment with omeprazole. Up to 3% of patients have values exceeding 400 picogram/mL.

Clinical trials.

1. Gastroesophageal reflux disease (GORD).

Symptomatic GORD.

Randomised, controlled clinical trials (n = 1,710) were evaluated to assess the efficacy of omeprazole in the complete relief of heartburn in adult patients with symptomatic GORD after 4 weeks treatment comparing omeprazole 10 mg and 20 mg once daily with control groups of ranitidine 150 mg twice daily or placebo. The percentage of patients with complete relief of heartburn after 4 weeks is presented in Table 1.

2. Erosive oesophagitis.

At the time of registration, seven randomised controlled clinical trials (n = 1,674) were evaluated to assess the efficacy of omeprazole in the prevention of relapse in patients with healed reflux oesophagitis. Omeprazole 10 mg and 20 mg once daily maintained endoscopic remission rates which substantially exceeded ranitidine 150 mg twice daily or placebo at 6 months. The difference in remission rates between omeprazole 10 mg and 20 mg favoured 20 mg. Three studies recorded remission rates over 12 months and an additional study continued for 18 months.
In a meta-analysis of five of the clinical trials (n = 1,154), 72% and 82% of patients remained in remission at 6 months on omeprazole 10 mg and 20 mg once daily, respectively. In a separate large study (n = 327), the remission rate following omeprazole 10 mg once daily for 18 months was 60%.
In two of the studies, patients who relapsed in the first 3 months of maintenance treatment were then healed and treated with a maintenance dose of omeprazole 20 mg. The difference in the total remission rate over 6 or 12 months, while small, suggests that it may be more difficult, or take longer, to obtain subsequent healing and control if 10 mg rather than 20 mg had been used for initial maintenance therapy.
Gastric safety data are available from seven controlled clinical trials of up to 2 years duration (irrespective of indication). A full analysis of these trials was undertaken as a consequence of histological changes observed in animals (see Section 4.4 Special Warnings and Precautions for Use). This involved a total of 1,128 patients with an evaluable series of biopsies; 843 patients treated continuously with omeprazole for 6-12 months, 77 patients completing 18 months, and 208 patients completing 2 years of continuous omeprazole treatment.
Additionally, in open studies at least 109 patients were assessed by annual biopsy during continuous treatment for 4 years, and in this continuing study, biopsies are available for at least 14 patients treated for up to 8 years. No instances of dysplasia or carcinoids of the gastric ECL cells have been reported in these studies. An association between focal hyperplasia and chronic gastritis with atrophy was found during long-term therapy. However, this finding is also observed in patients with untreated gastric ulcer disease with normal gastrin levels and is thus not a treatment related effect.

5.2 Pharmacokinetic Properties

Absorption.

Omeprazole is acid labile and is administered orally as enteric coated tablets. Omeprazole is not released until the enteric coated tablet is dissolved in the duodenum.
Absorption is rapid with peak plasma levels of omeprazole occurring within 4 hours and is usually complete within 3-6 hours. The systemic bioavailability of omeprazole from a single oral dose of omeprazole enteric coated tablets is approximately 35%. After repeated once daily administration, the bioavailability increases to about 60%. Concomitant intake of food has no influence on oral bioavailability, but may reduce the rate of absorption of omeprazole.

Distribution.

The plasma protein binding of omeprazole is approximately 95%. The inhibition of acid secretion is related to the area under the plasma concentration time curve (AUC), but not to the actual plasma concentration at any given time.

Metabolism.

Omeprazole is entirely metabolised by the cytochrome P450 system (CYP), mainly in the liver. The major part of its metabolism is dependent on the polymorphic CYP2C19. This CYP is responsible for the formation of hydroxyomeprazole, one of the major metabolites in plasma, and to a lesser extent, for the formation of 5-O-desmethyl omeprazole. The remaining part is mainly dependent on another specific isoform, CYP3A4, responsible for the formation of omeprazole sulfone.
Identified metabolites in plasma are the sulfone, the sulfide and hydroxyomeprazole. These metabolites have no significant effect on acid secretion. The average half-life of the terminal phase of the plasma concentration time curve following intravenous administration of omeprazole is approximately 40 minutes; the total plasma clearance is 0.3-0.6 L/minute. There is no change in half-life during repeated dosage.
The parameters below reflect mainly the pharmacokinetics in individuals with a functional CYP2C19 enzyme, extensive metabolisers.
Total plasma clearance is about 30-40 L/h after a single dose. The plasma elimination half-life of omeprazole is usually shorter than one hour both after single and repeated once daily dosing. The AUC of omeprazole increases with repeated administration. This increase is dose dependent and results in a nonlinear 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 omeprazole and/or its metabolites (e.g. the sulphone). Omeprazole is completely eliminated from plasma between doses with no tendency for accumulation during once daily administration.

Excretion.

About 80% of the metabolites are excreted in urine and the remainder in faeces. The two main urinary metabolites are hydroxyomeprazole and the corresponding carboxylic acid.

5.3 Preclinical Safety Data

Genotoxicity.

Omeprazole has been subjected to a battery of in vitro and in vivo genotoxicity tests to examine the mutagenic, clastogenic and DNA damaging potential of the drug. The in vitro assays include the Ames test, mouse lymphoma TK locus forward mutation assay and a chromosome aberration test in human lymphocytes. The in vivo tests were a chromosome aberration test in mouse bone marrow, an alkaline elution/rat liver DNA damage assay and two mouse micronucleus tests.
No evidence of significant genotoxicity was seen in these tests.

Carcinogenicity.

In a two-year carcinogenicity study in rats, omeprazole at daily doses of 13.8, 44.0 and 140.8 mg/kg/day produced gastric ECL cell hyperplasia and carcinoid tumours in a dose-related manner, in both male and female rats. The incidence of these effects was markedly higher in female rats.
The same effects were seen in an additional two-year study in female rats at daily doses of 1.7, 3.4 and 13.8 mg/kg/day. A no-effect dose was not established in female rats in the dose ranges studied.
In mice, a 78-week carcinogenicity study was performed according to relevant regulatory and scientific standards. No gastric ECL cell carcinoids were seen. However, longer term studies have not been performed in this species.
Hypergastrinaemia, ECL cell hyperplasia and gastric carcinoids have also been produced in the rat by other treatments or procedures not related to omeprazole. These include the following:

a. Exogenous gastrin infusion.

Subcutaneous infusion of gastrin-17 has resulted in a significant hyperplasia of ECL cells following treatment for 1 month.

b. H2-receptor antagonists.

In rats administered ranitidine 2 g/kg/day in their diet over 106 weeks, argyrophilic cell hyperplasia was observed in 37% of the animals and gastric carcinoids were found in 19% of the treated group.

c. Surgical resection of the acid producing oxyntic mucosa.

In rats in whom 75% of the stomach corpus was surgically removed, 26 of 75 animals developed ECL cell carcinoids during the 124-week study.
These findings show that the development of ECL cell carcinoids in the rat is directly related to hypergastrinaemia rather than a direct effect of omeprazole on the ECL cell.
Omeprazole may also affect other cells in the gastrointestinal tract (e.g. G cells) either directly or by inducing sustained hypochlorhydria, but this possibility has not been extensively studied.

6 Pharmaceutical Particulars

6.1 List of Excipients

Ascorbyl palmitate, microcrystalline cellulose, crospovidone, magnesium stearate, povidone, lactose monohydrate, purified talc, hypromellose phthalate, triacetin, iron oxide red, iron oxide black.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

APO-Omeprazole enteric-coated tablets.

Blister pack (aluminium/aluminium) of 5, 10 or 30 enteric-coated tablets (AUST R 243812).
Bottle (white, round HDPE) of 30 enteric-coated tablets (AUST R 243813).
APO and Apotex are registered trade marks of Apotex Inc.
Not all pack types and/or pack sizes may be available.

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

Omeprazole is a white or almost white powder, very slightly soluble in water, soluble in methylene chloride, sparingly soluble in alcohol and in methanol. It dissolves in dilute solutions of alkali hydroxides.

Chemical structure.


Chemical Name: 5-methoxy-2-[(RS)-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-sulphinyl]-1H-benzimidazole.
Empirical Formula: C17H19N3O3S.
Molecular Weight: 345.4.

CAS number.

73590-58-6.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes