annex i list of the names, pharmaceutical...

ANNEX I

LIST OF THE NAMES, PHARMACEUTICAL FORMS, STRENGTHS OF THE MEDICINAL PRODUCTS, ROUTES OF ADMINISTRATION, MARKETING AUTHORISATION HOLDERS

IN THE MEMBER STATES

2

Member State EU/EEA

Marketing Authorisation Holder (Invented) name

Strength Pharmaceutical Form

Route of administration

Content (concentration)

Austria Nycomed Pharma GmbH Euro Plaza Gebäude F Technologiestrasse 5 1120 Vienna Austria

Pantoloc 20 mg -Filmtabletten

20 mg Gastro-resistant tablet

oral use

Austria

Nycomed Pharma GmbH Euro Plaza Gebäude F Technologiestrasse 5 1120 Vienna Austria

Pantoloc 40 mg -Filmtabletten


oral use

Austria

Nycomed Pharma GmbH Euro Plaza Gebäude F Technologiestrasse 5 1120 Vienna Austria

Pantoloc 40 mg -Trockenstech- ampulle

40 mg Powder for solution for injection

intravenous use 40 mg

Austria

Nycomed Austria GmbH St. Peter Strasse 25 4020 Linz Austria

Zurcal 20 mg -Filmtabletten 20 mg Gastro-resistant tablet

oral use

Austria


Zurcal 40 mg -Filmtabletten 40 mg Gastro-resistant tablet

oral use

Austria


Zurcal 40 mg -Trockenstech-ampulle



3

Member State EU/EEA





Belgium

Nycomed Belgium SCA/CVA Gentsesteenweg 615 1080 Brussels Belgium

Pantozol 40 mg Gastro-resistant tablet

oral use

Belgium


Pantozol 20 mg Gastro-resistant tablet

oral use

Belgium


Pantozol IV 40 mg Powder for solution for injection


Belgium


Zurcale 40 mg Gastro-resistant tablet

oral use

Belgium


Zurcale 20 mg 20 mg Gastro-resistant tablet

oral use

Belgium


Zurcale IV 40 mg Powder for solution for injection


4

Member State EU/EEA





Bulgaria

Nycomed GmbH Byk-Gulden-Str.2 78467 Constance Germany

Controloc 20 mg Gastro-resistant tablet

oral use

Bulgaria



oral use

Cyprus

Mundipharma Pharmaceuticals Ltd.Othellos str. 13 Dhali Industrial Zone 1685 Nicosia Cyprus


oral use

Cyprus



oral use

Cyprus


Controloc i.v. 40 mg Powder for solution for injection


5

Member State EU/EEA





Czech Republic

Nycomed GmbH Byk-Gulden-Str.2 78467 Konstanz Germany

Controloc 20 mg 20 mg Gastro-resistant tablet

oral use

Czech Republic



oral use

Czech Republic




Denmark

Nycomed Denmark ApS Langebjerg 1 4000 Roskilde Denmark

Pantoloc 20 mg Gastro-resistant tablet

oral use

Denmark



oral use

Denmark


Pantoloc 40 mg Powder for solution for injection


6

Member State EU/EEA





Estonia



oral use

Estonia



oral use

Finland


Somac 20 mg enterotabletti 20 mg Gastro-resistant tablet

oral use

Finland


Somac 40 mg enterotabletti 40 mg Gastro-resistant tablet

oral use

Finland


Somac 40 mg injektiokuiva-aine, liuosta varten



France

Nycomed France 13, rue Watt 75013 Paris France

Eupantol 20 mg, comprimé gastro- résistant


oral use

France


Eupantol 40 mg, comprimé gastro- résistant


oral use

7

Member State EU/EEA





France


Eupantol 40 mg poudre pour solution injectable IV



France


Inipomp 20 mg, comprimé gastro- résistant


oral use

France Nycomed France 13, rue Watt 75013 Paris France

Inipomp 40 mg, comprimé gastro- résistant


oral use


Inipomp 40 mg; poudre pour IV



France


Pantec 20 mg, comprimé gastro- résistant


oral use

France


Pantec 40 mg, comprimé gastro- résistant


oral use

France


Pantipp 20 mg, comprimé gastro- résistant


oral use

8

Member State EU/EEA






Pantipp 40 mg, comprimé gastro- résistant


oral use

Germany


Pantoprazol NYC 20 mg 20 mg Gastro-resistant tablet

oral use

Germany


Pantoprazol NYC 40 mg 40 mg Gastro-resistant tablet

oral use

Germany


Pantoloc i.v. 40 mg Powder for solution for injection


Germany


Pantoprazol 20 mg Byk 20 mg Gastro-resistant tablet

oral use

Germany


Pantoprazol-Byk i.v. 40 mg Powder for solution for injection

intravenous use

Germany


Pantozol 20 mg 20 mg Gastro-resistant tablet

oral use

9

Member State EU/EEA





Germany


Pantozol 40 mg 40 mg Gastro-resistant tablet

oral use

Germany


Pantozol i.v. 40 mg Powder for solution for injection


Germany


PantoLomberg 20 mg


oral use

Germany


Pantoprazole Lomberg 20 mg 20 mg Gastro-resistant tablet

oral use

Germany


Rifun 20 mg 20 mg Gastro-resistant tablet

oral use

Germany


Rifun 40 mg 40 mg Gastro-resistant tablet

oral use

Germany

Byk Tosse Arzneimittel GmbH, Moltkestr. 4 78467 Constance Germany

Zurcal S 20 mg magensaftresistente Tabletten


oral use

10

Member State EU/EEA





Germany

Byk Tosse Arzneimittel GmbH, Moltkestr. 4 78467 Constance Germany

Zurcal S 40 mg magensaftresistente Tabletten


oral use

Greece

Sanofi-Aventis Greece 348, Syngrou Avenue Building A 176 74 Kallithea Greece


oral use

Greece



oral use

Greece




Greece

Nycomed Hellas S.A. 196, Kifissias Ave. 152 31 Chalandri Athens Greece

Zurcazol 20 mg 20 mg Gastro-resistant tablet

oral use

Greece


Zurcazol 40 mg Gastro-resistant tablet

oral use

11

Member State EU/EEA





Greece


Zurcazol i.v. 40 mg Powder for solution for injection


Hungary



oral use

Hungary


Controloc 40 mg


oral use

Hungary




Ireland


Protium 40 mg Gastro-resistant tablet

oral use

Ireland


Protium 20 mg 20 mg Gastro-resistant tablet

oral use

Ireland


Protium i.v. 40 mg Powder for solution for injection


12

Member State EU/EEA





Italy Nycomed Italia S.r.l via Libero Temolo 4 20126 Milan Italy

Pantecta 40 mg Gastro-resistant tablet

oral use

Italy

Nycomed Italia S.r.l via Libero Temolo 4 20126 Milan Italy

Pantecta 20 mg Gastro-resistant tablet

oral use

Italy

Almirall S.p.A via Messina, 38 Torre C 20154 Milan Italy

Pantopan 40 mg Gastro-resistant tablet

oral use

Italy

Almirall S.p.A via Messina, 38 Torre C 20154 Milan Italy

Pantopan 20 mg Gastro-resistant tablet

oral use

Italy

Nycomed S.p.A. Via Temolo 4 20126 Milan Italy

Pantorc 40 mg Gastro-resistant tablet

oral use

Italy


Pantorc 20 mg Gastro-resistant tablet

oral use

Italy


Pantorc. 40 mg Powder for solution for injection


13

Member State EU/EEA





Italy

Recordati Industria Chimica e Farmaceutica S.p.A Via M. Civitali 1 20148 Milan Italy

Peptazol 40 mg Gastro-resistant tablet

oral use

Italy

Recordati Industria Chimica e Farmaceutica S.p.A Via M. Civitali 1 20148 Milan Italy

Peptazol 20 mg Gastro-resistant tablet

oral use

Latvia



oral use

Latvia



oral use

Lithuania



oral use

Lithuania



oral use

14

Member State EU/EEA





Luxembourg Nycomed Belgium SCA/CVA Gentsesteenweg 615 1080 Brussels Belgium

Panto-Byk-20 20 mg Gastro-resistant tablet

oral use


Panto-Byk-40 40 mg Gastro-resistant tablet

oral use


Panto-Byk-IV 40 mg Powder for solution for injection



Pantozol-20 20 mg Gastro-resistant tablet

oral use


Pantozol 40 40 mg Gastro-resistant tablet

oral use


Pantozol-IV 40 mg Powder for solution for injection


15

Member State EU/EEA





Netherlands

Nycomed bv Jupiterstraat 250 2132 HK Hoofddorp Netherlands


oral use

Netherlands



oral use

Netherlands


Pantozol i.v. 40 mg Powder for solution for injection


Netherlands


Pantoprazol Nycomed 40 mg 40 mg Gastro-resistant tablet

oral use

Norway


Somac 20 mg Gastro-resistant tablet

oral use

Norway


Somac 40 mg Gastro-resistant tablet

oral use

Norway


Somac 40 mg Powder for solution for injection


16

Member State EU/EEA





Poland

Nycomed Pharma Sp.z o.o. Al. Jerozolimskie 146A 02-305 Warsaw Poland

Controloc 20 20 mg Gastro-resistant tablet

oral use

Poland


Controloc 40 40 mg Gastro-resistant tablet

oral use

Poland


Controloc 40 mg Powder for solution for injection


Portugal

Laboratórios Delta, Lda. Rua Direita, 148 Massamá 2745-751 QUELUZ Portugal

Apton 40 mg 40 mg Gastro-resistant tablet

oral use

Portugal

Laboratórios Delta, Lda. Rua Direita, 148 Massamá 2745-751 QUELUZ Portugal

Apton 20 mg Gastro-resistant tablet

oral use

Portugal

Nycomed Portugal Produtos Farmaceuticos, Lda. Quinta da Fonte Edificio Gil Eanes Paço D´Arcos 2770-192 Paço D` Arcos Portugal

Pantoc 40 mg 40 mg Gastro-resistant tablet

oral use

17

Member State EU/EEA





Portugal

Nycomed Portugal - Produtos Farmacêuticos, Lda. Quinta da Fonte Edificio Gil Eanes Paço D´Arcos 2770-192 Paço D` Arcos Portugal

Pantoc 20 mg Gastro-resistant tablet

oral use

Portugal


Pantoc IV 40 mg Powder for solution for injection


Portugal


Zurcal 20 mg Gastro-resistant tablet

oral use

Portugal

Nycomed Portugal Produtos Farmaceuticos, Lda. Quinta da Fonte Edificio Gil Eanes Paço D´Arcos 2770-192 Paço D` Arcos Portugal

Zurcal 40 mg 40 mg Gastro-resistant tablet

oral use

Portugal


Pantoprazole ALTANA 20 mg


oral use

18

Member State EU/EEA





Portugal


Pantoprazole ALTANA 40 mg


oral use

Romania



oral use

Romania

Nycomed GmbH Byk-Gulden-Str.2 78467 Konstance Germany


oral use

Romania




Slovak Republic


Controloc 20 mg gastrorezistentné tablety


oral use

Slovak Republic



oral use

Slovak Republic




19

Member State EU/EEA





Slovenia


Controloc 20 mg gastrorezistentne tablete


oral use

Slovenia


Controloc 40 mg gastrorezistentne tablete


oral use

Slovenia


Controloc 40 mg prašek za raztopino za injiciranje



Spain


Anagastra 20 mg Blister 20 mg Gastro-resistant tablet

oral use

Spain


Anagastra 40 mg blister 40 mg Gastro-resistant tablet

oral use

Spain


Anagastra 40 mg polvo para solución inyectable I.V.



Spain


Pantecta 20 mg comprimidos gastrorresistentes Blister


oral use

20

Member State EU/EEA





Spain


Pantecta 40 mg Blister


oral use

Spain


Ulcotenal 20 mg comprimidos gastrorresistentes Blister


oral use

Spain


Ulcotenal 40 mg Blister 40 mg Gastro-resistant tablet

oral use

Sweden

Nycomed AB Box 27264 102 53 Stockholm Sweden


oral use

Sweden



oral use

Sweden


Pantoloc 40 mg Powder for solution for injection


United Kingdom



oral use

21

Member State EU/EEA





United Kingdom



oral use

United Kingdom


Protium i.v. 40 mg Powder for solution for injection


22

ANNEX II

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR AMENDMENT OF THE SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE LEAFLET PRESENTED BY

THE EMEA

23

SCIENTIFIC CONCLUSIONS OVERALL SUMMARY OF THE SCIENTIFIC EVALUATION OF PROTIUM AND ASSOCIATED NAMES (SEE ANNEX I) Protium (pantoprazole) is a proton-pump inhibitor and is used to treat gastroesophageal reflux disease (GERD), a condition in which backward flow of acid from the stomach causes heartburn and injury of the food pipe (oesophagus). It is also used to treat conditions where the stomach produces too much acid, such as Zollinger-Ellison syndrome. It works by decreasing the amount of acid made in the stomach. Pantoprazole is not registered in Iceland and Malta. In all other EU countries and Norway pantoprazole 20 mg and 40 mg, gastro-resistant tablets, are registered. No marketing authorisations exist for Pantoprazole i.v., powder for solution for injection, in Bulgaria, Estonia, Latvia and Lithuania. Protium was included in the list of products for Summary of Product Characteristics (SPC) harmonisation, drawn up by the CMD(h), in accordance with Article 30(2) of Directive 2001/83/EC, as amended. In agreement with the EMEA, Module 3 was also harmonised during this procedure. Section 4.1: Therapeutic indications Indications proposed for pantoprazole 20 mg gastro-resistant tablets: The CHMP noted the MAH proposal. For the treatment of mild reflux disease and associated symptoms, several studies in adult patients with mild GERD have shown pantoprazole to be superior to placebo and ranitidine for the relief from the key GERD symptoms (heartburn, acid regurgitation, pain on swallowing) and healing of lesions and comparable to omeprazole and lansoprazole regarding the rate of symptom relief and healing in patients with mild GERD. This was supported by several guidelines recommending the use of PPIs in GERD regardless of severity. For the long-term management and prevention of relapse in reflux oesophagitis the MAH summarised 7 studies in long term treatment (between 6-12 months) showing that pantoprazole is superior in maintaining the healing and relapse rates compared to placebo and ranitidine. The relapse of erosive oesophagitis in subjects with GERD was shown to be dramatically decreased by PPI treatment and reflux symptoms were also better controlled with maintenance-dose PPI therapy than with placebo. In the case of non-erosive disease, PPI treatment also proved a reasonable strategy in symptoms control but the role of daily maintenance therapy is less clear than the “on demand” use. For the prevention of gastroduodenal ulcers induced by non-selective non-steroidal anti-inflammatory drugs, a summary of three clinical trials was provided, showing superiority of pantoprazole versus placebo and misoprostol and similar effectiveness to omeprazole. The association between NSAIDs and the presence of upper gastrointestinal (GI) complications is considered well established and evidence that acid aggravates NSAID-induced injury provides a rationale for minimizing such damage by acid suppression. In conclusion, based on the data provided by the MAH and the existing clinical evidence the CHMP adopted three harmonised therapeutic indications for the 20 mg gastro-resistant tablets. Indications proposed for pantoprazole 40 mg gastro-resistant tablets: The CHMP noted the submitted randomized clinical trials results demonstrating that pantoprazole is therapeutically superior to placebo and to ranitidine in patients with moderate and severe reflux oesophagitis and equivalent in healing rates after 4/8 weeks and/or symptom relief after 2/4 weeks of treatment with omeprazole, esomeprazole and lansoprazole. Abundant data supports treating patients with oesophageal GERD syndromes with antisecretory drugs and there is ample evidence that, as a drug class, PPIs are more effective in these patients than H2 receptor antagonist. For the combination with two appropriate antibiotics for the eradication of H. pylori in patients with peptic ulcers with the objective of reducing the recurrence of duodenal and gastric ulcers caused by this microorganism, there is a vast knowledge about the eradication of H. Pylori and the role of PPIs.

24

Currently, ulcers related to H. Pylori infection can be healed and prevented from recurring and in NSAIDs naïve patients with H. Pylori infection, pantoprazole is better than placebo in preventing peptic ulcer and upper gastrointestinal bleeding at six months. Antibiotic resistance is a major cause of treatment failure and as the prevalence of resistance in H. pylori shows regional variation, alternative antibiotics based on local resistance rates may improve eradication rates. Regarding duodenal ulcer, data from several randomized trials was provided, comparing pantoprazole with ranitidine. Superiority of pantoprazole over ranitidine and comparable healing rates after two and four weeks of treatment with omeprazole were demonstrated. A randomized, dose-finding study showed statistically significant differences between 20 mg and 40 mg, thus indicating that pantoprazole at a daily dose of 40 mg is the recommended efficacious and safe dosage. For gastric ulcer, data from two clinical trials and one meta-analysis was provided. The trials showed that pantoprazole is superior to ranitidine and comparable to omeprazole in ulcer healing while the meta-analysis suggests that first-line drug therapy for patients diagnosed with gastric ulcer should preferably be PPI, rather than a H2 antagonist. Finally, for the Zollinger-Ellison syndrome (ZES) and other pathological hypersecretory conditions, data from two studies comparing the efficacy of pantoprazole in reducing gastric acid secretion in 11 ZES patients who previously had received omeprazole and lansoprazole was provided. Pantoprazole was shown to be equally effective to the other PPIs in terms of antisecretory potency. Numerous studies have demonstrated that PPIs are both efficacious and well tolerated in patients with hypersecretory conditions; consequently, they are currently the anti-secretory agents of choice to control gastric acid hypersecretion. In conclusion, based on the data provided by the MAH and the existing clinical evidence, the proposed indications are considered appropriate; however, the CHMP proposed a new wording for the moderate and severe reflux oesophagitis, taking into account the current classification of gastroesophageal reflux disease. In addition the indication for H. Pylori eradication was simplified. The CHMP adopted four harmonised therapeutic indications for the 40 mg gastro-resistant tablets. Indications proposed for pantoprazole 40 mg i.v.: For duodenal ulcer, gastric ulcer, moderate and severe reflux oesophagitis, open-label studies have shown that pantoprazole 40 mg/d, p.o. is comparably effective and safe to pantoprazole 40 mg/d, i.v. in the healing of reflux oesophagitis, and that 40 mg pantoprazole p.o. and i.v. formulations are equivalent in their ability to suppress gastric acid output. Pantoprazole treatment in these studies was well tolerated and had a favourable benefit-risk ratio. For the Zollinger Ellison syndrome and other pathological hypersecretory conditions, two studies showed that pantoprazole 80 mg i.v. bid for up to 6 days was efficacious and safe for controlling gastric acid. A further study in patients with ZES under stable oral PPI therapy showed that a switch to pantoprazole i.v. at doses of 80 mg up to 120 mg every 8 to 12 hours was able to control acid output. The CHMP considered that the proven clinical efficacy of pantoprazole 40 mg p.o. and the documented equivalence of pantoprazole 40 mg p.o. and pantoprazole 40 mg i.v. justify use in the treatment of moderate and severe reflux oesophagitis, duodenal ulcer, gastric ulcer and ZES and other pathological hypersecretory conditions. The CHMP noted that all the indications have been previously fully justified and adopted three harmonised therapeutic indications for the 40 mg intravenous formulation. Section 4.2 - Posology and method of administration Pantoprazole 20 mg gastro-resistant tablets The CHMP noted the MAH proposal and adopted a harmonised text for this section. It was noted that concomitant intake of food had no influence on AUC and maximum serum concentration but that the variability of the lag-time will be increased. Instructions that the tablets should not be chewed or crushed, and should be swallowed whole 1 hour before a meal with some water was harmonised. The safety in long-term treatment was discussed and the data collected since the original licensing of the product is re-assuring for long-term safety.

25

Treatment for 2 to 4 weeks usually results in relief of symptoms and if this is not sufficient, symptom relief will normally be achieved within a further 4 weeks in patients 12 years and above. When symptom relief has been achieved, reoccurring symptoms can be controlled using an on-demand regimen of 20 mg once daily, when required. It was considered that patients under long-term treatment should be kept under regular surveillance, especially when exceeding a treatment period of 1 year. Regarding use in adolescents and the safety and efficacy in children, Protium is not recommended for use in children below 12 years of age due to limited data on safety and efficacy in this age group. Regarding on-demand treatment, data shows that pantoprazole at a daily dose of 20 mg for 4 weeks is effective and safe in the treatment of mild GERD and its associated symptoms and that an extension of treatment duration to 8 weeks resulted in an increase in cumulative healing rates. The CHMP agreed that on demand treatment is an appropriate option for symptomatic gastro-oesophageal reflux disease. Regarding special populations, the CHMP noted that for patients with hepatic impairment, specific information related to monitoring liver enzymes and discontinuation of treatment in severe liver impairment is available and concluded that a daily dose of 20 mg pantoprazole should not be exceeded. No dose adjustment is considered necessary for patients with renal impairment and elderly patients as the primary route of elimination for pantoprazole is hepatic, thus elimination of pantoprazole is minimally affected by renal dysfunction and the slight increase in AUC and Cmax in elderly compared with younger volunteers is not considered clinically relevant. Pantoprazole 40 mg gastro-resistant tablets The CHMP noted the MAH proposal and adopted a harmonised text for this section. The recommendation on how to take the tablets was aligned with the 20 mg formulation. The dose, schedule and duration of treatment are in line with the clinical practices. Expert opinions are unanimous in recommending twice-daily dosing of PPIs to improve symptom relief in patients with an oesophageal GERD syndrome with an unsatisfactory response to once daily treatment. The provided meta-analyses and controlled clinical studies support the efficacy of the proposed H. Pylori eradication combinations but with wide divergences between member states. Clarithromycin, metronidazole, tinidazole and amoxicillin are widely used in Europe for eradication of H. Pylori, however the prevalence of antimicrobial resistance in H. pylori shows regional variability and alternative antibiotics based on local resistance rates may improve eradication rates. Similarly, the most effective length of treatment is debated as European guidelines contradict recent studies, which may reflect varying resistance rates within the populations studied. Currently, triple therapy for seven days is still a valid and cost effective duration of treatment. The CHMP considered that the optimal duration is one week, and that another course of seven days might be recommended in individual cases. The text referring to “official local guidance” is agreed as it allows the inclusion of alternative antibiotics without stating all the alternatives used nationally. Based on the available data from clinical trials, the harmonised dosage guidelines for monotherapy where combination therapy is not an option and the posology for Zollinger-Ellison syndrome and other pathological hypersecretory conditions were considered justified. In line with the assessment of the 20 mg gastro-resistant tablets, Protium is not recommended in children below 12 years. The CHMP also stated that a daily dose of 20 mg pantoprazole should not be exceeded in patients with severe liver impairment. For patients with impaired renal function, no dose adjustment is necessary as the primary route of elimination of pantoprazole is hepatic; therefore, elimination is minimally affected by renal dysfunction. Protium should not be used in combination treatment for eradication of H. pylori in patients with impaired renal function or moderate to severe hepatic dysfunction since currently no data is available on the efficacy and safety in combination treatment for these patients. Regarding elderly patients, and patients with mild hepatic impairment, no dose adjustment is necessary.

26

Pantoprazole 40 mg i.v. The CHMP noted the MAH proposal and adopted a harmonised text for this section. The dose and schedule for the indications is appropriate, based on the available data with pantoprazole 40 mg p.o. and the pharmacodynamic and therapeutic equivalence of pantoprazole 40 mg i.v. The experience in children is limited and therefore Protium i.v. 40 mg powder for solution for injection is not recommended in patients below 18 years of age until further data become available. Dose recommendations in special populations were inserted in section 4.2. For patients with hepatic impairment, only a maximum of 20 mg daily is recommended although the proposed posology of 40 mg on alternate days can not be supported as the lack of efficacy data has not been addressed. Section 4.3 – Contraindications For the pantoprazole 20 mg tablets, the CHMP noted the MAH proposal and adopted a harmonised text. In particular, the interaction between atazanavir and others PPIs has been moved to Sections 4.4 and 4.5. The literature shows that this interaction exists and is related to changes in gastric pH that can lead to a reduction in the bioavailability of atazanavir and other HIV medications whose absorption is pH-dependent. However, as it can be overcome, a contraindication is inappropriate. Co-administration of atazanavir with proton pump inhibitors is not recommended and if the combination of atazanavir with a proton pump inhibitor is judged unavoidable, close clinical monitoring is recommended while high doses of proton pump inhibitors should be avoided. Section 4.5 states that 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 efficacy. The CHMP did not consider it justified to contraindicate pantoprazole 20 mg in hepatically impaired patients. For the pantoprazole 40 mg tablet formulation, the CHMP noted the MAH proposal and adopted a harmonised text. The dosage of pantoprazole may need to be reduced in patients with severe hepatic impairment, and liver enzymes should be monitored regularly during treatment with pantoprazole. Since efficacy of low dose (20 mg) pantoprazole in triple therapy for the eradication of H. pylori has not been investigated, the use of Protium is considered contraindicated and the dose needed to eradicate this infection (40 mg twice daily) cannot be administrated to these patients. In order to reduce the risk in this population, the statement was moved to Section 4.2. Regarding hypersensitivity and concomitant use with atazanavir, the comments provided for the 20 mg tablet dose apply. For the pantoprazole 40 mg i.v. formulation, the CHMP noted the MAH proposal and adopted a harmonised text, in particular regarding hypersensitivity to the active substance or to any of the excipients. Regarding hypersensitivity and concomitant use with atazanavir, the comments provided for the 20 mg tablet dose apply. Section 4.4 - Special warnings and precautions for use The CHMP noted the MAH proposal for this section. The statement on a possible increase in gastrointestinal infections is supported by a case-control study comparing 6,414 patients with an episode of gastroenteritis (GE) with a healthy control group of 50,000 and showing that the use of PPIs is associated with an increased risk of bacterial GE, regardless of the treatment duration. Doubling the PPI dose further increased the risk of GE, with Campylobacter and Salmonella the most frequently responsible. The CHMP also noted that the published literature on the concomitant use of PPIs and clopidogrel suggests that clopidogrel may be less effective in patients receiving PPIs and requested the MAH to discuss this potential interaction. The MAH discussed the concomitant use of PPIs and clopidogrel, noting a trend towards a potential clinical interaction between PPIs and clopidogrel. However, the epidemiological studies were considered to be conflicting and heterogeneous and the clinical PD/PK studies failed to demonstrate any impact on the antiplatelet effect of clopidogrel on pantoprazole specifically, which was reassuring. The CHMP requested the input of the cardiovascular subgroup of the Efficacy Working Party (EWP-CVS) on this issue. The EWP-CVS concluded that there

27

was no evidence supporting an interaction between pantoprazole and clopidogrel. The CHMP therefore decided that a statement regarding this interaction was unwarranted. In conclusion, the CHMP adopted a harmonised text for section 4.4. Specifically for 20 mg tablets, a statement was inserted recommending that patients under long treatments should be kept under regular surveillance, especially when exceeding a treatment period of 1 year. Warnings related to prevention of gastroduodenal ulcers induced by NSAIDs were added. Specifically for the 40 mg tablets, information regarding patients with Zollinger-Ellison syndrome and other pathological hypersecretory conditions was included and the statement "Diagnosis of reflux oesophagitis should be confirmed by endoscopy" was removed as this is no longer the clinical practice. Warnings related to long term treatment and for prevention of gastroduodenal ulcers induced by NSAIDs were added, and the statement on hepatically impaired patients was maintained. Section 4.5 - Interaction with other medicinal products and other forms of interaction The CHMP noted the MAH proposal and adopted a harmonised text for this section. In particular, a description of the metabolic pathway which adequately reflects what is known about pantoprazole metabolism and a text on antibiotics interactions were adopted. The specific mention of levonorgestrel and ethinyl oestradiol is justified as a general extrapolation to the whole group of oral contraceptives cannot be made. The inclusion of substances for which an involvement of CYP 3A4 or CYP 2C19 is known (such as carbamazepine, diazepam, glibenclamide, and nifedipine) is justified. The inclusion of the substances diclofenac, naproxen, and piroxicam is justified by their recommended co-prescription according to the NSAID related ulcer prevention indication and are mentioned separately. The separate inclusion of caffeine and ethanol is justified by their widespread use. Section 4.6 - Pregnancy and Lactation The CHMP noted the MAH proposal and adopted a harmonised text for this section, applicable to all Protium formulations. Although one multi-centre study indicates that the use of PPIs during the first trimester of pregnancy is not associated with an increased teratogenic risk, clinical experience is limited during pregnancy. Therefore, pantoprazole should only be used when the benefit exceeds the potential risk. The same applies for the lactation period. Apart from a single case report which indicated a slight burden for the infant, further clinical experience is missing. Section 4.6 now states that “a decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Protium should be made taking into account the benefit of breast-feeding to the child and the benefit of Protium therapy to the woman.” Section 4.7 - Effects on ability to drive and use machines The CHMP noted the MAH proposal and adopted a harmonised text for this section, applicable to all Protium formulations. Because the MAH presented a study performed to provide information regarding the effects of pantoprazole on the ability to drive and use machines, Section 4.7 now states that “adverse drug reactions such as dizziness and visual disturbances may occur (see section 4.8). If affected, patients should not drive or operate machines.” Section 4.8 - Undesirable effects The CHMP noted the MAH proposal and adopted a harmonised text for this section, applicable to all Protium formulations. The general text of frequencies classification, and the adverse reaction obtained from postmarketing experience were clarified, and the frequency of a number of events was revised. In particular, gynaecomastia was added to the list of undesirable effects. The method and the statistical approach together with the data provided were reviewed and the CHMP considered the estimated frequency to be appropriate.

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Section 4.9 – Overdose The CHMP noted the MAH proposal and adopted a harmonised text for this section. In particular, no particular risks regarding overdosing are anticipated and the MAH quoted a number of studies showing that doses of 120 mg/d, po. and even up to 320 mg/d, p.o. for years in single patients and 240 mg i.v. were well tolerated. Section 5 – Pharmacological properties The CHMP adopted a harmonised text for all sections under Section 5. In particular, the text on the general pharmacokinetics, the bioavailability, the characteristics in patients/special groups of subjects and the characteristics in patients/special groups of subjects and in children was harmonized. Under Section 6.6, for the i.v. formulation, a text with detailed information on the reconstitution of the solution and on the special precautions was adopted. CMC Harmonisation The MAH submitted the module 2.3 for pantoprazole gastro-resistant tablets 20 and 40mg dated March 2009 and for pantoprazole powder for solution for injection dated December 2008 as well as the module 3 for pantoprazole gastro-resistant tablets 20 and 40mg and for pantoprazole powder for solution for injection dated April 2009. The dossier for the Drug Substance was harmonised and the CHMP noted the Ph. Eur. monograph. The CHMP considered the general information of drug substance to be acceptable. In general, the elucidation of structure, the batch testing, the specifications and the stability tests were considered acceptable. Similarly, the dossier for the Drug Product (gastro-resistant tablets) was harmonised. Tablet characterisation, excipient compliance with the requirements of the Ph. Eur, specifications for dissolution, tests on colorants, stress and impurities, certificates of analysis of the reference substances and packaging and containers are considered generally acceptable. Finally, the dossier for the Drug Product (powder for solution for injection) was harmonised. The pharmaceutical development, the description of the manufacturers and their activities, the packaging and containers, the excipients used, the release specifications, the lower assay limit in drug product shelf-life specifications, the inclusion of related substances, the peak purity test, the reference standards of the drug substance and related substances and the stability of the drug product are considered generally acceptable. For Module 1, the submitted current manufacturing authorisations for all manufacturers of the drug products in EU countries and GMP certificates of EU inspectorates for manufacturers of the drug products in non-EU countries, together with the declaration of the QP of the manufacturer for drug product release in the EU were considered acceptable. In conclusion, the provided information was in general adequate; however, a number of unresolved minor concerns were identified. The CHMP is of the opinion that a commitment to address these concerns is sufficient, and to reduce administrative work, a common time of 1 year after the issue of the EC decision is proposed for all response documents to be handed in as a single data package (see Annex IV). In conclusion, the harmonisation procedure led to the adoption by the CHMP of a harmonised set of Product Informations for the three Protium formulations included in the scope and the CHMP was of the opinion that the benefit/risk ratio of Protium and associated names is considered to be favourable. In summary, the CHMP adopted the following sets of indications for Protium and associated names: 20 mg gastro-resistant tablets

• Symptomatic gastro-oesophageal reflux disease • For long-term management and prevention of relapse in reflux oesophagitis

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• 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)

40 mg gastro-resistant tablets

• Reflux oesophagitis • 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

Intravenous (i.v.) 40 mg powder for solution for injection

• Reflux oesophagitis • Gastric and duodenal ulcer • Zollinger-Ellison-Syndrome and other pathological hypersecretory conditions

GROUNDS FOR AMENDMENT OF THE SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE LEAFLET Whereas - the scope of the referral was the harmonisation of the Summary of Products Characteristics, labelling and package leaflet. - the Summary of Products Characteristic, labelling and package leaflet proposed by the Marketing Authorisation Holders have been assessed based on the documentation submitted and the scientific discussion within the Committee, the CHMP has recommended the amendment of the Marketing Authorisations for which the Summary of Product Characteristics, labelling and package leaflet are set out in Annex III for Protium and associated names (see Annex I). The recommend conditions of the Marketing Authorisations are listed in Annex IV.

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ANNEX III

SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE LEAFLET

Note: This SPC, labelling and packages leaflet is the version valid at the time of Commission Decision.

After the Commission Decision the Member State Competent Authorities, in liaison with the

Reference Member State, will update the product information as required. Therefore, this SPC, labelling and package leaflet may not necessarily represent the current text.

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SUMMARY OF PRODUCT CHARACTERISTICS

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1. NAME OF THE MEDICINAL PRODUCT Protium and associated names (see Annex I) 20 mg gastro-resistant tablets [See Annex I - To be completed nationally] 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each gastro-resistant tablet contains 20 mg of pantoprazole (as sodium sesquihydrate).

Excipient Each gastro-resistant tablet contains 1.06 microgram soya oil. For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Gastro-resistant tablet (tablet). Yellow, oval biconvex film coated tablet imprinted with “P20” in brown ink on one side. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Adults and adolescents 12 years of age and above Symptomatic gastro-oesophageal reflux disease. For long-term management and prevention of relapse in reflux oesophagitis. Adults 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 Tablets should not be chewed or crushed, and should be swallowed whole 1 hour before a meal with some water. Recommended dose Adults and adolescents 12 years of age and above Symptomatic gastro-oesophageal reflux disease The recommended oral dose is one gastro-resistant tablet Protium 20 mg per day. Symptom relief is generally accomplished within 2-4 weeks. If this is not sufficient, symptom relief 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

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For long-term management, a maintenance dose of one gastro-resistant tablet Protium 20 mg per day is recommended, increasing to 40 mg pantoprazole per day if a relapse occurs. Protium 40 mg is available for this case. After healing of the relapse the dose can be reduced again to 20 mg pantoprazole. Adults 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 oral dose is one gastro-resistant tablet Protium 20 mg per day. Special populations Children below 12 years of age Protium is not recommended for use in children below 12 years of age due to limited data on safety and efficacy in this age group. Hepatic Impairment A daily dose of 20 mg pantoprazole should not be exceeded in patients with severe liver impairment (see section 4.4). Renal Impairment No dose adjustment is necessary in patients with impaired renal function. Elderly No dose adjustment is necessary in elderly patients. 4.3 Contraindications Hypersensitivity to the active substance, substituted benzimidazoles, soya oil or to any of the other excipients. 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). Co-administration with NSAIDs The use of Protium 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. 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

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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 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. 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 Protium may lead to a slightly increased risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter. Soya oil This medicinal product contains soya oil. If the patient is allergic to peanut or soya, do not use this medicinal product (see section 4.3). 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.g some 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 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). 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. 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 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.

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Results from a range of interaction studies demonstrate that pantoprazole does not effect 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. 4.6 Pregnancy and lactation Pregnancy There are no adequate data from the use of pantoprazole in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Protium should not be used during pregnancy unless clearly necessary. Lactation Animal 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 Protium should be made taking into account the benefit of breast-feeding to the child and the benefit of Protium 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. 4.8 Undesirable effects 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 Frequency System Organ Class

Uncommon Rare Very rare Not known

Blood and lymphatic system disorders

Thrombocytopenia; Leukopenia

Immune system Hypersensitivity

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Frequency System Organ Class


disorders (including anaphylactic reactions and anaphylactic shock)

Metabolism and nutrition disorders

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

Hyponatraemia

Psychiatric disorders

Sleep disorders Depression (and all aggravations)

Disorientation (and all aggravations)

Hallucination; Confusion (especially in pre-disposed patients, as well as the aggra-vation of these symptoms in case of pre-existence)

Nervous system disorders

Headache; Dizziness

Eye disorders Disturbances in vision / blurred vision

Gastrointestinal disorders

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

Hepatobiliary disorders

Liver enzymes increased (transaminases, γ-GT)

Bilirubin increased Hepatocellular injury; Jaun-dice; Hepato-cellular failure

Skin and sub-cutaneous tissue disorders

Rash / exanthema / eruption; Pruritus

Urticaria; Angioedema

Stevens-John-son syndrome; Lyell syndrome; Erythema multiforme; Photosensitivity

Musculoskeletal and connective tissue disorders

Arthralgia; Myalgia

Renal and urinary Interstitial

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disorders nephritis Reproductive system and breast disorders

Gynaecomastia

General disorders and administration site conditions

Asthenia, fatigue and malaise

Body temperature increased; Oedema peripheral

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 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 Mechanism of action Pantoprazole is a substituted benzimidazole which inhibits the secretion of hydrochloric acid in the stomach by specific blockade of the proton pumps of the parietal cells. Pantoprazole is converted to its active form in the acidic environment in 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 within 2 weeks. As with other proton pump inhibitors and H2 receptor inhibitors, treatment with pantoprazole reduces acidity in the stomach and thereby increases 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, it can inhibit hydrochloric acid secretion independently of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same whether the product is given orally or intravenously. The fasting gastrin values increase under pantoprazole. On short-term use, in most cases they do not exceed the upper limit of normal. 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) have not been observed in humans. An influence of a long term treatment with pantoprazole exceeding one year cannot be completely ruled out on endocrine parameters of the thyroid according to results in animal studies.

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5.2 Pharmacokinetic properties Absorption Pantoprazole is rapidly absorbed and the maximal plasma concentration is achieved even after one single 20 mg oral dose. On average at about 2.0 h - 2.5 h p.a. the maximum serum concentrations of about 1-1.5 µg/ml are achieved, and these values remain constant after multiple administration. 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. 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. Distribution Pantoprazole's serum protein binding is about 98 %. Volume of distribution is about 0.15 l/kg Elimination The substance is almost exclusively metabolized in the liver. The main metabolic pathway is demethylation by CYP2C19 with subsequent sulphate conjugation, other metabolic pathway include oxidation by CYP3A4. Terminal half-life is about 1 hour and clearance is about 0.1 l/h/kg. 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). 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 hours) is not much longer than that of pantoprazole. Characteristics in patients/special groups of subjects Approximately 3 % of the European population lack a functional CYP2C19 enzyme and are called poor metabolisers. In these individuals the metabolism of pantoprazole is probably mainly catalysed by CYP3A4. After a single-dose administration of 40 mg pantoprazole, the mean area under the plasma concentration-time curve was approximately 6 times higher in poor metabolisers than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations were increased by about 60 %. These findings have no implications for the posology of pantoprazole. No dose reduction is recommended when pantoprazole is administered to patients with impaired renal function (including dialysis patients). As with healthy subjects, pantoprazole's half-life is short. Only very small amounts of pantoprazole are dialyzed. Although the main metabolite has a moderately delayed half-life (2 - 3h), excretion is still rapid and thus accumulation does not occur. 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 or 40 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.

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5.3 Preclinical safety data Preclinical data reveal no special hazard to humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity. In the two-year carcinogenicity studies 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 the two-year rodent studies an increased number of liver tumors was observed in rats 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). 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 harmful effects on the thyroid glands are expected. In animal reproduction studies, signs of slight fetotoxicity were observed at doses above 5 mg/kg. 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 Core: Sodium carbonate, anhydrous Mannitol (E421) Crospovidone Povidone K90 Calcium stearate Coating: Hypromellose Povidone K25 Titanium dioxide (E171) Yellow iron oxide (E172) Propylene glycol Methacrylic acid-ethyl acrylate copolymer (1:1) Polysorbate 80 Sodium laurilsulfate Triethyl citrate Printing ink: Shellac Red iron oxide (E172) Black iron oxide (E172) Yellow iron oxide (E172) Soya lecithin Titanium dioxide (E171) Antifoam DC 1510 (dimeticone emulsion)

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6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container HDPE bottles with LDPE screw cap closure. 7 gastro-resistant tablets 10 gastro-resistant tablets 14 gastro-resistant tablets 15 gastro-resistant tablets 24 gastro-resistant tablets 28 gastro-resistant tablets 30 gastro-resistant tablets 48 gastro-resistant tablets 49 gastro-resistant tablets 56 gastro-resistant tablets 60 gastro-resistant tablets 84 gastro-resistant tablets 90 gastro-resistant tablets 98 gastro-resistant tablets 98 (2x49) gastro-resistant tablets 100 gastro-resistant tablets 112 gastro-resistant tablets 168 gastro-resistant tablets Hospital pack with 50 gastro-resistant tablets 56 gastro-resistant tablets

84 gastro-resistant tablets 90 gastro-resistant tablets 112 gastro-resistant tablets 140 gastro-resistant tablets

140 (10x14) (5x28) gastro-resistant tablets 150 (10x15) gastro-resistant tablets 280 (20x14), (10x28) gastro-resistant tablets 500 gastro-resistant tablets 700 (5x140) gastro-resistant tablets Blister (ALU/ALU blister) without cardboard reinforcement. Blister (ALU/ALU blister) with cardboard reinforcement (blister wallet). 7 gastro-resistant tablets 10 gastro-resistant tablets 14 gastro-resistant tablets

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15 gastro-resistant tablets 28 gastro-resistant tablets 30 gastro-resistant tablets 49 gastro-resistant tablets 56 gastro-resistant tablets 60 gastro-resistant tablets 84 gastro-resistant tablets 90 gastro-resistant tablets 98 gastro-resistant tablets 98 (2x49) gastro-resistant tablets 100 gastro-resistant tablets 112 gastro-resistant tablets 168 gastro-resistant tablets Hospital pack with 50 gastro-resistant tablets 56 gastro-resistant tablets

84 gastro-resistant tablets 90 gastro-resistant tablets 112 gastro-resistant tablets 140 gastro-resistant tablets

140 (10x14) (5x28) gastro-resistant tablets 150 (10x15) gastro-resistant tablets 280 (20x14), (10x28) gastro-resistant tablets 500 gastro-resistant tablets 700 (5x140) gastro-resistant tablets Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements. Any unused product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] {Name and address} <{tel}> <{fax}> <{e-mail}> 8. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION {DD/MM/YYYY}

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[To be completed nationally] 10. DATE OF REVISION OF THE TEXT {MM/YYYY} [To be completed nationally] Detailed information on this medicinal product is available on the website of the Heads of Medicines Agencies (HMA) http://www.hma.eu

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1. NAME OF THE MEDICINAL PRODUCT Protium and associated names (see Annex I) 40 mg gastro-resistant tablets [See Annex I - To be completed nationally] 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each gastro-resistant tablet contains 40 mg of pantoprazole (as sodium sesquihydrate). Excipient Each gastro-resistant tablet contains 1.06 microgram soya oil. For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Gastro-resistant tablet (tablet). Yellow, oval, biconvex film-coated tablet imprinted with “P 40” in brown ink on one side. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Adults and adolescents 12 years of age and above − Reflux oesophagitis. Adults − 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 Tablets should not be chewed or crushed, and should be swallowed whole 1 hour before a meal with some water. Recommended dose Adults and adolescents 12 years of age and above Reflux oesophagitis One tablet of Protium per day. In individual cases the dose may be doubled (increase to 2 tablets Protium 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

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agents. Depending upon the resistance pattern, the following combinations can be recommended for the eradication of H. pylori: a) twice daily one tablet Protium

+ twice daily 1000 mg amoxicillin + twice daily 500 mg clarithromycin

b) twice daily one tablet Protium

+ twice daily 400 - 500 mg metronidazole (or 500 mg tinidazole) + twice daily 250 - 500 mg clarithromycin

c) twice daily one tablet Protium

+ twice daily 1000 mg amoxicillin + twice daily 400 - 500 mg metronidazole (or 500 mg tinidazole)

In combination therapy for eradication of H. pylori infection, the second Protium 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 Protium monotherapy: Treatment of gastric ulcer One tablet of Protium per day. In individual cases the dose may be doubled (increase to 2 tablets Protium 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 Protium per day. In individual cases the dose may be doubled (increase to 2 tablets Protium 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 80 mg (2 tablets of Protium 40 mg). 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. Treatment duration in Zollinger-Ellison syndrome and other pathological hypersecretory conditions is not limited and should be adapted according to clinical needs. Special populations Children below 12 years of age Protium is not recommended for use in children below 12 years of age due to limited data on safety and efficacy in this age group. Hepatic Impairment

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A daily dose of 20 mg pantoprazole (1 tablet of 20 mg pantoprazole) should not be exceeded in patients with severe liver impairment. Protium 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 Protium in combination treatment of these patients (see section 4.4). Renal Impairment No dose adjustment is necessary in patients with impaired renal function. Protium 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 Protium in combination treatment for these patients. Elderly No dose adjustment is necessary in elderly patients. 4.3 Contraindications Hypersensitivity to the active substance, substituted benzimidazoles, soya oil or to any of the other excipients or of the combination partners. 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 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.

46

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 Protium may lead to a slightly increased risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter. Soya oil This medicinal product contains soya oil. If the patient is allergic to peanut or soya, do not use this medicinal product (see section 4.3). 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.g some 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 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). 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. 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 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 effect 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. 4.6 Pregnancy and lactation Pregnancy

47

There are no adequate data from the use of pantoprazole in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Protium should not be used during pregnancy unless clearly necessary. Lactation Animal 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 Protium should be made taking into account the benefit of breast-feeding to the child and the benefit of Protium 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. 4.8 Undesirable effects 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 Frequency System Organ Class



Thrombocytopenia; Leukopenia

Immune system disorders

Hypersensitivity (including anaphylactic reactions and anaphylactic shock)



Hyponatraemia


Sleep disorders Depression (and all aggravations)

Disorientation (and all aggravations)

Hallucination; Confusion (especially in pre-disposed

48



patients, as well as the aggravation of these symptoms in case of pre-existence)


Headache; Dizziness






Bilirubin increased

Hepatocellular injury; Jaundice; Hepatocellular failure




Stevens-Johnson syndrome; Lyell syndrome; Erythema multiforme; Photosensitivity


Arthralgia; Myalgia

Renal and urinary disorders

Interstitial nephritis

Reproductive system and breast disorders

Gynaecomastia




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.

49

In the case of 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 Mechanism of action Pantoprazole is a substituted benzimidazole which inhibits the secretion of hydrochloric acid in the stomach by specific blockade of the proton pumps of the parietal cells. Pantoprazole is converted to its active form in the acidic environment in 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 within 2 weeks. As with other proton pump inhibitors and H2 receptor inhibitors, treatment with pantoprazole reduces acidity in the stomach and thereby increases 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, it can inhibit hydrochloric acid secretion independently of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same whether the product is given orally or intravenously. The fasting gastrin values increase under pantoprazole. On short-term use, in most cases they do not exceed the upper limit of normal. 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) have not been observed in humans. An influence of a long term treatment with pantoprazole exceeding one year cannot be completely ruled out on endocrine parameters of the thyroid according to results in animal studies. 5.2 Pharmacokinetic properties Absorption Pantoprazole is rapidly absorbed and the maximal plasma concentration is achieved even after one single 40 mg oral dose. On average at about 2.5 h p.a. the maximum serum concentrations of about 2 - 3 µg/ml are achieved, and these values remain constant after multiple administration. 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. 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. Distribution Pantoprazole's serum protein binding is about 98 %. Volume of distribution is about 0.15 l/kg Elimination The substance is almost exclusively metabolized in the liver. The main metabolic pathway is demethylation by CYP2C19 with subsequent sulphate conjugation, other metabolic pathway include oxidation by CYP3A4. Terminal half-life is about 1 hour and clearance is about 0.1 l/h/kg. There were a

50

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). 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 hours) is not much longer than that of pantoprazole. Characteristics in patients/special groups of subjects Approximately 3 % of the European population lack a functional CYP2C19 enzyme and are called poor metabolisers. In these individuals the metabolism of pantoprazole is probably mainly catalysed by CYP3A4. After a single-dose administration of 40 mg pantoprazole, the mean area under the plasma concentration-time curve was approximately 6 times higher in poor metabolisers than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations were increased by about 60 %. These findings have no implications for the posology of pantoprazole. No dose reduction is recommended when pantoprazole is administered to patients with impaired renal function (including dialysis patients). As with healthy subjects, pantoprazole's half-life is short. Only very small amounts of pantoprazole are dialyzed. Although the main metabolite has a moderately delayed half-life (2 - 3 h), excretion is still rapid and thus accumulation does not occur. Although for patients with liver cirrhosis (classes A and B according to Child) the half-life values increased to between 7 and 9 h and the AUC values increased by a factor of 5 - 7, the maximum serum concentration only increased slightly by a factor of 1.5 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 or 40 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 Preclinical data reveal no special hazard to humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity. In the two-year carcinogenicity studies 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 the two-year rodent studies an increased number of liver tumors was observed in rats 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). 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 harmful effects on the thyroid glands are expected. In animal reproduction studies, signs of slight fetotoxicity were observed at doses above 5 mg/kg.

51

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 Core: Sodium carbonate, anhydrous Mannitol (E421) Crospovidone Povidone K90 Calcium stearate Coating: Hypromellose Povidone K25 Titanium dioxide (E171) Yellow iron oxide (E172) Propylene glycol Methacrylic acid-ethyl acrylate copolymer (1:1) Polysorbate 80 Sodium laurilsulfate Triethyl citrate Printing ink: Shellac Red iron oxide (E172) Black iron oxide (E172) Yellow iron oxide (E172) Soya lecithin Titanium dioxide (E171) Antifoam DC 1510 (dimeticone emulsion) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container HDPE bottles with LDPE screw cap closure. 7 gastro-resistant tablets 10 gastro-resistant tablets

52

14 gastro-resistant tablets 15 gastro-resistant tablets 24 gastro-resistant tablets 28 gastro-resistant tablets 30 gastro-resistant tablets 48 gastro-resistant tablets

49gastro-resistant tablets 56 gastro-resistant tablets 60 gastro-resistant tablets 84 gastro-resistant tablets 90 gastro-resistant tablets 98 gastro-resistant tablets 98 (2x49) gastro-resistant tablets 100 gastro-resistant tablets 112 gastro-resistant tablets 168 gastro-resistant tablets Hospital pack with 50 gastro-resistant tablets 90 gastro-resistant tablets

100 gastro-resistant tablets 140 gastro-resistant tablets 140 (10x14) gastro-resistant tablets 150 (10x15) gastro-resistant tablets 700 (5x140) gastro-resistant tablets Blister (ALU/ALU blister) without cardboard reinforcement. Blister (ALU/ALU blister) with cardboard reinforcement (blister wallet). 7 gastro-resistant tablets 10 gastro-resistant tablets 14 gastro-resistant tablets 15 gastro-resistant tablets 28 gastro-resistant tablets 30 gastro-resistant tablets

49gastro-resistant tablets 56 gastro-resistant tablets 60 gastro-resistant tablets 84 gastro-resistant tablets 90 gastro-resistant tablets 98 gastro-resistant tablets 98 (2x49) gastro-resistant tablets 100 gastro-resistant tablets 112 gastro-resistant tablets 168 gastro-resistant tablets Hospital pack with 50 gastro-resistant tablets 90 gastro-resistant tablets 100 gastro-resistant tablets 140 gastro-resistant tablets 140 (10x14) gastro-resistant tablets 150 (10x15) gastro-resistant tablets 700 (5x140) gastro-resistant tablets

53

Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements. Any unused product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] {Name and address} <{tel}> <{fax}> <{e-mail}> 8. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION {DD/MM/YYYY} [To be completed nationally] 10. DATE OF REVISION OF THE TEXT {MM/YYYY} [To be completed nationally] Detailed information on this medicinal product is available on the website of the Heads of Medicines Agencies (HMA) http://www.hma.eu

54

1. NAME OF THE MEDICINAL PRODUCT Protium and associated names (see Annex I) 40 mg powder for solution for injection [See Annex I - To be completed nationally] 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each vial contains 40 mg of pantoprazole (as sodium sesquihydrate). Excipients Each vial contains 1 mg disodium edetate and 0.24 mg sodium hydroxide. This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. is essentially ‘sodium-free’. For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Powder for solution for injection. White to off-white powder. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications - Reflux oesophagitis. - Gastric and duodenal ulcer. - Zollinger-Ellison-Syndrome and other pathological hypersecretory 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. Recommended dose 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 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 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.

55

Special populations Paediatric patients The experience in children is limited. Therefore, Protium 40 mg powder for solution for injection is not recommended for use in patients below 18 years of age until further data become available. 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). Renal Impairment No dose adjustment is necessary in patients with impaired renal function. Elderly No dose adjustment is necessary in elderly patients. 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 55 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. 4.4 Special warnings and precautions for use 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 Protium may lead to a slightly increased risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter.

56

Sodium This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. is essentially ‘sodium-free’. 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.g some 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 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). 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. 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 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 effect 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. 4.6 Pregnancy and lactation Pregnancy There are no adequate data from the use of pantoprazole in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Protium should not be used during pregnancy unless clearly necessary. Lactation

57

Animal 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 Protium should be made taking into account the benefit of breast-feeding to the child and the benefit of Protium 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. 4.8 Undesirable effects 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 Frequency System Organ Class

Common Uncommon Rare Very rare Not known


Thrombo-cytopenia; Leukopenia

Immune system disorders

Hypersensitivity (including anaphylactic reactions and anaphylactic shock)



Hyponatrae-mia


Sleep disorders

Depression (and all aggravations)

Disorien-tation (and all aggrava-tions)

Hallucination; Confusion (especially in pre-disposed patients, as well as the aggravation of these sym-

58


Common Uncommon Rare Very rare Not known

ptoms in case of pre-exis-tence)


Headache; Dizziness






Bilirubin increased

Hepatocellular injury; Jaun-dice; Hepato-cellular failure




Stevens-John-son syndrome; Lyell syn-drome; Ery-thema multi-forme; Photo-sensitivity


Arthralgia; Myalgia

Renal and urinary disorders

Interstitial nephritis

Reproductive system and breast disorders

Gynaecomastia


Injection site thrombo-phlebitis



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.

59

In the case of 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 Mechanism of action Pantoprazole is a substituted benzimidazole which inhibits the secretion of hydrochloric acid in the stomach by specific blockade of the proton pumps of the parietal cells. Pantoprazole is converted to its active form in the acidic environment in 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 within 2 weeks. As with other proton pump inhibitors and H2 receptor inhibitors, treatment with pantoprazole reduces acidity in the stomach and thereby increases 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, it can inhibit hydrochloric acid secretion independently of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same whether the product is given orally or intravenously. The fasting gastrin values increase under pantoprazole. On short-term use, in most cases they do not exceed the upper limit of normal. 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) have not been observed in humans. An influence of a long term treatment with pantoprazole exceeding one year cannot be completely ruled out on endocrine parameters of the thyroid according to results in animal studies. 5.2 Pharmacokinetic properties General pharmacokinetics 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. Distribution Pantoprazole's serum protein binding is about 98 %. Volume of distribution is about 0.15 l/kg Elimination The substance is almost exclusively metabolized in the liver. The main metabolic pathway is demethylation by CYP2C19 with subsequent sulphate conjugation, other metabolic pathway include oxidation by CYP3A4. Terminal half-life is about 1 hour and clearance is about 0.1 l/h/kg. 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). 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

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desmethylpantoprazole which is conjugated with sulphate. The half-life of the main metabolite (about 1.5 hours) is not much longer than that of pantoprazole. Characteristics in patients/special groups of subjects Approximately 3 % of the European population lack a functional CYP2C19 enzyme and are called poor metabolisers. In these individuals the metabolism of pantoprazole is probably mainly catalysed by CYP3A4. After a single-dose administration of 40 mg pantoprazole, the mean area under the plasma concentration-time curve was approximately 6 times higher in poor metabolisers than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations were increased by about 60 %. These findings have no implications for the posology of pantoprazole. No dose reduction is recommended when pantoprazole is administered to patients with impaired renal function (incl. dialysis patients). As with healthy subjects, pantoprazole's half-life is short. Only very small amounts of pantoprazole are dialyzed. Although the main metabolite has a moderately delayed half-life (2 - 3 h), excretion is still rapid and thus accumulation does not occur. Although for patients with liver cirrhosis (classes A and B according to Child) the half-life values increased to between 7 and 9 h and the AUC values increased by a factor of 5 - 7, the maximum serum concentration only increased slightly by a factor of 1.5 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 intravenous 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 Preclinical data reveal no special hazard to humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity. In the two-year carcinogenicity studies 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 the two-year rodent studies an increased number of liver tumors was observed in rats 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). 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 harmful effects on the thyroid glands are expected. In animal reproduction studies, signs of slight fetotoxicity were observed at doses above 5 mg/kg. 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

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Disodium edetate Sodium hydroxide (for pH adjustment) 6.2 Incompatibilities This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6. 6.3 Shelf life Unopened vial: 2 years After reconstitution, or reconstitution and dilution, chemical and physical in use stability has been demonstrated for 12 hours at 25 °C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user. 6.4 Special precautions for storage Do not store above 25 °C. Keep the vial in the outer carton in order to protect from light. For storage conditions of the reconstituted and diluted medicinal product see section 6.3. 6.5 Nature and contents of container 10 ml clear glass (type I) vial with aluminum cap and grey rubber stopper containing 40 mg powder for solution for injection. Pack sizes of 1 vial and 5 (5x1) vials with powder for solution for injection. Hospital packs: 1 vial, 5 (5x1) vials, 10 (10x1) vials and 20 (20x1) vials with powder for solution for injection. Not all pack sizes may be marketed. 6.6 Special precautions for disposal A ready-to-use solution is prepared by injecting 10 ml of sodium chloride 9 mg/ml (0.9 %) solution for injection into the vial containing the powder. The appearance of the product after reconstitution is a clear yellowish solution. This 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 55 mg/ml (5 %) solution for injection. Glass or plastic containers should be used for dilution. After reconstitution, or reconstitution and dilution, chemical and physical in use stability has been demonstrated for 12 hours at 25 °C. From a microbiological point of view, the product should be used immediately. Protium should not be prepared or mixed with solvents other than those stated. The medicine should be administered intravenously over 2-15 minutes. The contents of the vial are for single use only. Any product that has remained in the container or the visual appearance of which has changed (e.g. if cloudiness or precipitation is observed) should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER

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[See Annex I - To be completed nationally] {Name and address} <{tel}> <{fax}> <{e-mail}> 8. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION {DD/MM/YYYY} [To be completed nationally] 10. DATE OF REVISION OF THE TEXT {MM/YYYY} [To be completed nationally] Detailed information on this medicinal product is available on the website of the Heads of Medicines Agencies (HMA) http://www.hma.eu

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LABELLING

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING Carton 1. NAME OF THE MEDICINAL PRODUCT Protium and associated names (see Annex I) 20 mg gastro-resistant tablets [See Annex I - To be completed nationally] Pantoprazole 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains 20 mg of pantoprazole (as sodium sesquihydrate). 3. LIST OF EXCIPIENTS Contains soya oil. See the package leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Pack with 7, 10, 14, 15, 24, 28, 30, 48, 49, 56, 60, 84, 90, 98, 98 (2x49), 100, 112, 168 gastro-resistant tablets. Hospital pack with 50, 56, 84, 90, 112, 140, 140 (10x14 or 5x28), 150 (10x15), 280 (20x14 or 10x28), 500, 700 (5x140) gastro-resistant tablets. (Part of a) hospital pack - not to be sold separately. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. Swallow whole, do not chew. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF

THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP

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9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] {Name and Address} <{tel}> <{fax}> <{e-mail}> 12. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 13. BATCH NUMBER Batch 14. GENERAL CLASSIFICATION FOR SUPPLY [To be completed nationally] 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE [To be completed nationally]

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PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING Blister wallet 1. NAME OF THE MEDICINAL PRODUCT Protium and associated names (see Annex I) 20 mg gastro-resistant tablets [See Annex I - To be completed nationally] Pantoprazole 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each gastro-resistant tablet contains 20 mg of pantoprazole (as sodium sesquihydrate). 3. LIST OF EXCIPIENTS Contains soya oil. See the package leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Pack with 5 gastro-resistant tablets. Pack with 7 gastro-resistant tablets. (Part of a) hospital pack - not to be sold separately. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. Swallow whole, do not chew. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF


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9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] {Name and Address} <{tel}> <{fax}> <{e-mail}> 12. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 13. BATCH NUMBER Batch 14. GENERAL CLASSIFICATION FOR SUPPLY [To be completed nationally] 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS Blister 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Protium and associated names (see Annex I) 20 mg tablets [See Annex I - To be completed nationally] Pantoprazole 2. NAME OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] {Name} 3. EXPIRY DATE EXP 4. BATCH NUMBER Batch 5. OTHER

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PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING Bottle label 1. NAME OF THE MEDICINAL PRODUCT Protium and associated names (see Annex I) 20 mg gastro-resistant tablets [See Annex I - To be completed nationally] Pantoprazole 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each gastro-resistant tablet contains 20 mg of pantoprazole (as sodium sesquihydrate). 3. LIST OF EXCIPIENTS Contains soya oil. See the package leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Pack with 7, 10, 14, 15, 24, 28, 30, 48, 49, 56, 60, 84, 90, 98, 100, 112, 168 gastro-resistant tablets. Hospital pack with 50, 56, 84, 90, 112, 140, 140 (10x14 or 5x28), 150 (10x15), 280 (20x14 or 10x28), 500, 700 (5x140) gastro-resistant tablets. (Part of a) hospital pack - not to be sold separately. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. Swallow whole, do not chew. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF


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PARTICULARS TO APPEAR ON THE OUTER PACKAGING Carton 1. NAME OF THE MEDICINAL PRODUCT Protium and associated names (see Annex I) 40 mg gastro-resistant tablets [See Annex I - To be completed nationally] Pantoprazole 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains 40 mg of pantoprazole (as sodium sesquihydrate). 3. LIST OF EXCIPIENTS Contains soya oil. See the package leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Pack with 7, 10, 14, 15, 24, 28, 30, 48, 49, 56, 60, 84, 90, 98, 98 (2x49), 100, 112, 168 gastro-resistant tablets. Hospital pack with 50, 90, 100, 140, 140 (10x14), 150 (10x15), 700 (5x140) gastro-resistant tablets. (Part of a) hospital pack - not to be sold separately. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. Swallow whole, do not chew. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF


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PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING Blister wallet 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Protium and associated names (see Annex I) 40 mg gastro-resistant tablets [See Annex I - To be completed nationally] Pantoprazole 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each gastro-resistant tablet contains 40 mg of pantoprazole (as sodium sesquihydrate). 3. LIST OF EXCIPIENTS Contains soya oil. See the package leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Pack with 5 gastro-resistant tablets. Pack with 7 gastro-resistant tablets. (Part of a) hospital pack - not to be sold separately. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. Swallow whole, do not chew. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF


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9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] {Name and Address} <{tel}> <{fax}> <{e-mail}> 12. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 13. BATCH NUMBER Batch 14. GENERAL CLASSIFICATION FOR SUPPLY [To be completed nationally] 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS Blister 1. NAME OF THE MEDICINAL PRODUCT Protium and associated names (see Annex I) 40 mg tablets [See Annex I - To be completed nationally] Pantoprazole 2. NAME OF THE MARKETING AUTHORISATION [See Annex I - To be completed nationally] {Name} 3. EXPIRY DATE EXP 4. PHARMACEUTICAL FORM AND CONTENTS Batch 5. OTHER

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PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING Bottle Label 1. NAME OF THE MEDICINAL PRODUCT Protium and associated names (see Annex I) 40 mg gastro-resistant tablets [See Annex I - To be completed nationally] Pantoprazole 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each gastro-resistant tablet contains 40 mg of pantoprazole (as sodium sesquihydrate). 3. LIST OF EXCIPIENTS Contains soya oil. See the package leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Pack with 7, 10, 14, 15, 24, 28, 30, 48, 49, 56, 60, 84, 90, 98, 100, 112, 168 gastro-resistant tablets. Hospital pack with 50, 90, 100, 140, 140 (10x14), 150 (10x15), 700 (5x140) gastro-resistant tablets. (Part of a) hospital pack - not to be sold separately. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. Swallow whole, do not chew. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF


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9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] {Name and Address} <{tel}> <{fax}> <{e-mail}> 12. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 13. BATCH NUMBER Batch 14. GENERAL CLASSIFICATION FOR SUPPLY [To be completed nationally] 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE [See Annex I - To be completed nationally]

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING Carton 1. NAME OF THE MEDICINAL PRODUCT Protium and associated names (see Annex I) 40 mg powder for solution for injection [See Annex I - To be completed nationally] Pantoprazole 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each vial contains 40 mg pantoprazole (as sodium sesquihydrate). 3. LIST OF EXCIPIENTS Each vial contains 1 mg disodium edetate and 0.24 mg sodium hydroxide. See the package leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Powder for solution for injection. Pack with 1 vial. Pack with 5 (5x1) vials. Hospital pack with 1 vial. Hospital pack with 5 (5x1) vials. Hospital pack with 10 (10x1) vials. Hospital pack with 20 (20x1) vials. (Part of a) hospital pack - not to be sold separately. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Intravenous use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF

THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children.

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7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP Shelf life after reconstitution (and dilution): 12 hours 9. SPECIAL STORAGE CONDITIONS Do not store above 25 °C. Keep the vial in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] {Name and Address} <{tel}> <{fax}> <{e-mail}> 12. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 13. BATCH NUMBER Batch 14. GENERAL CLASSIFICATION FOR SUPPLY [To be completed nationally] 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE [To be completed nationally]

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PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING Vial Label 1. NAME OF THE MEDICINAL PRODUCT Protium and associated names (see Annex I) 40 mg powder for solution for injection. [See Annex I - To be completed nationally] Pantoprazole 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each vial contains 40 mg pantoprazole (as sodium sesquihydrate). 3. METHOD AND ROUTE(S) OF ADMINISTRATION Intravenous use. 4. EXPIRY DATE EXP Shelf life after reconstitution: 12 hours 5. SPECIAL STORAGE CONDITIONS Do not store above 25 °C. Keep the vial in the outer carton in order to protect from light. 6. BATCH NUMBER Batch

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PACKAGE LEAFLET

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PACKAGE LEAFLET: INFORMATION FOR THE USER

Protium and associated names (see Annex I) 20 mg gastro-resistant tablets [See Annex I - To be completed nationally]

Pantoprazole

Read all of this leaflet carefully before you start taking this medicine. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if

their symptoms are the same as yours. - If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,

please tell your doctor or pharmacist. In this leaflet: 1. What Protium is and what it is used for 2. Before you take Protium 3. How to take Protium 4. Possible side effects 5. How to store Protium 6. Further information 1. WHAT PROTIUM IS AND WHAT IT IS USED FOR Protium is a selective “proton pump inhibitor”, a medicine which reduces the amount of acid produced in your stomach. It is used for treating acid-related diseases of the stomach and intestine. Protium is used for: Adults and adolescents 12 years of age and above: - Treating symptoms (e.g. heartburn, acid regurgitation, pain on swallowing) associated to gastro-

oesophageal reflux disease caused by reflux of acid from the stomach. - Long-term management of reflux oesophagitis (inflammation of the oesophagus accompanied by

the regurgitation of stomach acid) and preventing its return. Adults: - Preventing duodenal and stomach ulcers caused by non-steroidal anti-inflammatory drugs

(NSAIDs, for example, ibuprofen) in patients at risk who need to take NSAIDs continuously. 2. BEFORE YOU TAKE PROTIUM Do not take Protium - If you are allergic (hypersensitive) to pantoprazole, soya oil or to any of the other ingredients of

Protium (see section 6). - If you are allergic to medicines containing other proton pump inhibitors. Take special care with Protium

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- If you have severe liver problems. Please tell your doctor if you have ever had problems with your liver. He will check your liver enzymes more frequently, especially when you are taking Protium as a long-term treatment. In the case of a rise of liver enzymes the treatment should be stopped.

- If you need to take medicines called NSAIDs continuously and receive Protium because you have an increased risk of developing stomach and intestinal complications. Any increased risk will be assessed according to your own personal risk factors such as your age (65 years old or more), a history of stomach or duodenal ulcers or of stomach or intestinal bleeding.

- If you have reduced body stores or risk factors for reduced vitamin B12 and receive pantoprazole long-term treatment. As with all acid reducing agents, pantoprazole may lead to a reduced absorption of vitamin B12.

- If you are taking a medicine containing atazanavir (for the treatment of HIV-infection) at the same time as pantoprazole, ask your doctor for specific advise.

Tell your doctor immediately if you notice any of the following symptoms: - an unintentional loss of weight - repeated vomiting - difficulty in swallowing - vomiting blood - you look pale and feel weak (anaemia) - you notice blood in your stools - severe and/or persistent diarrhoea, as Protium has been associated with a small increase in

infectious diarrhoea. Your doctor may decide that you need some tests to rule out malignant disease because pantoprazole also alleviates the symptoms of cancer and could cause delay in diagnosing it. If your symptoms continue in spite of your treatment, further investigations will be considered. If you take Protium on a long-term basis (longer than 1 year) your doctor will probably keep you under regular surveillance. You should report any new and exceptional symptoms and circumstances whenever you see your doctor. Taking other medicines Protium may influence the effectiveness of other medicines, so tell your doctor if your are taking - Medicines such as ketoconazole, itraconazole and posaconazole (used to treat fungal infections) or

erlotinib (used for certain types of cancer) because Protium may stop these and other medicines from working properly.

- Warfarin and phenprocoumon, which affect the thickening, or thinning of the blood. You may need further checks.

- Atazanavir (used to treat HIV-infection). Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. Pregnancy and breast-feeding There are no adequate data from the use of pantoprazole in pregnant women. Excretion into human milk has been reported.If you are pregnant, or think you may be pregnant, or if you are breast-feeding, you should use this medicine only if your doctor considers the benefit for you greater than the potential risk for your unborn child or baby. Ask your doctor or pharmacist for advice before taking any medicine. Driving and using machines If you experience side effects like dizziness or disturbed vision, you should not drive or operate machines.

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Important information about some of the ingredients of Protium Protium contains soya oil. If you are allergic to peanut or soya, do not use this medicine. 3. HOW TO TAKE PROTIUM Always take Protium exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. When and how should you take Protium? Take the tablets 1 hour before a meal without chewing or breaking them and swallow them whole with some water. Unless told otherwise by your doctor, the usual dose is: Adults and adolescents 12 years of age and above: To treat symptoms (e.g. heartburn, acid regurgitation, pain on swallowing) associated to gastro-oesophageal reflux disease The usual dose is one tablet a day.This dose usually brings relief within 2 - 4 weeks – at most after another 4 weeks. Your doctor will tell you how long to continue taking the medicine. After this any recurring symptoms can be controlled by taking one tablet daily, when required. For long-term management and for preventing the return of reflux oesophagitis The usual dose is one tablet a day. If the illness returns, your doctor can double the dose, in which case you can use Protium 40 mg tablets instead, one a day. After healing, you can reduce the dose back again to one tablet 20 mg a day. Adults: To prevent duodenal and stomach ulcers in patients who need to take NSAIDs continuously The usual dose is one tablet a day.

Special patient groups: - If you suffer from severe liver problems, you should not take more than one 20 mg tablet a day. - Children below 12 years. These tablets are not recommended for use in children below 12 years. If you take more Protium than you should Tell your doctor or pharmacist. There are no known symptoms of overdose. If you forget to take Protium Do not take a double dose to make up for the forgotten dose. Take your next normal dose at the usual time. If you stop taking Protium Do not stop taking these tablets without first talking to your doctor or pharmacist. If you have any further questions about the use of this product, ask your doctor or pharmacist. 4. POSSIBLE SIDE EFFECTS Like all medicines, Protium can cause side effects, although not everybody gets them.

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The frequency of possible side effects listed below is defined using the following convention: very common (affects more than 1 user in 10) common (affects 1 to 10 users in 100) uncommon (affects 1 to 10 users in 1,000) rare (affects 1 to 10 users in 10,000) very rare (affects less than 1 user in 10,000) not known (frequency cannot be estimated from the available data) If you get any of the following side effects, stop taking these tablets and tell your doctor immediately, or contact the casualty department at your nearest hospital: - Serious allergic reactions (frequency rare): swelling of the tongue and/or throat, difficulty in

swallowing, hives (nettle rash), difficulties in breathing, allergic facial swelling (Quincke’s oedema / angioedema), severe dizziness with very fast heartbeat and heavy sweating.

- Serious skin conditions (frequency not known): blistering of the skin and rapid deterioration of

your general condition, erosion (including slight bleeding) of eyes, nose, mouth/lips or genitals (Stevens-Johnson-Syndrome, Lyell-Syndrome, Erythema multiforme) and sensitivity to light.

- Other serious conditions (frequency not known): yellowing of the skin or whites of the eyes

(severe damage to liver cells, jaundice) or fever, rash, and enlarged kidneys sometimes with painful urination and lower back pain (serious inflammation of the kidneys).

Other side effects are:

- Uncommon (affects 1 to 10 users in 1,000) headache; dizziness; diarrhoea; feeling sick, vomiting; bloating and flatulence (wind); constipation; dry mouth; abdominal pain and discomfort; skin rash, exanthema, eruption; itching; feeling weak, exhausted or generally unwell; sleep disorders.

- Rare (affects 1 to 10 users in 10,000) disturbances in vision such as blurred vision; hives; pain in the joints; muscle pains; weight changes; raised body temperature; swelling of the extremities (peripheral oedema); allergic reactions; depression; breast enlargement in males.

- Very Rare (affects less than 1 user in 10,000) disorientation.

- Not known (frequency cannot be estimated from the available data) Hallucination, confusion (especially in patients with a history of these symptoms); decreased sodium level in blood.

Side effects identified through blood tests: - Uncommon (affects 1 to 10 users in 1,000)

an increase in liver enzymes. - Rare (affects 1 to 10 users in 10,000)

an increase in bilirubin; increased fats in the blood. - Very Rare (affects less than 1 user in 10,000)

a reduction in the number of blood platelets, which may cause you to bleed or bruise more than normal; a reduction in the number of white blood cells, which may lead to more frequent infections.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. 5. HOW TO STORE PROTIUM

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Keep out of the reach and sight of children. Do not use Protium after the expiry date, which is stated on the carton and the container after EXP. The expiry date refers to the last day of that month. This medicine does not require any special storage conditions. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. 6. FURTHER INFORMATION What Protium contains - The active substance is pantoprazole. Each gastro-resistant tablet contains 20 mg of pantoprazole

(as sodium sesquihydrate).

- The other ingredients are: Core: sodium carbonate (anhydrous), mannitol, crospovidone, povidone K90, calcium stearate. Coating: hypromellose, povidone K25, titanium dioxide (E171), yellow iron oxide (E172), propylene glycol, methacrylic acid-ethyl acrylate copolymer (1:1), polysorbate 80, sodium laurilsulfate, triethyl citrate. Printing ink: shellac, red, black and yellow iron oxide (E172), soya lecithin, titanium dioxide (E171) and antifoam DC 1510 (dimeticone emulsion). [To be completed nationally]

What Protium looks like and contents of the pack Yellow, oval, biconvex gastro-resistant tablet imprinted with “P 20” on one side. Packs: bottles (high density polyethylene container with low density polyethylene screw cap closure) and blister (ALU/ALU blister) without cardboard reinforcement or with cardboard reinforcement (blister wallet). Protium is available in the following pack sizes: Packs with 7, 10, 14, 15, 24, 28, 30, 48, 49, 56, 60, 84, 90, 98, 98 (2x49), 100, 112, 168 gastro-resistant tablets. Hospital packs with 50, 56, 84, 90, 112, 140, 140 (10x14 or 5x28), 150 (10x15), 280 (20x14 or 10x28), 500, 700 (5x140) gastro-resistant tablets. Not all pack sizes may be marketed. Marketing Authorisation Holder and Manufacturer [See Annex I - To be completed nationally] {Name and address} <{tel}> <{fax}> <{e-mail}>

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This medicine is authorised in the Member States of the EEA under the following names: Name of Member State

Name of the medicine

Austria Belgium Bulgaria Cyprus Czech Republic Denmark Estonia Finland France Germany Greece Hungary Ireland Italy Latvia Lithuania Luxembourg Netherlands Norway Poland Portugal Romania Slovakia Slovenia Spain Sweden United Kingdom

Pantoloc 20 mg-Filmtabletten, Zurcal 20 mg-Filmtabletten Pantozol, Zurcale Controloc Controloc Controloc 20 mg Pantoloc Controloc 20 mg Somac 20 mg Eupantol 20 mg, Inipomp 20 mg, Pantec 20 mg, Pantipp 20 mg Pantozol 20 mg, Pantoprazol NYC 20 mg, Pantoprazol 20 mg Byk, Rifun 20 mg, Pantoprazole Lomberg 20 mg, PantoLomberg 20 mg, Zurcal S 20 mg Controloc 20 mg, Zurcazol 20 mg Controloc 20 mg Protium 20 mg Pantorc, Pantopan, Pantecta, Peptazol Controloc 20 mg Controloc 20 mg Pantozol-20, Panto-Byk-20 Pantozol 20 mg Somac Controloc 20 Pantoc, Zurcal, Apton, Pantoprazole ALTANA 20 mg Controloc 20 mg Controloc 20 mg Controloc 20 mg Pantecta 20 mg comprimidos gastrorresistentes Blister, Anagastra 20 mg Blister, Ulcotenal 20 mg comprimidos gastrorresistentes Blister Pantoloc Protium 20 mg

[See Annex I - To be completed nationally] This leaflet was last approved in {MM/YYYY}. Detailed information on this medicinal product is available on the website of the Heads of Medicines Agencies (HMA) http://www.hma.eu

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Protium and associated names (see Annex I) 40 mg gastro-resistant tablets [See Annex I - To be completed nationally]

Pantoprazole

Read all of this leaflet carefully before you start taking this medicine. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if

their symptoms are the same as yours. - If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,

please tell your doctor or pharmacist. In this leaflet: 1. What Protiumis and what it is used for 2. Before you take Protium 3. How to take Protium 4. Possible side effects 5. How to store Protium 6. Further information 1. WHAT PROTIUM IS AND WHAT IT IS USED FOR Protium is a selective “proton pump inhibitor”, a medicine which reduces the amount of acid produced in your stomach. It is used for treating acid-related diseases of the stomach and intestine. Protium is used for treating:

Adults and adolescents 12 years of age and above: - Reflux oesophagitis.An inflammation of your oesophagus (the tube which connects your throat to

your stomach) accompanied by the regurgitation of stomach acid. Adults: - An infection with a bacterium called Helicobacter pylori in patients with duodenal ulcers and

stomach ulcers in combination with two antibiotics (Eradication therapy). The aim is to get rid of the bacteria and so reduce the likelihood of these ulcers returning.

- Stomach and duodenal ulcers. - Zollinger-Ellison-Syndrome and other conditions producing too much acid in the stomach. 2. BEFORE YOU TAKE PROTIUM Do not take Protium - If you are allergic (hypersensitive) to pantoprazole, soya oil or to any of the other ingredients of

Protium (see section 6).

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- If you are allergic to medicines containing other proton pump inhibitors. Take special care with Protium - If you have severe liver problems. Please tell your doctor if you ever had problems with your liver in

the past. He will check your liver enzymes more frequently, especially when you are taking Protium as a long-term treatment. In the case of a rise of liver enzymes the treatment should be stopped.

- If you have reduced body stores or risk factors for reduced vitamin B12 and receive pantoprazole long-term treatment. As with all acid reducing agents, pantoprazole may lead to a reduced absorption of vitamin B12.


Tell your doctor immediately if you notice any of the following symptoms: - an unintentional loss of weight - repeated vomiting - difficulty in swallowing - vomiting blood - you look pale and feel weak (anaemia) - you notice blood in your stools - severe and/or persistent diarrhoea, as Protium has been associated with a small increase in infectious

diarrhoea. Your doctor may decide that you need some tests to rule out malignant disease because pantoprazole also alleviates the symptoms of cancer and could cause delay in diagnosing it. If your symptoms continue in spite of your treatment, further investigations will be considered. If you take Protium on a long-term basis (longer than 1 year) your doctor will probably keep you under regular surveillance. You should report any new and exceptional symptoms and circumstances whenever you see your doctor. Taking other medicines Protium may influence the effectiveness of other medicines, so tell you doctor if you are taking - Medicines such as ketoconazole, itraconazole and posaconazole (used to treat fungal infections) or



- Atazanavir (used to treat HIV-infection). - Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. Pregnancy and breast-feeding There are no adequate data from the use of pantoprazole in pregnant women. Excretion into human milk has been reported.If you are pregnant, or think you may be pregnant, or if you are breast-feeding, you should use this medicine only if your doctor considers the benefit for you greater than the potential risk for your unborn child or baby. Ask your doctor or pharmacist for advice before taking any medicine. Driving and using machines If you experience side effects like dizziness or disturbed vision, you should not drive or operate machines.

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Important information about some of the ingredients of Protium Protium contains soya oil. If you are allergic to peanut or soya, do not use this medicine. 3. HOW TO TAKE PROTIUM Always take Protium exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. When and how should you take Protium? Take the tablets 1 hour before a meal without chewing or breaking them and swallow them whole with some water. Unless told otherwise by your doctor, the usual dose is: Adults and adolescents 12 years of age and above: To treat reflux oesophagitis The usual dose is one tablet a day. Your doctor may tell you to increase to 2 tablets daily. The treatment period for reflux oesophagitis is usually between 4 and 8 weeks. Your doctor will tell you how long to take your medicine. Adults: For the treatment of an infection with a bacterium called Helicobacter pylori in patients with duodenal ulcers and stomach ulcers in combination with two antibiotics (Eradication therapy). One tablet, two times a day plus two antibiotic tablets of either amoxicillin, clarithromycin and metronidazole (or tinidazole), each to be taken two times a day with your pantoprazole tablet. Take the first pantoprazole tablet 1 hour before breakfast and the second pantoprazole tablet 1 hour before your evening meal. Follow your doctor’s instructions and make sure you read the package leaflets for these antibiotics. The usual treatment period is one to two weeks. For the treatment of stomach and duodenal ulcers. The usual dose is one tablet a day. After consultation with your doctor, the dose may be doubled. Your doctor will tell you how long to take your medicine. The treatment period for stomach ulcers is usually between 4 and 8 weeks. The treatment period for duodenal ulcers is usually between 2 and 4 weeks. For the long-term treatment of Zollinger-Ellison-Syndrome and of other conditions in which too much stomach acid is produced. The recommended starting dose is usually two tablets a day. Take the two tablets 1 hour before a meal. Your doctor may later adjust the dose, depending on the amount of stomach acid you produce. If prescribed more than two tablets a day, the tablets should be taken twice daily. If your doctor prescribes a daily dose of more than four tablets a day, you will be told exactly when to stop taking the medicine. Special patient groups: - If you have kidney problems, moderate or severe liver problems, you should not take Protium for

eradication of Helicobacter pylori. - If you suffer from severe liver problems, you should not take more than one tablet 20 mg

pantoprazole a day (for this purpose tablets containing 20 mg pantoprazole are available).

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- Children below 12 years. These tablets are not recommended for use in children below 12 years. If you take more Protium than you should Consult your doctor or pharmacist. There are no known symptoms of overdose. If you forget to take Protium Do not take a double dose to make up for the forgotten dose. Take your next, normal dose at the usual time. If you stop taking Protium Do not stop taking these tablets without first talking to your doctor or pharmacist. If you have any further questions about the use of this product, ask your doctor or pharmacist. 4. POSSIBLE SIDE EFFECTS Like all medicines, Protium can cause side effects, although not everybody gets them. The frequency of possible side effects listed below is defined using the following convention: very common (affects more than 1 user in 10) common (affects 1 to 10 users in 100) uncommon (affects 1 to 10 users in 1,000) rare (affects 1 to 10 users in 10,000) very rare (affects less than 1 user in 10,000) not known (frequency cannot be estimated from the available data) If you get any of the following side effects, stop taking these tablets and tell your doctor immediately, or contact the casualty department at your nearest hospital: - Serious allergic reactions (frequency rare): swelling of the tongue and/or throat, difficulty in







- Uncommon (affects 1 to 10 users in 1,000) headache; dizziness; diarrhoea; feeling sick, vomiting; bloating and flatulence (wind); constipation; dry mouth; abdominal pain and discomfort; skin rash, exanthema, eruption; itching; feeling weak, exhausted or generally unwell; sleep disorders.


- Very Rare (affects less than 1 user in 10,000) disorientation.

- Not known (frequency cannot be estimated from the available data)

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Hallucination, confusion (especially in patients with a history of these symptoms); decreased sodium level in blood.


an increase in liver enzymes. - Rare (affects 1 to 10 users in 10,000)

an increase in bilirubin; increased fats in the blood. - Very Rare (affects less than 1 user in 10,000)


If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. 5. HOW TO STORE PROTIUM Keep out of the reach and sight of children. Do not use Protium after the expiry date, which is stated on the carton and the container after EXP. The expiry date refers to the last day of that month. This medicine does not require any special storage conditions. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. 6. FURTHER INFORMATION What Protium contains - The active substance is pantoprazole. Each gastro-resistant tablet contains 40 mg of pantoprazole

(as sodium sesquihydrate). - The other ingredients are:

Core: sodium carbonate (anhydrous), mannitol, crospovidone, povidone K90, calcium stearate. Coating: hypromellose, povidone K25, titanium dioxide (E171), yellow iron oxide (E172), propylene glycol, methacrylic acid-ethyl acrylate copolymer (1:1), polysorbate 80, sodium laurilsulfate, triethyl citrate. Printing ink: shellac, red, black and yellow iron oxide (E172), soya lecithin, titanium dioxide (E171) and antifoam DC 1510 (dimeticone emulsion). [To be completed nationally]

What Protium looks like and contents of the pack Yellow, oval, biconvex gastro-resistant tablet imprinted with “P 40” on one side. Packs: bottles (high density polyethylene container with low density polyethylene screw cap closure) and blister (ALU/ALU blister) without cardboard reinforcement or with cardboard reinforcement (blister wallet). Protium is available in the following pack sizes:

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Packs with 7, 10, 14, 15, 24, 28, 30, 48, 49, 56, 60, 84, 90, 98, 98 (2x49), 100, 112, 168 gastro-resistant tablets. Hospital packs with 50, 90, 100, 140, 140 (10x14), 150 (10x15), 700 (5x140) gastro-resistant tablets. Not all pack sizes may be marketed. Marketing Authorisation Holder and Manufacturer [See Annex I - To be completed nationally] {Name and address} <{tel}> <{fax}> <{e-mail}> This medicine is authorised in the Member States of the EEA under the following names: Name of Member State


Austria Belgium Bulgaria Cyprus Czech Republic Denmark Estonia Finland France Germany Greece Hungary Ireland Italy Latvia Lithuania Luxembourg Netherlands Norway Poland Portugal Romania Slovakia Slovenia Spain Sweden United Kingdom

Pantoloc 40 mg-Filmtabletten, Zurcal 40 mg-Filmtabletten Pantozol, Zurcale Controloc Controloc Controloc 40 mg Pantoloc Controloc 40 mg Somac 40 mg Eupantol 40 mg, Inipomp 40 mg, Pantec 40 mg, Pantipp 40 mg Pantozol 40 mg, Pantoprazol NYC 40 mg, Rifun 40 mg, Zurcal S 40 mg Controloc, Zurcazol Controloc 40 mg Protium Pantorc, Pantopan, Pantecta, Peptazol Controloc 40 mg Controloc 40 mg Pantozol-40, Panto-Byk-40 Pantozol, Pantoprazol Nycomed 40 mg Somac Controloc 40 Pantoc 40 mg, Zurcal 40 mg, Apton 40 mg, Pantoprazole ALTANA 40 mg Controloc 40 mg Controloc 40 mg Controloc 40 mg Pantecta 40 mg Blister, Anagastra 40 mg Blister, Ulcotenal 40 mg Blister Pantoloc Protium 40 mg

[See Annex I - To be completed nationally]

94

This leaflet was last approved in {MM/YYYY}. Detailed information on this medicinal product is available on the website of the Heads of Medicines Agencies (HMA) http://www.hma.eu

95


Protium and associated names (see Annex I) 40 mg powder for solution for injection [See Annex I - To be completed nationally]

Pantoprazole

Read all of this leaflet carefully before you start using this medicine. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please

tell your doctor. In this leaflet: 1. What Protiumis and what it is used for 2. Before you use Protium 3. How to use Protium 4. Possible side effects 5. How to store Protium 6. Further information 1. WHAT PROTIUM IS AND WHAT IT IS USED FOR Protium is a selective “proton pump inhibitor”, a medicine which reduces the amount of acid produced in your stomach. It is used for treating acid-related diseases of the stomach and intestine. This preparation is injected into a vein and will only be given to you if your doctor thinks pantoprazole injections are more suitable for you at the moment than pantoprazole tablets. Tablets will replace your injections as soon as your doctor sees fit. Protium is used for treating: - Reflux oesophagitis. An inflammation of your oesophagus (the tube which connects your throat to

your stomach) accompanied by the regurgitation of stomach acid. - Stomach and duodenal ulcers. - Zollinger-Ellison-Syndrome and other conditions producing too much acid in the stomach. 2. BEFORE YOU USE PROTIUM Do not use Protium - If you are allergic (hypersensitive) to pantoprazole or any of the other ingredients of Protium (see

section 6). - If you are allergic to medicines containing other proton pump inhibitors. Take special care with Protium - If you have severe liver problems. Please tell your doctor if you ever had problems with your liver

in the past. He will check your liver enzymes more frequently. In the case of a rise of liver enzymes the treatment should be stopped.


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Tell your doctor immediately if you notice any of the following symptoms: - an unintentional loss of weight - repeated vomiting - difficulty in swallowing - vomiting blood - you look pale and feel weak (anaemia) - you notice blood in your stools - severe and/or persistent diarrhoea, as Protium has been associated with a small increase in

infectious diarrhoea. Your doctor may decide that you need some tests to rule out malignant disease because pantoprazole also alleviates the symptoms of cancer and could cause delay in diagnosing it. If your symptoms continue in spite of your treatment, further investigations will be considered. Taking other medicines Protium injections may influence the effectiveness of other medicines, so tell your doctor if you are taking - Medicines such as ketoconazole, itraconazole and posaconazole (used to treat fungal infections) or



- Atazanavir (used to treat HIV-infection). Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. Pregnancy and breast-feeding There are no adequate data from the use of pantoprazole in pregnant women. Excretion into human milk has been reported.If you are pregnant, or think you may be pregnant, or if you are breast-feeding, you should use this medicine only if your doctor considers the benefit for you greater than the potential risk for your unborn child or baby. Ask your doctor or pharmacist for advice before taking any medicine. Driving and using machines If you experience side effects like dizziness or disturbed vision, you should not drive or operate machines. Important information about some of the ingredients of Protium This medicine contains less than 1 mmol sodium (23 mg) per vial, i.e. is essentially ‘sodium- free’. 3. HOW TO USE PROTIUM Your nurse or your doctor will administer the daily dose to you as an injection into a vein over a period of 2 - 15 minutes. The usual dose is: For gastric ulcers, duodenal ulcers and reflux oesophagitis. One vial (40 mg pantoprazole) a day. For the long-term treatment of Zollinger-Ellison syndrome and other conditions in which too much stomach acid is produced.

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Two vials (80 mg pantoprazole) a day. Your doctor may later adjust the dose, depending on the amount of stomach acid you produce. If you are prescribed more than two vials (80 mg) a day, the injections will be given in two equal doses. Your doctor may prescribe a temporary dose of more than four vials (160 mg) a day. If your stomach acid level needs to be controlled rapidly, a starting dose of 160 mg (four vials) should be enough to lower the amount of stomach acid sufficiently. Special patient groups: - If you suffer from severe liver problems, the daily injection should be only 20 mg (half a vial). - Children (under 18 years). These injections are not recommended for use in children. If you use more Protium than you should These doses are carefully checked by your nurse or your doctor so an overdose is extremely unlikely. There are no known symptoms of overdose. If you have any further questions about the use of this medicine, ask your doctor or pharmacist. 4. POSSIBLE SIDE EFFECTS Like all medicines, Protium can cause side effects, although not everybody gets them. The frequency of possible side effects listed below is defined using the following convention: very common (affects more than 1 user in 10) common (affects 1 to 10 users in 100) uncommon (affects 1 to 10 users in 1,000) rare (affects 1 to 10 users in 10,000) very rare (affects less than 1 user in 10,000) not known (frequency cannot be estimated from the available data) If you get any of the following side effects, tell your doctor immediately, or contact the casualty department at your nearest hospital: - Serious allergic reactions (frequency rare): swelling of the tongue and/or throat, difficulty in







- Common (affects 1 to 10 users in 100) inflammation of the wall of the vein and blood clotting (thrombophlebitis) where the medicine is injected.

- Uncommon (affects 1 to 10 users in 1,000)

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headache; dizziness; diarrhoea; feeling sick, vomiting; bloating and flatulence (wind); constipation; dry mouth; abdominal pain and discomfort; skin rash, exanthema, eruption; itching; feeling weak, exhausted or generally unwell; sleep disorders.


- Very Rare (affects less than 1 user in 10,000) disorientation. - Not known (frequency cannot be estimated from the available data)

Hallucination, confusion (especially in patients with a history of these symptoms); decreased sodium level in blood.


an increase in liver enzymes. - Rare (affect 1 to 10 users in 10,000) an increase in bilirubin; increased fats in the blood. - Very Rare (affects less than 1 user in 10,000)


If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. 5. HOW TO STORE PROTIUM Keep out of the reach and sight of children. Do not use Protium after the expiry date, which is stated on the carton and the vial after EXP. The expiry date refers to the last day of that month. Do not store above 25 °C. Keep the vial in the outer carton in order to protect it from light. Use the reconstituted solution within 12 hours. Use the reconstituted and diluted solution within 12 hours. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 12 hours at not more than 25 °C. Do not use Protium if you notice that the visual appearance has changed (e.g. if cloudiness or precipitation is observed). Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. 6. FURTHER INFORMATION What Protium contains

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- The active substance is pantoprazole. Each vial contains 40 mg of pantoprazole (as sodium

sequihydrate). - The other ingredients are: disodium edetate and sodium hydroxide (for pH adjustment). What Protium looks like and contents of the pack Protium is a white to off-white powder for solution for injection. It comes in a 10 ml clear glass vialclosed with an aluminium cap and grey rubber stopper containing 40 mg powder for solution for injection. Protium is available in the following pack sizes: Pack with 1 vial. Pack with 5 (5x1) vials. Hospital pack with 1 vial. Hospital pack with 5 (5x1) vials. Hospital pack with 10 (10x1) vials. Hospital pack with 20 (20x1) vials. Not all pack sizes may be marketed. Marketing Authorisation Holder [See Annex I - To be completed nationally] {Name and address} <{tel}> <{fax}> <{e-mail}> Manufacturer {Name and address} <{tel}> <{fax}> <{e-mail}> This medicine is authorised in the Member States of the EEA under the following names: Name of Member State


Austria Belgium Cyprus Czech Republic Denmark Finland France Germany Greece Hungary Ireland

Pantoloc 40 mg Trockenstechampulle, Zurcal 40 mg Trockenstechampulle Pantozol IV, Zurcale IV Controloc i.v. Controloc i.v. Pantoloc Somac 40 mg powder for solution for injection Eupantol 40 mg poudre pour solution injectable IV, Inipomp 40 mg Pantozol i.v., Pantoloc i.v., Pantoprazol-Byk i.v. Controloc i.v., Zurcazol i.v. Controloc i.v. Protium i.v.

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Name of Member State


Italy Luxembourg Netherlands Norway Poland Portugal Romania Slovakia Slovenia Spain Sweden United Kingdom

Pantorc Pantozol-IV, Panto-Byk-IV Pantozol i.v. Somac Controloc 40 mg Pantoc IV Controloc i.v. Controloc i.v. Controloc 40 mg prašek za raztopino za injiciranje Anagastra 40 mg polvo para solución inyectable I.V. Pantoloc Protium i.v.

[See Annex I - To be completed nationally] This leaflet was last approved in {MM/YYYY}. Detailed information on this medicinal product is available on the website of the Heads of Medicines Agencies (HMA) http://www.hma.eu --------------------------------------------------------------------------------------------------------------------------- The following information is intended for medical or healthcare professionals only: A ready-to-use solution is prepared by injecting 10 ml of sodium chloride 9 mg/ml (0.9 %) solution for injection into the vial containing the dry powder. This solution may either be administered directly or after mixing it with 100 ml sodium chloride 9 mg/ml (0.9 %) solution for injection or glucose 55 mg/ml (5 %) solution for injection. Glass or plastic containers should be used for dilution. Protium should not be prepared or mixed with solvents other than those stated. After preparation, the solution must be used within 12 hours. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 12 hours, at no more than 25 °C. The medicine should be administered intravenously over 2 - 15 minutes. The content of the vial is for single intravenous use only. Any product that has remained in the container or whose visual appearance has changed (e.g. if cloudiness or precipitation is observed) must be discarded.

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ANNEX IV

CONDITIONS OF THE MARKETING AUTHORISATIONS

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The National Competent Authorities, coordinated by the Reference Member State, shall ensure that the following conditions are fulfilled by the Marketing Authorisation Holders: The MAH commits to respond to a number of unresolved quality related issues by presenting relevant and adequate documents and data as outlined in the Letter of Undertaking dated 9 December 2009. To reduce administrative work, all response documents should be submitted as a single data package one year after the issue of the EC decision.

annex i list of the names, pharmaceutical...

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