Consumer medicine information

OZPAN

Pantoprazole

BRAND INFORMATION

Brand name

Ozpan

Active ingredient

Pantoprazole

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using OZPAN.

What is in this leaflet

This leaflet answers some common questions about OZPAN (Pantoprazole enteric-coated tablets 20/40 mg).

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking pantoprazole against the benefits it is expected to have for you.

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

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

What OZPAN is used for

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

Ulcers
OZPAN 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.

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

Reflux disease
OZPAN 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.

OZPAN is also used to prevent reflux oesophagitis from coming back.

Zollinger-Ellison syndrome
OZPAN 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.

Other uses
Your doctor may have prescribed OZPAN for another reason. Ask your doctor if you have any questions about why OZPAN has been prescribed for you.

How OZPAN works

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

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

There is no evidence that OZPAN is addictive.

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

Before you take OZPAN

When you must not take it

Do not take OZPAN if:

  1. you have an allergy to:
  • pantoprazole
  • any of the ingredients listed at the end of this leaflet
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.
  1. you have severe liver disease or cirrhosis

Do not take OZPAN if the packaging is torn or shows signs of tampering.

Do not take OZPAN after the expiry date (EXP) printed on the pack has passed.

Do not take OZPAN in combination with any other medicine if:

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

Do not take OZPAN in combination with atazanavir (an anti-viral medication).

OZPAN should not be given to children. Safety and effectiveness of OZPAN in children have not been established.

If you are not sure whether you should start taking OZPAN, talk to your doctor.

Before you start to take it

You must tell your doctor if:

  1. you have any allergies to:
  • pantoprazole
  • any of the ingredients listed at the end of this leaflet
  • any other medicines, or any other substances, such as foods, preservatives or dyes.
  1. you are pregnant, intend to become pregnant, are breast-feeding or intend to breast-feed.
Your doctor will discuss the risks and benefits of taking OZPAN during pregnancy or while breast-feeding.
  1. you have or have had any other medical conditions.

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

Taking other medicines

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

Some medicines may be affected by OZPAN, or may affect how well it works. These may include medicines used to prevent blood clots anticoagulants) and medicines whose activity depend on the acidity of the stomach e.g. ketoconazole.

You may need different amounts of your medicine, or you may need to take different medicines. Your doctor will advise you.

How to take OZPAN

How much to take

The usual dose is one tablet per day.

The dose and frequency of OZPAN that your doctor prescribes for you depends on your medical condition. Your doctor may change the dose as your condition changes.

How and when to take it

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

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

How long to take it

Your doctor will tell you how long to take your tablets.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to. Otherwise, take it as soon as you remember, and then go back to taking it as you would normally.

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

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

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre for advice - the telephone number in Australia is 13  11  26 or go to Accident and Emergency (Casualty) at your nearest hospital, if you think that you or anyone else may have taken too much OZPAN. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention. Keep telephone numbers for these places handy.

While you are taking OZPAN

Things you must do

Use OZPAN exactly as your doctor has prescribed.

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

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

If you take OZPAN for a long period of time, e.g. over 1 year, you will need to see your doctor regularly so that he/she can monitor your condition.

Tell your doctor if you do not feel better while taking OZPAN. Your doctor may recommend further examination.

Things you must not do

Do not give OZPAN to anyone else, even if they have the same symptoms as you.

Do not use OZPAN to treat any other complaints unless your doctor tells you to.

Things that may help your condition

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

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

Side effects

Tell your doctor as soon as possible if you have any problems while taking OZPAN, even if you do not think the problems are connected with the medicine or they are not listed in this leaflet.

Like other medicines, OZPAN can cause some side effects. If they occur, most are likely to be minor and temporary. However, some may be serious and need medical attention.

Ask your doctor or pharmacist any questions you may have.

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

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

These are the more common side effects of pantoprazole . Some of these side effects may be due to the combination of other medicines you are taking with OZPAN.

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

  • unusual tiredness or weakness
  • nausea, vomiting, loss of appetite, feeling generally unwell, fever, itching, yellowing of the skin and eyes, and dark coloured urine.
  • skin problems such as itchiness and rash, or swelling, blistering or peeling of the skin.
  • 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
  • swelling of the legs
  • bleeding or bruising more easily than normal
  • depression, confusion or anxiety

These may be serious side effects and you may need urgent medical attention. Serious side effects are rare.

Other side effects not listed above may occur in some people. Tell your doctor if you notice anything that is making you feel unwell when you are taking, or soon after you have finished taking, OZPAN.

Ask your doctor or pharmacist if you do not understand some of the information in this list.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After taking OZPAN

Storage

Keep your tablets in their blister pack until it is time to take them.

If you take the tablets out of the blister pack they may not keep well.

Keep OZPAN tablets in a cool dry place where the temperature stays below 25°C.

Do not store OZPAN or any other medicines in a bathroom or near a sink. Do not leave it in the car or on window sills.

Heat and dampness can destroy some medicines.

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

Disposal

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

Product Description

What OZPAN looks like

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

OZPAN 20 mg are yellow, enteric-coated, oval-shaped, biconvex tablets imprinted with ‘II’ in black ink on one side and plain on other side.

OZPAN 40 mg are yellow, enteric-coated, oval-shaped, biconvex tablets imprinted with ‘IV’ in black ink on one side and plain on other side.

Ingredients

Active ingredient

  • OZPAN 20 mg tablets contains pantoprazole sodium equivalent to 20 mg of pantoprazole.
  • OZPAN 40 mg tablets contains pantoprazole sodium equivalent to 40 mg of pantoprazole.

Inactive ingredients

OZPAN contains the following inactive ingredients: sodium carbonate anhydrous, mannitol, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, calcium stearate, Opadry 02H52369 yellow, methacrylic acid – ethyl acrylate copolymer (1:1) , triethyl citrate, sodium lauryl sulfate, titanium dioxide, yellow iron oxide, purified talc, Opacode S-1-17823 black.

Australian Registration Numbers

OZPAN 20 mg tablets: AUST R 151290
OZPAN 40 mg tablets: AUST R 151291

Sponsor

OZPAN tablets are supplied in Australia by:
Ranbaxy Australia Pty. Ltd
Suite 4.02, Building D, Level 4
12 - 24 Talavera Road
North Ryde, NSW 2113
Australia

This leaflet was prepared in July 2010.

Published by MIMS November 2010

BRAND INFORMATION

Brand name

Ozpan

Active ingredient

Pantoprazole

Schedule

S4

 

1 Name of Medicine

Pantoprazole sodium sesquihydrate.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

138 786-67-1 (pantoprazole sodium).
The molecular weight of pantoprazole, sodium salt x 1.5 H2O is 432.4.

2 Qualitative and Quantitative Composition

Each tablet of Ozpan contains pantoprazole sodium sesquihydrate equivalent to 20 mg or 40 mg of pantoprazole.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Ozpan 20 mg tablets are available as yellow-coloured, enteric-coated oval-shaped, biconvex tablets imprinted with 'II' in black ink on one side and plain on other side. Ozpan 40 mg tablets are available as yellow coloured, enteric-coated oval shaped, biconvex tablets imprinted with 'IV' in black ink on one side and plain on other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Pantoprazole is a substituted benzimidazole proton pump inhibitor which inhibits basal and stimulated gastric secretion. 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 sulphenamide 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 3 months prior to entry into the study. Efficacy of pantoprazole 20 mg is shown in Table 3.

Acute treatment of mild reflux oesophagitis.

In two randomised, double-blind, multi-centre studies, 410 patients with mild GORD (Savary-Miller stage 1) were treated with either pantoprazole 20 mg once daily before breakfast or ranitidine 300 mg once daily at bedtime. Superiority of pantoprazole 20 mg in terms of healing rates as compared to ranitidine after 4 and 8 weeks is shown in Table 4. The difference in healing rates was statistically significant at all time points in the intention-to-treat and per protocol patient groups.

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

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

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

Two randomised, double-blind, multi-centre studies examined the efficacy and safety of pantoprazole in the prevention of NSAID-associated gastroduodenal ulcers, petechiae, erosions and dyspeptic symptoms in patients with arthritis on continuous treatment with NSAIDs and an increased risk to develop gastrointestinal lesions.
The primary endpoint for both studies was the “therapeutic failure” rate after 6 months, defined as “endoscopic failure” (i.e. more than 10 erosions or petechiae, peptic ulcer, reflux oesophagitis) or premature study termination due to at least “likely” related adverse event or due to severe gastrointestinal symptoms.

Study 1.

A total of 515 patients were included into the study. Patients were randomised to receive either pantoprazole 20 mg daily (n = 257) or misoprostol 200 microgram twice daily (n = 258).
Efficacy of pantoprazole 20 mg is shown in Table 6.
Pantoprazole 20 mg once daily was statistically significantly superior to misoprostol 200 microgram twice daily with regard to “therapeutic failure” and to “endoscopic failure”.
Reflux oesophagitis was included as an efficacy end-point in the study which may have biased the results in favour of pantoprazole. A causal association between NSAIDs and reflux oesophagitis has not been established. In addition, proton pump inhibitors such as pantoprazole have documented beneficial treatment effects on reflux oesophagitis while misoprostol (a prostaglandin E1 analogue) has negligible therapeutic effects.

Study 2.

A total of 595 patients were included into the study. Patients were randomised to receive either pantoprazole 20 mg daily (n = 196), pantoprazole 40 mg daily (n = 199) or omeprazole 20 mg daily (n = 200). Efficacy results are shown in Table 7.
All three treatments, 20 mg pantoprazole, 40 mg pantoprazole and 20 mg omeprazole, were proven to be of equivalent and high efficacy.

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 h, with a Cmax of approximately 1.2 microgram/mL. Terminal half-life is approximately 1 h. Pharmacokinetics do not vary after single or repeated administration. The plasma kinetics of pantoprazole are linear (in the dose range of 10 to 80 mg) after both oral and intravenous administration.
Pantoprazole is completely absorbed after oral administration. The absolute bioavailability of the tablet is approximately 77%. Concomitant intake of food had no influence on AUC, 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 and clearance is approximately 0.1 L/h/kg.

Metabolism.

Pantoprazole is extensively metabolised in the liver through the cytochrome P450 (CYP) system. Pantoprazole metabolism is independent of the route of administration (intravenous or oral). The main metabolic pathway is demethylation, by CYP2C19, with subsequent sulfation; other metabolic pathways include oxidation by CYP3A4. There is no evidence that any of the pantoprazole metabolites have significant pharmacologic activity. CYP2C19 displays a known genetic polymorphism due to its deficiency in some 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 to 10.0 hours, they still have minimal accumulation (δ 23%) with once daily dosing.

Excretion.

Pantoprazole is rapidly eliminated from serum and is almost exclusively metabolised in the liver. Renal elimination represents the most important route of excretion (approximately 80%) for the metabolites of pantoprazole, the rest are excreted with the faeces. The main metabolite in both the serum and urine is 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.

Special populations.

In patients with liver cirrhosis given a single 40 mg tablet, the half-life increases to between 7 and 9 h and the AUC values are increased by a factor of 6-8 but the maximum serum concentration increases only slightly by a factor of 1.5 in comparison with healthy subjects. After a single 20 mg tablet, AUC increased 3-fold in patients with mild hepatic impairment and 5-fold in patients with severe hepatic impairment compared with healthy controls. Mean elimination half-life was 3.3 h in mild hepatic impairment and 6.0 h in severe hepatic impairment compared with 1.1 h in controls. The maximum serum concentration only increased slightly by a factor of 1.3 compared with healthy subjects. 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 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 end points 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, mouse lymphoma test and a gene mutation test in Chinese hamster ovary cells (in vitro). In addition, toxicokinetic studies were conducted in rats at the doses used in the bone marrow assay (50 to 1200 mg/kg) and in mice at the high dose from the earlier micronucleus test (710 mg/kg). 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 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.

4 Clinical Particulars

4.1 Therapeutic Indications

Ozpan is indicated for the following.
1. Symptomatic improvement and healing of gastrointestinal diseases which require a reduction in acid secretion.
Duodenal ulcer.
Gastric ulcer.
Gastro-oesophageal reflux disease (GORD):
Symptomatic GORD, the treatment of heartburn and other symptoms associated with GORD;
Reflux oesophagitis.
Gastrointestinal lesions refractory to H2 blockers.
Zollinger-Ellison syndrome.
Patients whose gastric or duodenal ulceration is not associated with ingestion of nonsteroidal anti-inflammatory drugs (NSAIDs) require treatment with antimicrobial agents in addition to antisecretory drugs whether on first presentation or on recurrence.
2. Maintenance of healed reflux oesophagitis in patients previously treated for moderate to severe reflux oesophagitis.
3. Prevention of gastroduodenal lesions and dyspeptic symptoms associated with non-selective non-steroidal anti-inflammatory drugs (NSAIDs) in increased risk patients with a need for continuous non-selective NSAID treatment.

4.3 Contraindications

Pantoprazole may not be used in cases of known hypersensitivity to any components of the formulation, substituted benzimidazoles 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.

In the presence of any alarm symptoms (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis, anaemia or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment with pantoprazole may alleviate symptoms and delay diagnosis. Further investigation is to be considered if symptoms persist despite adequate treatment.

Clostridium difficile.

PPI therapy may be associated with an increased risk of Clostridium difficile infection.
Pantoprazole, like all proton pump inhibitors, might be expected to increase the counts of bacterial 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 hypo- or achlorhydria. This should be considered in patients with reduced body stores or risk factors for reduced vitamin B12 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.

Non-steroidal anti-inflammatory drugs.

Use of pantoprazole enteric coated tablets 20 mg for prevention of gastroduodenal lesions and dyspeptic symptoms associated with non-selective non-steroidal anti-inflammatory drugs (NSAIDs) should be restricted to patients who require continued non-selective NSAID treatment and have an increased risk to develop gastrointestinal complications. The increased risk should be assessed according to individual risk factors, e.g. high age (> 65 years), history of gastric or duodenal ulcer or upper gastrointestinal bleeding.

Subacute cutaneous lupus erythematosus (SCLE).

Proton pump inhibitors are associated in rare cases with the occurrence of subacute cutaneous lupus erythematosus (SCLE). If lesions occur, especially in sun exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical help promptly and the healthcare professional should consider stopping the product.

Bone fracture.

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

Acute interstitial nephritis.

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

Hypomagnesaemia.

Hypomagnesaemia has been rarely reported in patients treated with PPIs for at least three month (in most cases after a year of therapy). Serious consequences of hypomagnesaemia include tetany, arrhythmia and seizure.

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 one study after up to 5 years of treatment with regular and high doses, but no increase was observed in a second study). No dysplasic 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.

Monitoring.

In long-term treatment, especially when exceeding a treatment period of 1 year, patients should be kept under regular surveillance.
Patients being treated for symptomatic GORD with pantoprazole 20 mg who do not respond after 4 weeks should be investigated.

Use in the elderly.

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

Paediatric use.

To date there 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 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 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 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 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).

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 normalised ratio (INR) have been reported during concomitant treatment in the post-marketing period. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Therefore, in patients being treated with coumarin anticoagulants (e.g. warfarin or phenprocoumon), monitoring of prothrombin time/ INR is recommended after initiation, termination or during irregular use of pantoprazole.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Pantoprazole at oral doses up to 500 mg/kg/day in male rats and 450 mg/kg/day in female rats (estimated exposure at least 60-fold the clinical exposure from the 40 mg tablet) was found to have no effect on fertility and reproductive performance.
(Category B3)
Teratological studies in rats and rabbits gave no evidence of a teratogenic potential for pantoprazole. In oral rat studies, dose-dependent toxic effects were observed on fetuses and pups: increased pre- and postnatal 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 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 fetus.
A pre/post-natal 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 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 breast feeding in humans. Therefore, pantoprazole should only be used during lactation if the benefits clearly outweigh the risks.

4.8 Adverse Effects (Undesirable Effects)

Pantoprazole tablets are 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 postmarketing surveillance:
Adverse reactions within each body system are listed in descending order of frequency (Very common: ≥ 10%; common: ≥ 1% and < 10%; uncommon: ≥ 0.1% and < 1%; rare ≥ 0.01% and < 0.1%; very rare: < 0.01%; not known: cannot be estimated from the available data). These include the following:

General disorders and administration site conditions.

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

Cardiovascular disorders general.

Rare: hypertension.
Very rare: circulatory collapse.

Nervous system disorders.

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

Gastrointestinal system disorders.

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

Hearing and vestibular disorders.

Very rare: tinnitus.

Immune system disorders.

Rare reports of anaphylactic reactions including anaphylactic shock.

Hepatobiliary disorders.

Uncommon: increased liver enzymes (transaminases, gamma-GT) have occurred in patients receiving long-term maintenance therapy.
Rare: bilirubin increased.
Very rare: hepatocellular failure, cholestatic hepatitis, bilirubinaemia and jaundice.
The occurrence of severe hepatocellular damage leading to jaundice or hepatic failure having a temporal relationship to the intake of pantoprazole has been reported with a frequency of approximately one in a million patients.

Metabolism and nutrition disorders.

Rare: hyperlipidaemias, hypertriglyceridaemia, weight changes.
Not known: hyponatraemia, hypomagnesaemia.

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: interstitial nephritis.

Platelet, bleeding, clotting disorders.

Very rare: thrombocytopenia and 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, pancytopaenia.

Resistance mechanism disorders.

Rare: sepsis.

Respiratory system disorders.

Very rare: dyspnoea.

Reproductive system and breast disorders.

Rare: gynaecomastia.

Skin and subcutaneous tissue disorders.

Uncommon: pruritus, skin rash/exanthema/eruption.
Rare: angioedema, urticaria.
Very rare: flushing, severe skin reactions such as Stevens Johnson Syndrome, toxic epidermal necrolysis, erythema multiforme, Lyell Syndrome and photosensitivity.
Not known: subacute cutaneous lupus erythematosus.

Eye disorders.

Uncommon: disturbances in vision (blurred vision).
Very rare: conjunctivitis.
See Tables 1 and 2.

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.

4.2 Dose and Method of Administration

Ozpan tablets should not be chewed or crushed but swallowed whole with a little water.
In H. pylori negative patients, the following dosage guidelines apply for monotherapy with pantoprazole.

Duodenal ulcer.

Ozpan 40 mg (1 tablet) should be given once a day. In most patients freedom from symptoms is achieved rapidly and healing generally occurs within 2 weeks. If a 2 week period of treatment is not sufficient, healing will be achieved in almost all cases within a further 2 weeks.

Gastric ulcer.

Ozpan 40 mg (1 tablet) should be given once a day. In most patients freedom from symptoms is achieved rapidly and healing usually takes 4 weeks. If a 4 week period of treatment is not sufficient, healing will usually be achieved in a further 4 weeks.

Lesions refractory to H2-receptor antagonists.

Ozpan 40 mg (1 tablet) should be given once a day. In most patients freedom from symptoms is achieved rapidly and healing usually takes 4 weeks. If a 4 week period of treatment is not sufficient, healing is achieved in the majority of patients in a further 4 weeks. In a small group of patients, there may be benefit in extending pantoprazole therapy to a total of 12 weeks.

Zollinger-Ellison syndrome.

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

GORD.

Symptomatic GORD (treatment of symptomatic reflux).

The recommended dosage is one Ozpan 20 mg tablet per day. If symptom control has not been achieved after four weeks treatment with Ozpan 20 mg tablets daily, further investigation is recommended, for example endoscopy.

Treatment of reflux oesophagitis.

The recommended oral dosage is one Ozpan 20 mg or 40 mg tablet per day. A 4 week period is usually required for healing, however if this is not sufficient, healing will usually be achieved within a further 4 weeks. This dosage may be increased up to 80 mg pantoprazole per day.

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

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

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

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

Use in 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.

Impaired renal function.

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

Impaired hepatic function.

Pantoprazole is contraindicated in patients with cirrhosis or severe liver disease (see Section 4.3 Contraindications).
With milder forms of liver disease, the minimum effective dose has not been determined and the initial dose should be reduced.

4.7 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.

4.9 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. 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 utilised.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium carbonate, mannitol, crospovidone, hyprolose, microcrystalline cellulose, calcium stearate, Opadry complete film coating system 02H52369 Yellow (PI 12867), methacrylic acid - ethyl acrylate copolymer (1:1), triethyl citrate, sodium lauryl sulfate, titanium dioxide, iron oxide yellow, purified talc. Both 20 mg and 40 mg tablets contains Opacode monogramming ink S-1-17823 Black (PI 12108).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Ozpan tablets are supplied in cold form blister pack (PA/Al/PVC/Al - polyamidealuminium foil-polyvinylchloride/aluminium foil) containing 30 tablets of 20 mg and 40 mg tablets.

6.6 Special Precautions for Disposal

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

Summary Table of Changes