Consumer medicine information

Pantoprazole-AFT

Pantoprazole

BRAND INFORMATION

Brand name

Pantoprazole-AFT

Active ingredient

Pantoprazole

Schedule

SUMMARY CMI

Pantoprazole-AFT

Consumer Medicine Information (CMI) summary

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

1. Why am I using Pantoprazole-AFT?

Pantoprazole-AFT contains the active ingredient pantoprazole. Pantoprazole-AFT works by decreasing the amount of acid the stomach makes to give relief from the symptoms and allow healing to take place.

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

2. What should I know before I use Pantoprazole-AFT?

Do not use if you have ever had an allergic reaction to pantoprazole or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

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

3. What if I am taking other medicines?

Some medicines may interfere with Pantoprazole-AFT and affect how it works.

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

4. How do I use Pantoprazole-AFT?

Follow all directions given to you by your doctor or pharmacist carefully.
The dose and frequency of your injection will be determined by your doctor and will depend on your medical condition.

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

5. What should I know while using Pantoprazole-AFT?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are using Pantoprazole-AFT. Tell your doctor if you become pregnant while you are being given this medicine.
Driving or using machines	Do not drive a car or operate machines if you experience side effects such as dizziness or blurred vision.
Looking after your medicine	Normally your doctor will provide your Pantoprazole-AFT injection. If however, you do take your Pantoprazole-AFT injection from the pharmacy to your doctor, it is important to store it in a safe place away from heat (below 25°C) and away from light.

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

6. Are there any side effects?

Like all medicines, Pantoprazole-AFT can cause side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

Pantoprazole-AFT

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

Consumer Medicine Information (CMI)

This leaflet provides important information about using Pantoprazole-AFT. 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 Pantoprazole-AFT.

Where to find information in this leaflet:

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

1. Why am I using Pantoprazole-AFT?

Pantoprazole-AFT contains the active ingredient pantoprazole. Pantoprazole-AFT belongs to a group of medicines called proton pump inhibitors (PPIs). This medicine works by decreasing the amount of acid the stomach makes to give relief from the symptoms and allow healing to take place.

Ulcers

Pantoprazole-AFT is used to treat and help heal duodenal and gastric ulcers. Depending on the position of the ulcer it is called a gastric or duodenal ulcer. A gastric ulcer occurs in the stomach. A duodenal ulcer occurs in the duodenum which is the tube leading out of the stomach. These can be caused in part by too much acid being made in the stomach.

Reflux disease

Pantoprazole-AFT is also used to treat reflux oesophagitis or reflux disease. This can be caused by “washing back” (reflux) of food and acid from the stomach into the food pipe, also known as the oesophagus.

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

Pantoprazole-AFT is also used to prevent reflux oesophagitis from coming back.

Zollinger-Ellison syndrome

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

Ask your doctor if you have any questions about why it has been prescribed for you.

Your doctor may have prescribed it for another purpose.

This medicine is not addictive.

2. What should I know before I use Pantoprazole-AFT?

Warnings

Do not use Pantoprazole-AFT:

If you are allergic to pantoprazole, 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.
if you have severe liver disease or cirrhosis.
in combination with atazanavir or nelfinavir (antiviral medications).
In children. Safety and effectiveness in children have not been established.
After the expiry date printed on the pack or if the packaging is damaged or shows signs of tampering. If it has expired or is damaged return it to your pharmacist for disposal.

Check with your doctor if you:

have any allergies to any other medicines, foods, preservatives or dyes.
have or have had any other medical conditions.
have any of the following symptoms:
- unintentional weight loss
- repeated vomiting
- vomiting blood
- difficulty or pain when swallowing
- you look pale and feel weak
- you notice blood in your stools

If you have not told your doctor about any of the above, tell them before you use Pantoprazole-AFT injection. Your doctor may need to perform some additional tests before you take Pantoprazole-AFT Injection.

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 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-AFT injection may interfere with each other. These include:

warfarin, phenprocoumon – medicines used to prevent blood clots (anticoagulants)
ketoconazole, itraconazole, posaconazole – medicines used to treat fungal infection
atazanavir, nelfinavir – medicines used to treat viral infections such as HIV
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-AFT injection or may affect how well it works. You may need to use different amounts of your medicine or take different medicines. Your doctor has more information on medicines to be careful with or to avoid while taking Pantoprazole-AFT injection.

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

4. How do I use Pantoprazole-AFT?

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet. If you do not understand the instructions, ask your doctor or pharmacist for help.

How much to use & when to use

The dose and frequency of your injection will be determined by your doctor and will depend on your medical condition. Your doctor may change the dose as your condition changes.

How to use Pantoprazole-AFT

Pantoprazole-AFT injection is reconstituted by your doctor or pharmacist.

How long to use to Pantoprazole-AFT

Continue using your medicine for as long as your doctor tells you. Your doctor will determine how long you need to be treated with Pantoprazole-AFT injection.

If you forget to use Pantoprazole-AFT

If a dose of Pantoprazole-AFT injection is missed, your doctor will determine when your next dose is due.

If you use too much Pantoprazole-AFT

Your doctor will ensure that you receive the correct dose of Pantoprazole-AFT injection. Never administer this medicine to yourself.

Overdose is unlikely with Pantoprazole-AFT. However, it may cause an increase in side effects. (The side effects are listed under the heading, ‘Side effects’ in this leaflet.)

If you think that you have used too much Pantoprazole-AFT, you may need urgent medical attention.

You should immediately:

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

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

5. What should I know while using Pantoprazole-AFT?

Things you should do

Call your doctor straight away if:

You become pregnant while you are being given this medicine
Your reflux symptoms return after you stop taking this medicine. The symptoms of reflux may return after stopping this medicine suddenly, especially if you have taken it for a while.

Remind any doctor, dentist or pharmacist you visit that you are using Pantoprazole-AFT.

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

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

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Pantoprazole-AFT affects you.

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

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

Looking after your medicine

Storage

Normally your doctor will provide your Pantoprazole-AFT injection. If however, you do take your Pantoprazole-AFT injection from the pharmacy to your doctor, it is important to store it in a safe place away from heat (below 25°C) and away from light. Do not leave your Pantoprazole-AFT injection in a car.

If for any reason you take your Pantoprazole-AFT injection home, use it as soon as possible after preparation. If storage is necessary, store at 2-8°C for no longer than 12 hours.

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

When taking Pantoprazole-AFT injection at home, always ensure that it is stored in a place where children cannot reach it i.e. a locked cupboard at least one-and-a-half meters (5 feet) above the ground is a good place to store medicine.

Getting rid of any unwanted medicine

If your doctor stops treating you with Pantoprazole-AFT injection, your hospital pharmacist will dispose of any unused 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.

Tell your doctor as soon as possible if you do not feel well while you are given Pantoprazole injection.

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 effects

What to do

Gastrointestinal/ digestion related:

Diarrhoea
Nausea or vomiting
Stomach pain
Excessive gas in the stomach or bowel
Indigestion
Constipation

Local/ skin related:

Pain and swelling at the site of injection
Skin problems such as itchiness and rash

Body as whole:

Headache
Increased sweating or body temperature
Dry mouth
Dizziness
Weakness or tiredness
Metallic taste
Blurred vision
Trouble sleeping

Speak to your doctor if you have any of these less serious side effects and they worry you.
These are more common side effects of your medicine. They are usually mild and short-lived.

Serious side effects

Serious side effects

What to do

unusual tiredness or weakness
nausea, vomiting, loss of appetite, feeling generally unwell, fever, itching, yellowing of the skin and eyes, and dark coloured urine
blood in the urine
increased or decreased need to urinate
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 infections such as fever, severe chills, sore throat or mouth ulcers
chest pain
shortness of breath
high blood pressure
water retention, swelling
bleeding or bruising more easily than normal
depression, confusion or anxiety
bone fracture of the hip, wrist or spine (mainly a risk in people who take high doses of PPIs or use them long term (a year or longer))
symptoms such as seizures, abnormal or fast heartbeat, 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.
These side effects are rare.

Other side effects not listed above may occur in some people. Some of the side effects can only be found when your doctor does tests from time to time to check your progress.

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

Reporting side effects

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

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

7. Product details

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

What Pantoprazole-AFT contains

Active ingredient (main ingredient)	Pantoprazole (as sodium sesquihydrate)
Other ingredients (inactive ingredients)	Mannitol Tribasic sodium phosphate dodecahydrate

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

What Pantoprazole-AFT looks like

Pantoprazole-AFT Injection is a white to off-white powder provided in a glass vial. (Aust R 288085).

Who distributes Pantoprazole-AFT

AFT Pharmaceuticals Pty Ltd.
113 Wicks Road
North Ryde, NSW 2113

This leaflet was prepared in August 2024.

Published by MIMS December 2024

BRAND INFORMATION

Brand name

Pantoprazole-AFT

Active ingredient

Pantoprazole

Schedule

1 Name of Medicine

Pantoprazole (as sodium sesquihydrate).

2 Qualitative and Quantitative Composition

One vial contains 40 mg pantoprazole (as pantoprazole sodium sesquihydrate).
Pantoprazole sodium sesquihydrate is a white to off white amorphous powder. Solubility is low at neutral pH and increases with increasing pH.
The 40 mg powder for injection contains the inactive ingredients mannitol and tribasic sodium phosphate dodecahydrate. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for solution for injection.
A white to off-white powder.

4 Clinical Particulars

4.1 Therapeutic Indications

Short-term use where oral therapy is not appropriate for:
1. Symptomatic improvement and healing of gastrointestinal diseases which require a reduction in acid secretion:
Duodenal ulcer;
Gastric ulcer;
Reflux oesophagitis;
Gastrointestinal lesions refractory to H₂ blockers;
Zollinger-Ellison syndrome;
2. Maintenance of healed reflux oesophagitis in patients previously treated for moderate to severe reflux oesophagitis.

Note.

Patients whose gastric or duodenal ulceration is not associated with ingestion of non-steroidal anti-inflammatory drugs require treatment with anti-microbial agents in addition to anti-secretory drugs, whether on first presentation or recurrence.

4.2 Dose and Method of Administration

Duodenal ulcer, gastric ulcer, gastrointestinal lesions refractory to H₂ blockers, Zollinger-Ellison syndrome.

40 mg per day.

Reflux oesophagitis.

20-40 mg per day.
Intravenous Pantoprazole-AFT should be replaced with oral therapy as soon as practicable.

Method of administration.

A ready-to-use solution is prepared by injecting 10 mL Sodium Chloride Intravenous Infusion 0.9% into the vial containing the dry powder. This solution may be administered directly or may be administered after mixing with 100 mL Sodium Chloride Intravenous Infusion 0.9% or 100 mL Glucose Intravenous Infusion 5 or 10%. The resulting solution should be used within 12 hours stored at 2-8°C and is for single use only.
After preparation, the solution should be administered over 2 to 15 minutes.

Instructions for use and handling.

To reduce microbiological hazard, use as soon as practicable after reconstitution/preparation. If storage is necessary, hold at 2°C-8°C for not more than 12 hours.
This product contains no antimicrobial agent. Pantoprazole-AFT injection is for single use in one patient only. Any unused product remaining or the visual appearance of which has changed (e.g. if cloudiness or precipitation is observed), should be discarded.

Infants and children.

There are no data currently available on the use of pantoprazole in children.

Use in the elderly.

The usual daily dose of 20 mg or 40 mg can be given.

Use in patients with renal impairment.

The usual daily dose of 20 mg or 40 mg can be given.

Use in patients with hepatic impairment.

Pantoprazole is contraindicated in patients with cirrhosis or severe liver disease (see Section 4.3 Contraindications). With milder forms of liver disease, the initial dose should be reduced.

4.3 Contraindications

Known hypersensitivity to pantoprazole, substituted benzimidazoles or any other components of the formulation or in cases of cirrhosis or severe liver disease.
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.

The intravenous administration of Pantoprazole-AFT powder for injection is recommended only if oral application is not appropriate.
In the presence of any alarm symptoms (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis, anaemia or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment with pantoprazole may alleviate symptoms and delay diagnosis. Further investigation is to be considered if symptoms persist despite adequate treatment.

Clostridium difficile.

PPI therapy may be associated with an increased risk of Clostridium difficile infection.
Pantoprazole, like all proton pump inhibitors (PPIs), 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 C. difficile.

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 health care professional should consider stopping the product.

Bone fractures.

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)).

Influence on vitamin B₁₂ absorption.

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

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 2-fold increase was observed in study RR126/97 after up to 5 years of treatment with regular and high doses, but no increase was observed in study RR125/97). No dysplastic or neoplastic changes were observed in gastric endocrine cells in either study.

Ocular toxicity and dermal phototoxicity/ sensitivity.

Studies have shown that pantoprazole is retained in low levels in the eyes and skin of pigmented rats. It is likely that the retention reflects a reversible association with melanin. Animal studies investigating the potential for phototoxicity/ photosensitivity have not been conducted. A 2-week dog study, conducted specifically to investigate the effects on the eye and ear, did not reveal any changes relating to pantoprazole treatment, but the doses chosen were relatively low (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 4 weeks.

Use in the elderly.

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

Paediatric use.

To date there has been no experience with treatment in children.

Effects on laboratory tests.

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

4.5 Interactions with Other Medicines and Other Forms of Interactions

Pantoprazole is metabolised in the liver via the cytochrome P450 enzyme system. A study using human liver microsomes suggested that the P450 enzymes CYP2C19 and CYP3A4 are involved in its metabolism. In addition, CYP2D6 and CYP2C9-10 were implicated in another study. An interaction of pantoprazole with other drugs or compounds which are metabolised using the same enzyme system cannot be excluded. However, no clinically significant interactions were observed in specific tests with a number of such drugs or compounds, namely carbamazepine, caffeine, diazepam, diclofenac, digoxin, ethanol, glibenclamide, metoprolol, naproxen, nifedipine, phenytoin, piroxicam, theophylline, and the low dose oral contraceptive Triphasil (levonorgestrel and ethinyl oestradiol). 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 co-administration of atazanavir 300 mg/ ritonavir 100 mg with omeprazole (40 mg once daily) or atazanavir 400 mg with lansoprazole (60 mg single dose) to healthy volunteers resulted in a substantial reduction in the bioavailability of atazanavir. The absorption of atazanavir is pH dependent. Therefore, proton pump inhibitors including pantoprazole, should not be co-administered with HIV protease inhibitors for which absorption is dependent on acidic intragastric pH, such as atazanavir or nelfinavir (see Section 4.3 Contraindications).

Mycophenolate mofetil.

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

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

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

Coumarin anticoagulants (phenprocoumon or warfarin).

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

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available (see Section 5.3 Preclinical Safety Data).
(Category B3)
Teratological studies in rats and rabbits gave no evidence of a teratogenic potential for pantoprazole. In oral rat studies, dose-dependent toxic effects were observed on fetuses and pups: increased pre- and post-natal deaths at 450 mg/kg/day, reduced fetal weight at ≥ 150 mg/kg/day and delayed skeletal ossification and reduced pup growth at ≥ 15 mg/kg/day. For the latter a no effect dose was not 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 fetus are increased shortly before birth regardless of the route of administration.
The significance of these findings in humans is unknown. As there is no information on the safety of the drug during pregnancy in women, pantoprazole should not be used during pregnancy, unless the benefit clearly outweighs the potential risk to the fetus.
A peri/ postnatal study in rats found that treatment with pantoprazole at doses of 10 mg/kg/day 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 group at an age when male and female offspring showed lower bodyweights, paralleled with lower brain weight, than the controls. The significance of these findings for humans is unknown, and there is currently no information on the safety of pantoprazole during breastfeeding in humans. Excretion into human milk has been reported. Therefore, pantoprazole should only be used during lactation if the benefits clearly outweigh the risks.

4.7 Effects on Ability to Drive and Use Machines

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 injection 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 combination with antibiotics for H. pylori eradication in clinical trials and post-marketing surveillance.
Adverse reactions within each body system are listed in descending order of frequency (very common: ≥ 10%; common: ≥ 1% and < 10%; uncommon: ≥ 0.1% and < 1%; rare ≥ 0.01% and < 0.1%; very rare: < 0.01%; not known: cannot be estimated from the available data). These include the following:

General disorders and administration site conditions.

Common: injection site thrombophlebitis.
Uncommon: fatigue and malaise, asthenia and increased sweating.
Rare: fever, peripheral oedema.
Very rare: substernal chest pain and hot flushes.

Cardiovascular disorders general.

Rare: hypertension.
Very rare: circulatory collapse.

Nervous system disorders.

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

Gastrointestinal system disorders.

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

Hearing and vestibular disorders.

Very rare: tinnitus.

Immune system disorders.

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

Hepatobiliary disorders.

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

Metabolism and nutrition disorders.

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

Musculoskeletal and connective tissue disorders.

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

Renal and urinary disorders.

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

Platelet, bleeding, clotting disorders.

Very rare: increased coagulation time.

Psychiatric disorders.

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

Blood and lymphatic system disorders.

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

Resistance mechanism disorders.

Rare: sepsis.

Respiratory system disorders.

Very rare: dyspnoea.

Reproductive system and breast disorders.

Rare: gynaecomastia.

Skin and subcutaneous tissue disorders.

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

Eye disorders.

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

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

There are no known symptoms of overdosage in humans. In individual cases, 240 mg was administered i.v or p.o. and was well tolerated. Standard detoxification procedures apply.
For information of the management of overdose, contact the Poisons information Centre on 131126.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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).
Oral and intravenous pantoprazole 40 mg/day for 5 days had equivalent effect on intra-gastric pH in 20 healthy adult male volunteers in a randomised, open, 2-period crossover trial with 14-day wash-out. The pre-defined equivalence range was ± 20% for percentage of time with pH < 3 and 4 and ± 1 pH unit for 24 h median pH. The 24 h median pH on day 5 was 2.7 on oral treatment and 3.2 on intravenous treatment.
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.

Two uncontrolled trials in adults assessed the efficacy of pantoprazole 40 mg/day, administered intravenously for 5-7 days then orally for 3-7 weeks, in the endoscopic healing of Savary-Miller stage 2-3 reflux oesophagitis (Table 1). Using historical data, it was concluded that the intravenous plus oral regimen was at least equivalent to an exclusively oral regimen. The criterion for at least equivalence was: lower limit of 90% confidence interval of the difference, (IV + oral) - oral, > -15%.

5.2 Pharmacokinetic Properties

Absorption.

A considerably higher C_max occurs after intravenous administration compared with oral administration. In a study in healthy volunteers given 40 mg/day for 5 days, the steady state C_max was 5.9 mg/L after intravenous administration and 1.7 mg/L after oral administration. Terminal half-life is approximately 1 h. Pharmacokinetics do not vary after single or repeated administration. The plasma kinetics of pantoprazole are linear (in the dose range of 10 to 80 mg) after both oral and intravenous administration.

Distribution.

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

Metabolism.

Pantoprazole is metabolised in the liver via the cytochrome P450 enzyme system.

Excretion.

Pantoprazole is rapidly eliminated from serum and is almost exclusively metabolised in the liver. Renal elimination represents the most important route of excretion (approximately 80%) for the metabolites of pantoprazole, the rest are excreted with the faeces. The main metabolite in both the serum and urine is desmethyl-pantoprazole which is conjugated with the sulphate. The half-life of the main metabolites (approximately 1.5 h) is not much longer than that of pantoprazole.
In studies in healthy volunteers, 2% of subjects showed a slower elimination of pantoprazole from serum/ plasma, with an increase in terminal elimination half-life of up to 10 h. Patients with a half-life of greater than 3.5 h and with an apparent clearance of less than 2 L/h/kg are considered to be slow metabolisers of pantoprazole.
In patients with liver impairment, pantoprazole elimination is significantly delayed. After a 40 mg tablet, AUC increased by a factor of 6-8 and terminal half-life increased from 1 h to 7-9 h in patients with liver cirrhosis 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 dialyzable.
The slight increase in AUC and C_max 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 200 mg/kg/day pantoprazole for 14 days. However, no distinct DNA-adduct has been detected.
Pantoprazole was found to be negative in the following studies: in vivo chromosome aberration assay in rat and bone marrow (126E/95), mouse lymphoma test (222E/95) and a gene mutation test in Chinese hamster ovary cells (in vitro) (188E/95). In addition, toxicokinetic studies were conducted in rats at the doses used in the bone marrow assay (50 to 1200 mg/kg) (56E/96) and in mice at the high dose from the earlier micronucleus test (710 mg/kg) (89E/96). In both species, pantoprazole exposure was high with the AUCs being 26 to 30 times higher in the rat or mouse respectively, than humans using the 20 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 development of gastric tumours is attributed to chronic elevation of serum gastrin levels with associated histopathological changes in the gastrointestinal system.
In both male and female rats, the development of hepatocellular adenomas was increased at doses greater than 5 mg/kg/day and the development of hepatocellular carcinomas was increased at doses greater than 50 mg/kg/day. 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 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 doses (5, 15 and 50 mg/kg). 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 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

Mannitol, tribasic sodium phosphate dodecahydrate.

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in Section 4.2 Dose and Method of Administration.

6.3 Shelf Life

As packaged for sale, the duration of approved shelf-life is 36 months.
To reduce microbiological hazard, use as soon as practicable after reconstitution. If storage is necessary, hold at 2°C-8°C for not more than 12 hours.
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. Keep the vial in the outer carton to protect from light.
For storage conditions of the reconstituted/prepared medicinal product see Section 6.3 Shelf Life.

6.5 Nature and Contents of Container

Pantoprazole-AFT 40 mg powder for injection contains 40 mg pantoprazole (as sodium sesquihydrate), a white to off white powder, in a clear glass vial with a blue rubber stopper and aluminium "flip-off" cap.
Available in cartons containing 10 vials.

6.6 Special Precautions for Disposal

The content of the vial is for single use only.
In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

Sodium 5-(difluoromethoxy)-2-[(RS)-[(3,4-dimethoxypyridin-2-yl)methyl]-sulfiny]-benzimidazol-1-ide sesquihydrate.

CAS number.

164579-32-2 (pantoprazole sodium sesquihydrate).
Empirical formula: C₁₆H₁₄F₂N₃NaO₄S.
Molecular weight: 432.4 g.mol^-1.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription only medicine.

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