Consumer medicine information

Probitor

Omeprazole

BRAND INFORMATION

Brand name

Probitor

Active ingredient

Omeprazole

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Probitor.

SUMMARY CMI

Probitor®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Probitor?

Probitor contains the active ingredient omeprazole. Probitor is used to treat: the symptoms of reflux oesophagitis or reflux disease; peptic ulcers; peptic ulcers associated with helicobacter pylori infection; peptic ulcers associated with non-steroidal anti-inflammatory drugs (NSAIDs); and a rare condition called Zollinger-Ellison syndrome.

For more information, see Section 1. Why am I using Probitor? in the full CMI.

2. What should I know before I use Probitor?

Do not use if you have ever had an allergic reaction to omeprazole or any of the ingredients listed at the end of the CMI. Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Probitor? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Probitor and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Probitor?

  • Take one Probitor capsule each day, unless your doctor has told you otherwise.
  • Swallow Probitor whole with a glass of water. Do not crush or chew the pellets or granules.

More instructions can be found in Section 4. How do I use Probitor? in the full CMI.

5. What should I know while using Probitor?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Probitor.
  • Tell your doctor if you become pregnant while you are taking Probitor.
  • Tell your doctor if your symptoms return.
Things you should not do
  • Do not take Probitor to treat any other complaints unless your doctor tells you to.
  • Do not stop taking your medicine or change the dosage without checking with your doctor.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how Probitor affects you.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
Looking after your medicine
  • Keep it in a cool, dry place where the temperature stays below 25°C.
  • Keep your Probitor in the original container until it is time to take them.

For more information, see Section 5. What should I know while using Probitor? in the full CMI.

6. Are there any side effects?

Mild side effects include: constipation, nausea or vomiting, diarrhoea, wind, stomach pain, headache, dizziness, skin rash, itchy skin, dry or sore mouth.

Serious side effects (Call your doctor straight away, or go straight to the Emergency Department) include: swelling of the face, lips, mouth, tongue or throat, shortness of breath or difficulty in breathing, skin reaction (which may include rash, itching, redness, blistering or peeling of the skin) especially in sun-exposed areas with joint pain, ulcers, blisters or bleeding of the lips, eyes, mouth, nose and genitals, blood in the urine, swelling of hands, feet or ankles, yellowing of the skin or eyes, feeling generally unwell, nausea, vomiting, loss of appetite. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Probitor®

Active ingredient(s): omeprazole

Consumer Medicine Information (CMI)

This leaflet provides important information about using Probitor. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Probitor.

Where to find information in this leaflet:

1. Why am I using Probitor?
2. What should I know before I use Probitor?
3. What if I am taking other medicines?
4. How do I use Probitor?
5. What should I know while using Probitor?
6. Are there any side effects?
7. Product details

1. Why am I using Probitor?

Probitor contains the active ingredient omeprazole. Probitor 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.

Reflux Oesophagitis

Probitor 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.

Probitor is also taken to help stop reflux oesophagitis coming back or relapsing.

Peptic Ulcers

Probitor 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.

Probitor is also used to help stop gastric or duodenal ulcers coming back.

Peptic Ulcers Associated with Helicobacter pylori Infection

Probitor is used to treat peptic ulcers associated with helicobacter pylori infection.

Most people who have a peptic ulcer also have a bacterium called Helicobacter pylori in their stomach.

When Probitor is taken with antibiotics, they work to kill the bacterium and let your ulcer heal. You may need further treatment with antibiotics.

Peptic Ulcers Associated with Non-steroidal Anti-Inflammatory Drugs (NSAIDs)

Probitor is used to treat 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 or inflammation.

Probitor is also used to heal and prevent ulcers associated with NSAIDs.

Zollinger-Ellison Syndrome

Probitor is also used to treat a rare condition called Zollinger-Ellison syndrome.

This syndrome is where the stomach produces large amounts of acid, much more than in ulcers or reflux disease.

There is no evidence that Probitor is addictive.

2. What should I know before I use Probitor?

Warnings

Do not use Probitor if:

  • you are allergic to omeprazole, or any of the ingredients listed at the end of this leaflet.
  • you are allergic to any medicine containing a proton pump inhibitor.
  • Always check the ingredients to make sure you can use this medicine.
    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.
  • you are also taking cilostazol.
    Please check with your doctor or pharmacist if you are taking cilostazol. This medicine will be affected by Probitor.
  • 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.

Check with your doctor if you:

  • allergies to any other medicines, foods, dyes or preservatives.
  • take any medicines for any other condition.
  • any problems with your liver.
  • any other medical conditions
  • been diagnosed with osteoporosis.
  • ever had a skin reaction after treatment with a medicine similar to Probitor that reduces stomach acid.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Do not take Probitor if you are pregnant or breastfeeding unless your doctor says so. Ask your doctor about the risks and benefits involved.

Check with your doctor if you are pregnant or intend to become pregnant.

It is not known if it is safe for you to take Probitor while you are pregnant. It may affect your baby.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

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

3. What if I am taking other medicines?

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

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

  • cilostazol - a medicine used to treat intermittent claudication.

Some medicines may interfere with Probitor and affect how it works.

  • 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 Probitor 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.

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

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Probitor.

4. How do I use Probitor?

How much to take

  • Take one Probitor capsule each day, unless your doctor has told you otherwise.
  • Adults: The dose of Probitor is usually 20 mg a day.
    The dose for Probitor varies from patient to patient.
    Your doctor will decide the right dose for you.

When to take Probitor

  • Take Probitor at about the same time each day.
  • Keeping a regular time for taking Probitor will help to remind you to take it.
  • Probitor can be taken with food or on an empty stomach.

How to take Probitor

  • Swallow Probitor whole with a glass of water. If the granules or pellets contained in the capsules are crushed or chewed, they will not work properly.
  • Keep taking Probitor for as long as your doctor recommends.
  • In most patients, Probitor relieves symptoms rapidly and healing is usually complete within 4 weeks.
    Continue taking Probitor for as long as your doctor tells you to.

If you forget to use Probitor

Probitor should be used regularly at the same time each day. If you miss your dose at the usual time, 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 you missed.

If you use too much Probitor

If you think that you have used too much Probitor, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Probitor?

Things you should do

Take Probitor exactly as your doctor has prescribed.

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

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

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

Tell your doctor if your symptoms return.

Although Probitor 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 Probitor, tell your doctor.

It may affect the results of some tests.

Remind any doctor, dentist or pharmacist you visit that you are using Probitor.

Things you should not do

  • Do not take Probitor 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 unwantedside effects.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Probitor affects you.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

  • Keep your Probitor in the original container until it is time to take them.
    If you take Probitor out of the original container they will not keep well.
  • Do not use after the printed expiry date. Keep the container tightly closed.
  • Keep it in a cool, dry place where the temperature stays below 25°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

When to discard your medicine

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

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
These side effects are usually mild.
Gut or Gastrointestinal related:
  • constipation
  • nausea or vomiting
  • diarrhoea
  • wind
  • stomach pain
  • dry or sore mouth
General Disorders:
  • headache
  • dizziness
Skin related:
  • skin rash, itchy skin
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
These are serious side effects that may require medical attention. Serious side effects are rare.
Muscle-Joint Related:
  • muscle pain or weakness, joint pain
  • "pins and needles"
  • tremor
Bleeding related:
  • increased bruising
Electrolytes related:
  • treatment > 3 month possibly decrease magnesium blood levels resulting in fatigue, involuntary muscle contractions, disorientation, convulsions, dizziness or increased heart rate
  • low magnesium blood levels may cause decrease of potassium or calcium levels in blood
Gut or Gastro-intestinal related:
  • pain or indigestion that occurs during treatment with Probitor
  • you begin to vomit blood or food
  • you pass black (blood-stained) motions
Mood and brain related:
  • changes in sleep patterns
  • mood changes, confusion or depression
Eye related:
  • blurred vision
Others:
  • increase in breast size (males)
  • fever
  • increased sweating
  • hair loss
Tell your doctor immediately if you notice any of these serious side effects.
These are very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are rare.
Allergy related:
  • 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 hands, feet or ankles
Skin related:
  • ulcers, blisters or bleeding of the lips, eyes, mouth, nose and genitals
  • skin reaction, especially in sun-exposed areas, with joint pain
Liver Related:
  • signs of liver inflammation including yellowing of the skin or eyes, feeling generally unwell, nausea, vomiting, loss of appetite
Others:
  • blood in the urine
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

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

When taking Probitor, inflammation in your kidney may occur. Signs and symptoms may include decreased volume of urine or blood in your urine and/or hypersensitivity reactions such as fever, rash, and joint stiffness. You should report such signs to the treating physician.

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

Tell your doctor if your reflux symptoms return after you stop taking Probitor.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What Probitor contains

Active ingredient
(main ingredient)		Omeprazole
Other ingredients
(inactive ingredients)		Pellets
  • sodium lauryl sulfate
  • dibasic anhydrous sodium phosphate
  • hypromellose
  • mannitol
  • macrogol 6000
  • purified talc
  • polysorbate-80
  • titanium dioxide
  • eudragit L30D-55 (PI 3700)
  • maize starch
  • sucrose
Capsule
  • gelatin
  • titanium dioxide
  • quinoline yellow.
Potential allergens
  • sugars

This medicine does not contain lactose, gluten, tartrazine or any other azo dyes.

Do not take this medicine if you are allergic to any of these ingredients.

What Probitor looks like

Probitor 20 mg capsules - opaque yellow cap and body enteric capsule containing off-white to cream-white spherical pellets.

Available in bottles of 5, 30 and 100 enteric capsules and in blister packs of 6, 7, 28, 30 and 35 enteric capsules.

Not all presentations are available in Australia.

Australian Registration Numbers:
20 mg capsules: AUST R 82757 (blister packs)
20 mg capsules: AUST R 78186 (bottles)

Who distributes Probitor

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park
NSW, Australia 2113
Tel: 1800 726 369

This leaflet was prepared in August 2023.

Published by MIMS October 2023

BRAND INFORMATION

Brand name

Probitor

Active ingredient

Omeprazole

Schedule

S4

 

1 Name of Medicine

Omeprazole.

2 Qualitative and Quantitative Composition

Each Probitor enteric capsule contains omeprazole 20 mg.

Excipient with known effect.

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

3 Pharmaceutical Form

Probitor are enteric-coated, off-white to cream-white spherical pellets. The pellets are contained in an opaque yellow cap and body, unprinted, hard gelatin capsules.

Note.

Probitor is available in 20 mg enteric capsules only.

4 Clinical Particulars

4.1 Therapeutic Indications

Probitor enteric capsules are indicated for:
The relief of heartburn and other symptoms associated with GORD.
Treatment and prevention of relapse in erosive oesophagitis.
Treatment of duodenal and gastric ulcer.
Combination therapy for the treatment of peptic ulcer disease associated with Helicobacter pylori infection.
Treatment of gastric and duodenal ulcers and erosions associated with nonsteroidal anti-inflammatory drugs (NSAIDs).
Prevention of gastric and duodenal ulcers and erosions associated with NSAIDs 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 H. pylori negative or in whom eradication is inappropriate (e.g. the elderly) or ineffective.
Treatment of Zollinger-Ellison syndrome.

4.2 Dose and Method of Administration

Dosage.

Symptomatic GORD.

Recommended dose for symptom relief.

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

Recommended healing dosage.

Omeprazole 20 mg once daily for four to eight weeks. In most patients symptomatic relief is rapid and healing is usually complete within four weeks. In those patients not fully healed on endoscopic examination during initial treatment, a further four week treatment period usually results in endoscopic healing.
Omeprazole 40 mg once daily usually produces healing within eight weeks in patients with ulcerative reflux oesophagitis refractory to treatment.

Maintenance.

After healing, it is recommended that maintenance therapy be commenced with omeprazole 10 mg once daily. If needed, this dose should be increased to omeprazole 20 mg once daily.
Helicobacter pylori associated peptic ulcer disease. Patients whose gastric or duodenal ulceration is not associated with NSAID ingestion require antimicrobial treatment 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%:
amoxicillin 500 mg and metronidazole 400 mg both three times a day for two weeks; or
amoxicillin 1 g and clarithromycin 500 mg both twice a day for one week; or
clarithromycin 250 mg and metronidazole 400 mg twice a day for one week.
Patients should be retreated if there is a return of symptoms and H. pylori infection. The possibility of resistance of the organism to the antimicrobial agents should be taken into consideration when deciding on the combination to be used in this situation to ensure healing in patients with active peptic ulcer disease (see further dosage recommendations for duodenal and gastric ulcer).
Duodenal ulcer.

Recommended healing dosage.

Oral administration of omeprazole 20 mg once daily for four to eight weeks. In most patients symptomatic relief is rapid and healing is usually complete within four weeks. In those patients not fully healed during the initial four weeks of treatment, healing usually occurs during a further four weeks of treatment.
Omeprazole 40 mg once daily usually produces healing within four to eight weeks in patients with duodenal ulcer refractory to treatment.

Maintenance.

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 mg to 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 four to eight weeks. In most patients symptomatic relief is rapid and healing is usually complete within four weeks. In those patients not fully healed during the initial four weeks of treatment, healing usually occurs during a further four weeks of treatment. Omeprazole 40 mg once daily usually produces healing within eight weeks in patients with gastric ulcer refractory to treatment.

Maintenance.

The recommended dose 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 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. The recommended dose in patients with or without continued NSAID treatment is omeprazole 20 to 40 mg daily.
In most patients symptomatic relief is rapid and healing occurs within four weeks. In those patients not fully healed during the initial four weeks of treatment, healing usually occurs during a further four weeks of treatment.
The recommended dose for the prevention of NSAID associated gastric or duodenal ulcers or erosions and dyspeptic symptoms is omeprazole 20 mg once daily.
Zollinger-Ellison syndrome.

Recommended initial dose.

Omeprazole 60 mg once daily. The dosage should be adjusted to the individual patient's response and treatment continued for as long as is clinically indicated. Effective control has been achieved for more than 90% of patients with severe disease and inadequate response to other therapies, using dosages ranging from 20 to 120 mg daily. Where the daily oral dose exceeds 80 mg, omeprazole should be given in divided doses twice daily.

Method of administration.

Probitor should be swallowed whole with water. It should be noted that Probitor is only available in 20 mg.

Dosage adjustment.

Renal impairment.

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

Hepatic impairment.

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

Elderly.

It is not necessary to adjust the dosage of omeprazole for the elderly.

4.3 Contraindications

Hypersensitivity to omeprazole, substituted benzimidazoles or any other ingredient of Probitor.
Omeprazole, an inhibitor of CYP2C19, is contraindicated in patients taking cilostazol.
Omeprazole, like other proton pump inhibitors (PPIs), must not be used concomitantly with nelfinavir.

4.4 Special Warnings and Precautions for Use

Undiagnosed malignancy.

As with all antisecretory agents, the presence of any alarm symptoms (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 omeprazole may alleviate symptoms and delay diagnosis.

Concomitant therapy with clopidogrel.

Results from studies in healthy subjects have shown a pharmacokinetic/pharmacodynamic (PK/PD) interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and 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).

Antimicrobial resistance.

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

Subacute cutaneous lupus erythematosus (SCLE).

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

Effects related to acid inhibition.

Decreased gastric acidity due to any means including PPIs 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.

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.

Hypomagnesaemia.

Hypomagnesaemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs. Serious adverse events include tetany, delirium, 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 digoxin or drugs that may cause hypomagnesaemia (e.g. diuretics), healthcare professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment.
Hypomagnesaemia may lead to hypocalcaemia and/or hypokalaemia (see Section 4.8 Adverse Effects (Undesirable Effects)).

Osteoporotic fractures.

PPIs, especially if used in high doses and over long durations, may modestly increase the risk of hip, wrist and spine fracture, predominantly in the elderly or in the presence of other recognised risk factors. Observational studies suggest that PPIs may increase the overall risk of fracture. Some of this increase may be due to other risk factors. Patients at risk of osteoporosis should receive care according to current clinical guidelines and they should have an adequate intake of vitamin D and calcium.
Patients on long-term treatment should be kept under regular surveillance.

Acute interstitial nephritis.

Acute interstitial nephritis has been observed in patients taking 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.

Renal impairment.

Acute tubulointerstitial nephritis (TIN) has been observed in patients taking omeprazole and may occur at any point during omeprazole therapy (see Section 4.8 Adverse Effects (Undesirable Effects)). Acute tubulointerstitial nephritis can progress to renal failure.
Omeprazole should be discontinued in case of suspected TIN, and appropriate treatment should be promptly initiated.

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.

Use in hepatic impairment.

Patients with impaired liver function have shown a marked increase in bioavailability, a reduction in total plasma clearance and an up to four-fold prolongation of the elimination half-life of omeprazole. However, urinary recovery over 96 hours remains unchanged, indicating that there is no accumulation of omeprazole or its metabolites. The normal dose of omeprazole 20 mg a day may be used in patients with severe liver disease (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

See Section 4.2 Dose and Method of Administration.

Paediatric use.

See Section 4.2 Dose and Method of Administration; Section 5.1 Pharmacodynamic Properties, Clinical trials.

Effects on laboratory tests.

Increased CgA level may interfere with investigations for neuroendocrine tumours. To avoid this interference, omeprazole treatment should be stopped for at least 5 days before CgA measurements (see Section 5.1 Pharmacodynamic Properties, Mechanism of action). If CgA and gastrin levels have not returned to reference range after initial measurement, measurements, should be repeated 14 days after cessation of PPI treatment.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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

Food.

Concomitant administration of omeprazole and food does not affect the extent of bioavailability of omeprazole, however, the rate of absorption may be reduced.

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.
Coadministration 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.
Omeprazole produces a profound and sustained inhibition of gastric acid secretion. The absorption of compounds whose absorption depends on gastric pH may decrease during treatment with omeprazole. The absorption of posaconazole, erlotinib, ketoconazole and itraconazole is significantly reduced and thus clinical efficacy may be impaired. For posaconazole and erlotinib concomitant use should be avoided.
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). Digoxin toxicity has been rarely reported. However caution should be exercised when omeprazole is given at high doses in elderly patients. Therapeutic drug monitoring of digoxin should then be reinforced.

Potential interactions that have been excluded.

Results from a range of in vivo interaction studies with omeprazole versus other drugs indicate that omeprazole 20 to 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 (ciclosporin, lignocaine, quinidine and estradiol).

Effects of omeprazole on other medicines.

Demonstrated interactions.

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 of diazepam dosage when Probitor is coprescribed.

Phenytoin.

Omeprazole 40 mg daily for seven days reduced plasma clearance of intravenous phenytoin by 15 to 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 patients with epilepsy, steady-state plasma levels of phenytoin were unchanged during omeprazole treatment.

Warfarin.

Concomitant administration of omeprazole 20 mg and warfarin to healthy volunteers resulted in 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. This stereoselective interaction resulted in a small but statistically significant increase in warfarin's anticoagulant activity.
In patients receiving warfarin or other vitamin K antagonists, monitoring of International Normalised Ratio (INR) is recommended and a reduction of the warfarin (or other vitamin K antagonist) dose may be necessary.

Cilostazol.

Omeprazole given in doses of 40 mg daily to healthy subjects in a crossover study 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 PPIs, 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.

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. Concomitant administration of omeprazole and medicines such as atazanavir is not recommended. Concomitant administration with nelfinavir is contraindicated (see Section 4.3 Contraindications). 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.

Clopidogrel is metabolised to its active metabolite by CYP2C19. Inhibition of CYP2C19 by omeprazole would be expected to result in reduced drug levels of the active metabolite of clopidogrel and a reduction in its antiplatelet activity and therefore its clinical efficacy. Results from studies in healthy subjects have shown a pharmacokinetic/pharmacodynamic (PK/PD) interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and 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 with clopidogrel should be avoided.
When clopidogrel was given together with a fixed dose combination of esomeprazole 20 mg + ASA 81 mg compared to clopidogrel alone in a study in healthy subjects there was a decreased exposure by almost 40% of the active metabolite of clopidogrel. However, the maximum levels of inhibition of (ADP induced) platelet aggregation in these subjects were similar in the clopidogrel and the clopidogrel + the combined (esomeprazole + ASA) product groups.
These are both observational and clinical studies on the clinical implication 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.

St. John's wort.

Because of potential clinically significant interaction, St. John's wort should not be used concomitantly with omeprazole.

Effects of other medicines on omeprazole.

Demonstrated interactions. 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.

Voriconazole.

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

Clarithromycin.

Plasma concentrations of omeprazole are increased during concomitant administration with clarithromycin.

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 embryofetal toxicity.
(Category B3)
Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.
Results from three prospective epidemiological studies indicate that while 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).
Embryofetal 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 (sevenfold 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. Adverse drug reactions such as somnolence, dizziness and visual disturbances may occur. If affected, patients should not drive or operate machinery.

4.8 Adverse Effects (Undesirable Effects)

Omeprazole is well tolerated. Most adverse effects have been mild and transient and there has been no consistent relationship with treatment.
The most common side effects (1-10% of patients) are headache, abdominal pain, constipation, diarrhoea, flatulence and nausea/vomiting.
The following adverse drug reactions have been identified or suspected in the clinical trials programme for omeprazole and postmarketing.
Adverse reactions within each body system are listed in descending order of frequency: very common: ≥ 10%; common: ≥ 1.0% and < 10%; uncommon: ≥ 0.1% and < 1%; rare: ≥ 0.01% and < 0.1%; very rare: < 0.01%. These include the following:

Skin and subcutaneous tissue disorders.

Uncommon: rash, pruritus, urticaria, dermatitis, alopecia, photosensitivity, erythema multiforme, skin eruptions.
Rare: Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), acute generalised exanthematous pustulosis (AGEP), drug rash with eosinophilia and systemic symptoms (DRESS).
Not known: subacute cutaneous lupus erythematosus (see Section 4.4 Special Warnings and Precautions for Use).

Musculoskeletal, connective tissue and bone disorders.

Uncommon: fracture of the hip, wrist or spine.
Rare: muscular weakness, arthralgia, myalgia.

Psychiatric disorders.

Common: insomnia.
Rare: reversible mental confusion, agitation, aggression, lightheadedness, depression and hallucinations, predominantly in severely ill patients or elderly patients.

Nervous system disorders.

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

Gastrointestinal disorders.

Common: abdominal pain, nausea/vomiting, constipation, diarrhoea, flatulence, fundic gland polyps (benign).
Rare: stomatitis, gastrointestinal candidiasis, microscopic colitis, dry mouth.
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 severe liver disease; hepatitis with or without jaundice, hepatic failure.

Reproductive system and breast disorders.

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

Blood and lymphatic system disorders.

Rare: hypochromic, microcytic anaemia in children, leukopenia, agranulocytosis, thrombocytopenia, pancytopenia.

Eye disorders.

Rare: blurred vision.

Ear and labyrinth disorders.

Uncommon: vertigo.

Immune system disorders.

Rare: hypersensitivity reactions, e.g. bronchospasm, angioedema, fever, anaphylactic reaction/shock.
Very rare: allergic vasculitis.

Respiratory, thoracic and mediastinal disorders.

Rare: bronchospasm.
Very rare: dyspnoea.

Renal and urinary disorders.

Rare: tubulointerstitial nephritis (with possible progression to renal failure).
Very rare: impaired renal function, including nephrosis.

Metabolism and nutrition disorders.

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

General disorders and administration site conditions.

Uncommon: malaise, peripheral oedema, increased sweating.
Very rare: elevated body temperature.

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

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 2,400 mg omeprazole (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 belongs to the group of drugs known as proton pump inhibitors (PPIs). It acts to reversibly reduce gastric acid secretion by inhibiting the enzyme H+, K+-ATPase in the acid environment of the intracellular canaliculi within the parietal cell. Omeprazole has a dose dependent effect on the final step of the gastric acid formation process. Basal acid secretion and stimulated acid secretion are both effectively inhibited by omeprazole.
No clinically significant pharmacodynamic effects have been observed apart from those explained by the effect of omeprazole on acid secretion. Omeprazole has no effect on histamine or acetylcholine receptors.
Oral administration of omeprazole 20 mg once a day provides a rapid and effective reduction of gastric acid secretion beginning within one hour and is maximal within two hours of a single dose. Repeated once daily dosing achieves its maximal effect within four days of the start of treatment.
Helicobacter pylori is the major factor in the development of gastritis and ulcer in patients with duodenal and gastric ulcer disease. H. pylori is associated with about 95% of patients suffering from duodenal ulcer disease and 70% of patients with gastric ulcer disease. Recent evidence has also suggested 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). Successful eradication of H. pylori is associated with a reduced incidence of peptic ulcer recurrence.
Any attempt to eradicate H. pylori requires combined treatment with omeprazole and antimicrobial agents. Omeprazole was shown to have a MIC90 of 25 microgram/mL against H. pylori in vitro. However, its action in vivo results only in the suppression of H. pylori, not its eradication. Results have shown that the use of antimicrobial agents alone has been ineffective in eradicating the organism. The eradication rates for H. pylori are optimal when omeprazole is combined with two antimicrobial agents, although the exact mechanism of the synergy between omeprazole and antimicrobial agents is not understood.
Duodenal ulcer patients treated with an oral dose of omeprazole 20 mg maintain an average reduction in 24 hour intragastric acidity of approximately 80%. Omeprazole produces a mean decrease of approximately 70% in peak pentagastrin stimulated acid output 24 hours after dosing. Secretory activity returns to approximately 50% of maximum 24 hours after discontinuation of omeprazole, and then gradually returns to normal over three to five days.

Other effects related to acid inhibition.

Decreased gastric acidity due to any means including PPIs 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.
A two to fourfold increase in fasting serum gastrin levels has been noted during treatment with omeprazole in some patients with up to 3% of patients having values in excess of 400 picogram/mL.
During treatment with antisecretory medicinal products, serum gastrin increases in response to the decreased acid secretion. Also Chromogranin A (CgA) increases due to decreased gastric acidity. The increased CgA level may interfere with investigations for neuroendocrine tumours. Available published evidence suggests that PPIs should be discontinued between 5 days and 2 weeks prior to CgA measurements. This is to allow CgA levels that might be spuriously elevated following PPI treatment to return to reference range.

Clinical trials.

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 four 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 four weeks is presented in Table 1.

Erosive oesophagitis.

The efficacy of omeprazole in the prevention of relapse in patients with healed reflux oesophagitis has been assessed and evaluated in seven randomised controlled clinical trials (n = 1,674). Once daily doses of omeprazole 10 mg and omeprazole 20 mg maintained endoscopic remission rates which substantially exceeded those of ranitidine 150 mg twice a day or placebo at six months. The difference in remission rates favoured omeprazole 20 mg over omeprazole 10 mg. Remission rates were recorded over twelve months in three studies and an additional study continued for 18 months.
In a meta-analysis of five of the clinical trials (n = 1,154), 72% of patients on omeprazole 10 mg once daily and 82% of patients on omeprazole 20 mg once daily, remained in remission at six months. In a separate large study (n = 327), once daily dosing of omeprazole 10 mg for 18 months had a remission rate of 60%. In two of the studies, patients on maintenance therapy who relapsed in the first three months of 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 indicates that it may take longer or be more difficult to obtain subsequent healing and control if omeprazole 10 mg had been used rather than 20 mg for initial maintenance therapy.
Due to histological changes observed in animals a full analysis of gastric safety data from seven controlled clinical trials was undertaken (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 to 12 months, 77 patients completing 18 months, and 208 completing two years of continuous omeprazole treatment. Additionally, in open studies at least 109 patients were assessed by annual biopsy during continuous treatment for four years, and in this continuing study, biopsies are available for at least 14 patients treated for up to eight years. There have been no instances of dysplasia or carcinoids of the gastric enterochromaffin like (ECL) cells 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

In a single dose, four way crossover study in 48 subjects, Probitor (omeprazole) 20 mg enteric capsules were found to be bioequivalent to Losec (omeprazole magnesium, AstraZeneca) 20 mg tablets under fed and fasting conditions.

Absorption.

Omeprazole is administered orally as enteric coated granules in capsules since it is acid labile. Omeprazole is rapidly absorbed, with peak plasma levels occurring within four hours, and is usually complete within three to six hours. Following a single oral dose the systemic bioavailability of omeprazole is approximately 35%, with repeated once daily administration increasing bioavailability to about 60%. Food has no effect on the oral bioavailability of omeprazole but the rate of absorption may be reduced.

Distribution.

Omeprazole is approximately 95% bound to plasma proteins. The inhibitory effect of omeprazole on 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.

The liver is the main site of metabolism for omeprazole. The metabolites identified in plasma following the complete metabolism of omeprazole are the sulfone, the sulfide and hydroxyomeprazole. These metabolites do not have a significant effect on acid secretion.
The average half-life of the terminal phase of the plasma concentration time curve is approximately 40 minutes following intravenous administration of omeprazole; total plasma clearance is 0.3 to 0.6 L/minute. During repeated dosing the half-life is not altered.

Excretion.

About 80% of the metabolites are renally cleared with the two main urinary metabolites being hydroxyomeprazole and the corresponding carboxylic acid. The remaining metabolites are excreted in the faeces.

5.3 Preclinical Safety Data

Genotoxicity.

A range of genotoxicity tests, in vitro and in vivo, have been used to examine the mutagenic, clastogenic and DNA damaging potential of omeprazole. 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 observed in the tests used.

Carcinogenicity.

In a two year carcinogenicity study involving male and female rats, omeprazole at 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 sexes. A markedly higher incidence of these effects occurred in female rats. An additional two year study in female rats at doses of 1.7, 3.4 and 13.8 mg/kg/day produced the same effects. In the dose ranges studied a no effect dose was not established in female rats.
In a carcinogenicity study performed in mice over 78 weeks, no gastric ECL cell carcinoids were seen. However, longer-term studies have not been performed in this species. ECL cell hyperplasia, hypergastrinaemia 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.

Treatment with a subcutaneous infusion of gastrin-17 for one month produced a significant hyperplasia of ECL cells.

(b) H2-receptor antagonists.

Administration of ranitidine 2 g/kg/day to rats in their diet over 106 weeks resulted in argyrophilic cell hyperplasia being 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 which had 75% of the stomach corpus surgically removed, 26 of 75 animals developed ECL cell carcinoids during the 124 week study.
These findings indicate 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. Other cells in the gastrointestinal tract (e.g. G cells) may also be affected by omeprazole, either directly or by inducing sustained hypochlorhydria, however this possibility has not been extensively studied. (See Section 5.1 Pharmacodynamic Properties, Clinical trials).

6 Pharmaceutical Particulars

6.1 List of Excipients

Probitor enteric coated pellets contain sodium lauryl sulfate, dibasic sodium phosphate, hypromellose, mannitol, macrogol 6000, purified talc, polysorbate 80, titanium dioxide, Eudragit L30D-55 (PI 3700), maize starch and sucrose. The capsules contain gelatin, titanium dioxide and quinoline yellow.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
For further information on interactions with other medicines and other forms of interactions, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25°C.
Protect from moisture.

6.5 Nature and Contents of Container

Probitor enteric capsules are registered in blister packs containing 6*, 7*, 28*, 30 or 35* capsules and bottles containing 5*, 30 or 100* capsules.
* Not currently marketed in Australia.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Omeprazole is a white to off-white powder, very slightly soluble in water, soluble in ethanol, in methanol and in methylene chloride. It dissolves in dilute solutions of alkali hydroxides.

Chemical structure.

Probitor contains the active ingredient omeprazole. The structural formula is shown below:
Molecular formula: C17H19N3O3S.
Molecular weight: 345.4.
Chemical name: 5-methoxy-2-[(RS)- [(4-methoxy-3,5-dimethylpyridin-2-yl) methyl]sulfinyl]-1H-benzimidazole.

CAS number.

73590-58-6.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes