Pantoprazole sodium sesquihydrate.
Each gastro-resistant tablet contains 40 mg pantoprazole (as pantoprazole sodium sesquihydrate).
Excipient/Inactive Ingredient: Each gastro-resistant tablet contains 2 μg of the colouring agent Ponceau 4R aluminium lake (E124) per gastro-resistant tablet.
Pharmacotherapeutic group: Proton pump inhibitors. ATC Code: A02BC02.
Pharmacology: Pharmacodynamics: 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 long-term treatment (simple to adenomatoid hyperplasia).
During treatment with antisecretory medicinal products, serum gastrin increases in response to the decreased acid secretion. Also CgA increases due to decreased gastric acidity. The increased CgA level may interfere with investigations for neuroendocrine tumours.
Available published evidence suggests that proton pump inhibitors (PPI) should be discontinued between 5 days and 2 weeks prior to CgA measurements. This is to allow CgA levels that might be spuriously elevated following PPI treatment to return to reference range.
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.
Pharmacokinetics: Absorption: Pantoprazole is rapidly absorbed and the maximal plasma concentration is achieved even after one single 40 mg 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 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.
Biotransformation: 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.
Elimination: Terminal half-life is about 1 hour and clearance is about 0.1 l/h/kg. 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.
Special populations: Renal Impairment: No dose reduction is recommended when pantoprazole is administered to patients with impaired renal function (including dialysis patients). 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.
Hepatic impairment: Although for patients with liver cirrhosis, (classes A and B according to Child), the half-life values increased to between 7 to 9 h, and the AUC values increased by a factor of 5-7 (pantoprazole 40 mg), the maximum serum concentration only increased slightly by a factor of 1.5 (pantoprazole 40 mg) compared with healthy subjects.
Elderly: A slight increase in AUC and Cmax in elderly volunteers compared with younger counterparts is also not clinically relevant.
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.
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.
Tablets should not be chewed or crushed, and should be swallowed whole 1 hour before a meal with some water.
Reflux esophagitis: One tablet of Pantoprazole 40 mg per day. In individual cases, the dose may be doubled (increase to 2 tablets of Pantoprazole 40 mg daily) especially when there has been no response to other treatment.
Eradication of H. pylori in Combination with Appropriate Antibiotics: In cases of duodenal or gastric ulcer in which infection with Helicobacter pylori has been confirmed, the microorganism should be eradicated by combination treatment.
Depending upon the resistance pattern, the following combinations can be recommended: One pantoprazole 40-mg tab twice daily + amoxicillin 1000 mg twice daily + clarithromycin 500 mg twice daily; One pantoprazole 40-mg tab twice daily + metronidazole 500 mg twice daily + clarithromycin 500 mg twice daily; One pantoprazole 40-mg tab twice daily + amoxicillin 1000 mg twice daily + metronidazole 500 mg twice daily.
Treatment of gastric and duodenal ulcer: One tablet of Pantoprazole 40 mg per day. In individual cases, the dose may be doubled (increase to 2 tablets of Pantoprazole 40 mg daily) especially when there has been no response to other treatment.
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 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.
Type and duration of treatment: Combination therapy for eradication of Helicobacter pylori infection usually lasts 7 days and can be extended to a maximum of 2 weeks. If after this time further treatment with Pantoprazole 40 mg is indicated to ensure that the ulcer heals completely, the dose recommendations for gastric and duodenal ulcers must be observed.
In the majority of cases, a duodenal ulcer heals completely within 2 weeks. If a two-week treatment period is not sufficient, healing will be achieved in almost all cases within a further 2 weeks.
Gastric ulcers and reflux esophagitis usually require a 4-week course of treatment. If this should be inadequate, healing will in most cases be achieved within a further 4 weeks. Treatment should not exceed 8 weeks as experience with long-term use is limited.
Treatment duration in Zollinger-Ellison-Syndrome and other pathological hypersecretory conditions is not limited and should be adapted according to clinical needs.
Children below 12 years of age: Pantoprazole 40 mg is not recommended for use in children below 12 years of age due to limited data in this age group.
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 overdose with clinical signs of intoxication, apart from symptomatic and supportive treatment, no specific therapeutic recommendations can be made.
Hypersensitivity to the active substance, substituted benzimidazoles or to any of the excipients of Pantoprazole Sandoz.
Pantoprazole Sandoz must not be used in combination treatment for eradication of Helicobacter pylori in patients with moderate to severe hepatic or renal dysfunction, since currently no data are available on the efficacy and safety of Pantoprazole Sandoz in combination treatment of these patients.
Combination therapy: In case of combination therapy, the summaries of product characteristics of the respective drugs should be observed.
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 medicinal products, 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.
Gastric malignancy: Symptomatic response to pantoprazole may mask the symptoms of gastric malignancy and may delay diagnosis. 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. Further investigation is to be considered if symptoms persist despite adequate treatment.
Co-administration with HIV protease inhibitors: Co-administration of pantoprazole is not recommended with HIV protease inhibitors for which absorption is dependent on acidic intragastric pH such as atazanavir, due to significant reduction in their bioavailability.
Regular Surveillance: Patients on proton pump inhibitor treatment (particularly those treated for long term) should be kept under regular surveillance.
Gastrointestinal infections caused by bacteria: Treatment with pantoprazole may lead to a slightly increased risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter or C. difficile.
Subacute cutaneous lupus erythematosus (SCLE): Proton pump inhibitors are associated with very infrequent cases of subacute cutaneous lupus erythematous (SCLE). If lesions occur, especially in sun-exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical help promptly and the health care professional should consider stopping Pantoprazole Sandoz. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.
Hypomagnesaemia: Severe hypomagnesaemia has been reported in patients treated with PPI like Pantoprazole Sandoz 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 PPI with digoxin or active substances that may cause hypomagnesaemia (e.g. diuretics), healthcare 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 (more than 1 year), may modestly increase the risk of hip, wrist and spine fracture, predominantly in the elderly or in presence of other recognized 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.
Clostridium Difficile Diarrhoea: Published observational studies suggest that PPI therapy may be associated with an increased risk of Clostridium difficile-associated diarrhoea, especially in hospitalized patients. This diagnosis should be considered for diarrhoea that does not improve. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.
Vitamin B12 Deficiency: Daily treatment with acid-suppressing medications over a long period of time (e.g. longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed.
Interference with laboratory tests: Increased chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours. If the patient(s) are due to have a test on chromogranin A level, Pantoprazole Sandoz treatment should be stopped for at least 5 days before CgA measurements to avoid this interference (see Pharmacology: Pharmacodynamics under Actions). If CgA and gastrin levels have not returned to reference range after initial measurement, measurements should be repeated 14 days after cessation of proton pump inhibitor treatment.
This medicinal product contains colouring agent Ponceau 4R Aluminium Lake (E 124), which may cause allergic reactions.
Effects on ability to drive and use machines: Pantoprazole has no or negligible influence on the ability to drive and use machines.
Adverse drug reactions such as dizziness and visual disturbances may occur (see Adverse Reactions).
If affected, patients should not drive or operate machines.
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.
Use in children: To date, there has been no experience with treatment in children. Pantoprazole Sandoz 40 mg is not recommended for use in children less than 12 years due to the limited experience in this age group.
Pregnancy: A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative or foeto/neonatal toxicity of pantoprazole. Animal studies have shown reproductive toxicity.
As a precautionary measure, it is preferable to avoid the use of pantoprazole during pregnancy.
Breast-feeding: Animal studies have shown excretion of pantoprazole in breast milk.
There is insufficient information on the excretion of pantoprazole in human milk but excretion into human milk has been reported. A risk to the newborns/infants cannot be excluded.
Therefore, a decision on whether to discontinue breast-feeding or to discontinue/abstain from pantoprazole therapy taking into account the benefit of breast-feeding for the child, and the benefit of pantoprazole therapy for the woman.
Fertility: There was no evidence of impaired fertility following the administration of pantoprazole in animal studies.
Summary of the safety profile:
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 list as follows shows adverse reactions reported with pantoprazole, ranked under the following frequency classification: Very common; common; uncommon; rare; very rare; not known.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. (See table.)
Click on icon to see table/diagram/image
Medicinal products with pH-dependent absorption pharmacokinetics: Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with the absorption of other medicinal products where gastric pH is an important determinant of oral bioavailability, e.g. some azole antifungals such as ketoconazole, itraconazole, posaconazole and other medicines such as erlotinib.
HIV protease inhibitors: Co-administration of pantoprazole is not recommended with HIV protease inhibitors for which absorption is dependent on acidic intragastric pH such as atazanavir due to significant reduction in their bioavailability.
If the combination of HIV protease inhibitors with a proton pump inhibitor is judged unavoidable, close clinical monitoring is recommended. Dose of the HIV protease inhibitors may need to be adjusted.
Coumarin anticoagulants (phenprocoumon or warfarin): Co-administration of pantoprazole with warfarin or phenprocoumon did not affect the pharmacokinetics of warfarin, phenprocoumon or INR. However, there have been reports of increased INR and prothrombin time in patients receiving PPIs and warfarin or phenprocoumon concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding, and even death. Patients treated with pantoprazole and warfarin or phenprocoumon may need to be monitored for increase in INR and prothrombin time.
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 active substances 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.
An interaction of pantoprazole with other medicinal products or compounds, which are metabolised using the same enzyme system, cannot be excluded.
Results from a range of interaction studies demonstrate that pantoprazole does not affect 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.
Medicinal products that inhibit or induce CYP2C19: Inhibitors of CYP2C19 such as fluvoxamine could increase the systemic exposure of pantoprazole. A dose reduction may be considered for patients treated long-term with high doses of pantoprazole, or those with hepatic impairment.
Enzyme inducers affecting CYP2C19 and CYP3A4 such as rifampicin and St John's wort (Hypericum perforatum) may reduce the plasma concentrations of PPIs that are metabolised through these enzyme systems.
Methotrexate: Concomitant use of high dose methotrexate (e.g. 300 mg) and proton-pump inhibitors has been reported to increase methotrexate levels in some patients. Therefore in settings where high-dose methotrexate is used, for example cancer and psoriasis, a temporary withdrawal of pantoprazole may need to be considered.
Incompatibilities: Not applicable.
Do not store above 30°C.
Shelf life: 2 years.
A02BC02 - pantoprazole ; Belongs to the class of proton pump inhibitors. Used in the treatment of peptic ulcer and gastro-oesophageal reflux disease (GERD).
Pantoprazole Sandoz gastro-resistant tab 40 mg