Pantoprazole 40 Mg Gastro-Resistant Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
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).
Excipient: maximum of 0.13 mg phenylalanine/tablet.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Gastro-resistant tablet
Yellow, round, biconvex coated tablets printed with “P40” on one side with black ink and plain on the other side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
For relieving the symptoms and for short-term treatment of gastrointestinal diseases which require a reduction in acid secretion:
- duodenal ulcer
- gastric ulcer
- moderate and severe reflux oesophagitis
- eradication of Helicobacter pylori in combination with antibiotic therapy in patients with peptic ulcer
- Zollinger-Ellison syndrome and other hypersecretory conditions
4.2 Posology and method of administration Method of administration:
The gastro-resistant tablets should be taken 1 hour before food. The tablets should be swallowed whole, with sufficient fluid (e.g. one glass of water) and should not be chewed or crushed.
Adults and adolescents 12 years of age and above:
Moderate and severe reflux oesophagitis
The recommended dosage is 40mg pantoprazole daily (1 x 40mg gastro-resistant tablet). A four-week period is usually required for the treatment of reflux oesophagitis. If this is not sufficient, healing will usually be achieved within a further four weeks.
Adults:
Duodenal ulcer
The recommended dosage is 40mg pantoprazole daily (1 x 40mg gastro-resistant tablet). Duodenal ulcers generally heal within two weeks. If a two-week period of treatment is not sufficient, healing will be achieved in almost all cases within a further two weeks.
Gastric ulcer
The recommended dosage is 40mg pantoprazole daily (1 x 40mg gastro-resistant tablet). A four-week period is usually required for the treatment of gastric ulcers. If this is not sufficient, healing will usually be achieved within a further four weeks.
Eradication of Helicobacter pylori (H. pylori)
The recommended dose is 40mg pantoprazole 2 times daily (1 x 40mg gastro-resistant tablet 2 times daily) in combination with one of the following three combinations:
a) amoxicillin 1g twice daily + clarithromycin 500mg twice daily
b) clarithromycin 250 - 500mg twice daily + metronidazole 400 - 500mg twice daily
c) amoxicillin 1g twice daily + metronidazole 400 - 500mg twice daily
The second pantoprazole tablet should be taken before the evening meal. Combination therapy should be administered for 7 days in most cases but sometimes up to 14 days.
Consideration should be given to official local guidance (e.g. national recommendations) regarding bacterial resistance and the appropriate use and prescription of antibacterial agents.
Zollinger-Ellison-Syndrome and other hypersecretory conditions In the treatment of Zollinger-Ellison syndrome and other hypersecretory conditions, the initial dose is 80mg daily (2 x 40mg gastro-resistant tablets). Thereafter, the dosage can be increased or decreased as needed using measurements of gastric acid secretion to guide. With doses above 80mg daily, the dose should be divided and given twice daily. A temporary increase of the dosage above 160mg 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.
Elderly
A daily dose of 40mg pantoprazole should not be exceeded except in eradication treatment of H. pylori, where elderly patients should receive the standard pantoprazole dose (2 x 40mg/day) during one week treatment.
Patients with renal impairment
The daily dose of 40mg pantoprazole should not be exceeded in patients with impaired renal function. For this reason, H. pylori triple therapy is not appropriate in these patients (see section 4.3).
Patients with hepatic impairment
Patients with severe hepatic impairment should be given 40mg of pantoprazole every other day (see sections 4.3 and 4.4). In these patients, hepatic enzyme levels should be monitored during the treatment. If hepatic enzyme levels become elevated, treatment with pantoprazole should be discontinued. For this reason, H. pylori triple therapy is not appropriate in these patients.
Children below 12 years of age:
Pantoprazole 40mg gastro-resistant Tablets are not recommended for use in children below 12 years of age due to limited data in this age group.
4.3 Contraindications
Hypersensitivity to pantoprazole or to any of the excipients.
Pantoprazole like other proton pump inhibitors should not be administered with atazanavir (see section 4.5).
There is no data available to make dose adjustment in patients with moderate and severe renal impairment. In patient with severe hepatic impairment, the dose regimen should be reduced to 40mg of pantoprazole every other day. For this reason, H. pylori triple therapy is not appropriate in these patients.
4.4 Special warnings and precautions for use
There is no data available to make dose adjustment in patients with moderate and severe renal impairment. For patient with severe hepatic impairment, patients should be given 40mg of pantoprazole every other day. 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 and 4.3).
Pantoprazole 40mg is not intended for the treatment of mild gastrointestinal complaints, such as functional indigestion.
In combination therapy, the Summaries of Product Characteristics of all respective medicinal products should be observed.
Decreased gastric acidity due to any means - including proton pump inhibitors - increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with acid-reducing drugs may lead to a slightly increased risk of gastrointestinal infections, such as Salmonella and Campylobacter.
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.
Prior to treatment a malignant disease of the oesophagus or stomach should be excluded as the treatment with pantoprazole may alleviate the symptoms of malignant diseases and can thus delay diagnosis.
Patients who do not respond after 4 weeks should be investigated.
Proton pump inhibitors, especially if used in high doses and over long durations (>1 year), may modestly increase the risk of hip, wrist and spine fracture, predominantly in the elderly or in presence of other recognised risk factors. Observational studies suggest that proton pump inhibitors may increase the overall risk of fracture by 10 - 40%. Some of this increase may be due to other risk factors. Patients at risk of osteoporosis should receive care according to current clinical guidelines and they should have an adequate intake of vitamin D and calcium.
Hypomagnesaemia
Severe hypomagnesaemia has been reported in patients treated with PPIs like pantoprazole for at least three months, and in most cases for a year. Serious manifestations of hypomagnesaemia such as fatigue, tetany, delirium, convulsions, dizziness and ventricular arrhythmia can occur but they may begin insidiously and be overlooked. In most affected patients,
This medicinal product contains phenylalanine. May be harmful for the people with phenylketonuria.
4.5 Interaction with other medicinal products and other forms of interaction
Pantoprazole may reduce the absorption of drugs whose bioavailability is pH-dependent (e.g. ketoconazole, itraconazole, atazanavir).
It has been shown that co-administration of atazanavir 300mg/ritonavir 100mg with omeprazole (40mg once daily) or atazanavir 400mg with lansoprazole (60mg single dose) to healthy volunteers resulted in a substantial reduction in the bioavailability of atazanavir. The absorption of atazanavir is pH dependent. Therefore, PPIs, including pantoprazole, should not be coadministered with atazanavir (see section 4.3.).
Pantoprazole is metabolized in the liver via the cytochrome P450 enzyme system. Interactions of pantoprazole with other drugs or compounds which are metabolized using the same enzyme system cannot be excluded. However, no clinically significant interactions were observed with a number of such medicinal products or compounds, such as carbamazepine, caffeine, diazepam, diclofenac, digoxin, ethanol, glibenclamide, metoprolol, naproxen, nifedipine, phenytoin, piroxicam, theophylline and oral contraceptives.
Even though no interactions with pantoprazole and phenprocoumon or warfarin have been observed in clinical pharmacokinetics studies, a few isolated post-marketing cases of INR value changes in concomitant treatment with these substances have been reported. If the patient is using coumarin-type anticoagulants, measurements of prothrombin time/ INR values are recommended after the initiation and discontinuation of pantoprazole and in irregular use of pantoprazole.
In human kinetic interaction studies, pantoprazole was administered together with the appropriate antibiotics (clarithromycin, metronidazole, amoxicillin). No clinically relevant interactions were observed.
There were also no interactions with concomitantly administered antacids.
4.6 Fertility, pregnancy and lactation
Clinical experience in pregnant women is limited. In animal reproduction studies, signs of slight fetotoxicity were observed at doses above 5mg/kg. There is no information on the excretion of pantoprazole into human breast milk. During pregnancy and breast feeding, pantoprazole tablets should only be used when the benefit to the mother is considered greater than the potential risk to the foetus or child.
4.7 Effects on ability to drive and use machines
There are no known effects on the ability to drive and use machines. Adverse drug reactions such as dizziness and visual disturbances may occur (see section 4.8). Under these conditions the ability to react may be decreased.
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 following undesirable effects have been reported with pantoprazole.
Within the following table, undesirable effects are 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).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 1. Undesirable effects with pantoprazole in clinical trials and postmarketing experience
|
requency System Organ Class |
Uncommon |
Rare |
Very rare |
Not known |
|
Blood and lymphatic system disorders |
Thrombocytopenia; Leukopenia | |||
|
Nervous system disorders |
Headache; Dizziness | |||
|
Eye disorders |
Disturbances in vision/ blurred vision | |||
|
Gastrointestinal disorders |
Diarrhoea; Nausea / vomiting; Abdominal distension and bloating; Constipation; Dry mouth; Abdominal pain and discomfort |
|
requency System Organ Class |
Uncommon |
Rare |
Very rare |
Not known |
|
Renal and urinary disorders |
Interstitial nephritis | |||
|
Skin and subcutaneous tissue disorders |
Rash / exanthema / eruption; Pruritus |
Urticaria; Angioedema |
Stevens-Johnson syndrome; Lyell syndrome; Erythema multiforme; Photosensitivity | |
|
Musculoskeletal, connective tissue disorders |
Fracture of the hip, wrist or spine (see section 4.4) |
Arthralgia; Myalgia | ||
|
Metabolism and nutrition disorders |
Hyperlipidaemias and lipid increases (triglycerides, cholesterol); Weight changes |
Hyponatraemia, hypomagnasaemia, [See Special warnings and precautions for use (4.4)] | ||
|
General disorders and administration site conditions |
Asthenia, fatigue and malaise |
Body temperature increased; Oedema peripheral | ||
|
Immune system disorders |
Hypersensitivity (incl. anaphylactic reactions and anaphylactic shock) | |||
|
Hepatobiliary disorders |
Liver enzymes increased (transaminases, Y-GT) |
Bilirubin increased |
Hepatocellular injury; Jaundice; Hepatocellular failure | |
|
Psychiatric disorders |
Sleep disorders |
Depression (and all aggravations) |
Disorientation (and all aggravations) |
Hallucination; Confusion (especially in predisposed patients, as well as the aggravation of these symptoms in case of preexistence) |
4.9 Overdose
There are no known symptoms of over dosage in man.
Doses up to 240mg intravenous were administered over 2 minutes and were well tolerated. As pantoprazole is extensively protein bound, it is not readily dialyzable.
Cases of overdosage or poisoning should be treated according to the standard treatment practice of toxic conditions.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Proton pump inhibitors ATC code: A02BC02
Pantoprazole is a substituted benzimidazole which inhibits the secretion of hydrochloric acid in the stomach by specific action on the proton pumps of the parietal cells.
Pantoprazole is converted to its active form in the acidic channel of 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 in 2 weeks. 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. Since pantoprazole binds to the enzyme distal to the cell receptor level, the substance can affect hydrochloric acid secretion independently of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same whether the product is administered orally or intravenously.
5.2 Pharmacokinetic properties General pharmacokinetics
Pantoprazole is rapidly absorbed and the maximal plasma concentration is achieved even after one single oral dose. On average, the maximum serum concentrations are 2 - 3pg/ml after 2.5 hours post-administration and these values remain constant after multiple administration. Volume of distribution is about 0.15 l/kg and clearance is about 0.1 l/h/kg.
Terminal half-life is about 1 h. 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).
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.
Pantoprazole's serum protein binding is about 98%. The substance is almost exclusively metabolized in the liver. 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 h) is not much longer than that of pantoprazole.
Bioavailability
Pantoprazole is completely absorbed after oral 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.
Characteristics in patients/special groups of subjects
No dose reduction is requested when pantoprazole is administered to patients with restricted kidney function (incl. dialysis patients). As with healthy subjects, pantoprazole's half-life is short. Only very small amounts of pantoprazole can be dialyzed. Although the main metabolite has a moderately delayed half-life (2 - 3 h), excretion is still rapid and thus accumulation does not occur. However, the daily dose of 40mg pantoprazole should not be exceeded in patients with impaired renal function.
Although for patients with liver cirrhosis (classes A and B according to Child) the half-time values increased to between 7 and 9 hours and the AUC values increased by a factor of 5 to 7, the maximum plasma 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 40mg 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 1.6mg/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
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.
In a two-year carcinogenicity study 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 two-year rodent studies an increased number of liver tumours was observed in rats (in one rat study only) 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 (200mg/kg) in one 2 year study. 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 side effects on the thyroid glands are expected.
From mutagenicity studies, cell transformation tests and DNA binding studies it is concluded that pantoprazole has no genotoxic potential.
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 Core:
Mannitol (E 421)
Sodium carbonate, anhydrous (E 500) Crospovidone Hydroxypropylcellulose Talc (E 553b)
Calcium stearate
Barrier coating:
Zein F4000 (containing phenylalanine) Methacrylic acid-ethyl acrylate copolymer (1:1)
Enteric coating:
Methacrylic acid-ethyl acrylate copolymer (1:1) Triethyl citrate (E 1505)
Titanium dioxide (E 171)
Talc (E 553b)
Film coating
Hypromellose Titanium dioxide (E 171)
Macrogol 400
Iron oxide, yellow (E 172)
Printing ink
Shellac (E 904)
Iron oxide, black (E 172)
Propylene glycol (E 1520)
Ammonium hydroxide (E527)
6.2 Incompatibilities
None
6.3 Shelf life
3 years
6.4 Special precautions for storage
Do not store above 30°C
6.5 Nature and contents of container
Blister pack (plain or unit dose): Cold formable foil as the base material and hard tempered aluminium foil as lidding foil material: 2, 7, 14, 15, 28, 30, 50, 60, 100 gastro-resistant tablets Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements
7 MARKETING AUTHORISATION HOLDER
Dr. Reddy’s Laboratories (UK) Ltd
6 Riverview Road
Beverley
East Yorkshire
HU17 0LD
8 MARKETING AUTHORISATION NUMBER(S)
PL 08553/0271
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
23/07/2009
DATE OF REVISION OF THE TEXT
19/01/2013
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