1. Name Of The Medicinal Product
Pantoprazole 40 mg gastro-resistant tablets
2. Qualitative And Quantitative Composition
Each gastro-resistant tablet contains 40 mg pantoprazole
(as pantoprazole sodium sesquihydrate 45.16 mg)
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Gastro-resistant tablet
Elliptical, biconvex, dark yellow gastro-resistant tablet
4. Clinical Particulars
4.1 Therapeutic Indications
Adults and adolescents 12 years of age and above
• Reflux oesophagitis.
Adults
• Eradication of Helicobacter pylori (H. pylori) in combination with appropriate antibiotic therapy in patients with H. pylori associated ulcers.
• Gastric and duodenal ulcer.
• Zollinger-Ellison-Syndrome and other pathological hypersecretory conditions.
4.2 Posology And Method Of Administration
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
Reflux oesophagitis
One tablet of Pantoprazole tablets per day. In individual cases the dose may be doubled (increase to 2 tablets Pantoprazole tablets daily) especially when there has been no response to other treatment. A 4-week period is usually required for the treatment of reflux oesophagitis. If this is not sufficient, healing will usually be achieved within a further 4 weeks.
Adults
Eradication of H. pylori in combination with two appropriate antibiotics in H. pylori positive patients with gastric and duodenal ulcers, eradication of the germ by a combination therapy should be achieved. Considerations should be given to official local guidance (e.g. national recommendations) regarding bacterial resistance and the appropriate use and prescription of antibacterial agents. Depending upon the resistance pattern, the following combinations can be recommended for the eradication of H. pylori:
a) twice daily one tablet Pantoprazole tablets
+ twice daily 1000 mg amoxicillin
+ twice daily 500 mg clarithromycin
b) twice daily one tablet Pantoprazole tablets
+ twice daily 400 - 500 mg metronidazole (or 500 mg tinidazole)
+ twice daily 250 - 500 mg clarithromycin
c) twice daily one tablet Pantoprazole tablets
+ twice daily 1000 mg amoxicillin
+ twice daily 400 - 500 mg metronidazole (or 500 mg tinidazole)
In combination therapy for eradication of H. pylori infection, the second Pantoprazole tablets tablet should be taken 1 hour before the evening meal. The combination therapy is implemented for 7 days in general and can be prolonged for a further 7 days to a total duration of up to two weeks. If, to ensure healing of the ulcers, further treatment with pantoprazole is indicated, the dose recommendations for duodenal and gastric ulcers should be considered.
If combination therapy is not an option, e.g. if the patient has tested negative for H. pylori, the following dose guidelines apply for Pantoprazole tablets monotherapy:
Treatment of gastric ulcer
One tablet of Pantoprazole tablets per day. In individual cases the dose may be doubled (increase to 2 tablets Pantoprazole tablets daily) especially when there has been no response to other treatment. A 4-week period is usually required for the treatment of gastric ulcers. If this is not sufficient, healing will usually be achieved within a further 4 weeks.
Treatment of duodenal ulcer
One tablet of Pantoprazole tablets per day. In individual cases the dose may be doubled (increase to 2 tablets Pantoprazole tablets daily) especially when there has been no response to other treatment. A duodenal ulcer generally heals 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.
Zollinger-Ellison-Syndrome and other pathological hypersecretory conditions
For the long-term management of Zollinger-Ellison-Syndrome and other pathological hypersecretory conditions patients should start their treatment with a daily dose of 80 mg (2 tablets of Pantoprazole tablets 40 mg). Thereafter, the dose can be titrated up or down as needed using measurements of gastric acid secretion to guide. With doses above 80 mg daily, the dose should be divided and given twice daily. A temporary increase of the dose above 160 mg pantoprazole is possible but should not be applied longer than required for adequate acid control.
Treatment duration in Zollinger-Ellison syndrome and other pathological hypersecretory conditions is not limited and should be adapted according to clinical needs.
Special populations
Children below 12 years of age
Pantoprazole tablets 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 (1 tablet of 20 mg pantoprazole) should not be exceeded in patients with severe liver impairment. Pantoprazole tablets must not be used in combination treatment for eradication of H. pylori in patients with moderate to severe hepatic dysfunction since currently no data are available on the efficacy and safety of Pantoprazole tablets in combination treatment of these patients (see section 4.4).
Renal Impairment
No dose adjustment is necessary in patients with impaired renal function. Pantoprazole tablets must not be used in combination treatment for eradication of H. pylori in patients with impaired renal function since currently no data are available on the efficacy and safety of Pantoprazole tablets in combination treatment for these patients.
Elderly
No dose adjustment is necessary in elderly patients.
4.3 Contraindications
Hypersensitivity to the active substance, substituted benzimidazoles or to any of the excipients
4.4 Special Warnings And Precautions For Use
Hepatic Impairment
In patients with severe liver impairment, particularly those on long-term use, liver enzymes should be monitored regularly during treatment with pantoprazole. In the case of a rise in liver enzymes, pantoprazole 40mg gastro-resistant tablets should be discontinued.
Combination therapy
In the case of combination therapy, the summaries of product characteristics of the respective medicinal products should be observed.
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 400mg with 100mg of ritonavir. A pantoprazole dose of 20mg per day should not be exceeded.
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 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 Pantoprazole may lead to a slightly increased risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter.
To date, there has been no experience with treatment in children.
Note:
Prior to treatment of gastric ulcer, the possibility of malignancy should be excluded as treatment with pantoprazole 40mg gastro-resistant tablets may alleviate the symptoms of malignant ulcers and can thus delay diagnosis.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
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 pH-dependent 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 INR have been reported during concomitant treatment in the post-marketing period. Therefore, in patients treated with coumarin anticoagulants, 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 administering pantoprazole concomitantly with the respective antibiotics (clarithromycin, metronidazole, amoxicillin) No clinically relevant interactions were found.
4.6 Pregnancy And Lactation
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. Pantoprazole 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 pantoprazole should be made taking into account the benefit of breastfeeding to the child and the benefit of pantoprazole therapy to women.
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). If affected, patients should not drive or operate machines.
4.8 Undesirable Effects
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 (
common (
uncommon (
rare (
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
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4.9 Overdose
There are no known symptoms of overdose in man.
Systemic exposure with up to 240mg administered intravenously over 2 minutes were well tolerated.
As pantoprazole is extensively protein bound, it is not readily dialysable.
In the case of overdose with clinical signs of intoxication, apart from symptomatic and supportive treatment, no specific therapeutic recommendations can be made.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
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.
5.2 Pharmacokinetic Properties
General pharmacokinetics
Absorption
Pantoprazole is rapidly absorbed and the maximal plasma concentration is achieved even after one single 40mg oral dose. On average at about 2.5 h p.a. the maximum serum concentrations of about 2 - 3 μg/ml are achieved, and these values remain constant after multiple administration.
Pharmacokinetics do not vary after single or repeated administration. In the dose range of 10 to 80mg, 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 include 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 halflife (2 - 3 h), excretion is still rapid and thus accumulation does not occur.
Although for patients with liver cirrhosis (classes A and B according to Child) the half-life values increased to between 7 and 9 h and the AUC values increased by a factor of 5 - 7, the maximum serum concentration only increased slightly by a factor of 1.5 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.
5.3 Preclinical Safety Data
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.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Mannitol
Sodium carbonate anhydrous
Sodium starch glycolate, Type A
Methacrylic acid copolymer
Calcium stearate
Opadry white OY-D-7233 (hypromellose, titanium dioxide, talc, macrogol, sodium lauryl sulphate)
Kollicoat MAE 30 DP yellow (methacrylic acid-ethyl acrylate copolymer dispersion 30%, propylene glycol, yellow iron oxide, titanium dioxide, talc)
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
24 months
6.4 Special Precautions For Storage
This medicinal product does not require any special storage conditions.
6.5 Nature And Contents Of Container
Pantoprazole 40mg gastro-resistant tablets are provided in aluminium/aluminium blister packs of 2, 7, 14, 15, 28, 30, 50, 56, 60, 84, 90, 100, 112, 140, 280, 500, or 700 tablets.
Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
No special requirements
7. Marketing Authorisation Holder
Actavis Group PTC ehf
Reykjavikurvegur 76-78
220 Hafnarfjordur
Iceland
8. Marketing Authorisation Number(S)
PL 30306/0299
9. Date Of First Authorisation/Renewal Of The Authorisation
29/04/2010
10. Date Of Revision Of The Text
20.10.2011
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