TOPRAFLUX Enteric coated tablet Ref.[51184] Active ingredients: Pantoprazole

Influence on vitamin B12 absorption

In patients with Zollinger-Ellison syndrome and other pathological hypersecretory conditions requiring long-term treatment, TOPRAFLUX, 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.

Co-administration with NSAIDs

The use of TOPRAFLUX 20 mg as a preventive of gastroduodenal ulcers induced by non-selective non-steroidal anti-inflammatory drugs (NSAIDs) should be restricted to patients who require continued NSAID treatment and have an increased risk to develop gastrointestinal complications. The increased risk should be assessed according to individual risk factors, e.g. high age (>65 years), history of gastric or duodenal ulcer or upper gastrointestinal bleeding.

Hepatic impairment

In patients with severe liver impairment the liver enzymes should be monitored regularly during treatment with TOPRAFLUX, particularly on long-term use. In the case of a rise of the liver enzymes TOPRAFLUX should be discontinued (see section 4.2).

Gastric malignancy

TOPRAFLUX is not indicated for mild gastrointestinal complaints such as nervous dyspepsia. 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. Diagnosis of reflux oesophagitis should be confirmed by endoscopy.

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 section 4.5).

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

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 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. 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 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 active substances that may cause hypomagnesaemia (e.g., diuretics), health care professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment.

Bone fractures

Proton pump inhibitors, especially if used in high doses and over long durations (>1 year), may modestly increase the risk of hip, wrist and spine fracture, predominantly in the elderly or in presence of other recognised risk factors. Observational studies suggest that proton pump inhibitors may increase the overall risk of fracture by 10-40%. Some of this increase may be due to other risk factors. Patients at risk of osteoporosis should receive care according to current clinical guidelines and they should have an adequate intake of vitamin D and calcium.

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 section 5.1). 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.

Concomitant intake of food has no influence on the bioavailability.

Medicinal products with pH-dependent absorption pharmacokinetics

Because of profound and long lasting inhibition of gastric acid secretion, TOPRAFLUX may interfere with the absorption of other medicinal products where gastric pH is an important determinant of oral availability, e.g. some azole antifungals such as ketoconazole, itraconazole, posaconazole and other medicinal products such as erlotinib.

HIV protease inhibitors

Co-administration of TOPRAFLUX 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 section 4.3).

Coumarin anticoagulants (phenprocoumon or warfarin)

Co-administration of TOPRAFLUX 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 TOPRAFLUX and warfarin or phenprocoumon may need to be monitored for increase in INR and prothrombin time.

Other interactions studies

TOPRAFLUX is extensively metabolised 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 metabolised with these pathways, like antipyrine, carbamazepine, diazepam, glibenclamide, nifedipine, phenytoin, and an oral contraceptive containing levonorgestrel and ethinyloestradiol did not reveal clinically significant interactions.

An interaction of TOPRAFLUX with other medicines or compounds which are metabolized using the same enzyme system cannot be excluded.

Results from a range of interaction studies demonstrate that TOPRAFLUX 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 with 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.

Pregnancy

There are no adequate data from the use of TOPRAFLUX in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. TOPRAFLUX should not be used during pregnancy.

Breastfeeding

Animal studies have shown excretion of pantoprazole in breast milk. A risk to the newborns/infants cannot be excluded. Therefore, breastfeeding while on TOPRAFLUX is not recommended.

Undesirable effects such as dizziness and visual disturbances may occur (see section 4.8). If affected, patients should not drive or operate machines.

Summary of the safety profile

Approximately 5% of patients can be expected to experience undesirable effects. The most commonly reported undesirable effects are diarrhoea and headache, both occurring in approximately 1% of patients.

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, undesirable effects are presented in order of decreasing seriousness.

Adverse reactions with pantoprazole in clinical trials and post-marketing experience

Blood and lymphatic system

Less frequent: Agranulocytosis, leucopoenia, thrombocytopenia, pancytopenia

Immune system disorders

Less frequent: Hypersensitivity (incl. anaphylactic reactions and anaphylactic shock)

Metabolism and nutrition disorders

Less frequent: Hyperlipidaemias and lipid increases (triglycerides, cholesterol), weight changes

Not known: Hyponatraemia, hypomagnesaemia (see section 4.4), hypocalcaemia¹, hypokalaemia

¹ Hypocalcaemia in association with hypomagnesemia

Psychiatric disorders

Less frequent: Sleep disorders, depression (and all aggravations), disorientation (and all aggravations)

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

Nervous system disorders

Less frequent: Headache, dizziness, taste disorders

Not known: Paraesthesia

Eye disorders

Less frequent: Disturbances in vision/blurred vision

Gastrointestinal disorders

Frequent: Fundic gland polyps (benign)

Less frequent: Diarrhoea, nausea/vomiting, abdominal distension and bloating, constipation, dry mouth, abdominal pain and discomfort

Not known: Microscopic colitis

Hepatobiliary disorders

Less frequent: Liver enzymes increased (transaminases, γ-GT), bilirubin increased

Not known: Hepatocellular injury, jaundice, hepatocellular failure

Skin and subcutaneous tissue disorders

Less frequent: Rash/exanthema/eruption, pruritus, urticaria, angioedema

Not known: Stevens-Johnson syndrome, Lyell syndrome, erythema multiforme, photosensitivity, drug reaction with eosinophilia and systemic symptoms (DRESS) and subacute cutaneous lupus erythematosus (see section 4.4)

Musculoskeletal and connective tissue disorders

Less frequent: Fracture of the hip, wrist or spine (see section 4.4), arthralgia, myalgia.

Not known: Muscle spasm as a consequence of electrolyte disturbances

Renal and urinary disorders

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

Reproductive system and breast disorders

Less frequent: Gynaecomastia

General disorders and administration site conditions

Less frequent: Asthenia, fatigue and malaise, body temperature increased, oedema peripheral

Not applicable.