PANTOPRAZOLE Powder for solution for injection Ref.[7033] Active ingredients: Pantoprazole

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.

Hepatic Impairment

In patients with severe liver impairment, the liver enzymes should be monitored during therapy. In the case of a rise of the liver enzymes, the treatment should be discontinued (see section 4.2).

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.

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.

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.

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.

This medicine contains less than 1 mmol sodium (23 mg) per maximum daily dose, that is to say ‘sodium-free’.

Medicinal products with pH Dependent Absorption Pharmacokinetics

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 as ketoconazole, itraconazole, posaconazole and other medicine as erlotinib.

HIV protease inhibitors

Co-administration of atazanavir and other HIV medications whose absorption is pH-dependent with proton-pump inhibitors 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 (see section 4.4).

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 inhibitor may need to be adjusted.

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. Increases in INR and prothrombin time may lead to abnormal bleeding, and even death. 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.

Other interactions studies

Pantoprazole 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 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.

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 administering pantoprazole concomitantly 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.

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

A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity of pantoprazole. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Pantoprazole should not be used during pregnancy unless clearly necessary.

Breast-feeding

Animal studies have shown excretion of pantoprazole in breast milk. There is insufficient information on the excretion into human milk but excretion into human milk has been reported. A risk to the newborn/infant cannot be excluded. Therefore, a decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Pantoprazole should be made taking into account the benefit of breast-feeding to the child and the benefit of Pantoprazole therapy to woman.

Fertility

There was no evidence of impaired fertility following the administration of pantoprazole in animal studies (see section 5.3).

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 section 4.8). If affected, patients should not drive or operate machines.

Approximately 5% of patients can be expected to experience adverse drug reactions (ADRs). The most commonly reported ADR is injection site thrombophlebitis. Diarrhoea and headache occurred 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:

Blood and lymphatic system disorders

Rare: Agranulocytosis

Very rare: Thrombocytopenia; Leukopenia; Pancytopenia

Immune system disorders

Rare: Hypersensitivity (including anaphylactic reactions and anaphylactic shock)

Metabolism and nutrition disorders

Rare: Hyperlipidaemias and lipid increases (triglycerides, cholesterol); Weight changes

Not known: Hyponatraemia, Hypomagnesaemia (see section 4.4), Hypocalcaemia¹; Hypokalaemia

Psychiatric disorders

Uncommon: Sleep disorders

Rare: Depression (and all aggravations)

Very rare: 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

Uncommon: Headache, Dizziness

Rare: Taste disorders

Not known: Parasthesia

Eye disorders

Rare: Disturbances in vision/blurred vision

Gastrointestinal disorders

Common: Fundic gland polyps (benign)

Uncommon: Diarrhoea; Nausea/vomiting; Abdominal distension and bloating; Constipation; Dry mouth; Abdominal pain and discomfort

Hepatobiliary disorders

Uncommon: Liver enzymes increased (transaminases, γ-GT)

Rare: Bilirubin increased

Not known: Hepatocellular injury; Jaun-dice; Hepato-cellular failure

Skin and subcutaneous tissue disorders

Uncommon: Rash/exanthema/eruption; Pruritus

Rare: Urticaria; Angioedema

Not known: Stevens-Johnson syndrome; Lyell syndrome; Erythema multiforme; Photosensitivity; Subacute cutaneous lupus erythematosus (see section 4.4)

Musculo-skeletal and connective tissue disorders

Uncommon: Fracture of the hip, wrist or spine (see section 4.4)

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 and administration site conditions

Common: Injection site thrombo-phlebitis

Uncommon: Asthenia, fatigue and malaise

Rare: Body temperature increased; Oedema peripheral

¹ Hypocalcemia in association with hypomagnesemia
² Muscle spasm as a consequence of electrolyte disturbance

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.