Consumer medicine information

APOHEALTH Pantoprazole Heartburn Relief

Pantoprazole

BRAND INFORMATION

Brand name

APOHealth Pantoprazole Heartburn Relief

Active ingredient

Pantoprazole

Schedule

S2 | S3

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APOHEALTH Pantoprazole Heartburn Relief.

FULL CMI

APOHEALTH Pantoprazole Heartburn Relief Tablets

Active ingredient(s): Pantoprazole (as sodium sesquihydrate)

Consumer Medicine Information (CMI)

This leaflet provides important information about using this medicine. 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 this medicine.

Where to find information in this leaflet:

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

1. Why am I using this medicine?

APOHEALTH Pantoprazole Heartburn Relief contains the active ingredient Pantoprazole (as sodium sesquihydrate).

Pantoprazole is used for symptomatic relief of frequent heartburn and stomach acid complaints due to gastro-oesophageal reflux (GORD).

Reflux 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.

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

How it works

Pantoprazole belongs to a group of medicines called proton pump inhibitors (PPIs). It works by decreasing the amount of acid the stomach makes to give relief from the symptoms of reflux and heartburn.

This medicine will start to suppress acid within a few hours; however, it will not give instant symptom relief. You may need to take it for a few days before experiencing the full effect.

This medicine is recommended for adults suffering from heartburn at least two times a week. It is not the right medicine for you if you suffer heartburn only occasionally (one episode of heartburn a week or less), or if you want immediate relief of heartburn.

Ask your doctor or pharmacist if you have any questions about why this medicine has been recommended for you.

This medicine is available without a doctor's prescription, but your pharmacist's advice is required.

This medicine is not addictive.

Do not give this medicine to children or adolescents under 18 years of age.

There is not enough information to recommend the use of this medicine in children under 18 years of age.

2. What should I know before I use this medicine?

Warnings

Do not use this medicine if:

  • you are allergic to pantoprazole, any other PPI (such as omeprazole, rabeprazole or lansoprazole) or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine. Some symptoms of an allergic reaction include skin rash, itching, shortness of breath or swelling of the face, lips or tongue, which may cause difficulty in swallowing or breathing.
  • you have severe liver disease or cirrhosis.
  • have recently had trouble swallowing, pain when swallowing, persistent vomiting or experienced unintended weight loss
  • have recently vomited blood, had black stools or notice blood in your stools
  • are taking atazanavir or nelfinavir (anti-viral medications)
  • the packaging is torn or shows signs of tampering.
  • the expiry date printed on the pack has passed.

Before you start to take it

Check with your doctor or pharmacist if you have:

  • jaundice, liver problems or anaemia
  • a feeling of weakness or you look pale
  • previously taken heartburn or indigestion medications continuously for 4 or more weeks
  • persisting heartburn symptoms despite taking this medication (or similar medication) continuously for 2 weeks, or your symptoms have recently changed
  • been told by your doctor that you have a stomach ulcer, or gastrointestinal surgery is planned.
  • heartburn or indigestion symptoms for the first time and you are over 40 years of age
  • a scheduled endoscopy (investigation of your stomach lining performed by a specialist)
  • any allergies to any medicines or other substances, such as foods, preservatives or dyes.

Your doctor or pharmacist can provide specific advice on whether you should take this medication. Tell your doctor or pharmacist if you have any other medical conditions.

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

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

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

Your doctor can discuss with you the risks and benefits involved.

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.

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

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

These medicines may be affected by pantoprazole or may affect how well it works. You may need to use different amounts of your medicine or take different medicines. Other interactions not listed above may also occur.

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

4. How do I use this medicine?

The directions for use are included on the Medicine Information panel on the pack. If you do not understand the instructions on the pack, ask your pharmacist or doctor for help.

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

How much to take

  • The usual dose is one tablet every day (once every 24 hours).

How to take this medicine

  • Swallow tablets whole with water.
  • Do not crush or chew the tablets. this medicine tablets have a special coating to protect them from the acidic contents of your stomach. For the tablets to work effectively, this coating must not be broken.

It does not matter if you are taking this medicine before or after food.

How long to take this medicine

For effective, long-lasting relief, take this medicine strictly according to the directions on your pack. This medication should be taken for at least seven (7) days, or up to fourteen (14) days.

If you purchased a pack containing 7 days supply and you need to take it for longer than 7 days, ask your pharmacist for advice.

Do not take beyond 14 days without consulting your doctor. This medication is not intended to provide instant relief from your heartburn or indigestion symptoms.

If you forget to take this medicine

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 pharmacist or doctor.

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

If you use too much this medicine

If you think that you have used too much this medicine, 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. Urgent medical attention may be needed.

5. What should I know while using this medicine?

Things you should do

Tell any doctor, dentist or pharmacist you visit that you are using this medicine.

If you are going to have surgery or an endoscopy, tell your doctor that you are taking this medicine.

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.

Tell your doctor or pharmacist if you do not feel better while taking this medicine.

If your symptoms recur within two (2) weeks of completing your course, consult your doctor.

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

Call your doctor straight away if you:

  • become pregnant while taking this medicine.

Things you should not do

  • Do not take this medicine to treat any other complaints unless your doctor or pharmacist tells you to.
  • Do not give this medicine to anyone else, even if they have the same condition as you.

Driving or using machines

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

This medicine may cause dizziness and visual disturbances in some people.

Drinking alcohol

Tell your doctor if you drink alcohol.

Alcohol may contribute to your condition.

Things that may help your condition

Some self-help measures suggested below may help your condition. Your doctor or pharmacist can give you more information about these measures.

  • 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.

Looking after your medicine

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

Follow the instructions on 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 windowsills.

Keep it where young children cannot reach it.

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
  • headache
  • dizziness
  • diarrhoea
  • constipation
  • nausea or vomiting
  • stomach pain
  • pain, discomfort or excessive gas in the stomach or bowel
  • indigestion
  • dry mouth
  • metallic taste
  • mild weakness or tiredness
  • increased sweating or body temperature
  • blurred vision
  • skin problems, such as itchiness and rash
  • trouble sleeping
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
  • unusual tiredness, weakness, dizziness or fainting
  • chest pain, fast heartbeat, shortness of breath
  • loss of appetite, feeling generally unwell, fever, itching, yellowing of the skin and eyes, and dark coloured urine or bowel movements
  • blood in the urine
  • increased or decreased need to urinate
  • bleeding or bruising more easily than normal
  • severe skin problems such as itchiness, redness, 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 symptoms of infections such as fever, severe chills, sore throat or mouth ulcers
  • high blood pressure
  • water retention, swelling
  • 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, 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
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.

Reporting side effects

After you have received medical advice for any side affects 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 this medicine contains

Active ingredient
(main ingredient)		pantoprazole (as sodium sesquihydrate)
Other ingredients
(inactive ingredients)		mannitol
sodium carbonate
sodium starch glycollate
crospovidone
colloidal anhydrous silica
calcium stearate
hypromellose
macrogol 6000
sodium hydroxide
Eudragit L30-D55
Opadry AMB Aqueous Moisture Barrier Coating System 80W52172 Yellow
Potential allergensSoya bean products.
May contain trace levels of sulfites.

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

What APOHEALTH Pantoprazole Heartburn Relief looks like

The tablets are available in a 20 mg strength and have an acid-resistant coating called an enteric coating.

The tablets are yellow to pale yellow, oval, biconvex enteric-coated tablets, plain on both sides.

Available in blister packs of 7 or 14 tablets (AUST R 229698).

*Not all pack sizes may be available.

Who distributes APOHEALTH Pantoprazole Heartburn Relief

Arrotex Pharmaceuticals Pty Ltd
15 – 17 Chapel Street
CREMORNE VIC 3121

www.arrotex.com.au

This leaflet was prepared in August 2024.

Published by MIMS December 2024

BRAND INFORMATION

Brand name

APOHealth Pantoprazole Heartburn Relief

Active ingredient

Pantoprazole

Schedule

S2 | S3

 

Notes

Distributed by Arrotex Pharmaceuticals Pty Ltd

1 Name of Medicine

Pantoprazole sodium sesquihydrate.

2 Qualitative and Quantitative Composition

Each enteric coated tablet contains the active ingredient pantoprazole 20 mg (as sodium sesquihydrate).

Excipients with known effect.

Contains soya bean products as a component of the Opadry AMB Coating System (Proprietary Ingredient No. 106688).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

APOHealth Heartburn Relief pantoprazole 20 mg tablets are yellow to pale yellow, oval, biconvex enteric-coated tablets, plain on both sides.

4 Clinical Particulars

4.1 Therapeutic Indications

Gastroesophageal reflux disease (GORD). Symptomatic GORD: the treatment of heartburn and other symptoms associated with GORD.

4.2 Dose and Method of Administration

The enteric coated tablets are intended for oral administration.
Pantoprazole tablets should not be chewed or crushed, but swallowed whole with a little water.

Symptomatic GORD.

The recommended dosage is one pantoprazole 20 mg tablet/day for at least 7 days, and up to 14 days. If symptom control has not been achieved after two weeks of continuous treatment with pantoprazole 20 mg tablets daily, patients should be referred to their doctor.

Paediatric use.

There are limited data currently available on the use of pantoprazole in children. This medicine is not recommended in children and adolescents under 18 years of age.

Use in the elderly.

The usual daily dose can be given.

Impaired renal function.

The usual daily dose can be given.

Impaired hepatic function.

Pantoprazole is contraindicated in patients with cirrhosis or severe liver disease (see Section 4.3 Contraindications). No dose adjustment is required when pantoprazole is administered to patients with milder forms of impaired liver function.

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.
Pantoprazole, like other proton pump inhibitors, should not be co-administered 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.

Patients should be referred to their doctor for review if:
they have unintentional weight loss, anaemia, gastrointestinal bleeding, dysphagia, persistent vomiting or vomiting with blood, malaena, gastric ulcer is suspected or present or gastrointestinal surgery, as treatment with pantoprazole may alleviate symptoms and delay diagnosis. In these cases, malignancy should be excluded;
they have had to take other medication for indigestion or heartburn continuously for four or more weeks in order to control their symptoms;
they are being treated for symptomatic GORD and require this medicine for more than 14 days;
they have jaundice or severe hepatic impairment (e.g. cirrhosis); or
they have any other significant medical condition.

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 (such as the elderly) absorption on long-term therapy and in patients with Zollinger-Ellison syndrome and other pathological hypersecretory conditions requiring long-term treatment if respective clinical symptoms are observed. Rare cases of cyanocobalamin (vitamin B12) deficiency following acid blocking therapy have been reported.

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)).

Severe cutaneous adverse reactions.

Severe cutaneous adverse reactions, including erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with the use of PPIs (see Section 4.8 Adverse Effects (Undesirable Effects)). Discontinue pantoprazole at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

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.

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; 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 two-fold increase was observed in study RR126/97 after up to five 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 two 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 (40 and 160 mg (about 4 and 15 mg/kg) orally and 60 mg (about 6 mg/kg) IV). No ophthalmological changes or changes in electroretinographs were observed in cynomolgus monkeys at IV doses of up to 15 mg/kg/day for four weeks.

Use in the elderly.

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.

Paediatric use.

There are limited data currently available on the use of pantoprazole in children. This medicine is not recommended for use in children and adolescents under 18 years of age.

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.
Patients should consult their doctor before taking this product if they are due to have an endoscopy.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Pantoprazole is metabolized 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 metabolized 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 ethinyloestradiol). There was also no interaction with a concomitantly administered antacid (aluminium hydroxide and magnesium hydroxide).
Treatment of dogs with IV famotidine shortened the duration of the pH elevation effect of pantoprazole.
Four cross-over 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 coadministration 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 coadministered with atazanavir or nelfinavir (see Section 4.3 Contraindications).

Mycophenolate mofetil.

Co-administration 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 of proton pump inhibitors with methotrexate (primarily at high dose), may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, 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).

Although no interaction during concomitant administration of phenprocoumon or warfarin has been observed in clinical pharmacokinetic studies, a few isolated cases of changes in international normalized ratio (INR) have been reported during concomitant treatment in the postmarketing period. 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 at 450 mg/kg/day (AUC exposure approximately 60-times the clinical exposure of the 40 mg oral dose), reduced foetal weight at 150 mg/kg/day or greater (AUC exposure approximately 18-fold clinical exposure) and delayed skeletal ossification and reduced pup growth at ≥ 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 unclear. 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 body weights, 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. 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 is well tolerated. Most of the adverse reactions seen with treatment were of mild or moderate intensity. The following adverse reactions have been reported in patients receiving pantoprazole alone, or in concomitant use with other antibiotics, 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%). 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.

Blood and lymphatic system disorders.

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

Cardiovascular disorders general.

Rare: hypertension.
Very rare: circulatory collapse.

Eye disorders.

Uncommon: disturbances in vision (blurred vision).
Very rare: conjunctivitis.

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.

Hepatobiliary system disorders.

Uncommon: liver enzymes increased (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.

Immune system disorders.

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

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

Nervous system disorders.

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

Platelet, bleeding, clotting disorders.

Very rare: increased coagulation time.

Psychiatric disorders.

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

Renal and urinary disorders.

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

Reproductive system and breast disorders.

Rare: gynaecomastia.

Resistance mechanism disorders.

Rare: sepsis.

Respiratory system disorders.

Very rare: dyspnoea.

Skin and subcutaneous tissue disorders.

Uncommon: pruritus rash/exanthema/eruption.
Rare: angioedema, urticarial.
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), acute generalised exanthematous pustulosis.

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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms.

There are no known symptoms of overdosage in humans. In individual cases 240 mg has been administered IV or orally and was well tolerated. As pantoprazole is extensively protein bound, it is not readily dialyzable. As in any case of overdosage, treatment should be symptomatic and supportive measures should be utilized.

Treatment.

Treatment should be symptomatic and supportive measures should be utilised.
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.

Pantoprazole is a substituted benzimidazole which inhibits basal and stimulated gastric secretion. Pantoprazole is a proton pump inhibitor. 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.

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, multi-centre, placebo controlled study (245/98) using pantoprazole 20 mg once daily. Overall, 219 patients were enrolled into 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 1.

5.2 Pharmacokinetic Properties

Absorption.

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 hours, with a Cmax of approximately 1.2 microgram/mL following a 20 mg dose. Pharmacokinetics do not vary after single or repeated administration. The plasma kinetics of pantoprazole are linear (in the dose range of 10-80 mg) after both oral and intravenous (IV) 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 area under the curve (AUC), maximum serum concentrations and thus bioavailability.

Distribution.

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

Metabolism.

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 desmethyl-pantoprazole which is conjugated with the sulfate. The half-life of the main metabolites (approximately 1.5 hours) is not much longer than that of pantoprazole.
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 sub-populations (e.g. 3% of Caucasians and African-Americans and 17-23% of Asians). Although these sub-populations of slow pantoprazole metabolisers have elimination half-life values of 3.5-10.0 hours, they still have minimal accumulation (δ 23%) with once daily dosing.

Excretion.

Terminal half-life is approximately one hour and clearance is approximately 0.1 L/hour/kg. After a single 20 mg tablet, AUC increased threefold in patients with mild hepatic impairment and fivefold in patients with severe hepatic impairment compared with healthy controls. Mean elimination half-life was 3.3 hours in mild hepatic impairment and six hours in severe hepatic impairment compared with 1.1 hours in controls. The maximum serum concentration only increased slightly by a factor of 1.3 compared with healthy subjects.
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.
The slight increase in AUC and Cmax in elderly volunteers compared with their younger counterparts is also not clinically relevant.

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 pantoprazole 200 mg/kg/day for 14 days. This is an estimated exposure 24-fold the clinical exposure from the 40 mg tablet. No distinct DNA adduct was 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 1,200 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 showed gastric carcinoids 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 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, 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, and none were detected in controls. No metastases of these carcinoids were detected. There was no increase in the 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

Each enteric coated tablet contains the following inactive ingredients: mannitol, sodium carbonate, sodium starch glycollate, crospovidone, colloidal anhydrous silica, calcium stearate, hypromellose, macrogol 6000, sodium hydroxide, Eudragit L30-D55 (3700), Opadry AMB Aqueous Moisture Barrier Coating System 80W52172 Yellow (106688).

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Blisters (Al/Al) of 7 or 14 tablets (AUST R 229698).

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Pantoprazole sodium sesquihydrate is a white to off-white crystalline powder. 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.
Structural Formula:
Molecular Formula: C16H14F2N3NaO4S.1.5H2O.
Molecular Weight: 432.4.

CAS number.

164579-32-2.

7 Medicine Schedule (Poisons Standard)

S2 - Pharmacy Medicine (7 tablets).
S3 - Pharmacist Only Medicine (14 tablets).

Summary Table of Changes