Symptomatic gastro-oesophageal reflux disease.
For long-term management and prevention of relapse in reflux oesophagitis.
 

Tablets should not be chewed or crushed, and should be swallowed whole 1 hour
before a meal with some water.
Recommended dose
Adults and adolescents 12 years of age and above
Symptomatic gastro-oesophageal reflux disease
The recommended oral dose is one gastro-resistant tablet Pantomax 20 mg per day.
Symptom relief is generally accomplished within 2-4 weeks. If this is not sufficient,
symptom relief will normally be achieved within a further 4 weeks. When symptom
relief has been achieved, reoccurring symptoms can be controlled using an ondemand regimen of 20 mg once daily, when required. A switch to continuous
therapy may be considered in case satisfactory symptom control cannot be
maintained with on-demand treatment.
Long-term management and prevention of relapse in reflux oesophagitis
For long-term management, a maintenance dose of one gastro-resistant tablet
Pantomax 20 mg per day is recommended, increasing to 40 mg pantoprazole per day
if a relapse occurs. Pantomax 40 mg is available for this case. After healing of the
relapse the dose can be reduced again to 20 mg pantoprazole.
Adults
Prevention of gastroduodenal ulcers induced by non-selective non-steroidal antiinflammatory drugs (NSAIDs) in patients at risk with a need for continuous NSAID
treatment
The recommended oral dose is one gastro-resistant tablet Pantomax 20 mg per day.
Special populations
Children below 12 years of age
Pantomax is not recommended for use in children below 12 years of age due to
limited data on safety and efficacy in this age group.
Hepatic Impairment
A daily dose of 20 mg pantoprazole should not be exceeded in patients with severe
liver impairment (see section 4.4).
Renal Impairment
No dose adjustment is necessary in patients with impaired renal function.
Elderly
No dose adjustment is necessary in elderly patients.
 

Hepatic Impairment
In patients with severe liver impairment the liver enzymes should be monitored
regularly during treatment with pantoprazole, particularly on long-term use. In the
case of a rise of the liver enzymes the treatment should be discontinued (see section
4.2).
Co-administration with NSAIDs
The use of Pantomax 20 mg as a preventive of gastroduodenal ulcers induced by
non-selective non-steroidal anti-inflammatory drugs (NSAIDs) should be restricted to
patients who require continued 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.
In presence of alarm symptoms
In the presence of any alarm symptom (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.
Co-administration with atazanavir
Co-administration of atazanavir with proton pump inhibitors is not recommended
(see section 4.5). If the combination of atazanavir with a proton pump inhibitor is
judged unavoidable, close clinical monitoring (e.g virus load) is recommended in
combination with an increase in the dose of atazanavir to 400 mg with 100 mg of
ritonavir. A pantoprazole dose of 20 mg per day should not be exceeded.
Influence on vitamin B12 absorption
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
on long-term therapy or if respective clinical symptoms are observed.
Long term treatment
In long-term treatment, especially when exceeding a treatment period of 1 year,
patients should be kept under regular surveillance.
Gastrointestinal infections caused by bacteria
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 Pantomax may lead to a slightly increased risk of gastrointestinal
infections caused by bacteria such as Salmonella and Campylobacter.
 

Effect of pantoprazole on the absorption of other medicinal products
Because of profound and long lasting inhibition of gastric acid secretion,
pantoprazole may reduce the absorption of drugs with a gastric pH dependent
bioavailability, e.g some azole antifungals as ketoconazole, itraconazole,
posaconazole and other medicine as erlotinib.
HIV medications (atazanavir)
Co-administration of atazanavir and other HIV medications whose absorption is pHdependent with proton-pump inhibitors, might result in a substantial reduction in
the bioavailability of these HIV medications and might impact the efficacy of these
medicines. Therefore, the co-administration of proton pump inhibitors with
atazanavir is not recommended (see section 4.4).
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. Therefore, in patients treated
with coumarin anticoagulants (e.g. phenprocoumon or warfarin), monitoring of
prothrombin time / INR is recommended after initiation, termination or during
irregular use of pantoprazole.
Other interactions studies
Pantoprazole is extensively metabolized in the liver via the cytochrome P450 enzyme
system. The main metabolic pathway is demethylation by CYP2C19 and other
metabolic pathways include oxidation by CYP3A4.
Interaction studies with drugs also metabolized with these pathways, like
carbamazepine, diazepam, glibenclamide, nifedipine, and an oral contraceptive
containing levonorgestrel and ethinyl oestradiol, did not reveal clinically significant
interactions.
Results from a range of interaction studies demonstrate that pantoprazole does not
effect the metabolism of active substances metabolised by CYP1A2 (such as caffeine,
theophylline), CYP2C9 (such as piroxicam, diclofenac, naproxen), CYP2D6 (such as
metoprolol), CYP2E1 (such as ethanol), or does not interfere with p-glycoprotein
related absorption of digoxin.
There were no interactions with concomitantly administered antacids.
Interaction studies have also been performed by concomitantly administering
pantoprazole with the respective antibiotics (clarithromycin, metronidazole,
amoxicillin). No clinically relevant interactions were found.
 

Pregnancy
There are no adequate data from the use of pantoprazole in pregnant women.
Studies in animals have shown reproductive toxicity (see section 5.3). The potential
risk for humans is unknown. Pantomax should not be used during pregnancy, unless
clearly necessary.
Lactation
Animal studies have shown excretion of pantoprazole in breast milk. Excretion into
human milk has been reported. Therefore, a decision on whether to
continue/discontinue breast-feeding or to continue/discontinue therapy with
Pantomax should be made taking into account the benefit of breast-feeding to the
child, and the benefit of Pantomax therapy to women.
 

Adverse drug reactions, such as dizziness and visual disturbances may occur (see
section 4.8). If affected, patients should not drive or operate machines.
 

Approximately 5 % of patients can be expected to experience adverse drug reactions
(ADRs). The most commonly reported ADRs are diarrhoea and headache, both
occurring in approximately 1 % of patients.
The table below lists adverse reactions reported with pantoprazole, ranked under
the following frequency classification:
Very common ( 1/10); common ( 1/100 to <1/10); uncommon ( 1/1,000 to
<1/100); rare ( 1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be
estimated from the available data).
For all adverse reactions reported from post-marketing experience, it is not possible
to apply any Adverse Reaction frequency and therefore they are mentioned with a
“not known” frequency.
Within each frequency grouping, adverse reactions are presented in order of
decreasing seriousness.
Table 1. Adverse reactions with pantoprazole in clinical trials and post-marketing
experience

There are no known symptoms of overdose in man.
Systemic exposure with up to 240 mg administered intravenously over 2 minutes,
were well tolerated.
As pantoprazole is extensively protein bound, it is not readily dialysable.
In the case of an overdose with clinical signs of intoxication, apart from symptomatic
and supportive treatment, no specific therapeutic recommendations can be made.
 

Pharmacotherapeutic group: Proton pump inhibitors, ATC code: A02BC02
Mechanism of action
Pantoprazole is a substituted benzimidazole which inhibits the secretion of
hydrochloric acid in the stomach by specific blockade of the proton pumps of the
parietal cells.
Pantoprazole is converted to its active form in the acidic environment in the parietal
cells where it inhibits the H+, K+-ATPase enzyme, i. e. the final stage in the
production of hydrochloric acid in the stomach. The inhibition is dose-dependent
and affects both basal and stimulated acid secretion. In most patients, freedom from
symptoms is achieved within 2 weeks. As with other proton pump inhibitors and H2
receptor inhibitors, treatment with pantoprazole reduces acidity in the stomach and
thereby increases gastrin in proportion to the reduction in acidity. The increase in
gastrin is reversible. Since pantoprazole binds to the enzyme distal to the cell
receptor level, it can inhibit hydrochloric acid secretion independently of stimulation
by other substances (acetylcholine, histamine, gastrin). The effect is the same
whether the product is given orally or intravenously.
The fasting gastrin values increase under pantoprazole. On short-term use, in most
cases they do not exceed the upper limit of normal. During long-term treatment,
gastrin levels double in most cases. An excessive increase, however, occurs only in
isolated cases. As a result, a mild to moderate increase in the number of specific
endocrine (ECL) cells in the stomach is observed in a minority of cases during longterm treatment (simple to adenomatoid hyperplasia). However, according to the
studies conducted so far, the formation of carcinoid precursors (atypical hyperplasia)
or gastric carcinoids as were found in animal experiments (see section 5.3) have not
been observed in humans.
An influence of a long term treatment with pantoprazole exceeding one year cannot
be completely ruled out on endocrine parameters of the thyroid according to results
in animal studies.
 

Absorption
Pantoprazole is rapidly absorbed and the maximal plasma concentration is achieved
even after one single 20 mg oral dose. On average at about 2.0 h - 2.5 h p.a. the
maximum serum concentrations of about 1-1.5 µg/ml are achieved, and these values
remain constant after multiple administration. Pharmacokinetics does not vary after
single or repeated administration. In the dose range of 10 to 80 mg, the plasma
kinetics of pantoprazole are linear after both oral and intravenous administration.
The absolute bioavailability from the tablet was found to be about 77 %.
Concomitant intake of food had no influence on AUC, maximum serum
concentration and thus bioavailability. Only the variability of the lag-time will be
increased by concomitant food intake.
Distribution
Pantoprazole's serum protein binding is about 98 %. Volume of distribution is about
0.15 l/kg.
Elimination
The substance is almost exclusively metabolized in the liver. The main metabolic
pathway is demethylation by CYP2C19 with subsequent sulphate conjugation, other
metabolic pathway includes oxidation by CYP3A4. Terminal half-life is about 1 hour
and clearance is about 0.1 l/h/kg. There were a few cases of subjects with delayed
elimination. Because of the specific binding of pantoprazole to the proton pumps of
the parietal cell the elimination half-life does not correlate with the much longer
duration of action (inhibition of acid secretion).
Renal elimination represents the major route of excretion (about 80 %) for the
metabolites of pantoprazole, the rest is excreted with the faeces. The main
metabolite in both the serum and urine is desmethylpantoprazole which is
conjugated with sulphate. The half-life of the main metabolite (about 1.5 hours) is
not much longer than that of pantoprazole.
Characteristics in patients/special groups of subjects
Approximately 3 % of the European population lack a functional CYP2C19 enzyme
and are called poor metabolisers. In these individuals the metabolism of
pantoprazole is probably mainly catalysed by CYP3A4. After a single-dose
administration of 40 mg pantoprazole, the mean area under the plasma
concentration-time curve was approximately 6 times higher in poor metabolisers
than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean
peak plasma concentrations were increased by about 60 %. These findings have no
implications for the posology of pantoprazole.
No dose reduction is recommended when pantoprazole is administered to patients
with impaired renal function (including dialysis patients). As with healthy subjects,
pantoprazole's half-life is short. Only very small amounts of pantoprazole are
dialyzed. Although the main metabolite has a moderately delayed half-life (2 - 3h),
excretion is still rapid and thus accumulation does not occur.
Although for patients with liver cirrhosis (classes A and B according to Child) the halflife values increased to between 3 and 6 h and the AUC values increased by a factor
of 3 - 5, the maximum serum concentration only increased slightly by a factor of 1.3
compared with healthy subjects.
A slight increase in AUC and Cmax in elderly volunteers compared with younger
counterparts is also not clinically relevant.
Children
Following administration of single oral doses of 20 or 40 mg pantoprazole to children
aged 5 - 16 years AUC and Cmax were in the range of corresponding values in adults.
Following administration of single i.v. doses of 0.8 or 1.6 mg/kg pantoprazole to
children aged 2 - 16 years there was no significant association between pantoprazole
clearance and age or weight. AUC and volume of distribution were in accordance
with data from adults.
 

Preclinical data reveal no special hazard to humans based on conventional
studies of safety pharmacology, repeated dose toxicity and genotoxicity.
In the two-year carcinogenicity studies in rats neuroendocrine neoplasms were
found. In addition, squamous cell papillomas were found in the forestomach of rats.
The mechanism leading to the formation of gastric carcinoids by substituted
benzimidazoles has been carefully investigated and allows the conclusion that it is a
secondary reaction to the massively elevated serum gastrin levels occurring in the
rat during chronic high-dose treatment. In the two-year rodent studies an increased
number of liver tumors was observed in rats and in female mice and was interpreted
as being due to pantoprazole's high metabolic rate in the liver.
A slight increase of neoplastic changes of the thyroid was observed in the group of
rats receiving the highest dose (200 mg/kg). The occurrence of these neoplasms is
associated with the pantoprazole-induced changes in the breakdown of thyroxine in
the rat liver. As the therapeutic dose in man is low, no harmful effects on the thyroid
glands are expected.
In animal reproduction studies, signs of slight fetotoxicity were observed at doses
above 5 mg/kg.
Investigations revealed no evidence of impaired fertility or teratogenic effects.
Penetration of the placenta was investigated in the rat and was found to increase
with advanced gestation. As a result, concentration of pantoprazole in the foetus is
increased shortly before birth.
 

Mannitol , Crospovidone,Sodium Carbonate Anhydrous,Hyreromellose,Calcium
Stearate, Opadry,Acryl eze.
 

Not applicable.
 

Store below 30°C.
Store in the original package
 

Forming Aluminium / Aluminium blister pack.
Packs of 15 or 30 enteric coated tablets
 

No special requirements.