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Summary of Product CharacteristicS

1. NAME OF THE MEDICINAL PRODUCT

Pantoprazole Bluefish 20 mg gastro-resistant tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each gastro-resistant tablet contains 20 mg pantoprazole (as pantoprazole sodium sesquihydrate 22.55 mg).

For thefull list of excipients, see section 6.1.

3. PHARMACEUTICAL form

Gastro-resistant tablet.

Yellow, oval, biconvex andsmooth tablets with a dimension of 8 mm x 5.5 mm.

4. Clinical particulars

4.1 Therapeutic indications

• For the treatment of mild reflux disease and associated symptoms (e.g. heartburn, acid regurgitation, pain on swallowing).

• For long-term management and prevention of relapse in reflux oesophagitis.

• Prevention of gastroduodenal ulcers induced by non-selective non-steroidal anti-inflammatory drugs (NSAIDs) in patients at risk with a need for continuous NSAID treatment (see section 4.4).

4.2 Posology and method of administration

Paediatric population

There is no information on the use of pantoprazole in children. Therefore pantoprazole tablets should not be used in children.

Method of administration

Pantoprazole Bluefish 20 mg gastro-resistant tablets should not be chewed or crushed, and should be swallowed whole with water one hour before a meal.

Treatment of mild reflux disease and associated symptoms (e.g. heartburn, acid regurgitation, pain on swallowing)

The recommended dosage is 20 mg pantoprazole daily (1 Pantoprazole Bluefish 20 mg gastro-resistant tablet). Symptom relief is generally accomplished within 24 weeks, and a 4-week treatment period is usually required for healing of associated oesophagitis. If this is not sufficient, healing will normally be achieved within a further 4 weeks. When symptom relief has been achieved, reoccurring symptoms can be controlled using an on-demand regimen of 20 mg once daily, when required. A switch to continuous therapy may be considered in case satisfactory symptom control cannot be maintained with on-demand treatment.

Long-term management and prevention of relapse in reflux oesophagitis

For long-term management, a maintenance dose of 20 mg pantoprazole daily (1 Pantoprazole Bluefish 20 mg gastro-resistant tablet) is recommended. If a relapse occurs, the dosage is increased to 40 mg pantoprazole per day. Pantoprazole Bluefish 40 mg gastro-resistant tablets are available for this case. After healing of the relapse the dosage can be reduced again to 20 mg pantoprazole.

Prevention of gastroduodenal ulcers induced by non-selective non-steroidal anti-inflammatory drugs (NSAIDs) in patients at risk with a need for continuous NSAID treatment

The recommended dosage is 20 mg pantoprazole daily (1 Pantoprazole Bluefish 20 mg gastro-resistant tablet).

Elderly and patients with renal impairment

A daily dose of 40 mg pantoprazole should not be exceeded in these patient groups.

Patients with hepatic impairment

A daily dose of 20 mg pantoprazole should not be exceeded in patients with severe liver impairment (see section 4.4). In these patients, hepatic enzyme levels should be monitored during the treatment. If hepatic enzyme levels become elevated, treatment with pantoprazole should be discontinued.

4.3 Contraindications

Hypersensitivity to the active substance, substituted benzimidazolesor to any of the other excipientslisted in section 6.1 of the combination partners.

Pantoprazole like other proton pump inhibitors should not be administered with atazanavir (see section 4.5).

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 of the liver enzymes, the treatment 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.

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.

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.

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 onlong-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.

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 Bluefish may lead to a slightly increased risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter and 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 Bluefish. 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 pantoprazolefor 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.

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 Bluefish 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

Effect of pantoprazole on the absorption of other medicinal products

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.gsome azole antifungals as ketoconazole, itraconazole, posaconazole and other medicine as erlotinib.

HIV medications (atazanavir)

Co-administration of atazanavir and other HIV medications whose absorption is pH-dependent with proton-pump inhibitors, might resultin 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 inhibitorswith atazanavir is not recommended (see section 4.4).

Coumarin anticoagulants (phenprocoumon or warfarin)

Although no interaction during concomitant administration of phenprocoumon or warfarin has been observed in clinical pharmacokineticstudies, a few isolated cases of changes in International Normalised Ratio (INR) have been reported during concomitant treatment in the post-marketing period. Therefore, in patients treated with coumarin anticoagulants(e.g. phenprocoumon or warfarin), monitoringof prothrombin time / INR isrecommended after initiation, termination or duringirregular use of pantoprazole.

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 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 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.

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.

4.6 Fertility,pregnancy and lactation

Pregnancy

There are no adequate data from the use ofpantoprazole in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Pantoprazole Bluefishshould notbe used during pregnancy, unless clearly necessary.

Breast-feedingAnimal studies have shown excretion of pantoprazole in breast milk. Excretion into human milk has been reported. Therefore, a decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Pantoprazole Bluefish should be made taking into accountthe benefit of breast-feeding tothe child, and the benefit of Pantoprazole Bluefish therapy to women.

4.7 Effects on 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 ADRs are diarrhoea and headache, both occurring 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

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 national reporting system listed in Appendix V.

4.9 Overdose

There are no known symptoms of over dosage in man.

Systemic exposure withup 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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Proton pump inhibitors, ATC code: A02BC02

Pantoprazole is a substituted benzimidazole which inhibits the secretion of hydrochloric acid in the stomach by specific action on the proton pumps of the parietal cells.

Pantoprazole is converted to its active form in the acidic channel of 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 in 2 weeks. As with other proton pump inhibitors and H2 receptor inhibitors, treatment with pantoprazole causes a reduced acidity in the stomach and thereby an increase in 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, the substance can affect hydrochloric acid secretion independently of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same whether the product is administered orally or intravenously.

The fasting gastrin values increase under pantoprazole. On short-term use, in most cases they do not exceed the normal upper limit. 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(see Section 5.3) can be ruled out for humans for a 1-year treatment period.

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.

An influence of a long term treatment with pantoprazole exceeding one year cannot be completely ruled out on endocrine parameters of the thyroid and liver enzymes according to results in animal studies.

5.2 Pharmacokinetic properties

General pharmacokinetics

Pantoprazole is rapidly absorbed and the maximal plasma concentration is achieved even after one single oral dose. On average, the maximum serum concentrations are 11.5 µg/ml at about 2.02.5 hours post-administration, and these values remain constant after multiple administration. Volume of distribution is about 0.15 l/kg and clearance is about 0.1 l/h/kg.

Terminal half-life is about 1 h. 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).

Pharmacokinetics do not vary after single or repeated administration. In the dose range of 10 to 80 mg, the plasma kinetics of pantoprazole are linear after both oral and intravenous administration.

Pantoprazole's serum protein binding is about 98%. The substance is almost exclusively metabolized in the liver. 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 h) is not much longer than that of pantoprazole.

Bioavailability

Pantoprazole is completely absorbed after oral administration. The absolute bioavailability from the tablet was found to be about 77%. Concomitant intake of food had no influence on AUC, maximum serum concentration and thus bioavailability. Only the variability of the lag-time will be increased by concomitant food intake.

Characteristics in patients/special groups of subjects

No dose reduction is requested when pantoprazole is administered to patients with restricted kidney function (incl. dialysis patients). As with healthy subjects, pantoprazole's half-life is short. Only very small amounts of pantoprazole can be dialyzed. Although the main metabolite has a moderately delayed half-life (23h), excretion is still rapid and thus accumulation does not occur. However, the daily dose of 40 mg pantoprazole should not be exceeded in patients with impaired renal function.

Although for patients with liver cirrhosis (classes A and B according to Child) the half-life values increased to between 3 and 6 h and the AUC values increased by a factor of 35, the maximum serum concentration only increased slightly by a factor of 1.3 compared with healthy subjects.

A slight increase in AUC and Cmax in elderly volunteers compared with younger counterparts is also not clinically relevant.

Children

Following administration of single oral doses of 20 mg pantoprazole to children aged 5 – 16 years AUC and Cmax were in the range of corresponding values in adults.

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.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.

In a two-year carcinogenicity study in rats, neuroendocrine neoplasms were found. In addition, squamous cell papillomas were found in the forestomach of rats. The mechanism leading to the formation of gastric carcinoids by substituted benzimidazoles has been carefully investigated and allows the conclusion that it is a secondary reaction to the massively elevated serum gastrin levels occurring in the rat during chronic high-dose treatment.

In two-year rodent studies an increased number of liver tumours was observed in rats (in one rat study only) and in female mice and was interpreted as being due to pantoprazole's high metabolic rate in the liver.

A slight increase of neoplastic changes of the thyroid was observed in the group of rats receiving the highest dose (200 mg/kg) in one 2 year study. The occurrence of these neoplasms is associated with the pantoprazole-induced changes in the breakdown of thyroxine in the rat liver. As the therapeutic dose in man is low, no side effects on the thyroid glands are expected.

From mutagenicity studies, cell transformation tests and DNA binding studies it is concluded that pantoprazole has no genotoxic potential.

Investigations revealed no evidence of impaired fertility or teratogenic effects. Penetration of the placenta was investigated in the rat and was found to increase with advanced gestation. As a result, concentration of pantoprazole in the foetus is increased shortly before birth.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Disodium phosphate anhydrous

Mannitol

Cellulose microcrystalline

Croscarmellose sodium

Magnesium stearate

Hypromellose

Triethyl citrate

Sodium starch glycolate (Type A)

Methacrylic acid-ethyl acrylate copolymer (1:1)

Yellow iron oxide (E 172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Store below 30ºC.

Alu/Alu blister: 14, 28, 56, 100 tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposaland other handling

No special requirementsfor disposal.

Any unusedmedicinalproduct or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Bluefish Pharmaceuticals AB

P.O. Box 49013

100 28 Stockholm

Sweden

8. MARKETING AUTHORISATION NUMBER(S)

[To be completed Nationally]

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

[To be completed Nationally]

10. DATE OF REVISION OF THE TEXT

2016-11-04