Panvell

Pantoprazole (as sodium sesquihydrate).

Tab: Each enteric-coated tablet contains: Pantoprazole, EP 40 mg (equivalent to Pantoprazole sodium sesquihydrate 45.1 mg).
IV: Pantoprazole Sodium Sesquihydrate (Panvell) 40 mg Lyophilized Powder for Injection is a hygroscopic, white and clear powder. After reconstitution, the solution is colorless to yellowish.

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, and gastrin). The effect is the same whether the product is given orally or intravenously.
Pharmacodynamic effects: 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). However, according to the studies conducted so far, the formation of carcinoid precursors (atypical hyperplasia) or gastric carcinoids as were found in animal experiments 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.
Tab: 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 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.
Pharmacokinetics: 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 includes oxidation by CYP3A4.
Elimination: 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 Desmethyl pantoprazole 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: Poor metabolizers: Approximately 3% of the European population lack a functional CYP2C19 enzyme and are called poor metabolizers. In these individuals the metabolism of pantoprazole is probably mainly catalyzed 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 metabolizers than in subjects having a functional CYP2C19 enzyme (extensive metabolizers). Mean peak plasma concentrations were increased by about 60%. These findings have no implications for the posology of Pantoprazole.
Renal impairment: 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 half-life (2-3 hours), 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 and 9 hours and the AUC values increased by a factor of 5 to 7, the maximum serum concentration only increased slightly by a factor of 1.5 compared with healthy subjects.
Older people: A slight increase in AUC and Cmax in elderly volunteers compared with younger counterparts is also not clinically relevant.
Paediatric population: Following administration of single intravenous 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.
Tab: 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 does 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.
Paediatric population: 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.

Pantoprazole is indicated for: Reflux oesophagitis; gastric and duodenal ulcer; Zollinger-Ellison Syndrome and other pathological hypersecretory conditions.
Tab: Pantoprazole is indicated for use in adults and adolescents 12 years of age and above for: Reflux oesophagitis.
Pantoprazole is indicated in adults for: Eradication of Helicobacter pylori (H. pylori) in combination with appropriate antibiotic therapy in patients with H. pylori associated ulcers.

Tab: Adults and adolescents 12 years of age and above: Reflux oesophagitis: One tablet of Pantoprazole per day. In individual cases the dose may be doubled (increase to 2 tablets Pantoprazole 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 + twice daily 1000 mg amoxicillin + twice daily 500 mg clarithromycin
b) Twice daily one tablet Pantoprazole + twice daily 400-500 mg metronidazole (or 500 mg tinidazole) + twice daily 250-500 mg clarithromycin
c) Twice daily one tablet Pantoprazole + 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 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 monotherapy.
Treatment of gastric ulcer: One tablet of Pantoprazole per day. In individual cases the dose may be doubled (increase to 2 tablets of Pantoprazole 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 per day. In individual cases the dose may be doubled (increase to 2 tablets of Pantoprazole 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 hyper secretory 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 hyper secretory conditions is not limited and should be adapted according to clinical needs.
Patients with 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 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 in combination treatment of these patients (see Precautions).
Patients with renal impairment: No dose adjustment is necessary in patients with impaired renal function. Pantoprazole 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 in combination treatment for these patients (see Pharmacology: Pharmacokinetics under Actions).
Older people: No dose adjustment is necessary in older people (see Pharmacology: Pharmacokinetics under Actions).
Paediatric population: Pantoprazole is not recommended for use in children below 12 years of age because of limited data on safety and efficacy in the age group (see Pharmacology: Pharmacokinetics under Actions).
Method of administration: Oral use.
The tablets should not be chewed or crushed, and should be swallowed whole 1 hour before a meal with some water
IV: Reflux oesophagitis, gastric and duodenal ulcer: The recommended intravenous dose is one vial of Pantoprazole 40 mg per day.
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 Pantoprazole. 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 Pantoprazole 160 mg is possible but should not be applied longer than required for adequate acid control. In case a rapid acid control is required, a starting dose of 2 x 80 mg is sufficient to manage a decrease of acid output into the target range (<10 mEq/h) within one hour in the majority of patients.
Paediatric population: The safety and efficacy of Pantoprazole 40 mg Lyophilized Powder for Injection in children age under 18 years have not been established. Therefore it is not recommended for use in patients below 18 years of age.
Patients with hepatic impairment: A daily dose of 20 mg (half a vial of 40 mg) should not be exceeded in patients with severe liver impairment.
Patients with renal impairment: No dose adjustment is necessary in patients with impaired renal function.
Older people: No dose adjustment is necessary in older people.
Route of administration: A ready-to-use solution is prepared by injecting 10 mL Sodium Chloride 9 mg/mL (0.9%) solution for injection into the vial containing the Pantoprazole Lyophilized Powder for Injection. Prepared solution may be administered directly or may be administered after mixing it with 100 mL Sodium Chloride 9 mg/mL (0.9%) solution for injection or Glucose 55 mg/mL (5%) solution for injection. After preparation the solution must be used within 12 hours. The medicinal product should be administered intravenously over 2-15 minutes.

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 an overdose with clinical signs of intoxication, apart from symptomatic and supportive treatment, no specific therapeutic recommendations can be made.

Hypersensitivity to the active substances, substituted Benzimidazoles or to any of the ingredients in the drug.

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 Dosage & Administration).
Combination therapy: In the case of combination therapy, the summaries of product characteristics of the respective medicinal products 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 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 or 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 older people or in the 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.
Tab: 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 (see Interactions).
Sub-acute cutaneous lupus erythematosus (SCLE): Proton pump inhibitors are associated with very infrequent cases of 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 healthcare professional should consider stopping Pantoprazole. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.
Interference with Laboratory Tests: Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours. To avoid this interference, Pantoprazole treatment should be stopped for at least 5 days before CgA measurements (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.
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.
IV: 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. 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.

Pregnancy: Tab: A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity of Pantoprazole.
Animal studies have shown reproductive toxicity.
IV: There are no adequate data from the use of Pantoprazole in pregnant women. Studies in animals have shown reproductive toxicity. 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 discontinue/abstain from Pantoprazole therapy should be made taking into account the benefit of breast-feeding for the child, and the benefit of Pantoprazole therapy for the woman.
Tab: 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.
Fertility: Tab: There was no evidence of impaired fertility following the administration of pantoprazole in animal studies.

Tab: 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 as follow 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. (See table.)

Click on icon to see table/diagram/image

IV: Approximately 5% of patient can be expected to experience adverse drug reactions. Adverse reactions listed as follows are classified according to frequency and System Organ Class (SOC). Frequency categories are defined according to the following convention: 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), and Not Known (cannot be estimated from the ≥ available data) is spontaneous reports from the post-marketing setting.
Gastrointestinal Disorders: Common: Fundic gland polyps (benign).
Uncommon: Diarrhoea; Nausea/vomiting; Abdominal distension and bloating; Constipation; Dry mouth; Abdominal pain and discomfort.
Hepatobiliary Disorders: Common: Liver enzymes increase (transaminase, g-GT).
Uncommon: Bilirubin increased.
Not Known: Hepatocellular injury; Jaundice; Hepatocellular failure.
General Disorders and Administration Site Conditions: Uncommon: Asthenia, fatigue, and malaise.
Psychiatric Disorders: Uncommon: Sleep disorders.
Nervous System Disorders: Uncommon: Headache; Dizziness.
Skin and Subcutaneous Tissue Disorders: Uncommon: Rash/Exanthema/Eruption; Pruritus.
Musculoskeletal Connective Tissue Disorders: Uncommon: Fracture of the hip, wrist or spine.

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 such as Ketoconazole, Itraconazole, Posaconazole and other medicines such as Erlotinib.
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.
Other interaction 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 affect the metabolism of active substances metabolized 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.
Tab: 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 (see Precautions).
If the combination of HIV protease inhibitors with a proton pump inhibitor is judged unavoidable, close clinical monitoring (e.g. virus load) is recommended. A pantoprazole dose of 20 mg per day should not be exceeded. Dosage 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.
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 metabolized through these enzyme systems.
IV: HIV medications (Atazanavir): Co-administration of Atazanavir and other HIV medications whose absorption is pH-dependent with PPI, 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.
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 International Normalised Ratio (INR) have been reported during concomitant treatment in the post-marketing period. Therefore, in patients treated with Coumarin anticoagulants (e.g. Phenprocoumon or Warfarin), monitoring of prothrombin time/INR is recommended after initiation, termination or during irregular use of Pantoprazole.

Store at temperature not exceeding 30°C.
IV: Protect from light.

Antacids, Antireflux Agents & Antiulcerants

A02BC02 - pantoprazole ; Belongs to the class of proton pump inhibitors. Used in the treatment of peptic ulcer and gastro-oesophageal reflux disease (GERD).

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