4.1. Therapeutic indications

Pantoprazole 40mg Gastro-resistant Tablet is indicated for use in adults and adolescents 12 years of age and above for:

• Reflux oesophagitis.

Pantoprazole 40mg Gastro-resistant Tablet is indicated for use in adults for:

• Eradication of Helicobacter pylori (H. pylori) in combination with appropriate antibiotic therapy in patients with H. pylori associated ulcers.

• Gastric and duodenal ulcer.

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

4.2. Posology and method of administration

Posology:

Adults and adolescents 12 years of age and above

Reflux oesophagitis

One tablet of Pantoprazole sodium 40mg per day. In individual cases the daily dose may be doubled (increase to 2 tablets Pantoprazole sodium 40mg 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:

The following combinations have been shown to be effective:

(a) Pantoprazole sodium 40 mg twice daily,

plus 1000 mg amoxicillin twice daily

and 500 mg clarithromycin twice daily

(b) Pantoprazole sodium 40 mg twice daily,

plus 400-500 mg metronidazole (or 500 mg tinidazole) twice daily

and 250-500 mg clarithromycin twice daily

(c) Pantoprazole sodium 40 mg twice daily

plus 1000 mg amoxicillin twice-daily

and 400-500 mg metronidazole (or 500 mg tinidazole) twice-daily

In combination therapy for eradication of H. pylori infection, the second Pantoprazole sodium 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 sodium monotherapy:

Treatment of gastric ulcer

One tablet of Pantoprazole sodium 40mg per day. In individual cases the dose may be doubled (increase to 2 tablets of Pantoprazole sodium 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 sodium 40mg per day. In individual cases the dose may be doubled (increase to 2 tablets Pantoprazole sodium 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 hypersecretory conditions patients should start their treatment with a daily dose of 80mg (2 tablets of Pantoprazole sodium 40mg). Thereafter, the dose can be titrated up or down as needed using measurements of gastric acid secretion to guide. With doses above 80mg daily, the dose should be divided and given twice daily. A temporary increase of the dosage above 160mg pantoprazole per day is possible but should not be applied longer than required for adequate acid control.

Treatment duration in Zollinger-Ellison-Syndrome and other pathological hypersecretory conditions is not limited and should be adapted according to clinical needs.

Special populations

Elderly:

No dose adjustment is necessary in elder people (see section 5.2).

Paediatric population :

Pantoprazole sodium 40 mg is not recommended for use in children below twelve years of age because of limited data on safety and efficacy in this age group (see section 5.2).

Renal Impairment

No dose adjustment is necessary in patients with impaired renal function. Pantoprazole sodium 40mg 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 sodium 40mg in combination treatment for these patients (see section 5.2).

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 sodium 40mg 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 sodium 40mg in combination treatment of these patients (see section 4.4).

Method of administration

Oral use

Tablets should not be chewed or crushed, and should be swallowed whole 1 hour before a meal with some water.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

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 in liver enzymes, Pantoprazole therapy should be discontinued (see section 4.2).

Combination therapy

In the case of combination therapy, the summaries of product characteristics of the respective medicinal products should be observed.

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 section 4.5).

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.

Bone Fracture

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.

Gastrointestinal infections caused by bacteria

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

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). 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.

Hypomagnesaemia

Severe hypomagnesaemia has been rarely 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. 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.

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 sodium 40mg. 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 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 availability, e.g some azole antifungals as ketoconazole, itraconazole, posaconazole and other medicine 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, 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 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 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 effect 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 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.

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 300-1000 pregnancy outcomes) indicate no malformative or feto/ neonatal toxicity of Pantoprazole.

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

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

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), Hypokalaemia1

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 disorder

Parasthesia

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 subcutaneous tissue disorders

Rash/exanthema/eruption; Pruritus

Urticaria;

Angioedema

Stevens- Johnson Syndrome, Lyell Syndrome (TEN);

Erythema multiforme;

Photosensitivity;

Subacute cutaneous lupus erythematosus (see section 4.4);

Drug reaction with eosinophilia and systemic symptoms DRESS.

Musculoskeletal, 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

thrombophlebitis

Asthenia, fatigue and malaise

Body temperature increased; Oedema peripheral

1. Hypocalcemia and/or hypokalaemia may be related to the occurrence of hypomagnesemia (see section 4.4)

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.

4.9. Overdose

There are no known symptoms of over dosage 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.