INSTRUCTION

for medical use of the medicinal product

 

PANOCID

 

Composition:

active substance: pantoprazole

1 vial contains 40 mg pantoprazole (as sodium sesquihydrate);

excipients: tetrasodium edetate, mannitol, tromethamine.

Pharmaceutical form. Powder for solution for injection.

Basic physical and chemical properties: a white to yellowish powder.

Pharmacotherapeutic group. Drugs for acid related disorders. Proton pump inhibitors.

ATC code A02BC02.

Pharmacological properties.

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). 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.

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.

Pharmacokinetics does not vary after single or repeated administration. In the dose range of 10 to 80 mg, the pharmacokinetics of pantoprazole in plasma is linear after both oral and intravenous administration.

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. 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 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.

Poor metabolisers. Approximately 3 % of the European population have a low functional activity of CYP2C19 enzyme and are called poor metabolisers. In these individuals the metabolism of pantoprazole is probably mainly catalysed 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 metabolisers than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). 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 h), 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–Pugh) the half-life values increased to between 7 and 9 h and the AUC values increased by a factor of 5 - 7, the maximum serum concentration only increased slightly by a factor of 1.5 compared with healthy subjects. 

Elderly. 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 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.

 

Clinical particulars.

Indications.

- Reflux oesophagitis.

- Duodenal ulcer.

- Gastric ulcer.

- Zollinger-Ellison-Syndrome and other pathological hypersecretory conditions.

Contraindications.

Hypersensitivity to the active substance, substituted benzimidazoles or to any of the other excipients.

Interaction with other medicinal products and other forms of interaction.

Medicinal products with pH-dependent absorption.

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 their bioavailability (e.g some antifungal drugs such as ketoconazole, itraconazole, posaconazole and other drugs such as erlotinib).

HIV protease inhibitors.

Co-administration of pantoprazole is not recommended with HIV protease inhibitors (e.g atazanavir) for which absorption is dependent on acidic intragastric pH due to significant reduction in their bioavailability (see section “Precautions for use”). 

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.

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 interactions.

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 medicinal products also metabolized with these pathways, such as 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 metabolized 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 metabolized through these enzyme systems.

Precautions for use.

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.

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 “Method of administration and dosages”).

HIV protease inhibitors. Co-administration of pantoprazole is not recommended with HIV protease inhibitors (e.g. atazanavir) for which absorption is dependent on acidic intragastric pH due to significant reduction in their bioavailability (see section “Interaction with other medicinal products and other forms of interaction”).

Gastrointestinal infections caused by bacteria. Treatment with pantoprazole preparation may lead to a slightly increased risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter and C. difficile.

Sodium. This medicinal product contains less than 1 mmol (23 mg) sodium per vial, that is to say essentially sodium free.

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 medicinal products 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 (more than 1 year), may modestly increase the risk of hip, wrist and spine fracture, predominantly in the elderly patients 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.

Subacute cutaneous lupus erythematosus. Proton pump inhibitors are associated with very infrequent cases of subacute cutaneous lupus erythematosus. 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. Subacute cutaneous lupus erythematosus after previous treatment with a proton pump inhibitor may increase the risk of subacute cutaneous lupus erythematosus with other proton pump inhibitors.

Interference with laboratory tests.

Increased 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 section “Pharmacodynamics”). 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.

Pregnancy and lactation.

Pregnancy. A moderate amount of Panocid data on pregnant women (between 300-1000 pregnancy outcomes) indicate no embryonic or feto/ neonatal toxicity of the preparation. Animal studies have shown reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of preparation 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. A decision on whether to discontinue breast-feeding or to discontinue/abstain from Panocid therapy should be made by taking into account the benefit of breast-feeding to the child and the benefit of pantoprazole therapy to women.

Fertility. There was no evidence of impaired fertility following the administration of pantoprazole in animal studies.

Effects on ability to drive and use machines.

Pantoprazole has no or negligible influence on the ability to drive and use machines. The possible development of adverse drug reactions such as dizziness and visual disturbances should be considered (see section “Adverse reactions”). In such cases, patients should not drive or operate machines.

Method of administrations and dosage.

This medicinal product should be used as prescribed by a healthcare professional and under appropriate medical supervision.

Intravenous administration of the preparation is recommended only if oral administration is not appropriate. Data are available on intravenous use for up to 7 days. Therefore, as soon as oral therapy is possible, intravenous treatment with pantoprazole should be discontinued and oral 40 mg pantoprazole should be administered instead.

Gastric and duodenal ulcer, reflux oesophagitis

The recommended intravenous dose is one vial of 40 mg pantoprazole (1 vial) 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 Panocid. If necessary, 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.

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.

Preparation for use.

The powder is diluted with 10 ml of 0.9% sodium chloride solution added to the vial. The solution can be administered directly or after mixing with 100 ml of 0.9% sodium chloride solution or 5% glucose solution in plastic or glass vials.

From a microbiological point of view, the diluted drug should be used immediately. If not used immediately, in-use stability time and conditions prior to use are the responsibility of the user. However, the physicochemical stability of the diluted drug is maintained for 12 hours at a temperature 25 ° C and for 24 hours at a temperature 2-8 ºC.

Panocid should not be prepared or mixed with solvents other than those mentioned above.

The medicinal product should be administered intravenously over 2 - 15 minutes.

The vial is for single use only. Residues of the preparation or the preparation which physicochemical properties have changed (in particular, the colour has changed, a precipitate has appeared) must be disposed of in accordance with the requirements of local legislation.

The diluted solution should have a clear yellowish colour.

Hepatic impairment. A daily dose of 20 mg pantoprazole (half a vial of Panocid, 40 mg powder) should not be exceeded in patients with severe liver impairment.

Renal impairment. No dose adjustment is necessary in patients with impaired renal function.

Elderly. No dose adjustment is necessary in elderly patients.

Paediatric population.

Panocid, powder for solution for injection, is not recommended for use in children (under 18 years of age), as data on the safety and efficacy of the drug for this age group are limited. The available data are described in the section "Pharmacokinetics", but dosing recommendations cannot be provided.

Overdose.

There are no known symptoms of overdose.

Doses up to 240 mg administered intravenously over 2 minutes were well tolerated. Since pantoprazole is extensively protein bound, it is not a drug that can be easily removed by dialysis.

In case of overdose with clinical signs of intoxication, symptomatic and supportive therapy is used. No specific therapeutic recommendations can be made.

Adverse reactions.

Approximately 5% of patients can be expected to experience adverse reactions. The most commonly reported adverse reaction is injection site thrombophlebitis. Diarrhoea and headache occurred in approximately 1% of patients.

The adverse reactions are characterized 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.

Blood and lymphatic system disorders.

Rare: agranulocytosis.

Very rare: leukopenia, thrombocytopenia, pancytopenia.

Immune system disorders.

Rare: hypersensitivity reactions (including anaphylactic reactions, anaphylactic shock).

Metabolism and nutrition disorders.

Rare: hyperlipidaemia and increased lipids (triglycerides, cholesterol), weight changes.

Not known: hyponatremia, hypomagnesaemia (see section "Precautions for use"), hypocalcemia¹, hypokalaemia.

Psychiatric disorders.

Uncommon: sleep disorders.

Rare: depression (including aggravations).

Very rare: disorientation (including aggravations).

Not known: hallucinations, confusion (especially in pre-disposed patients, as well as the aggravation of these symptoms in case of pre-existence).

Nervous system disorders.

Uncommon: headache, dizziness.

Rare: taste disturbances.

Not known: paraesthesia.

Eye disorders.

Rare: disturbances in vision / blurred vision.

Gastrointestinal disorders.

Common: fundic gland polyps (benign).

Uncommon: diarrhea, nausea, vomiting, bloating, constipation, dry mouth, abdominal pain and discomfort.

Hepatobiliary system disorders.

Uncommon: liver enzymes increased (transaminases, γ-GT).

Rare: increased bilirubin.

Not known: hepatocyte damage, jaundice, hepatocellular failure.

Skin and subcutaneous tissues disorders.

Uncommon: skin rash, exanthema, pruritus.

Rare: urticaria, angioneurotic edema.

Not known: Stevens-Johnson syndrome, Lyell syndrome, erythema multiforme, photosensitivity,

subacute cutaneous lupus erythematosus (see section "Precautions for use").

Musculoskeletal system and connective tissue disorders.

Uncommon: hip, wrist, spine fractures (see section "Precautions for use").

Rare: arthralgia, myalgia.

Not known: muscle spasm².

Renal and urinary disorders.

Not known: interstitial nephritis (with possible progression to renal failure).

Reproductive system and breast disorders.

Rare: gynaecomastia.

General disorders.

Common: injection site thrombophlebitis.

Uncommon: asthenia, fatigue, malaise.

Rare: body temperature increased, oedema peripheral.

1. Hypocalcemia along with hypomagnesemia.
2. Muscle spasms as a result of an imbalance of electrolytes.

Shelf life. 2 years.

From a microbiological point of view, the diluted drug should be used immediately. If not used immediately, in-use stability time and conditions prior to use are the responsibility of the user. However, the physicochemical stability of the diluted drug is maintained for 12 hours at a temperature 25 ° C and for 24 hours at a temperature 2-8 ºC.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30 °С. Keep out of reach of children.

Packaging. Powder for solution for injection. 1 or 5 or 20 vials in a carton.                            

Terms of dispensing. On prescription.

Manufacturer.

LABORATORIO REIG JOFRÉ, S.A.

Manufacturer’s registered address

C/Gran Capitàn, 10, Sant Joan Despí, Barcelona, 08970, Spain

Applicant.

Ananta Medicare Ltd.

Applicant’s registered address.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.