4.1. Therapeutic indications

Protium is indicated for use in adults for:

- Reflux oesophagitis.

- Gastric and duodenal ulcer.

- Zollinger-Ellison Syndrome and other pathological hyper secretory conditions.

4.2. Posology and method of administration

This medicine should be administered by a healthcare professional and under appropriate medical supervision.

Intravenous administration of Protium 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, treatment with Protium i.v. should be discontinued and 40 mg pantoprazole p.o. should be administered instead.

Posology

Gastric and duodenal ulcer, reflux oesophagitis

The recommended intravenous dose is one vial of Protium (40 mg pantoprazole) per day.

Zollinger-Ellison Syndrome and other pathological hyper secretory 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 Protium. 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.

In case a rapid acid control is required, a starting dose of 2 x 80 mg Protium is sufficient to manage a decrease of acid output into the target range (< 10 mEq/h) within one hour in the majority of patients.

Special populations

Patients with hepatic impairment

A daily dose of 20 mg pantoprazole (half a vial of 40 mg pantoprazole) should not be exceeded in patients with severe liver impairment (see section 4.4).

Patients with renal impairment

No dose adjustment is necessary in patients with impaired renal function (see section 5.2).

Elderly

No dose adjustment is necessary in the elderly (see section 5.2).

Paediatric population

The safety and efficacy of Protium 40 mg powder for solution for injection in children aged under 18 years have not been established. Therefore, Protium 40 mg powder for solution for injection is not recommended for use in patients below 18 years of age.

Currently available data are described in section 5.2 but no recommendation on a posology can be made.

Method of administration

A ready-to-use solution is prepared in 10 mL of sodium chloride 9 mg/mL (0.9 %) solution for injection. For instructions for preparation see section 6.6. The 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 50 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.

4.3. Contraindications

Hypersensitivity to the active substance, substituted benzimidazoles, or to any of the excipients listed in section 6.1.

4.4. Special warnings and 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 during therapy. In the case of a rise of the liver enzymes, the treatment should be discontinued (see section 4.2).

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).

Gastrointestinal infections caused by bacteria

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

Protium contains sodium

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

Hypomagnesaemia

Severe hypomagnesaemia has been rarely reported in patients treated with proton pump inhibitors (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. Hypomagnesaemia may lead to hypocalcaemia and/or hypokalaemia (see section 4.8). In most affected patients, hypomagnesaemia (and hypomagnesaemia associated hypocalcaemia and/or hypokalaemia) 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 (> 1 year), may modestly increase the risk of hip, wrist and spine fracture, predominantly in the elderly or in the 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.

Severe cutaneous adverse reactions (SCARs)

Severe cutaneous adverse reactions (SCARs) including erythema multiforme, Stevens‑Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) which can be life‑threatening or fatal, have been reported in association with pantoprazole with frequency not known (see section 4.8).

At the time of prescription, patients should be advised of the signs and symptoms and monitored closely for skin reactions.

If signs and symptoms suggestive of these reactions appear, pantoprazole should be withdrawn immediately and an alternative treatment considered.

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 healthcare professional should consider stopping Protium. 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, Protium 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.

4.5. Interaction with other medicinal products and other forms of interaction

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 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 (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)

Co-administration of pantoprazole with warfarin or phenprocoumon did not affect the pharmacokinetics of warfarin, phenoprocoumon or INR. However, there have been reports of increased INR and prothrombin time in patients receiving PPIs and warfarin or phenoprocoumon 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 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 medicinal products also metabolised 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.

Drug-laboratory test interactions

There have been reports of false-positive results in some urine screening tests for tetrahydrocannabinol (THC) in patients receiving pantoprazole. An alternative confirmatory method should be considered to verify positive results.

4.6. Fertility, pregnancy and lactation

Pregnancy

A moderate amount of data on pregnant women (between 300-1 000 pregnancy outcomes) indicate no malformative or feto/ neonatal toxicity of Protium.

Animal studies have shown reproductive toxicity (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of Protium 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 Protium therapy taking into account the benefit of breast-feeding for the child, and the benefit of Protium therapy for the woman.

Fertility

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

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

4.8. Undesirable effects

Approximately 5% of patients can be expected to experience adverse drug reactions (ADRs).

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

Frequency

Common

Uncommon

Rare

Very rare

Not known

System Organ Class

Blood and lymphatic system disorders

Agranulocytosis

Thrombocytopenia;

Leukopenia;

Pancytopenia

Immune system disorders

Hypersensitivity (including anaphylactic reactions and anaphylactic shock)

Metabolism and nutrition disorders

Hyperlipidaemias and lipid increases (triglycerides, cholesterol);

Weight changes

Hyponatraemia;

Hypomagnesaemia (see section 4.4);

Hypocalcaemia(1);

Hypokalaemia(1)

Psychiatric disorders

Sleep disorders

Depression (and all aggravations)

Disorientation (and all aggra­vations)

Hallucination;

Confusion (especially in pre-disposed patients, as well as the aggravation of these symptoms in case of pre-existence)

Nervous system disorders

Headache;

Dizziness

Taste disorders

Paraesthesia

Eye disorders

Disturbances in vision / blurred vision

Gastrointestinal disorders

Fundic gland polyps (benign)

Diarrhoea;

Nausea / vomiting;

Abdominal distension and bloating;

Constipation;

Dry mouth;

Abdominal pain and discomfort

Microscopic colitis

Hepatobiliary disorders

Liver enzymes increased (transaminases, γ-GT)

Bilirubin increased

Hepatocellular injury;

Jaundice;

Hepatocellular failure

Skin and sub-cutaneous tissue disorders

Rash / exanthema / eruption;

Pruritus

Urticaria;

Angioedema

Stevens-Johnson syndrome;

Lyell syn­drome (TEN);

Drug reaction with eosinophilia and systemic symptoms (DRESS);

Erythema multiforme;

Photosensitivity;

Subacute cutaneous lupus erythematosus (see section 4.4)

Musculoskeletal and connective tissue disorders

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

Arthralgia;

Myalgia

Muscle spasm (2)

Renal and urinary disorders

Tubulointerstitial nephritis (TIN) (with possible progression to renal failure)

Reproductive system and breast disorders

Gynaecomastia

General disorders and administration site conditions

Injection site thrombo-phlebitis

Asthenia, fatigue and malaise

Body temperature increased;

Oedema peripheral

1Hypocalcaemia and/or hypokalaemia may be related to the occurrence of hypomagnesaemia (see section 4.4)

2Muscle 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.

4.9. Overdose

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.