Pantoprazole 20 Mg Gastro-Resistant Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Pantoprazole 20 mg Gastro-resistant tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each gastro-resistant tablet contains 20 mg pantoprazole (as pantoprazole sodium sesquihydrate).
3 PHARMACEUTICAL FORM
Gastro-resistant tablet.
Yellow, oval, biconvex, smooth tablets, whose dimensions are 8 mm x 5.5 mm.
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 antiinflammatory drugs (NSAIDs) in patients at risk with a need for continuous NSAID treatment (see section 4.4).
4.2 Posology and method of administration
Method of administration
Pantoprazole 20 mg tablets should not be chewed or crushed, and should be swallowed whole with water before a meal.
Adults and adolescents 12 years of age and above
Treatment of mild reflux disease and associated symptoms (e.g. heartburn, acid regurgitation, pain on swallowing)
The recommended dosage is 20 mg pantoprazole daily. 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 20 mg pantoprazole daily is recommended. If a relapse occurs, the dosage is increased to 40 mg pantoprazole per day. Pantoprazole 40 mg gastro-resistant tablets are 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 antiinflammatory drugs (NSAIDs) in patients at risk who need continuous NSAID treatment
The recommended dosage is 20 mg pantoprazole daily.
Elderly and patients with renal impairment
A daily dose of 40 mg pantoprazole should not be exceeded in these patient groups.
Patients with hepatic impairment
A daily dose of 20 mg pantoprazole should not be exceeded in patients with severe liver impairment (see section 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.
Children below 12 years of age
There is no information on the use of pantoprazole in children. Therefore pantoprazole tablets should not be used in children.
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).
4.4 Special warnings and precautions for use
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 Pantoprazole 20 mg Tablets 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.
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.
Proton pump inhibitors, especially if used in high doses and over long durations (> 1 year), may modestly increase the risk of hip, wrist or spine fracture, predominantly in the elderly or in the presence of other recognised risk factors. Observational studies suggest that proton pump inhibitors may increase 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.
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 Tablets may lead to a slightly increased risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter.
Sodium
This medicinal product contains 2.93 mg sodium per dose. To be taken into consideration by patients on a controlled sodium diet (see section 4.3).
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).
Studies with other proton pump inhibitors have shown a marked reduction in atazanavir exposure during concomitant proton pump inhibitor treatment. Use of proton pump inhibitors is contraindicated during atazanavir treatment.
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.
There were also no interactions with concomitantly administered antacids
4.6 Pregnancy and lactation
Pregnancy
Clinical experience in pregnant women is limited. Experience with proton pump inhibitors as a class does not indicate an increased risk for major congenital malformations. In animal reproduction studies, signs of slight fetotoxicity were observed at doses above 5 mg/kg (see section 5.3). Caution should be exercised when prescribing to pregnant women.
Lactation
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 fetus 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 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.
|
^'\Frequency System'''^ Organ ClaSs''\ |
Uncommon |
Rare |
Very rare |
Not known |
|
Blood and lymphatic system disorders |
Thrombocytopenia; Leukopenia | |||
|
Immune system disorders |
Hypersensitivity (including anaphylactic reactions and anaphylactic shock) | |||
|
Metabolism and nutrition disorders |
Hyperlipidaemias and lipid increases (triglycerides, cholesterol); Weight changes |
Hyponatraemia, hypomagnesaemia [See Special warnings and precautions for use (4.4)] | ||
|
Psychiatric disorders |
Sleep disorders |
Depression (and all aggravations) |
Disorientation (and all aggravations) |
Hallucination; Confusion (especially in pre-disposed patients, as well as the aggravation of these symptoms in case of preexistence) |
|
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 | ||||
|
Hepatobiliary disorders |
Liver enzymes increased (transaminases, Y-GT) |
Bilirubin increased |
Hepatocellular injury; Jaundice; Hepatocellular failure | |
|
Skin and subcutaneous tissue disorders |
Rash / exanthema / eruption; Pruritus |
Urticaria; Angioedema |
Stevens-Johnson syndrome; Lyell syndrome; Erythema multiforme; Photosensitivity | |
|
Musculoskeletal and connective tissue disorders |
Fracture of the hip, wrist or spine (see section 4.4) |
Arthralgia; Myalgia | ||
|
Renal and urinary disorders |
Interstitial nephritis | |||
|
Reproductive system and breast disorders |
Gynaecomastia | |||
|
General disorders and administration site conditions |
Asthenia, fatigue and malaise |
Body temperature increased; Oedema peripheral |
4.9 Overdose
There are no known symptoms of over dosage in man.
Doses up to 240 mg i.v. 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.
5.1 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.
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 (see section 5.3), the formation of carcinoid precursors (atypical hyperplasia) or gastric carcinoids can be ruled out for humans.
An influence of a long term treatment with pantoprazole exceeding one year cannot be completely ruled out on endocrine parameters of the thyroid and liver enzymes 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 oral dose. On average, the maximum serum concentrations are 1-1.5 pg/ml at about 2.0-2.5 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 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 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 (2-3h), excretion is still rapid and thus accumulation does not occur. However, the daily dose of 40 mg 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-life 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
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 (200 mg/kg) in one two-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, the concentration of pantoprazole in the fetus is increased shortly before birth.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Disodium phosphate anhydrous Mannitol (75-315 pm)
Cellulose microcrystalline Croscarmellose sodium Magnesium stearate (vegetable)
Hypromellose (Type 6 cP)
Triethyl citrate
Sodium starch glycolate (Type A)
Methacrylic acid-ethyl acrylate copolymer (1:1), dispersion at 30% Yellow iron oxide
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
6.4 Special precautions for storage
Store below 30°C.
6.5 Nature and contents of container
1. Alu/Alu blister - packed in packs of 14, 15, 28, 30, 60 & 100 tablets
2. HDPE bottle and child-resistant polypropylene cap with desiccant compartment packaged in packs of 14, 15, 28, 30, 60, & 100 tablets.
Not all pack sizes may be marketed.
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
Laboratories Davur S.L.
C/ Anabel Segura Numero 11
Edificio Albatros B, 1
Alcobendas
Madrid
Spain
8. MARKETING AUTHORISATION NUMBER(S)
PL24577/0024
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
30/04/2010
10 DATE OF REVISION OF THE TEXT
26/11/2012