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.

What is in this leaflet

This leaflet answers some common questions about your medicine. 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 using this medicine 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 your medicine. You may want to read it again.

What this medicine is used for

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 a "Pharmacist Only Medicine". It 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.

Before you take this medicine

When you must not take it

Do not take this medicine if you have an allergy to:

  • pantoprazole
  • any other proton pump inhibitors
  • 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
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin.

Do not take this medicine if you have severe liver disease or cirrhosis.

Do not take this medicine 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
  • you have moderate to severe liver or kidney disease.

Do not take this medicine 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.

If you are not sure whether you should start taking this medicine, talk to your doctor or pharmacist.

Before you start to take it

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

Tell your doctor or pharmacist if you are pregnant or breastfeeding, or plan to become pregnant or breast-feed. Your doctor or pharmacist will discuss the risks and benefits involved.

Tell your doctor or pharmacist if you have:

  • jaundice, liver problems or anaemia
  • previously taken heartburn / indigestion medications continuously for 2 weeks, or your symptoms have recently changed
  • have 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)
  • unintentional weight loss
  • repeated vomiting
  • vomited blood
  • difficulty or pain when swallowing
  • a feeling of weakness or you look pale
  • noticed blood in your stools

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

If you have not told your doctor or pharmacist about any of the above, tell them before you start taking this medicine.

Taking other medicines

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

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

  • warfarin, phenprocoumon, medicines used to prevent blood clots (blood thinners)
  • atazanavir and nelfinavir, medicines used to treat viral infections such as HIV
  • ketoconazole, itraconazole or posaconazole, medicines used to treat fungal infection
  • 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 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 avoid while taking pantoprazole.

Other interactions not listed above may also occur.

How to take this medicine

The directions for use are included on the pack.

If you do not understand any written instructions, ask your doctor or pharmacist for help.

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

How much to take

The dose is one tablet per day.

How to take it

Swallow the tablet whole with a full glass of water, with or without food.

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

When to take it

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

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

How long to take it

For effective, lasting relief, take this medicine strictly according to the directions on your pack.

This medicine should be taken for at least seven days, and up to 14 days.

If you purchased the 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 medicine is not intended to provide instant relief from your heartburn/ indigestion symptoms.

If you are not sure, ask your pharmacist or doctor how to take your medicine.

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

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much pantoprazole.

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

While you are taking this medicine

Things you must do

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

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

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

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 if you do not feel better while taking this medicine. If symptoms persist or recur within two weeks of completing use of this medicine, consult a doctor. Further investigation may be recommended.

Things you must 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.

Things to be careful of

Be careful while driving or operating machinery until you know how this medicine affects you. This medicine may cause dizziness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

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 or pharmacist 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 or pharmacist 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 or pharmacist may advise you to stop smoking or at least cut down.
  • Weight - your doctor or pharmacist 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 this medicine.

This medicine helps most people with heartburn and reflux, but it may have unwanted side effects in a few people. All medicines 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 or dizziness
  • blurred vision
  • diarrhoea, constipation, nausea or vomiting
  • pain, discomfort or excessive gas in the stomach or bowel
  • indigestion
  • dry mouth
  • metallic taste
  • mild weakness, tiredness or sleep disturbances
  • increased sweating or body temperature
  • mild skin problems, such as itchiness and rash
  • reflux after stopping the medication suddenly, especially if you have taken it for a while without consulting your doctor

The above list includes the more common side effects of pantoprazole.

Tell your doctor or pharmacist immediately if you notice any of the following:

  • unusual tiredness,weakness, dizziness or fainting
  • high blood pressure
  • blood in the urine
  • increased or decreased need to urinate
  • depression, confusion or anxiety

The above list includes serious side effects that may require medical attention. Serious side effects are rare.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • chest pain, fast heartbeat, shortness of breath
  • 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
  • swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing
  • nausea, vomiting, loss of appetite, feeling generally unwell, fever, itching, yellowing of the skin and eyes, and dark coloured urine or bowel movements
  • frequent infections such as fever, severe chills, sore throat or mouth ulcers
  • 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. These can be a sign of low magnesium, calcium or potassium levels in your blood
  • water retention, swelling
  • bleeding or bruising more easily than normal
  • severe and/or persistent diarrhoea, because this medicine has been associated with a small increase in infectious diarrhoea

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

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

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

Storage and Presentation

Storage

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

Keep your medicine in a cool dry place where the temperature will stay below 25°C.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

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

Disposal

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

Product description

What APOHEALTH Pantoprazole Heartburn Relief looks like

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

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

Available in blister packs of 7 or 14 tablets.

Ingredients

The active ingredient in the tablets is pantoprazole (as sodium sesquihydrate).

The tablets also contain the following as inactive ingredients:

  • calcium stearate
  • colloidal anhydrous silica
  • crospovidone
  • hypromellose
  • macrogol 6000
  • mannitol
  • sodium carbonate
  • sodium hydroxide
  • sodium starch glycollate
  • Eudragit L30-D55 (3700)
  • Opadry AMB Aqueous Moisture Barrier Coating System 80W52172 Yellow (106688).

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

Australian Registration Number

APOHEALTH Pantoprazole Heartburn Relief tablets (blisters): AUST R 229698.

*Not all pack sizes may be available.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

APOHEALTH and APOTEX are the registered trademarks of Apotex Inc.

This leaflet was last updated in:
February 2021.

Published by MIMS April 2021

BRAND INFORMATION

Brand name

APOHealth Pantoprazole Heartburn Relief

Active ingredient

Pantoprazole

Schedule

S2 | S3

 

1 Name of Medicine

Pantoprazole sodium sesquihydrate.

2 Qualitative and Quantitative Composition

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

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: interstitial nephritis.

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).

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 Poison 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