Consumer medicine information

Pantoprazole MYL

Pantoprazole

BRAND INFORMATION

Brand name

Pantoprazole MYL

Active ingredient

Pantoprazole

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Pantoprazole MYL.

What is in this leaflet

This leaflet answers some common questions about PANTOPRAZOLE MYL. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

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

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

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

What PANTOPRAZOLE MYL is used for

The name of your medicine is PANTOPRAZOLE MYL. It contains the active ingredient pantoprazole.

Ulcers
PANTOPRAZOLE MYL is used to treat and help heal duodenal and gastric 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 of the stomach.

These can be caused in part by too much acid being made in the stomach.

Most people who have a peptic ulcer also have bacteria called Helicobacter pylori in their stomach. When PANTOPRAZOLE MYL is taken with antibiotics, the combination therapy will kill the Helicobacter pylori and let your ulcer heal.

PANTOPRAZOLE MYL may be used to prevent ulcers associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs). These are medicines used to relieve pain, swelling and other symptoms of inflammation, including arthritis (inflammation of the joints).

Reflux Disease
PANTOPRAZOLE MYL is used to treat reflux oesophagitis or reflux disease. This can be caused by "washing back" (reflux) of food and acid from the stomach into the food pipe, also known as the oesophagus.

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

PANTOPRAZOLE MYL is also used to prevent reflux oesophagitis from coming back.

Zollinger-Ellison Syndrome
PANTOPRAZOLE MYL is used to treat a rare condition called Zollinger-Ellison syndrome, where the stomach produces very large amounts of acid, much more than in ulcers and reflux disease.

This medicine belongs to a group of medicines called proton pump inhibitors (PPIs).

This medicine works by decreasing the amount of acid the stomach makes, to give relief from the symptoms and allow healing to take place.

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

This medicine is not addictive.

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

This medicine is not expected to affect your ability to drive a car or operate machinery.

However, do not drive a car or operate machinery if you experience side effects such as dizziness or blurred vision.

PANTOPRAZOLE MYL should not be given to children under 5 years of age. There is not enough information to recommend the use of this medicine for children under the age of 5 years.

Before you take PANTOPRAZOLE MYL

When you must not take it

Do not take PANTOPRAZOLE MYL if you have an allergy to:

  • any medicine containing pantoprazole
  • any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

  • shortness of breath, wheezing or difficulty breathing
  • Difficulty swallowing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not take PANTOPRAZOLE MYL if you have severe liver disease or cirrhosis.

Do not take PANTOPRAZOLE MYL in combination with antibiotics or any other medicine if:

  • you are allergic to any of the antibiotics or medicines your doctor may prescribe with PANTOPRAZOLE MYL
  • you have moderate to severe liver or kidney disease.

Do not take PANTOPRAZOLE MYL in combination with atazanavir or nelfinavir (anti-viral medications).

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any other medical conditions.

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. Your doctor can discuss the risks and benefits involved.

If you have not told your doctor about any of the above, tell them before you take PANTOPRAZOLE MYL.

Tell your doctor if you have any of the following symptoms:

  • unintentional weight loss
  • repeated vomiting
  • vomiting blood
  • difficulty or pain when swallowing
  • you look pale and feel weak
  • you notice blood in your stools

Your doctor may need to perform some additional tests before you take PANTOPRAZOLE MYL.

Taking other medicines

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

Some medicines and PANTOPRAZOLE MYL may interfere with each other. These include:

  • warfarin, phenprocoumon - medicines used to prevent blood clots (anticoagulants)
  • atazanavir, nelfinavir - medicines used to treat viral infections such as HIV
  • ketoconazole, itraconazole, posaconazole - medicines used to treat fungal infections
  • methotrexate - a medicine used to treat arthritis and some types of cancer
  • erlotinib or related medicines used to treat cancer
  • tacrolimus, mycophenolate mofetil - medicines used to suppress the immune system
  • fluvoxamine - a medicine used to treat anxiety and depression

These medicines may be affected by PANTOPRAZOLE MYL or may affect how well it works. You may need different amounts of your medicines or you may need to take different medicines.

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

How to take PANTOPRAZOLE MYL

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

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

How much to take

The usual dose is 40 mg per day.

If your doctor also prescribes antibiotics in combination with PANTOPRAZOLE MYL for the treatment of duodenal ulcers, the dose of PANTOPRAZOLE MYL is 80 mg per day.

The first 40 mg dose should be taken in the morning and the second 40 mg dose should be taken before the evening meal for 7 days.

Your doctor will prescribe the dose that is right for you.

In children over 5 years of age, the dose of PANTOPRAZOLE MYL for reflux oesophagitis or reflux disease is based on weight and may be 20 mg or 40 mg depending on the condition being treated.

PANTOPRAZOLE MYL should not be taken for longer than 8 weeks.

The dose and frequency of PANTOPRAZOLE MYL that your doctor prescribes for you depends on your medical condition.

Your doctor may change the dose as your condition changes.

How to take it

Swallow your tablets whole with a little water, with or without food.

Do not crush or chew your tablets.

PANTOPRAZOLE MYL tablets have a special coating to protect them from the acidic contents of your stomach.

For PANTOPRAZOLE MYL to work effectively, this coating must not be broken before you take this medicine.

When to take it

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

If you are taking other medicines, like antibiotics, in combination with PANTOPRAZOLE MYL therapy, follow the instructions for the use of each medicine carefully.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking it as you would normally.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

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

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

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26) for advice or go to Accident and Emergency at your nearest hospital, if you think that you or anyone else may have taken too much PANTOPRAZOLE MYL. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking PANTOPRAZOLE MYL

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking PANTOPRAZOLE MYL.

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

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.

Tell your doctor immediately if you become pregnant while you are taking PANTOPRAZOLE MYL.

If you are about to have any blood tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Tell your doctor if your reflux symptoms return after you stop taking this medicine. The symptoms of reflux may return after stopping this medicine suddenly, especially if you have taken it for a while.

Things you must not do

Do not take PANTOPRAZOLE MYL 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 symptoms as you.

Things that may help your condition

Some self-help measures suggested below may help your condition. Talk to your doctor or pharmacist about these measures and for more information.

  • alcohol - your doctor may advise you to limit your alcohol intake
  • aspirin and many other medicines used to treat arthritis/period pain/ headaches - these medicines may irritate the stomach and may make your condition worse. Your doctor or pharmacist may suggest other medicines you can take
  • caffeine - your doctor may advise you to limit the number of drinks which contain caffeine, such as coffee, tea, cocoa and cola drinks, because they contain ingredients that may irritate your stomach
  • eating habits - eat smaller, more frequent meals. Eat slowly and chew your food carefully. Try not to rush at meal times
  • smoking - your doctor may advise you to stop smoking or at least cut down
  • weight - your doctor may suggest losing some weight to help your condition

Side effects

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

This medicine helps most people with peptic ulcers or reflux disease, but it may have unwanted side effects in a few people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following list of side effects. You may not experience any of them.

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

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

  • headache
  • dizziness
  • diarrhoea
  • nausea or vomiting
  • stomach pain
  • excessive gas in the stomach or bowel
  • indigestion
  • constipation
  • dry mouth
  • metallic taste
  • weakness or tiredness
  • increased sweating or body temperature
  • blurred vision
  • skin problems such as itchiness and rash
  • trouble sleeping

These are the more common side effects of PANTOPRAZOLE MYL.

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

  • unusual tiredness or weakness
  • nausea, vomiting, loss of appetite, feeling generally unwell, fever, itching, yellowing of the skin and eyes and dark coloured urine
  • blood in the urine
  • increased or decreased need to urinate
  • skin problems such as itchiness, rash with swelling, blistering or peeling of the skin or rash when exposed to the sun, possibly with pain in the joints and general fever
  • swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing
  • frequent infections such as fever, severe chills, sore throat or mouth ulcers
  • chest pain
  • shortness of breath
  • high blood pressure
  • water retention, swelling
  • bleeding or bruising more easily than normal
  • depression, confusion or anxiety
  • bone fracture of the hip, wrist or spine (mainly a risk in people who take high doses of PPIs or use them long term (a year or longer))
  • symptoms such as seizures, abnormal or fast heartbeat or jerking/shaking movements or muscle cramps. These can be a sign of low magnesium, calcium or potassium levels in your blood
  • severe and/or persistent diarrhoea, because this medicine has been associated with a small increase in infectious diarrhoea

The above list includes serious side effects. You may need urgent medical attention or hospitalisation.

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

Other side effects not listed above may also occur in some people.

After taking PANTOPRAZOLE MYL

Storage

Keep your tablets in the pack until it is time to take them. If you take the tablets out of the pack, they may not keep well.

Keep your tablets in a cool dry place where the temperature stays below 30°C.

Do not store PANTOPRAZOLE MYL or any other medicines in a bathroom or near a sink. Do not leave it in the car or on window sills. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and- a-half metres (5 feet) above the ground is a good place to store medicines.

Disposal

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

Product description

What it looks like

PANTOPRAZOLE MYL is available as 20 mg and 40 mg tablets.

The tablets have an acid-resistant coating called an enteric coating.

The 20 mg tablets are yellow to light yellow, oval shaped, plain on both sides,

The 40 mg tablets are yellow to light yellow, oval shaped, plain on both sides.

The 20 mg and 40 mg tablets are available in packs of 30 tablets.

Ingredients

The active ingredient in PANTOPRAZOLE MYL tablets is pantoprazole.

PANTOPRAZOLE MYL 40 mg tablets contain the equivalent of 40 mg pantoprazole and;

PANTOPRAZOLE MYL 20 mg tablets contain the equivalent of 20 mg pantoprazole.

PANTOPRAZOLE MYL tablets also contain:

  • mannitol
  • sodium carbonate
  • sodium starch glycollate
  • crospovidone
  • colloidal anhydrous silica
  • calcium stearate
  • hypromellose
  • macrogol 6000
  • purified water
  • sodium hydroxide
  • Eudragit L30D-55
  • Opadry AMB Aqueous Moisture Barrier Coating System 80W52172 Yellow

PANTOPRAZOLE MYL also contains traces of soya bean products.

PANTOPRAZOLE MYL tablets do not contain sucrose, tartrazine or any other azo dyes.

Supplier

PANTOPRAZOLE MYL is supplied by:

Alphapharm Pty Ltd
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.mylan.com.au

This leaflet was prepared in July 2021.

Australian registration numbers:

20 mg tablets - AUST R 158202

40 mg tablets - AUST R 158203

PANTOPRAZOLE MYL_cmi\Jul21/00

Published by MIMS September 2021

BRAND INFORMATION

Brand name

Pantoprazole MYL

Active ingredient

Pantoprazole

Schedule

S4

 

1 Name of Medicine

Pantoprazole (as sodium sesquihydrate).

2 Qualitative and Quantitative Composition

Each Pantoprazole MYL 20 mg enteric coated tablet contains 22.56 mg pantoprazole sodium sesquihydrate equivalent to 20 mg of pantoprazole.
Each Pantoprazole MYL 40 mg enteric coated tablet contains 45.12 mg of pantoprazole sodium sesquihydrate equivalent to 40 mg of pantoprazole.

Excipients with known effect.

Pantoprazole MYL also contains traces of soya bean products.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Pantoprazole MYL 20 mg enteric-coated tablets are yellow to light yellow, oval shaped, biconvex enteric coated tablets plain on both sides.
Pantoprazole MYL 40 mg enteric-coated tablets are yellow to light yellow, oval shaped, biconvex enteric coated tablets plain on both sides.

4 Clinical Particulars

4.1 Therapeutic Indications

Adults.

1. Symptomatic improvement and healing of gastrointestinal diseases which require a reduction in acid secretion.
Duodenal ulcer.
Gastric ulcer.
Gastroesophageal reflux disease (GORD):
i. symptomatic GORD. The treatment of heartburn and other symptoms associated with GORD;
ii. reflux oesophagitis.
Gastrointestinal lesions refractory to H2 blockers.
Zollinger-Ellison syndrome.
Patients whose gastric or duodenal ulceration is not associated with ingestion of nonsteroidal anti-inflammatory drugs (NSAIDs) require treatment with antimicrobial agents in addition to antisecretory drugs whether on first presentation or on recurrence.
2. Maintenance of healed reflux oesophagitis in patients previously treated for moderate to severe reflux oesophagitis.
3. For eradication of Helicobacter pylori, treatment with pantoprazole and one of the following combinations of antibiotics:
Clarithromycin and amoxicillin, or clarithromycin and metronidazole, or amoxicillin and metronidazole is recommended in cases of duodenal ulcer and gastric ulcer with the objective of reducing the recurrence of duodenal and gastric ulcers caused by this microorganism (see Section 4.2 Dose and Method of Administration).
4. Pantoprazole in combination with bismuth, metronidazole and tetracycline is indicated for the eradication of Helicobacter pylori associated with peptic ulcer disease with the objective of reducing the recurrence of peptic ulcers caused by this organism.
5. Prevention of gastroduodenal lesions and dyspeptic symptoms associated with nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) in increased risk patients with a need for continuous nonselective NSAID treatment.

Children aged from 5 to 17 years.

Gastroesophageal reflux disease (GORD).

Symptomatic GORD. The treatment of heartburn and other symptoms associated with GORD.
Reflux oesophagitis.
The treatment duration should not exceed 8 weeks.

4.2 Dose and Method of Administration

Pantoprazole MYL is available as a tablet formulation. Pantoprazole MYL tablets should not be chewed or crushed but swallowed whole with a little water.
Patients who have difficulty swallowing tablets may use pantoprazole granules (available from other brands).
In H. pylori positive patients with gastric and duodenal ulcers, eradication of this microorganism by combination therapy should be achieved. One of the following combinations of pantoprazole with antibiotics is effective:
a) Pantoprazole MYL 40 mg twice daily plus amoxicillin 1000 mg (2 x 500 mg) twice daily plus clarithromycin 500 mg twice daily.
b) Pantoprazole MYL 40 mg twice daily plus metronidazole 400 mg in the morning and 600 mg at night plus clarithromycin 500 mg twice daily.
c) Pantoprazole MYL 40 mg twice daily plus amoxicillin 1000 mg (2 x 500 mg) twice daily plus metronidazole 400 mg in the morning and 600 mg at night.
d) Pantoprazole MYL 40 mg twice daily plus bismuth subcitrate 108 mg four times a day plus metronidazole 200 mg three times a day and 400 mg at night plus tetracycline 500 mg (2x 250 mg) four times a day.
In combination therapy for eradication of H. pylori infection, the second dose of Pantoprazole MYL 40 mg should be taken before the evening meal. The duration for combination therapy is 7 days. If further treatment with Pantoprazole MYL is indicated to ensure ulcer healing, dosage recommendations as listed below for duodenal and gastric ulcers should be followed.
In H. pylori negative patients, the following dosage guidelines apply for monotherapy with pantoprazole.

Duodenal ulcer.

Pantoprazole MYL 40 mg (one tablet) should be given once a day. In most patients freedom from symptoms is achieved rapidly and healing generally occurs within two weeks. If a two week period of treatment is not sufficient, healing will be achieved in almost all cases within a further two weeks.

Gastric ulcer.

Pantoprazole MYL 40 mg (one tablet) should be given once a day. In most patients freedom from symptoms is achieved rapidly and healing usually takes four weeks. If a four week period of treatment is not sufficient, healing will usually be achieved in a further four weeks.

Lesions refractory to H2-receptor antagonists.

Pantoprazole MYL 40 mg (one tablet) should be given once a day. In most patients freedom from symptoms is achieved rapidly and healing usually takes four weeks. If a four week period of treatment is not sufficient, healing is achieved in the majority of patients in a further four weeks. In a small group of patients, there may be benefit in extending pantoprazole therapy to a total of 12 weeks.

Zollinger-Ellison syndrome.

The number of Pantoprazole MYL 40 mg tablets should be individually adjusted so that the acid output remains below 10 mmol/L. No fixed period of time is proposed for treatment of Zollinger-Ellison syndrome.

Gastroesophageal reflux disease (GORD).

Symptomatic GORD (treatment of symptomatic reflux).

The recommended dosage is one Pantoprazole MYL 20 mg tablet per day for adults and children aged over 5 years. If symptom control has not been achieved after four weeks treatment with Pantoprazole MYL 20 mg tablets daily, further investigation is recommended, for example endoscopy.

Treatment of reflux oesophagitis.

The recommended oral dosage is one Pantoprazole MYL 20 or 40 mg tablet per day. In children over 5 years of age, the dosage should be adjusted according to weight - Pantoprazole MYL 20 mg (for children 19 - 35 kg) or Pantoprazole MYL 40 mg (for children > 35 kg) per day. A four week period is usually required for healing, however if this is not sufficient, healing will usually be achieved within a further four weeks. This dosage may be increased up to pantoprazole 80 mg per day in adults.
Treatment duration in children with symptomatic GORD or reflux oesophagitis should not exceed 8 weeks.

Maintenance of healed reflux oesophagitis in patients previously treated for moderate to severe reflux oesophagitis.

For long-term management, a maintenance dose of one Pantoprazole MYL 20 or 40 mg tablet/day is recommended, dependent upon patient response.

Prevention of gastroduodenal lesions and dyspeptic symptoms associated with nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) in increased risk patients with a need for continuous nonselective NSAID treatment.

The recommended oral dosage is one Pantoprazole MYL 20 mg tablet per day.

Use in children.

There is insufficient experience in children under 5 to justify a general recommendation.

Use in the elderly.

The usual daily dosage of 20 or 40 mg can be given.
During combination therapy for the eradication of H. pylori, elderly patients should receive the recommended pantoprazole dose of 40 mg twice daily for a 1-week treatment period.

Impaired renal function.

The usual daily dose of 20 or 40 mg can be given.
Combination therapy for the eradication of H. pylori should not be used in patients with moderate to severe renal dysfunction as no data are available on efficacy and safety in this population.

Impaired hepatic function.

Combination therapy for eradication of H. pylori should not be used in patients with moderate to severe hepatic dysfunction as no data are available on efficacy and safety in this population.
Pantoprazole is contraindicated in patients with cirrhosis or severe liver disease (see Section 4.3 Contraindications).
With milder forms of liver disease, the minimum effective dose has not been determined and the initial dose should be reduced.

4.3 Contraindications

Known hypersensitivity to pantoprazole, substituted benzimidazoles or any other components of the formulation; or in cases of cirrhosis or severe liver disease.
Combination therapy for eradication of H. pylori is contraindicated in patients with known hypersensitivity to any of the antibiotics proposed for combination therapy for eradication of H. pylori or in patients with moderate to severe hepatic or renal dysfunction. The product information for the individual components of the combination H. pylori eradication therapy should be consulted for any further contraindications.
Pantoprazole, like other proton pump inhibitors, should not be coadministered with HIV protease inhibitors, such as atazanavir or nelfinavir (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Check the following before use.

In the case of combination therapy for the eradication of H. pylori, the product information for the antibiotics used in the combination should be observed.
In the presence of any alarm symptoms (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis, anaemia or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment with pantoprazole may alleviate symptoms and delay diagnosis. Further investigation is to be considered if symptoms persist despite adequate treatment.

Clostridium difficile.

PPI therapy may be associated with an increased risk of Clostridium difficile infection.
Pantoprazole, like all proton pump inhibitors, might be expected to increase the counts of bacteria normally present in the upper gastrointestinal tract. Treatment with pantoprazole may lead to a slightly increased risk of gastrointestinal infections caused by bacteria such as Salmonella, Campylobacter and Clostridium difficile.

Influence on vitamin B12 absorption.

Pantoprazole, as all acid blocking medicines, may reduce the absorption of cyanocobalamin (vitamin B12) due to hypochlorhydria or achlorhydria. This should be considered in patients with reduced body stores or risk factors for reduced vitamin B12 absorption (such as the elderly) on long-term therapy and in patients with Zollinger-Ellison syndrome and other pathological hypersecretory conditions requiring long-term treatment, or, if respective clinical symptoms are observed. Rare cases of cyanocobalamin (vitamin B12) deficiency following acid blocking therapy have been reported.

Nonsteroidal anti-inflammatory drugs (NSAIDs).

Use of Pantoprazole MYL 20 mg for prevention of gastroduodenal lesions and dyspeptic symptoms associated with nonselective NSAIDs should be restricted to patients who require continued nonselective NSAID treatment and have an increased risk of developing gastrointestinal complications. The increased risk should be assessed according to individual risk factors, e.g. high age (> 65 years), history of gastric or duodenal ulcer or upper gastrointestinal bleeding.

Subacute cutaneous lupus erythematosus (SCLE).

Proton pump inhibitors are associated in rare cases with the occurrence of subacute cutaneous lupus erythematosus (SCLE). 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 healthcare professional should consider stopping the product.

Bone fracture.

PPI therapy may be associated with an increased risk for osteoporosis related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high doses; defined as multiple daily doses, and long-term PPI therapy (a year or longer).

Acute interstitial nephritis.

Acute interstitial nephritis has been observed in patients taking PPIs including pantoprazole. Acute interstitial nephritis may occur at any point during PPI therapy and is generally associated to an idiopathic hypersensitivity reaction. Discontinue pantoprazole if acute interstitial nephritis develops.

Hypomagnesaemia.

Hypomagnesaemia has been rarely reported in patients treated with PPIs for at least three months (in most cases after a year of therapy). Serious consequences of hypomagnesaemia include tetany, arrhythmia, and seizure. Hypomagnesaemia may lead to hypocalcaemia and/or hypokalaemia (see Section 4.8 Adverse Effects (Undesirable Effects)).

Monitoring.

In long-term treatment, especially when exceeding a treatment period of one year, patients should be kept under regular surveillance.
Patients being treated for symptomatic GORD with Pantoprazole MYL 20 mg who do not respond after four weeks should be investigated.

General toxicity.

Gastrointestinal system.

Treatment with pantoprazole causes dose dependent hypergastrinaemia as a result of inhibition of gastric acid secretion. Gastrin has a trophic effect on the gastric mucosa, and increases in gastric weight have been observed in rats and dogs to be dependent upon both dose and duration of treatment. Accompanying histopathological changes in the gastric mucosa were increased height, dilatation of fundic glands, chief cell hyperplasia and/or atrophy and parietal cell hyperplasia or vacuolation/ degeneration. Increased density of enterochromaffin-like (ECL) cells was observed after 12 months treatment at dose levels from 5 mg/kg/day in rats and 2.5 mg/kg/day in dogs; with estimated exposures at these doses at, or below, the clinical exposure, all changes were reversible after various recovery periods. Since these gastric effects are a consequence of the pharmacological effect of acid secretion inhibition, no-effect doses were not established in all instances.
Although rats might be more susceptible to this effect than other species because of their high ECL cell density and sensitivity to gastrin, ECL cell hyperplasia occurs in other species, including mice and dogs, and has been observed in one of two clinical trials in which ECL cell density was measured (a 2-fold increase was observed in study RR126/97 after up to 5 years of treatment with regular and high doses, but no increase was observed in study RR125/97). No dysplastic or neoplastic changes were observed in gastric endocrine cells in either study.

Ocular toxicity and dermal phototoxicity/sensitivity.

Studies have shown that pantoprazole is retained in low levels in the eyes and skin of pigmented rats. It is likely that the retention reflects a reversible association with melanin. Animal studies investigating the potential for phototoxicity/ photosensitivity have not been conducted. A 2 week dog study, conducted specifically to investigate the effects on the eye and ear, did not reveal any changes relating to pantoprazole treatment, but the doses chosen were relatively low with exposures (AUC) of 0.2- to 10-fold (oral) and 1- to 2-fold (IV) the clinical exposure. No ophthalmological changes or changes in electroretinographs were observed in cynomolgus monkeys at IV doses of up to 15 mg/kg/day (up to 7- to 9-fold the clinical exposure of the 40 mg IV dose) for 4 weeks.

Use in hepatic impairment.

See Section 4.2 Dose and Method of Administration, Impaired hepatic function.

Use in renal impairment.

See Section 4.2 Dose and Method of Administration, Impaired renal function.

Use in the elderly.

No dose adjustment is necessary in elderly patients (see Section 4.2 Dose and Method of Administration, Use in the elderly; Section 4.4 Special Warnings and Precautions for Use, Influence on vitamin B12 absorption; Section 5.2 Pharmacokinetic Properties, Special populations).

Paediatric use.

To date there is insufficient experience with treatment in children under 5 to justify a general recommendation.

Effects on laboratory tests.

Increased chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours. To avoid this interference, proton pump inhibitor treatment should be stopped 14 days before CgA measurements.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Pantoprazole is metabolised in the liver via the cytochrome P450 enzyme system. A study using human liver microsomes suggested that the P450 enzymes CYP2C19 and CYP3A4 are involved in its metabolism. In addition, CYP2D6 and CYP2C9-10 were implicated in another study. An interaction of pantoprazole with other drugs or compounds which are metabolised using the same enzyme system cannot be excluded. However, no clinically significant interactions were observed in specific tests with a number of such drugs or compounds, namely carbamazepine, caffeine, diazepam, diclofenac, digoxin, ethanol, glibenclamide, metoprolol, naproxen, nifedipine, phenytoin, piroxicam, theophylline, and the low dose oral contraceptive Triphasil (levonorgestrel and ethinylestradiol). There was also no interaction with a concomitantly administered antacid (aluminium hydroxide hydrate and magnesium hydroxide).
Treatment of dogs with IV famotidine shortened the duration of the pH elevation effect of pantoprazole.
Four crossover pharmacokinetic studies designed to examine any interactions between pantoprazole and the drugs clarithromycin, amoxicillin and metronidazole, conducted in 66 healthy volunteers, showed no interactions.

Drugs with pH dependent absorption pharmacokinetics.

As with all acid suppressant medications, the absorption of drugs whose bioavailability is pH dependent (e.g. ketoconazole, itraconazole, posaconazole, erlotinib) might be altered due to the decrease in gastric acidity.

HIV protease inhibitors.

It has been shown that co-administration of atazanavir 300 mg/ ritonavir 100 mg with omeprazole (40 mg once daily) or atazanavir 400 mg with lansoprazole (60 mg single dose) to healthy volunteers resulted in a substantial reduction in the bioavailability of atazanavir. The absorption of atazanavir is pH dependent. Therefore, proton pump inhibitors, including pantoprazole, should not be co-administered with HIV protease inhibitors for which absorption is dependent on acidic intragastric pH, such as atazanavir or nelfinavir (see Section 4.3 Contraindications).

Mycophenolate mofetil.

Coadministration of PPIs in healthy subjects and in transplant patients receiving mycophenolate mofetil has been reported to reduce the exposure to the active metabolite, mycophenolic acid. This is possibly due to a decrease in mycophenolate mofetil solubility at an increased gastric pH. The clinical relevance of reduced mycophenolic acid exposure on organ rejection has not been established in transplant patients receiving PPIs and mycophenolate mofetil. Use pantoprazole with caution in transplant patients receiving mycophenolate mofetil.

Methotrexate.

Concomitant use with methotrexate (primarily at high dose), may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities.

Drugs that inhibit or induce CYP2C19 (tacrolimus, fluvoxamine).

Concomitant administration of pantoprazole and tacrolimus may increase whole blood levels of tacrolimus, especially in transplant patients who are intermediate or poor metabolisers of CYP2C19. Inhibitors of CYP2C19, such as fluvoxamine, would likely increase the systemic exposure of pantoprazole.

Coumarin anticoagulants (phenprocoumon or warfarin).

Coadministration of pantoprazole with warfarin or phenprocoumon did not affect the pharmacokinetics of warfarin, phenprocoumon or international normalised ratio (INR). However, there have been reports of increased INR and prothrombin time in patients receiving PPIs and warfarin or phenprocoumon concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding, and even death. Therefore, in patients being treated with coumarin anticoagulants (e.g. warfarin or phenprocoumon), monitoring of prothrombin time/ INR is recommended after initiation, termination or during irregular use of pantoprazole.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Pantoprazole at oral doses up to 500 mg/kg/day in male rats and 450 mg/kg/day in female rats (estimated exposure at least 60-fold the clinical exposure from the 40 mg tablet) was found to have no effect on fertility and reproductive performance.
(Category B3)
Teratological studies in rats and rabbits gave no evidence of a teratogenic potential for pantoprazole. In oral studies in rats, dose dependent toxic effects were observed on foetuses and pups: increased prenatal and postnatal deaths (450 mg/kg/day) (AUC exposure approximately 60-times the clinical exposure of the 40 mg oral dose), reduced foetal weight (greater than or equal to 150 mg/kg/day) (AUC exposure approximately 18-fold the clinical exposure) and delayed skeletal ossification and reduced pup growth (greater than or equal to 15 mg/kg/day) (approximately clinical exposure). For the latter, a no-effect dose of 5 mg/kg was established. Doses of 450 mg/kg/day were maternotoxic and may have been associated with dystocia and incomplete parturition. Penetration of the placenta was investigated in the rat and was found to increase with advanced gestation. As a result, concentrations of pantoprazole in the foetus are increased shortly before birth regardless of the route of administration.
The significance of these findings in humans is unknown. As there is no information on the safety of the drug during pregnancy in women, pantoprazole should not be used during pregnancy unless the benefit clearly outweighs the potential risk to the foetus.
 Oral administration of pantoprazole to rats from late gestation to weaning at doses of 10 mg/kg/day (AUC exposure approximately the clinical exposure of the 40 mg oral dose) or greater decreased pup growth. A transient effect on one of a series of development tests (startle response) was only evident in the 30 mg/kg/day (AUC exposure approximately 3-fold the clinical exposure) group at an age when male and female offspring showed lower bodyweights, paralleled with lower brain weight, than the controls. The significance of these findings for humans is unknown, and there is currently no information on the safety of pantoprazole during breastfeeding in humans. Excretion into human milk has been reported. Therefore, pantoprazole should only be used during lactation if the benefits clearly outweigh the risks.

4.7 Effects on Ability to Drive and Use Machines

Pantoprazole does not exert its pharmacological action centrally, therefore it is not expected to adversely affect the ability to drive or use machines, however, adverse drug reactions such as dizziness and visual disturbances may occur (see Section 4.8 Adverse Effects (Undesirable Effects)). If affected, patients should not drive or operate machines.

4.8 Adverse Effects (Undesirable Effects)

Pantoprazole tablets are well tolerated. Most of the adverse reactions seen with treatment are of mild or moderate intensity. The following adverse reactions have been reported in patients receiving pantoprazole alone or in combination with antibiotics for H. pylori eradication in clinical trials and postmarketing surveillance.
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%; not known: cannot be estimated from the available data).
These include the following:

General disorders and administration site conditions.

Uncommon: fatigue and malaise, asthenia and increased sweating.
Rare: fever, peripheral oedema and increased body temperature.
Very rare: flushing, substernal chest pain and hot flushes.

Cardiovascular disorders, general.

Rare: hypertension.
Very rare: circulatory collapse.

Nervous system disorders.

Uncommon: headache, dizziness.
Rare: taste disorders, metallic taste.
Very rare: reduced movement and speech disorder, changes to the sense of smell and taste.

Gastrointestinal system disorders.

Uncommon: diarrhoea, nausea/ vomiting, abdominal distension and bloating, constipation, dry mouth, abdominal pain and discomfort.
Rare: rectal disorder and colonic polyp.
Very rare: faecal discolouration and increased saliva.
Not known: severe eructation, withdrawal of long-term PPI therapy can lead to aggravation of acid related symptoms and may result in rebound acid hypersecretion.

Hearing and vestibular disorders.

Very rare: tinnitus.

Immune system disorders.

Rare: hypersensitivity (including anaphylactic reactions and anaphylactic shock).

Hepatobiliary disorders.

Uncommon: increased liver enzymes (transaminases, gamma-GT).
Rare: bilirubin increased.
Very rare: hepatocellular failure, cholestatic hepatitis, jaundice.
Not known: hepatocellular injury.
The occurrence of severe hepatocellular damage leading to jaundice or hepatic failure having a temporal relationship to the intake of pantoprazole has been reported with a frequency of approximately one in a million patients.

Metabolism and nutrition disorders.

Rare: hyperlipidaemias and lipid increases (triglycerides, cholesterol), weight changes.
Not known: hyponatraemia, hypomagnesaemia, hypocalcaemia, hypokalaemia (hypocalcaemia and/or hypokalaemia may be related to the occurrence of hypomagnesaemia (see Section 4.4 Special Warnings and Precautions for Use)).

Musculoskeletal and connective tissue disorders.

Rare: myalgia and arthralgia.
Very rare: pain including skeletal pain.
Not known: fracture of wrist, hip and spine.

Renal and urinary disorders.

Very rare: tubulointerstitial nephritis (TIN) (with possible progression to renal failure).

Platelet, bleeding, clotting disorders.

Very rare: increased coagulation time.

Psychiatric disorders.

Uncommon: sleep disorders.
Rare: depression, hallucination, disorientation and confusion, especially in predisposed patients, as well as the aggravation of these symptoms in the case of pre-existence.
Very rare: anxiety.

Blood and lymphatic system disorders.

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

Resistance mechanism disorders.

Rare: sepsis.

Respiratory system disorders.

Very rare: dyspnoea.

Reproductive system and breast disorders.

Rare: gynaecomastia.

Skin and subcutaneous tissue disorders.

Uncommon: pruritus, skin rash/ exanthema/ eruption.
Rare: angioedema, urticaria.
Very rare: flushing, severe skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, Lyell syndrome and photosensitivity.
Not known: subacute cutaneous lupus erythematosus, drug reaction with eosinophilia and systemic symptoms (DRESS).

Eye disorders.

Uncommon: reports of disturbances in vision (blurred vision).
Very rare: conjunctivitis.
See Table 1 and Table 2.
The following safety data for patients aged 2 to 16 years (n = 250) is collated from 5 clinical studies (3001A1-109-US, 3001K1-110-US, 3001A1-322-US, 3001A1-326-US and BYK1023/MEX008). See Table 3.

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

There are no known symptoms of overdosage in humans. In individual cases, 240 mg was administered i.v. or p.o. and was well tolerated. As pantoprazole is extensively protein bound, it is not readily dialysable. As in any case of overdosage, treatment should be symptomatic and supportive measures should be utilised.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Pantoprazole is a proton pump inhibitor (PPI). It inhibits specifically and dose proportionately H+/K+-ATPase, the enzyme which is responsible for gastric acid secretion in the parietal cells of the stomach.
The substance is a substituted benzimidazole which accumulates in the acidic environment of the parietal cells after absorption. There, it is converted into the active form, a cyclic sulfenamide which binds to the H+/K+-ATPase, thus inhibiting the proton pump and causing potent and long lasting suppression of basal and stimulated gastric acid secretion. As pantoprazole acts distal to the receptor level, it can influence gastric acid secretion irrespective of the nature of the stimulus (acetylcholine, histamine, gastrin).
Pantoprazole's selectivity is due to the fact that it only exerts its full effect in a strongly acidic environment (pH < 3), remaining mostly inactive at higher pH values. As a result, its complete pharmacological, and thus therapeutic effect, can only be achieved in the acid secretory parietal cells. By means of a feedback mechanism this effect is diminished at the same rate as acid secretion is inhibited.
As with other proton pump inhibitors and H2 receptor inhibitors, treatment with pantoprazole causes a reduced acidity in the stomach and thereby an increase in gastrin in proportion to the reduction in acidity. The increase in gastrin is reversible.

Clinical trials in adults.

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 recommended in most patients with duodenal and gastric ulcer where the latter is not caused by NSAID ingestion (see Section 4.2 Dose and Method of Administration). In an experimental study in mice, pantoprazole at a dose of 100 mg/kg t.i.d. increased the inhibitory potency of amoxicillin, clarithromycin and tetracycline against Helicobacter felis.

Eradication of H. pylori.

The clinical trial program of pantoprazole for eradication of H. pylori has investigated four therapy combinations. A summary of the clinical trials is provided in Table 4 and Table 5:

Treatment of symptomatic reflux (GORD).

The relief of symptoms of reflux in patients who showed no oesophageal lesions on endoscopy has been shown in the following double blind, multicentre, placebo controlled study (245/98) using pantoprazole 20 mg once daily. Overall, 219 patients were enrolled in the study. Each patient was to have a normal oesophagus as assessed by endoscopy and to have suffered from at least one episode of heartburn of at least moderate intensity on all three days prior to inclusion into the study. Additionally, patients were to have a history of reflux symptoms (heartburn, acid eructation, pain on swallowing) for at least three months prior to entry into the study. Efficacy of pantoprazole 20 mg is shown in Table 6.

Acute treatment of mild reflux oesophagitis.

In two randomised, double blind, multicentre studies (BGSA006 and FK3034) 410 patients with mild gastroesophageal reflux disease (GORD) (Savary-Miller stage 1) were treated with either pantoprazole 20 mg once daily before breakfast or ranitidine 300 mg once daily at bedtime. Superiority of pantoprazole 20 mg in terms of healing rates compared to ranitidine after four and eight weeks is shown in Table 7. The difference in healing rates was statistically significant at all time points in the intention to treat and per protocol patient groups.

Maintenance of healed reflux oesophagitis in patients previously treated for moderate to severe reflux oesophagitis.

Three randomised, double blind, parallel group trials examined the efficacy of pantoprazole in the maintenance of healed reflux oesophagitis in patients aged 18 to 88 years treated for moderate to severe reflux oesophagitis over 12 months. The primary endpoint was time to endoscopically confirmed relapse; however, the median was not reached in the pantoprazole groups at the end of 12 months. The results for the incidence of relapse in patients with data from at least one follow-up visit are outlined in Table 8.
Pantoprazole 20 mg and 40 mg/day doses were therapeutically equivalent based on the predefined equivalence criterion of the 90% confidence interval of the difference between doses being within ± 20%.
Four uncontrolled trials with varying periods of follow up support the long-term efficacy of pantoprazole 40 to 80 mg/day in the maintenance of healed reflux oesophagitis in patients previously treated for moderate to severe reflux oesophagitis. Two of the trials included patients with gastric and duodenal ulcer. The incidence of relapse at 1 year was 12 to 15%, 2 years 22 to 25% and 6 years 40%.
Safety data is available from the 1584 patients involved in the 7 long-term clinical studies. 904 patients have been treated with pantoprazole for at least 1 year, and 273, 112, 68, 47 and 17 have been treated for at least 2, 3, 4, 5 and 6 years, respectively. In total, 108 (6.8%) patients experienced serious adverse events (EC definition), of which all but 6 were classified as being causally unrelated to pantoprazole (4 cases with 40 mg pantoprazole: colonic polyp; abdominal pain and rectal disorder; diarrhoea and abdominal pain, sepsis versus 2 cases with high dose pantoprazole: anaemia and hypertension) (see Section 4.8 Adverse Effects (Undesirable Effects)). Additionally, in the open ongoing studies, patients were assessed by biopsy and no evidence of dysplastic or neoplastic endocrine growth was found.

Prevention of gastroduodenal lesions and dyspeptic symptoms associated with nonselective NSAIDs in increased risk patients with a need for continuous nonselective NSAID treatment.

Two randomised, double blind, multicentre studies (205/2000 and 129/2000) examined the efficacy and safety of pantoprazole in the prevention of NSAID associated gastroduodenal ulcers, petechiae, erosions and dyspeptic symptoms in patients with arthritis on continuous treatment with NSAIDs and an increased risk of developing gastrointestinal lesions.
The primary endpoint for both studies was the therapeutic failure rate after six months, defined as endoscopic failure (i.e. more than ten erosions or petechiae, peptic ulcer, reflux oesophagitis) or premature study termination due to at least likely related adverse event or due to severe gastrointestinal symptoms.

Study 205/2000.

A total of 515 patients were included in the study. Patients were randomised to receive either pantoprazole 20 mg daily (n = 257) or misoprostol 200 microgram twice daily (n = 258). Efficacy of pantoprazole 20 mg is shown in Table 9.
Pantoprazole 20 mg once daily was statistically significantly superior to misoprostol 200 microgram twice daily with regard to therapeutic failure and to endoscopic failure. Reflux oesophagitis was included as an efficacy endpoint in the study which may have biased the results in favour of pantoprazole. A causal association between NSAIDs and reflux oesophagitis has not been established. In addition, proton pump inhibitors such as pantoprazole have documented beneficial treatment effects on reflux oesophagitis while misoprostol (a prostaglandin E1 analogue) has negligible therapeutic effects.

Study 129/2000.

A total of 595 patients were included into the study. Patients were randomised to receive either pantoprazole 20 mg daily (n = 196), pantoprazole 40 mg daily (n = 199) or omeprazole 20 mg daily (n = 200). Efficacy results are shown in Table 10.
All three treatments, pantoprazole 20 mg, pantoprazole 40 mg and omeprazole 20 mg, were proven to be of equivalent and high efficacy.

Clinical trials in children.

In 2 studies, pantoprazole 20 mg or 40 mg daily was given to 189 children aged from 5 to 16 years with symptomatic GORD. A similar reduction in symptoms of GORD was reported with both doses in both studies.

5.2 Pharmacokinetic Properties

Absorption.

Adults.

After administration of enteric-coated tablets, pantoprazole is rapidly absorbed and the maximal plasma concentration appears after one single oral dose. After single and multiple oral doses, the median time to reach maximum serum concentrations was approximately 2.5 h, with a Cmax of approximately 1.2 microgram/mL following a 20 mg dose. Terminal half-life is approximately 1 h. Pharmacokinetics do not vary after single or repeated administration. The plasma kinetics of pantoprazole are linear (in the dose range of 10 to 80 mg) after both oral and intravenous administration.
Pantoprazole is completely absorbed after oral administration. The absolute bioavailability of the tablet is approximately 77%. Concomitant intake of food had no influence on AUC and Cmax of the pantoprazole 40 mg tablet and thus its bioavailability.

Distribution.

The serum protein binding of pantoprazole is approximately 98%. Volume of distribution is approximately 0.15 L/kg and clearance is approximately 0.1 L/h/kg.

Metabolism.

Pantoprazole is extensively metabolised in the liver through the cytochrome P450 (CYP) system. Pantoprazole metabolism is independent of the route of administration (intravenous or oral). The main metabolic pathway is demethylation, by CYP2C19, with subsequent sulfation; other metabolic pathways include oxidation by CYP3A4.
There is no evidence that any of the pantoprazole metabolites have significant pharmacologic activity. CYP2C19 displays a known genetic polymorphism due to its deficiency in some subpopulations (e.g. 3% of Caucasians and African Americans and 17-23% of Asians). Although these subpopulations of slow pantoprazole metabolisers have elimination half-life values of 3.5 to 10.0 hours, they still have minimal accumulation (δ 23%) with once daily dosing.

Excretion.

Pantoprazole is rapidly eliminated from serum and is almost exclusively metabolised in the liver. Renal elimination represents the most important route of excretion (approximately 80%) for the metabolites of pantoprazole, the rest are excreted with the faeces. The main metabolite in both the serum and urine is desmethylpantoprazole which is conjugated with the sulphate. The half-life of the main metabolites (approximately 1.5 h) is not much longer than that of pantoprazole.

Special populations.

Hepatic impairment.

In patients with liver cirrhosis given a single 40 mg tablet, the half-life increases to between 7 and 9 h and the AUC values are increased by a factor of 6 to 8 but the maximum serum concentration increases only slightly by a factor of 1.5 in comparison with healthy subjects. After a single 20 mg tablet, AUC increased 3-fold in patients with mild hepatic impairment and 5-fold in patients with severe hepatic impairment compared with healthy controls. Mean elimination half-life was 3.3 h in mild hepatic impairment and 6.0 h in severe hepatic impairment compared with 1.1 h in controls. The maximum serum concentration only increased slightly by a factor of 1.3 compared with healthy subjects.

Renal impairment.

In patients with renal impairment (including those undergoing dialysis) no dose reduction is required. Although the main metabolite is moderately increased, there is no accumulation. The half-life of pantoprazole is as short as in healthy subjects. Pantoprazole is poorly dialysable.

Use in the elderly.

The slight increase in AUC and Cmax in elderly volunteers compared with their younger counterparts is also not clinically relevant.

Children.

Following administration of single oral doses of 20 mg or 40 mg pantoprazole to children aged 5 to 16 years, AUC and Cmax were in the same range as the corresponding values observed in adults.
Following administration of single IV doses of 0.8 or 1.6 mg/kg of pantoprazole to children aged 2 to 16 years, AUC and volume of distribution were in accordance with data from adults and there was no significant association between pantoprazole clearance and age or weight.

5.3 Preclinical Safety Data

Genotoxicity.

A number of in vitro and in vivo genotoxicity assays covering mutagenicity, clastogenicity and DNA damage endpoints were conducted on pantoprazole and the results were generally negative. Exposures achieved in the in vivo tests in mice and rats were well in excess of exposures expected clinically. However, pantoprazole was clearly positive in carefully conducted cytogenetic assays in human lymphocytes in vitro, both in the presence and absence of metabolic activation. Omeprazole was also positive in a comparable test conducted in the same laboratory, suggesting a possible class effect. A minute amount of radioactivity was bound to rat hepatic DNA after treatment with 200 mg/kg/day pantoprazole for 14 days. This is an estimated exposure 24-fold the clinical exposure from the 40 mg tablet. No distinct DNA adduct has been detected.
Pantoprazole was found to be negative in the following studies: in vivo chromosome aberration assay in rat and bone marrow (126E/95), mouse lymphoma test (222E/95) and a gene mutation test in Chinese hamster ovary cells (in vitro) (188E/95). In addition, toxicokinetic studies were conducted in rats at the doses used in the bone marrow assay (50 to 1200 mg/kg) (56E/96) and in mice at the high dose from the earlier micronucleus test (710 mg/kg) (89E/96). Pantoprazole exposure was high with the respective rat and mouse plasma AUCs being 7 to 100 and 9 to 12-fold the clinical exposure from a 40 mg tablet.

Carcinogenicity.

A two year oral carcinogenicity study in Sprague Dawley rats at doses up to 200 mg/kg/day gastric carcinoids were found after pantoprazole treatment at doses greater than 0.5 mg/kg/day in females and greater than 5 mg/kg/day in males, with none observed in controls. The estimated exposure (based on AUC) from these doses are at, or below, clinical exposure from a 40 mg tablet. The development of gastric tumours is attributed to chronic elevation of serum gastrin levels with associated histopathological changes in the gastrointestinal system.
In both male and female rats, the development of hepatocellular adenomas was increased at doses greater than 5 mg/kg/day and the development of hepatocellular carcinomas was increased at doses greater than 50 mg/kg/day, with respective estimated exposures of 1 and 9-fold the AUC of the 40 mg clinical dose. Hepatocellular tumours, which were also observed in female mice at oral doses greater than 25 mg/kg/day (exposure similar to clinical exposure), may be associated with pantoprazole induced increases in hepatic enzyme activity.
Treatment with pantoprazole at doses greater than 50 mg/kg/day (exposure approximately 9-fold clinical exposure) also increased the development of thyroid follicular cell adenomas in male and female rats. Several studies in rats were conducted to investigate the effect of pantoprazole on the thyroid, the results of which suggested that the effect may be secondary to the induction of enzymes in the liver.
In a more recent carcinogenicity study, Fischer rats were studied using lower oral doses (5, 15 and 50 mg/kg/day, 0.5, 2 and 7-fold the clinical AUC, respectively). Gastric carcinoids were detected at all doses in females and at the 15 and 50 mg/kg doses in males, while none were detected in controls. No metastases of these carcinoids were detected. There was no increase in incidence of liver tumours. The dose of 15 mg/kg is seen to be the no-effect level for liver tumours in rodents.
Consideration of the possible mechanisms involved in the development of the above drug related tumour types suggests that it is unlikely that there is any carcinogenic risk in humans at therapeutic dose levels of pantoprazole for short-term treatment.

6 Pharmaceutical Particulars

6.1 List of Excipients

Pantoprazole MYL tablets contain mannitol, sodium carbonate, sodium starch glycollate, crospovidone, colloidal anhydrous silica, calcium stearate, hypromellose, Macrogol 6000, sodium hydroxide, Eudragit L30-D55 (3700) and Opadry AMB Aqueous Moisture Barrier Coating System 80W52172 Yellow (106688).
Pantoprazole MYL tablets are gluten free.

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 30°C.

6.5 Nature and Contents of Container

Container type: Al/Al blister packs.
Pack sizes: 5, 14, 15, 28, 30, 50, 56, 60, 100 and 140 tablets.
Some strengths, pack sizes and/or pack types may not be marketed.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Pantoprazole is a substituted benzimidazole which inhibits basal and stimulated gastric secretion. It is a white to off white crystalline powder. Freely soluble in water and in ethanol (96 percent), practically insoluble in hexane. Solubility is low at neutral pH and increases with increasing pH.

Chemical structure.


Chemical name: Sodium-5-(difluoromethoxy)-2-[(RS)-[(3,4-Dimethoxypyridin-2-yl) methyl]sulphinyl] benzimidazol-1-ide sesquihydrate.
Molecular formula: C16H14F2N3NaO4S.1½H2O.
Molecular weight: 432.4 (sodium salt x 1.5 H2O).

CAS number.

164579-32-2.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes