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Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS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
45.1 mg of pantoprazole sodium sesquihydrate equivalent to 40 mg of pantoprazole
For full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Gastro-resistant tablet
Yellow oval, biconvex enteric coated tablets imprinted ‘CL25’ on one side and plain on other side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
For the treatment of mild reflux disease and associated symptoms (e.g. heartburn, acid regurgitation, pain on swallowing).
For long-term management and prevention of relapse in reflux oesophagitis.
Prevention of gastroduodenal ulcers induced by non-selective non-steroidal anti-inflammatory drugs (NSAIDs) in patients at risk with a need for continuous NSAID treatment (see section 4.4).
4.2 Posology and method of administration
Pantoprazole 40 mg gastro-resistant tablets should not be chewed or crushed, and should be swallowed whole with liquid before a meal.
Recommended dosage:
Adults and adolescents 12 years of age and above:
Mild reflux disease and associated symptoms (e.g. heartburn, acid regurgitation, pain on swallowing)
The recommended oral dosage is one gastro-resistant tablet Pantoprazole 20 mg per day. Symptom relief is generally accomplished within 2-4 weeks, and a 4-week treatment period is usually required for healing of associated oesophagitis. If this is not sufficient, healing will normally be achieved within a further 4 weeks. When symptom relief has been achieved, reoccurring symptoms can be controlled using an on-demand 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 Pantoprazole 20 mg per day is recommended, increasing to 40 mg pantoprazole per day if a relapse occurs. Pantoprazole 40 mg is available for this case. After healing of the relapse the dosage can be reduced again to 20 mg pantoprazole.
Adults:
Prevention of gastroduodenal ulcers induced by non-selective non-steroidal anti-inflammatory drugs (NSAIDs) in patients at risk with a need for continuous NSAID treatment
The recommended oral dosage is one gastro-resistant tablet Pantoprazole 20 mg per day.
Children below 12 years of age:
Pantoprazole is not recommended for use in children below 12 years of age due to limited data in this age group (see section 5.2).
Special populations:
A daily dose of 20 mg pantoprazole should not be exceeded in patients with severe liver impairment.
No dose adjustment is necessary in elderly patients or in those with impaired renal function.
4.3 Contraindications
Hypersensitivity to the active substance, or to any of the excipients of Pantoprazole.
Pantoprazole, like other PPIs, should not be co-administered with atazanavir (see section 4.5).
4.4 Special warnings and precautions for use
Special warnings
None
Special precautions for use
In patients with severe liver impairment the liver enzymes should be monitored regularly during treatment with pantoprazole, particularly on longterm use. In the case of a rise of the liver enzymes the treatment should be discontinued.
The use of Pantoprazole 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. 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.
In long-term treatment, especially when exceeding a treatment period of 1 year, patients should be kept under regular surveillance.
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.
Pantoprazole, like all proton pump inhibitors, 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 (e.g. Salmonella, Campylobacter, and C. difficile).
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, hypomagnesaemia improved after magnesium replacement and discontinuation of the PPI.
For patients expected to be on prolonged treatment or who take PPIs with digoxin or drugs that may cause hypomagnesaemia (e.g. diuretics), health care professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment.
Bone fractures
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.
4.5 Interaction with other medicinal products and other forms of interaction
Pantoprazole 20 mg may reduce the absorption of medicinal products whose bioavailability is pH-dependent (e.g. ketoconazole).
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 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. An interaction 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 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 an oral contraceptive.
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 being treated with coumarin anticoagulants, monitoring of prothrombin time / INR is recommended after initiation, termination or during irregular use of pantoprazole.
There were also no interactions with concomitantly administered antacids.
4.6 Fertility, 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 5.3). The potential risk for humans is unknown. Pantoprazole should not be used during pregnancy unless clearly necessary.
Lactation
It is unknown whether pantoprazole is excreted in human breast milk. Animal studies have shown excretion of pantoprazole in breast milk. 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 breast-feeding to the child and the benefit of Pantoprazole therapy to the woman.
4.7 Effects on ability to drive and use machines
Pantoprazole has no known influence 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
The following undesirable effects have been observed in clinical studies with pantoprazole.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
|
Frequency |
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) |
|
System Organ Class | |||||
|
Blood and lymphatic system |
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 | ||||
|
Skin and subcutaneous tissue disorders |
Rash / exanthema / eruption; Pruritus |
Urticaria; Angioedema | |||
|
Musculoskeletal, connective tissue disorders |
Arthralgia; Myalgia | ||||
|
Metabolism and nutrition disorders |
Hyperlipidaemias and lipid increases; Weight changes | ||||
|
General disorders and administration |
Asthenia, fatigue and malaise |
Body temperature increased; Oedema peripheral |
|
site conditions | |||||
|
Immune system disorders |
Hypersensitivity (incl. anaphylactic reactions and anaphylactic shock) | ||||
|
Hepatobiliary disorders |
Liver enzymes increased (transaminases, y-GT) |
Bilirubin increased | |||
|
Psychiatric disorders |
Sleep disorders |
Depression (and all aggravations) |
Disorientation (and all aggravations) |
The following additional undesirable effects have been reported postmarketing:
Hepatobiliary disorders: Hepatocellular injury, Jaundice, Hepatocellular failure
Psychiatric disorders: Hallucination, Confusion (especially in pre-disposed patients, as well as the aggravation of these symptoms in case of preexistence)
Renal and urinary disorders: Interstitial nephritis
Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, Lyell syndrome; Erythema multiforme, Photosensitivity
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
There are no known symptoms of overdose in man.
Doses up to 240 mg intravenous were administered over 2 minutes and were well tolerated. As pantoprazole is extensively protein bound, it is not readily dialyzable.
In the case of overdose with clinical signs of intoxication, the usual rules of intoxication therapy apply.
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 canaliculi 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 within 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 given orally or intravenously.
The fasting gastrin values increase under pantoprazole. On short-term use, in most cases they do not exceed the normal upper limit. 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 long-term 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
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 pg/ml are achieved 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 80 mg, 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 are 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 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 half-lifetime 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.
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 a 2-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 the two-year rodent studies an increased number of liver tumors 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 (200 mg/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.
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
Tablet core:
Mannitol (E421)
Crospovidone type A (E1202)
Sodium carbonate anhydrous Calcium stearate
Tablet coating:
Hydroxy propyl methyl cellulose 5cP (E464) Povidone K - 25 (E1201)
Propylene glycol (E1520)
Titanium dioxide (E171)
Iron oxide yellow (E172)
Methacrylic acid copolymer dispersion Triethyl citrate (E1505)
Opacode Black:
Shellac (E904)
Iron oxide black (E172)
Propylene glycol (E1520)
Ammonium hydroxide 28% (E527)
6.2 Incompatibilities
Not applicable
6.3 Shelf life
24 months
6.4 Special precautions for storage
Do not store above 25°C.
6.5 Nature and contents of container
Blister pack: OPA (Oriented polyamide)/ Aluminium/ PVC and Aluminium foil in a carton box.
Pack size: 28 Tablets.
6.6 Special precautions for disposal
No special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Bristol Laboratories Ltd.
Unit 3, Canalside, Northbridge Road,
Berkhamsted, Hertfordshire, HP4 1EG,
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 17907/0485
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
18/08/2014
10 DATE OF REVISION OF THE TEXT
18/08/2014