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

4

Member State EU/EEA

Marketing Authorisation Holder

(Invented) name

Strength Pharmaceutical Form Route of administration

Content (concentration)

Austria

AstraZeneca Österreich GmbH,Schwarzenbergplatz 7, A-1037 Wien Austria

Losec 10mg – Kapseln

10 mg

capsule, hard

Oral use

Austria


Losec 20mg – Kapseln

20 mg

capsule, hard Oral use

Austria


Losec 40 mg -Trockenstechampulle mit Lösungsmittel

40 mg

Powder for solution for injection

Intravenous use 40 mg

Belgium

NV AstraZeneca SA Egide Van Ophemstraat 110 1180 Brussels Belgium

Losec 40mg Forte, harde maagsapresistente capsules

40 mg Hard Gastroresistant capsules Oral use

Belgium


Losec 40 mg, poeder voor oplossing voor intraveneuze infusie

40 mg Powder for solution for infusion

Intravenous use

40 mg

Belgium


Losec-Mups 10mg, 10 mg, maagsapresistente tabletten

10 mg Gastroresistant tablets

Oral use

Belgium



20 mg

Gastroresistant tablets Oral use

5

Member State EU/EEA


(Invented) name



Belgium



40 mg Gastroresistant tablets Oral use

Belgium

NV AstraZeneca SA Egide Van Ophemstraat 110 1180 Brussel Belgium

Omeprazole AstraZeneca 20mg, harde maagsapresistente capsules


Belgium

NV AstraZeneca SA Egide Van Ophemstraat 110 1180 Brussel Belgium

Omeprazole AstraZeneca 40mg Forte, harde maagsapresistente capsules


Belgium


Omeprazole AstraZeneca 40mg, poeder voor oplossing voor intraveneuze infusie

40 mg Powder for solution for infusion Intravenous use

40 mg

Belgium


Logastric 10mg, maagsapresistente capsules


Belgium


Logastric 20mg, maagsapresistente capsules


Belgium


Logastric 40mg Forte, maagsapresistente capsules


6

Member State EU/EEA


(Invented) name



Belgium


Logastric-Mups 40mg, 40 mg, maagsapresistente tabletten

40 mg Gastroresistant tablets Oral use

Cyprus

AstraZeneca AB, 151 85 Södertälje Sweden

Losec Mups 10mg Gastro-resistant tablets

Oral use

Cyprus

AstraZeneca AB, 151 85 Södertälje Sweden

Losec Mups 20mg Gastro-resistant tablets

Oral use

Czech Republic

AstraZeneca UK Ltd., Silk Road Business Park ,SK10 2NA Macclesfield, Cheshire, United Kingdom

LOSEC 20 mg 20 mg Gastro-resistant capsule, hard Oral use

Czech Republic

AstraZeneca UK Ltd., Silk Road Business Park ,SK10 2NA Macclesfield, Cheshire, United Kingdom

LOSEC 40 mg 40 mg Powder for solution for infusion Intravenous use

Denmark

AstraZeneca A/S Roskildevej 22 2620 Albertslund Denmark

Losec 10 mg Gastroresistant tablets Oral use

Denmark



Denmark



7

Member State EU/EEA


(Invented) name



Denmark


Losec 40 mg/ml Powder and Solvens for solution for injection


Denmark


Losec 40 mg/ml Powder for solution for infusion Intravenous use 40 mg

Estonia

AstraZeneca AB, S-151 85 Södertälje Sweden

Losec MUPS 20 mg Gastroresistant tablets Oral use

Estonia


Losec 40 MG 40 mg Powder for solution for infusion Intravenous use 40 mg

Finland

AstraZeneca Oy Luomanportti 3 FI-02200 Espoo Finland

Losec Mups 10 mg enterotabletti

10 mg Gastroresistant tablet Oral use

Finland




Finland




France

AstraZeneca 1, Place Renault 92844 RUEIL-MALMAISON Cedex France

MOPRAL® 20 mg microgranules gastrorésistants en gélule

20 mg Capsules Oral use

8

Member State EU/EEA


(Invented) name



France


MOPRAL® 10 mg microgranules gastrorésistants en gélule


France


ZOLTUM® 20 mg microgranules gastrorésistants en gélule


France


ZOLTUM® 10 mg microgranules gastrorésistants en gélule


France


MOPRAL 40 mg, lyophilisat pour perfusion (IV).

40 mg Lyophylizat for perfusion Intravenous use 40 mg

Germany

AstraZeneca GmbH 22876 Wedel Germany

Antra pro infusione 40 mg Powder for solution for infusion Intravenous use 40 mg

Germany


Antra MUPS 10 mg 10 mg Gastro-resistant tablets Oral use

Germany


Antra MUPS 20 mg

20 mg Gastro-resistant tablets Oral use

9

Member State EU/EEA


(Invented) name



Germany


Antra MUPS 40 mg


Greece

AstraZeneca S.A. 4 Theotokopoulou & Astronafton str 151 25 Maroussi Athens Greece

Losec®, Γαστροανθεκτικό καψάκιο σκληρό 10 mg/CAP

10 mg Gastro-resistant capsules, hard Oral use

Greece




Greece




Greece


Losec MUPS®, Γαστροανθεκτικό δισκίο10 mg/TAB


Greece



20 m Gastro-resistant tablets Oral use

10

Member State EU/EEA


(Invented) name



Greece



40 mg

Gastro-resistant tablets Oral use

Greece


Losec®, Ενέσιµο λυόφιλο 40 mg/VIAL

40 mg

Powder and solvent for solution for injection


Greece


Losec®, Ενέσιµο λυόφιλο για ενδοφλέβια έγχυση 40 mg/VIAL

40 mg Powder for solution for infusion Intravenous use 40 mg

Hungary

AstraZeneca Kft. H-2045 Törökbálint, Park u. 3. Hungary

Losec 10 mg kapszula 10 mg Capsule, hard Oral use

Hungary


Losec 20 mg kapszulaz 20 mg Capsule, hard Oral use

Hungary


Losec 40 mg por infúzióhoz


Iceland

AstraZeneca A/S Roskildevej 22 DK-2620 Albertslund Denmark


11

Member State EU/EEA


(Invented) name



Iceland



Iceland


Losec 40 mg Powder for solution for infusion Intravenous use 40 mg

Ireland

AstraZeneca UK Limited 600 Capability Green Luton LU1 3LU United Kingdom

Losec MUPS Tablets 10mg

10mg Gastro-resistant, film-coated tablet

Oral use

Ireland



20mg

Gastro-resistant, film-coated tablet

Oral use

Ireland



40mg

Gastro-resistant, film-coated tablet

Oral use

Ireland


Losec Losec 40mg Powder for Solution for Infusion

40mg Powder for solution for infusion


Ireland


Losec IV 40mg Powder and Solvent for Solution for Injection

40mg Powder and solvent for solution for injection


12

Member State EU/EEA


(Invented) name



Italy

AstraZeneca S.p.A. Via F. Sforza Palazzo Volta 20080 Basiglio (MI) Italy

Antra 10 mg capsule rigide a rilascio modificato

10 mg Hard modified release capsules Oral use

Italy




Italy




Italy


Antra 40 mg polvere per soluzione per infusione


Italy


Losec 10 mg capsule rigide a rilascio modificato


Italy




Italy




13

Member State EU/EEA


(Invented) name



Italy


Losec 40 mg polvere per soluzione per infusione


Italy

Bracco S.p.A. Via E. Folli 50 20134 Milano Italy

Mepral 10 mg capsule rigide a rilascio modificato


Italy




Italy




Italy


Mepral 40 mg polvere per soluzione per infusione


Italy

Malesci Istituto Farmacobiologico S.p.A. Via Lungo l’Ema 7 50015 Bagno a Ripoli (FI) Italy

Omeprazen 10 mg capsule rigide a rilascio modificato


Italy




14

Member State EU/EEA


(Invented) name



Italy




Italy


Omeprazen 40 mg polvere per soluzione per infusione


Latvia


Losec 40 mg pulveris infūziju šķīduma pagatavošanai


Luxembourg


Losec Forte Gelules 40mg

40 mg Hard gastroresis-tant capsules Oral use

Luxembourg


Losec poudre pour perfusion 40 mg

40 mg Powder for solution for intravenous infusion


Luxembourg


Losec-Mups 10mg 10 mg Gastroresistant tablets Oral use

Luxembourg



15

Member State EU/EEA


(Invented) name



Luxembourg



Malta

AstraZeneca AB S-151 85 Södertälje Sweden



Oral use

Malta




Oral use

Netherlands

AstraZeneca BV Postbus 599 2700 AN, Zoetermeer The Netherlands

Losec 10 10 mg Gstroresistant capsules Oral use

Netherlands


Losec 20 20 mg Gastroresistant capsules Oral use

Netherlands


Losec 40 40 mg Gastroresistant capsules Oral use

Netherlands


Losec 40 mg Powder and solvent for solution for injection


Netherlands


Losec Infuus 40 mg Powder for solution for intravenous infusion


16

Member State EU/EEA


(Invented) name



Netherlands


Losec MUPS 10 10 mg Gastroresistant tablets Oral use

Netherlands


Losec MUPS 20 20 mg Gastroresistant tablets

Oral use

Netherlands


Losec MUPS 40 40 mg Gastroresistant tablets Oral use

Norway

AstraZeneca AS, Postboks 200 Vinderen, 0319 OSLO Norway

Losec® MUPS® 10 mg Gastroresistant tablets Oral use

Norway


Losec® MUPS® 20 mg Gastroresistant tablets Oral use

Norway


Losec® 40mg Powder for solution for infusion Intravenous use 40 mg

Poland


Losec 10 10mg Capsules Oral use

Poland


Losec 20mg Capsules Oral use

17

Member State EU/EEA


(Invented) name



Poland


Losec 40mg Powder for solution for infusion Intravenous use 40 mg

Portugal

AstraZeneca Produtos Farmacêuticos, Lda. Rua Humberto Madeira, n.º 7, Valejas 2745-663 Barcarena Portugal

Losec 20 mg Gastroresistant capsules Oral use

Portugal



Portugal


Losec 40 mg Powder and solvent for injectable solution


Romania


Losec MUPS 10 mg coprimate filmate gastrorezistente

10 mg Film-coated gastroresistant tablets

Oral use

Romania


Losec MUPS 20 mg comprimate filmate gastrorezistene

20mg Film-coated gastroresistant tablets

Oral use

Romania


Losec 40mg liofilizat pentru solutie perfuzabila

40mg Lyophilisate for solution for infusion


18

Member State EU/EEA


(Invented) name



Slovak Republic


Losec® 40 mg Powder for solution for infusion Intravenous use 40 mg

Spain

Laboratorio Tau, S.A. C/ Serrano Galvache, 56 Edificio Roble 28033 Madrid Spain

LOSEC infusión i.v. 40 mg Powder for infusion Intravenous use 40 mg

Spain

Laboratorio Tau, S.A. C/ Serrano Galvache, 56 Edificio Roble 28033 Madrid Spain

LOSEC cápsulas 20 mg 20 mg Capsules, hard Oral use

Sweden


Losec 10 mg

Gastro-resistant tablets Oral use

Sweden


Losec 20 mg Gastro-resistant tablets Oral use

Sweden


Losec 40 mg Gastro-resistant tablets Oral use

Sweden


Losec 40 mg Powder for solution for injection Intravenous use 40 mg

Sweden



19

Member State EU/EEA


(Invented) name



United Kingdom



10mg Film-coated Tablet Oral use

United Kingdom




United Kingdom




United Kingdom


Losec Capsules 10mg 10mg Hard gelatin capsules Oral use

United Kingdom


Losec Capsules 20mg 20mg Hard gelatin capsules Oral use

United Kingdom


Losec Capsules 40mg 40mg Hard gelatine capsules Oral use

United Kingdom


Losec Infusion 40mg 40mg Powder for solution for infusion Intravenous use 40 mg

20

Member State EU/EEA


(Invented) name



United Kingdom


Losec IV Injection 40mg 40mg Powder and solvent for solution for injection


21

ANNEX II

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

THE EMEA

22

SCIENTIFIC CONCLUSIONS OVERALL SUMMARY OF THE SCIENTIFIC EVALUATION OF LOSEC AND ASSOCIATED NAMES (SEE ANNEX I) Losec (omeprazole) was included in the list of products for SPC harmonisation and a referral was triggered in order to resolve divergences and harmonise the nationally authorised SPCs across Europe. The marketing authorisation holder (MAH) also took the opportunity to harmonise Module 3. The scope of the referral included all licences, whether prescription only (POM/Rx) or non-prescription (over-the-counter or OTC). There are currently 4 separate formulations of Losec on the market: gastro-resistant tablets, capsules, powder for solution for infusion and powder for solution for injection. Losec MUPS (multiple unit pellet system) tablets are also available as OTC. The MAH proposed 5 separate SPCs: one for the 10mg, 20 mg, and 40 mg capsules; one for the 10 mg, 20 mg, and 40 mg tablets, one for the 40 mg powder for infusion, one for the 40 mg powder for injection and one for the 10mg and 20 mg tablets for OTC use. With this proposal, prescription only tablets and capsules will have the same indications for all strengths (bioequivalence between the tablets and the capsules of same strength has been demonstrated), as will the solutions for infusion and injection. The OTC SPC will diverge most notably in the indications, posology and warnings sections. Omeprazole is a substituted benzimidazole belonging to the therapeutic group of proton pump inhibitors (PPIs). It is administered as a prodrug and specifically and dose-proportionally inhibits the gastric H+/K+-ATPase (proton pump) and thereby inhibits H+ ion transfer into the gastric lumen, which is responsible for acid secretion in the parietal cells of the stomach. PRESCRIPTION-ONLY PRESENTATIONS Section 4.1 - Therapeutics indications in adults - capsules and tablets The CHMP assessed the MAH proposal taking into account the current national SPCs and scientific knowledge and discussed indications for each individual medical condition. The prophylactic use of Losec, as distinct from the treatment indications was also discussed and justified. a) “Treatment of symptomatic gastro-oesophageal reflux disease (GERD)” The MAH proposed that both duodenal and gastric ulcers be presented in individual indications separate from the GERD indication. Whilst definition of what constitutes typical reflux disease may differ, in general terms, GERD is applied to patients with symptoms suggestive of reflux or complications thereof, but not necessarily with oesophageal inflammation. The cardinal symptoms associated with GERD are heartburn and regurgitation. The latest guidelines include symptoms as the most important part for the diagnosis of GERD. The most common and effective treatment of peptic oesophagitis or symptomatic GERD is to reduce gastric acid secretion with either H2 blockers or a PPI and the CHMP therefore considered this indication approvable. b) “Treatment of reflux oesophagitis” and “Long-term management of patients with healed reflux oesophagitis” Reflux oesophagitis results from the combination of excessive gastro-oesophageal reflux of gastric juice and impaired oesophageal clearance of the refluxate. The likelihood of developing reflux symptoms or oesophageal epithelial injury is a function of a quantitative abnormality of the number of reflux events and/or oesophageal acid exposure. Treatment of reflux oesophagitis includes acid reduction and PPIs are currently considered the most effective treatment for reflux oesophagitis and the CHMP therefore considered this indication to be approvable. c) “Treatment of duodenal ulcers” and “Prevention of relapse of duodenal ulcers” The indication in H. pylori negative ulcers was split from the indication with concomitant H. pylori infection. Regarding the prevention of relapse of H. pylori negative duodenal ulcers, the available

23

literature was reviewed. It is in the so-called “idiopathic ulcers” that the prevention of relapse of H. pylori negative duodenal and gastric ulcer indications are indicated. Since such ulcers are difficult to treat and are associated with more frequent and more serious complications, preventing relapse is a reasonable course of action. The CHMP considered that prevention of relapse of H. pylori negative duodenal ulcers is sufficiently demonstrated and considered these indications to be approvable. d) “Treatment of gastric ulcers” and “Prevention of relapse of gastric ulcers” The gastric ulcer indications were separated from the duodenal ulcer indications as well as from the NSAID-related and H. pylori positive ulcers. Gastric ulcers in elderly patients may be located more proximally in the stomach than in younger patients. Proximal gastric ulcers are often large, tend to heal slowly, and may be more prone to recur. Such ulcers are also associated with a high frequency of potentially fatal complications. Therefore, prevention of relapse of gastric ulcers is a reasonable course of action. The CHMP considered that the prevention of relapse of H. pylori negative gastric ulcers is sufficiently demonstrated and considered these indications to be approvable. e) “Treatment of NSAID-associated gastric and duodenal ulcers” and “Prevention of NSAID-associated gastric and duodenal ulcers in patients at risk” Regarding the prevention of non-steroidal anti-inflammatory drug (NSAID) -associated gastric ulcers, duodenal ulcers or gastroduodenal erosions in patients at risk, prevention of ulcer formation in at risk NSAID users is a reasonable course of action, given the high and increasing incidence. Prevention of ulcers is currently started on a regular basis in a considerable number of patients using NSAIDs and the superior efficacy PPIs over H2 antagonists in the healing of gastroduodenal ulcers associated with NSAIDs when NSAIDs cannot be discontinued has been demonstrated. PPIs are also effective for primary prevention of NSAID-associated ulcers. The CHMP considered that the prevention of NSAID ulcers is sufficiently demonstrated and considered these indications to be approvable. However, peptic ulcers and erosions are different clinical entities. Peptic ulcers are associated with increased risk of upper gastrointestinal complications, such as bleedings, but the same may not be true for the superficial erosions commonly seen during treatment with NSAIDs. The CHMP considered that the available data does not allow concluding on whether patients with erosions alone benefit from the treatment with PPI. The mention of erosions was therefore deleted from the indication. f) “In combination with appropriate antibiotics, Helicobacter pylori (H. pylori) eradication in peptic ulcer disease” The CHMP considered that according to almost all existing guidance, all patients with erosions or ulcers associated with H. pylori infection should undergo therapy to eradicate the organism. This recommendation is based upon overwhelming data showing that the cure of H. pylori infections reduces ulcer recurrence and complications such as bleeding. Further information on recommended antibiotic combinations is stated in Section 4.2. The CHMP considered this indication to be approvable. g) Acid-related dyspepsia The CHMP noted that heartburn was not included in the definition of dyspepsia agreed upon by an international committee of clinical investigators (Rome III Committee). In addition, H2 receptor antagonists have a more immediate effect. Based on the European guidelines and literature, and due to the lack of conclusive studies relevant to this indication, this indication and the associated posology was removed from the proposed harmonised SPC. h) “Treatment of Zollinger-Ellison syndrome” The indication for the treatment of Zollinger Ellison syndrome is already harmonised throughout the EU and the CHMP considered this indication to be approvable. i) Patients considered to be at risk of aspiration of gastric contents during general anaesthesia/Acid aspiration prophylaxis The CHMP considered that this indication is similar to chemical pneumonia (among others caused by gastric acid aspiration). This indication is not generally accepted and the use of PPIs in the treatment of

24

chemical pneumonia is not advocated in the various guidance on treatment/prevention of this pneumonia. The data submitted by the MAH did not sufficiently support the claimed indication and although no unexpected or new safety concerns emerged from these studies, the CHMP considered this indication to be unacceptable given the undemonstrated efficacy. The indication and the associated posology were removed from the harmonised SPC. Section 4.1 - Therapeutics indications in paediatric patients - capsules and tablets The CHMP agreed on the following indications in paediatric patients, in line with the outcome of the EU work-sharing assessment of paediatric data: In children over 1 year of age and ≥ 10 kg • Treatment of reflux esophagitis • Symptomatic treatment of heartburn and acid regurgitation in gastro-esophageal reflux disease In children and adolescents over 4 years of age • In combination with antibiotics in treatment of duodenal ulcer caused by H. pylori Section 4.1 - Therapeutics indications in adults - powder for injection and powder for infusion The intravenous indications were largely harmonised already. After discussing the various existing texts in the national SPCs and noting that experience on use of intravenous formulations of Losec in paediatric patients is limited, the CHMP adopted the following harmonised indications in adults for Losec for intravenous use, as an alternative to oral therapy:

• Treatment of duodenal ulcers • Prevention of relapse of duodenal ulcers • Treatment of gastric ulcers • Prevention of relapse of gastric ulcers • In combination with appropriate antibiotics, Helicobacter pylori (H. pylori) eradication in peptic

ulcer disease • Treatment of NSAID-associated gastric and duodenal ulcers • Prevention of NSAID-associated gastric and duodenal ulcers in patients at risk • Treatment of reflux esophagitis • Long-term management of patients with healed reflux esophagitis • Treatment of symptomatic gastro-esophageal reflux disease • Treatment of Zollinger-Ellison syndrome”

Section 4.2 - Posology and method of administration Regarding the method of administration of the capsules and tablets, with regards to patients with swallowing difficulties, the CHMP agreed that the capsule can be opened and the contents swallowed based on the in-vivo (bioequivalence) as well as in-vitro studies on the intake as dispersed/suspended tablets/granules of the oral pharmaceutical forms. Alternatively, patients can suck the capsule and swallow the pellets with water. The CHMP agreed that the available data on administration of the MUPS tablet immediately after a high-fat breakfast shows delayed and decreased absorption of omeprazole. Although this food interaction is not likely to be of any clinical relevance, it warrants the recommendation that Losec should preferably be taken without food. Adult posology: capsule and tablet For the treatment of symptomatic gastro-oesophageal reflux disease, the recommended dose is 20 mg daily. Patients may respond adequately to 10 mg daily, and therefore individual dose adjustment should

25

be considered. If symptom control has not been achieved after four weeks treatment with 20 mg daily, further investigation is recommended. For the treatment of reflux oesophagitis, the recommended dose is 20 mg once daily. In most patients healing occurs within four weeks. In patients with severe oesophagitis 40 mg once daily is recommended and healing is usually achieved within eight weeks. For long-term management of patients with healed reflux oesophagitis, the recommended dose is 10 mg once daily. For the treatment of duodenal ulcers, the recommended dose is 20 mg once daily. In most patients healing occurs within two weeks. In patients with poorly responsive duodenal ulcer 40 mg once daily is recommended and healing is usually achieved within four weeks. For the prevention of relapse of duodenal ulcer in H. pylori negative patients or when H. pylori eradication is not possible the recommended dose is 20 mg once daily. For the treatment of gastric ulcers, the recommended dose is 20 mg once daily. In most patients healing occurs within four weeks. In patients with poorly responsive gastric ulcer 40 mg once daily is recommended and healing is usually achieved within eight weeks. For prevention of relapse in patients with poorly responsive gastric ulcer the recommended dose is 20 mg once daily. For the treatment of NSAID-associated gastric and duodenal ulcers, the recommended dose is 20 mg once daily. In most patients healing occurs within four weeks. For the prevention of NSAID-associated gastric ulcers or duodenal ulcers in patients at risk (age> 60, previous history of gastric and duodenal ulcers, or of upper GI bleeding) the recommended dose is 20 mg once daily. Regarding the eradication of H. pylori in peptic ulcer disease, a number of triple-regimen therapies (Losec plus two antibiotics) are proposed. These are based on established data and are currently confirmed as the most efficacious combinations, and are intended to allow treatment alternatives according to local needs and clinical practice. The selection of antibiotics should consider the individual patient’s drug tolerance, and should be undertaken in accordance with national, regional and local resistance patterns and treatment guidelines. The CHMP considered that dual therapies are less effective than triple therapies, but that they could be considered in cases where known hypersensitivity precludes use of any triple combination. For the treatment of Zollinger-Ellison syndrome, the dose should be individually adjusted and treatment continued as long as clinically indicated. The recommended initial dose is 60 mg daily. All patients with severe disease and inadequate response to other therapies have been effectively controlled and more than 90% of the patients maintained on doses of 20-120 mg daily. When the dose exceeds 80 mg daily, it should be divided and given twice daily. Paediatric posology: capsule and tablet The CHMP agreed on specific dosage and treatment duration recommendations for each individual indication for paediatric patients, taking into account the patients age (≥ 1 year of age, ≥ 2 years of age and children and adolescents over 4 years of age) and weight. For children and adolescents over 4 years of age treated for duodenal ulcers caused by H. pylori, the selection of the appropriate combination therapy should take into consideration the official national, regional and local guidance regarding bacterial resistance, duration of treatment and appropriate use of antibacterial agents. Powder for infusion and powder for injection The CHMP considered the IV formulations to be alternatives to oral therapy in adult patients where the use of oral medicinal products is inappropriate. For most indications, a 40 mg daily dose is recommended, although in patients with Zollinger-Ellison Syndrome the recommended initial dose is 60 mg daily. The SPC also provides guidance on dose adjustments and practical advice on the administration of the formulations. Experience on use of intravenous formulations of Losec in paediatric patients is limited, however no specific safety issues are predicted.

26

Special populations: all formulations Regarding special populations, dose adjustment is not needed in patients with impaired renal function, as omeprazole is almost completely metabolized by CYP450, renal impairment does therefore not influence the pharmacokinetics. In patients with impaired hepatic function, however, a daily dose of 10–20 mg may be sufficient. For the elderly (>65 years old), no dose adjustment is needed. Section 4.3 - Contraindications Omeprazole has been reported to interact with some antiretroviral drugs. Increased gastric pH during omeprazole treatment may affect absorption, while other possible interaction mechanisms are via CYP2C19. The SPC therefore states that co-administration of atazanavir and nelfinavir with proton pump inhibitors is not recommended and that if co-administration is judged unavoidable, close clinical monitoring is recommended together with an increase of the anti-retroviral drug dose, as plasma levels of nelfinavir and atazanavir are decreased in case of co-administration with omeprazole. Nelfinavir co-administration is contraindicated, atazanavir co-administration is not recommended. While literature data strongly indicates that there is no cross-reactivity between the various substituted benzimidazoles, there is data indicating suspected cross-reactivity. Due to the high potential risk to patients, a statement contraindicating use in patients hypersensitive to omeprazole, substituted benzimidazoles or to any of the excipients was adopted by the CHMP. Section 4.4 - Special warnings and precautions for use A warning that the H. pylori status should be determined before treatment was included in the SPC. The use of endoscopy and/or x-ray in case of acid related ulcers is no longer necessary according to current practice and these techniques are therefore omitted. A statement on the potential increased or decreased absorption of active substances with a gastric pH dependent absorption due to decreased intragastric acidity was inserted. The SPC also mentions that the benefit-risk of omeprazole treatment in the maintenance setting should be continuously re-evaluated and that patients should be kept under regular surveillance, especially when exceeding a treatment period of 1 year. The CHMP considered that the increased occurrence of gastrointestinal bacterial infections due to decreased gastric acidity should be mentioned in the SPC. Salmonella and Campylobacter are mentioned; however the mention of C. difficile infections was removed, as the available data did not establish a possible causal relationship between C. difficile infection and the use of PPIs. The CHMP was of the opinion that prolonged acid inhibition by PPIs may promote vitamin B12 malabsorption and inserted a warning stating that omeprazole may reduce the absorption of vitamin B12 and that this should be considered in patients on long-term therapy. The CHMP assessed the potential omeprazole-clopidogrel interaction and considered that a warning is warranted, given the potential seriousness of the observed adverse events. After consultation of the Cardiovascular subgroup of the Efficacy Working Party, the CHMP confirmed that a PK and PD interaction between CYP2C19 inhibitors and clopidogrel is observed, although the clinical implication of this finding is not clear. The SPC therefore states that omeprazole is a CYP2C19 inhibitor and that inconsistent data has been reported from observational and clinical studies on the clinical implications of the PK/PD interaction in terms of major cardiovascular events. Concomitant use of omeprazole and clopidogrel is therefore discouraged Section 4.5 – Interactions with other medicinal products and other forms of interactions – all formulations This section was rewritten in a more reader friendly style by grouping the possible interactions, increasing

27

the visibility of the most severe clinical consequences and indicating the magnitude of the interaction effects. The interaction with tacrolimus and phenytoin were retained and monitoring was recommended but an interaction with methotrexate was considered unwarranted. Concomitant use with posaconazol and erlotinib should be avoided. Section 4.6: Pregnancy and lactation – all formulations The CHMP considered that there is sufficient information on human experience to state that excretion of omeprazole in milk is low and unlikely to influence the child. Data from epidemiological studies on use of Losec during pregnancy indicates no adverse effects and the CHMP considered that omeprazole can be used during pregnancy. Section 4.7: Effects on ability to drive and use machines – all formulations The CHMP noted that although Losec is not likely to affect the ability drive or use machines, dizziness and visual disturbances have been observed with the use of Losec, and stated that patients experiencing these adverse drug reactions should not drive or operate machinery. Section 4.8 - Undesirable effects Identified or suspected adverse drug reactions are listed in this sections. None have been found to be dose-related and the reactions are classified according to frequency. The SPC states that for the tablet and capsule formulations the clinical trial safety experience shows that the adverse event profile in children up to 16 years of age is generally the same as for adults in short- as well as in long-term treatment and that there is no long-term data on the effects on puberty and growth. Section 4.9 - Overdose There have been no reports of serious outcomes following overdoses with omeprazole, and thus, no specific treatment has been needed or can be recommended. The statement “symptomatic treatment”, provides some guidance to the physician on how to handle an overdose. An additional statement was inserted for the infusion and injection formulations, stating that based on clinical trials, excessive doses have not led to any dose-related adverse reactions. Section 5.1: Pharmacodynamic properties The CHMP discussed the association of omeprazole with the occurrence of bone fracture/hip fracture in the elderly, especially osteoporosis affected population. The CHMP considered that the currently available information is not sufficient for a warning in the SPC, however, due to the concerns raised, the outcome of the proposed MAH epidemiological study on the risk of falls and fractures will be assessed in order to determine the implications for the Losec SPC. Section 5.2 - Pharmacokinetic properties The CHMP noted data showing that omeprazole does not increase the incidence or seriousness of the side effects in the poor metaboliser population and considered that although poor metabolisers show 5 to 10 times higher mean AUC than subjects having a functional CYP2C19 enzyme, there is no evidence that patients who are poor CYP2C19 metabolisers are at increased risk when treated with omeprazole at recommended doses.. OVER THE COUNTER PRESENTATIONS: LOSEC 10 AND 20 MG TABLETS (OTC) Initial GERD treatment is managed by a symptom-based approach; an empiric trial of acid suppression can be used. Symptoms responding adequately to an acid suppressant and returning upon discontinuation

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allow a diagnosis of GERD. The CHMP considered that the available scientific information sufficiently demonstrates the efficacy of omeprazole in the treatment of heartburn and acid reflux and its superiority to placebo, in particular for the short-term OTC use of 20 mg daily. Similarly, the CHMP considered that there is sufficient evidence from the literature and long-term post marketing experience that omeprazole 20 mg daily is a safe dosage over 14 days. The legal status of Losec as a ”medicinal products not subject to medical prescription” was considered to be in accordance with the EC Guideline on Changing the Classification for the Supply of a Medicinal Product for Human Use. The known safety profile of omeprazole confirms the absence of direct or indirect danger to human health and the cautionary measures restricting the use to 2 weeks treatment are considered acceptable. The CHMP concluded that omeprazole is a suitable medication to relief heartburn and acid regurgitation in the OTC setting, provided that the patient complies with the recommended dosing and correct use, as instructed by the SPC and the Patient Leaflet. Harmonisation of the SPC and PL for the OTC product In general, the SPC and the PL of the OTC Losec presentation was aligned to that of the Prescription-only products. Regarding Section 4.1, the CHMP adopted the following harmonised indication: “Losec gastro-resistant tablets are indicated for the treatment of reflux symptoms (e.g. heartburn, acid regurgitation) in adults” The CHMP noted that study data showed that 20 mg once daily produces a more pronounced and consistent inhibition than the lower doses and therefore agreed on a maximum daily dose of 20 mg. Self-treatment should be limited to a maximum period of 14 days, and the patient should be instructed to consult a doctor if symptoms persist. Patients with impaired hepatic function should be advised by a doctor before taking Losec. Relief of symptoms after the start of treatment with PPIs may take time, therefore a statement informing patients that 2-3 days might be needed before symptom improvement is perceived was also added. In line with the indication, this product should not be used in children. Information on the need for regular surveillance when exceeding a treatment period of one year was inserted and patients with long-term recurrent symptoms of indigestion or heartburn should see their doctor at regular intervals, especially patients over 55 years as the increasing age is a risk factor for the development of gastric disorders. Patients are also instructed to consult a doctor if they have had previous gastric ulcer or gastrointestinal surgery, in case of jaundice, hepatic impairment, or liver disease and if they are on continuous symptomatic treatment of indigestion or heartburn for 4 or more weeks. Patients are also told not to take omeprazole as a preventive medication. Regarding the interaction with clopidogrel, in line with the prescription-only recommendation, patients should specifically tell their doctor or pharmacist if they are taking clopidogrel. QUALITY – MODULE 3 The MAH submitted a proposal for harmonisation of the Quality module. The proposed harmonisations mainly concern the drug product and the MAH provided satisfactory information on the appearance, polymorphisms, specifications and stability of the drug substances (omeprazole magnesium for the MUPS tablets, omeprazole for the capsules and omeprazole sodium for the injection and infusion formulations). Appropriate information on the drug product was also provided, and the physical appearance, manufacture, specification, stability, shelf-life, storage were covered. However a number of clarifications were requested, mainly with regards to the Manufacture, Control of Drug Product, Container Closure System and Stability sections, for all formulations. Based on the review of data and taking into account the commitments provided by the MAH to submit an update of Module 3 in May 2010, the CHMP adopted a harmonised Module 3.

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GROUNDS FOR AMENDMENT OF THE SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE LEAFLET In conclusion, based on the assessment of the MAH proposal and responses and following the discussions of the committee, the CHMP adopted harmonised sets of Product Information documents for the various presentations of Losec and associated names, taking into account the pharmaceutical forms and differentiating between the prescription-only and the OTC presentations. In particular, the indications and their associated posology recommendations were harmonised. A harmonised Module 3 was also adopted. Commitments by the MAH were agreed, as listed in the Letter of Undertaking dated 14 December 2009. Based on the above, the CHMP considers the benefit/risk ratio of Losec to be favourable and the harmonised Product Information documents to be approvable. 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 Losec and associated names (see Annex I). The conditions of the Marketing Authorisations are described in Annex IV.

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ANNEX III

SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE LEAFLET

Note: This SPC, labelling and package 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

For medicinal products available on prescription

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1. NAME OF THE MEDICINAL PRODUCT Losec and associated names (see Annex I) 10 mg hard capsules Losec and associated names (see Annex I) 20 mg hard capsules Losec and associated names (see Annex I) 40 mg hard capsules [See Annex I - To be completed nationally] 2. QUALITATIVE AND QUANTITATIVE COMPOSITION 10 mg: Each capsule contains 10 mg omeprazole. 20 mg: Each capsule contains 20 mg omeprazole. 40 mg: Each capsule contains 40 mg omeprazole. Excipient: 10 mg: Each capsule contains 4 mg lactose. 20 mg: Each capsule contains 8 mg lactose. 40 mg: Each capsule contains 9 mg lactose. For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL form Capsule, hard (capsule). 10 mg: hard gelatine capsules with an opaque pink body, marked 10 and an opaque pink cap marked A/OS, containing enteric coated pellets. 20 mg: hard gelatine capsules with an opaque pink body, marked 20 and an opaque reddish-brown cap marked A/OM, containing enteric coated pellets. 40 mg: hard gelatine capsules with an opaque reddish-brown body, marked 40 and an opaque reddish-brown cap marked A/OL, containing enteric coated pellets. 4. Clinical particulars 4.1 Therapeutic indications Losec capsules are indicated for: Adults • Treatment of duodenal ulcers • Prevention of relapse of duodenal ulcers • Treatment of gastric ulcers • Prevention of relapse of gastric ulcers • In combination with appropriate antibiotics, Helicobacter pylori (H. pylori) eradication in peptic

ulcer disease • Treatment of NSAID-associated gastric and duodenal ulcers • Prevention of NSAID-associated gastric and duodenal ulcers in patients at risk • Treatment of reflux esophagitis • Long-term management of patients with healed reflux esophagitis

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• Treatment of symptomatic gastro-esophageal reflux disease • Treatment of Zollinger-Ellison syndrome Paediatric use Children over 1 year of age and ≥ 10 kg • Treatment of reflux esophagitis • Symptomatic treatment of heartburn and acid regurgitation in gastro-esophageal reflux disease Children and adolescents over 4 years of age • In combination with antibiotics in treatment of duodenal ulcer caused by H. pylori 4.2 Posology and method of administration Posology in adults Treatment of duodenal ulcers The recommended dose in patients with an active duodenal ulcer is Losec 20 mg once daily. In most patients healing occurs within two weeks. For those patients who may not be fully healed after the initial course, healing usually occurs during a further two weeks treatment period. In patients with poorly responsive duodenal ulcer Losec 40 mg once daily is recommended and healing is usually achieved within four weeks. Prevention of relapse of duodenal ulcers For the prevention of relapse of duodenal ulcer in H. pylori negative patients or when H. pylori eradication is not possible the recommended dose is Losec 20 mg once daily. In some patients a daily dose of 10 mg may be sufficient. In case of therapy failure, the dose can be increased to 40 mg. Treatment of gastric ulcers The recommended dose is Losec 20 mg once daily. In most patients healing occurs within four weeks. For those patients who may not be fully healed after the initial course, healing usually occurs during a further four weeks treatment period. In patients with poorly responsive gastric ulcer Losec 40 mg once daily is recommended and healing is usually achieved within eight weeks. Prevention of relapse of gastric ulcers For the prevention of relapse in patients with poorly responsive gastric ulcer the recommended dose is Losec 20 mg once daily. If needed the dose can be increased to Losec 40 mg once daily. H. pylori eradication in peptic ulcer disease For the eradication of H. pylori the selection of antibiotics should consider the individual patient’s drug tolerance, and should be undertaken in accordance with national, regional and local resistance patterns and treatment guidelines. • Losec 20 mg + clarithromycin 500 mg + amoxicillin 1,000 mg, each twice daily for one week, or • Losec 20 mg + clarithromycin 250 mg (alternatively 500 mg) + metronidazole 400 mg (or 500 mg

or tinidazole 500 mg), each twice daily for one week or • Losec 40 mg once daily with amoxicillin 500 mg and metronidazole 400 mg (or 500 mg or

tinidazole 500 mg), both three times a day for one week. In each regimen, if the patient is still H. pylori positive, therapy may be repeated. Treatment of NSAID-associated gastric and duodenal ulcers For the treatment of NSAID-associated gastric and duodenal ulcers, the recommended dose is Losec 20 mg once daily. In most patients healing occurs within four weeks. For those patients who may not be fully healed after the initial course, healing usually occurs during a further four weeks treatment period.

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Prevention of NSAID-associated gastric and duodenal ulcers in patients at risk For the prevention of NSAID-associated gastric ulcers or duodenal ulcers in patients at risk (age> 60, previous history of gastric and duodenal ulcers, previous history of upper GI bleeding) the recommended dose is Losec 20 mg once daily. Treatment of reflux esophagitis The recommended dose is Losec 20 mg once daily. In most patients healing occurs within four weeks. For those patients who may not be fully healed after the initial course, healing usually occurs during a further four weeks treatment period. In patients with severe esophagitis Losec 40 mg once daily is recommended and healing is usually achieved within eight weeks. Long-term management of patients with healed reflux esophagitis For the long-term management of patients with healed reflux esophagitis the recommended dose is Losec 10 mg once daily. If needed, the dose can be increased to Losec 20-40 mg once daily. Treatment of symptomatic gastro-esophageal reflux disease The recommended dose is Losec 20 mg daily. Patients may respond adequately to 10 mg daily, and therefore individual dose adjustment should be considered. If symptom control has not been achieved after four weeks treatment with Losec 20 mg daily, further investigation is recommended. Treatment of Zollinger-Ellison syndrome In patients with Zollinger-Ellison syndrome the dose should be individually adjusted and treatment continued as long as clinically indicated. The recommended initial dose is Losec 60 mg daily. All patients with severe disease and inadequate response to other therapies have been effectively controlled and more than 90% of the patients maintained on doses of Losec 20-120 mg daily. When dose exceed Losec 80 mg daily, the dose should be divided and given twice daily. Posology in children Children over 1 year of age and ≥ 10 kg Treatment of reflux esophagitis Symptomatic treatment of heartburn and acid regurgitation in gastro-esophageal reflux disease The posology recommendations are as follows: Age Weight Posology ≥ 1 year of age 10-20 kg 10 mg once daily. The dose can be increased to 20 mg once daily if needed ≥ 2 years of age > 20 kg 20 mg once daily. The dose can be increased to 40 mg once daily if needed Reflux esophagitis: The treatment time is 4-8 weeks. Symptomatic treatment of heartburn and acid regurgitation in gastro-esophageal reflux disease: The treatment time is 2–4 weeks. If symptom control has not been achieved after 2–4 weeks the patient should be investigated further. Children and adolescents over 4 years of age Treatment of duodenal ulcer caused by H. pylori When selecting appropriate combination therapy, consideration should be given to official national, regional and local guidance regarding bacterial resistance, duration of treatment (most commonly 7 days but sometimes up to 14 days), and appropriate use of antibacterial agents.

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The treatment should be supervised by a specialist. The posology recommendations are as follows: Weight Posology 15–30 kg Combination with two antibiotics: Losec 10 mg, amoxicillin 25 mg/kg body weight and

clarithromycin 7.5 mg/kg body weight are all administrated together two times daily for one week.

31–40 kg Combination with two antibiotics: Losec 20 mg, amoxicillin 750 mg and clarithromycin 7.5 mg/kg body weight are all administrated two times daily for one week.

> 40 kg Combination with two antibiotics: Losec 20 mg, amoxicillin 1 g and clarithromycin 500 mg are all administrated two times daily for one week.

Special populations Impaired renal function Dose adjustment is not needed in patients with impaired renal function (see section 5.2). Impaired hepatic function In patients with impaired hepatic function a daily dose of 10–20 mg may be sufficient (see section 5.2). Elderly (> 65 years old) Dose adjustment is not needed in the elderly (see section 5.2). Method of administration It is recommended to take Losec capsules in the morning, preferably without food, swallowed whole with half a glass of water. The capsules must not be chewed or crushed. For patients with swallowing difficulties and for children who can drink or swallow semi-solid food Patients can open the capsule and swallow the contents with half a glass of water or after mixing the contents in a slightly acidic fluid e.g., fruit juice or applesauce, or in non-carbonated water. Patients should be advised that the dispersion should be taken immediately (or within 30 minutes) and always be stirred just before drinking and rinsed down with half a glass of water. Alternatively patients can suck the capsule and swallow the pellets with half a glass of water. The enteric-coated pellets must not be chewed. 4.3 Contraindications Hypersensitivity to omeprazole, substituted benzimidazoles or to any of the excipients. Omeprazole like other proton pump inhibitors (PPIs) must not be used concomitantly with nelfinavir (see section 4.5). 4.4 Special warnings and precautions for use In the presence of any alarm symptom (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment may alleviate symptoms and delay diagnosis. 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; omeprazole 20 mg should not be exceeded.

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Omeprazole, 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. Omeprazole is a CYP2C19 inhibitor. When starting or ending treatment with omeprazole, the potential for interactions with drugs metabolised through CYP2C19 should be considered. An interaction is observed between clopidogrel and omeprazole (see section 4.5). The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of omeprazole and clopidogrel should be discouraged. Some children with chronic illnesses may require long-term treatment although it is not recommended. Losec contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter (see section 5.1). As in all long-term treatments, especially when exceeding a treatment period of 1 year, patients should be kept under regular surveillance. 4.5 Interaction with other medicinal products and other forms of interaction Effects of omeprazole on the pharmacokinetics of other active substances Active substances with pH dependent absorption The decreased intragastric acidity during treatment with omeprazole might increase or decrease the absorption of active substances with a gastric pH dependent absorption. Nelfinavir, atazanavir The plasma levels of nelfinavir and atazanavir are decreased in case of co-administration with omeprazole. Concomitant administration of omeprazole with nelfinavir is contraindicated (see section 4.3). Co-administration of omeprazole (40 mg once daily) reduced mean nelvinavir exposure by ca. 40% and the mean exposure of the pharmacologically active metabolite M8 was reduced by ca. 75 –90%. The interaction may also involve CYP2C19 inhibition. Concomitant administration of omeprazole with atazanavir is not recommended (see section 4.4). Concomitant administration of omeprazole (40 mg once daily) and atazanavir 300 mg/ritonavir 100 mg to healthy volunteers resulted in a 75% decrease of the atazanavir exposure. Increasing the atazanavir dose to 400 mg did not compensate for the impact of omeprazole on atazanavir exposure. The co-administration of omeprazole (20 mg once daily) with atazanavir 400 mg/ritonavir 100 mg to healthy volunteers resulted in a decrease of approximately 30% in the atazanavir exposure as compared to atazanavir 300 mg/ritonavir 100 mg once daily. Digoxin Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10%. Digoxin toxicity has been rarely reported. However caution should be exercised when omeprazole is given at high doses in elderly patients. Therapeutic drug monitoring of digoxin should be then be reinforced. Clopidogrel In a crossover clinical study, clopidogrel (300 mg loading dose followed by 75 mg/day) alone and with omeprazole (80 mg at the same time as clopidogrel) were administered for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and

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omeprazole were administered together. Mean inhibition of platelet aggregation (IPA) was diminished by 47% (24 hours) and 30% (Day 5) when clopidogrel and omeprazole were administered together. In another study it was shown that administering clopidogrel and omeprazole at different times did not prevent their interaction that is likely to be driven by the inhibitory effect of omeprazole on CYP2C19. Inconsistent data on the clinical implications of this PK/PD interaction in terms of major cardiovascular events have been reported from observational and clinical studies. Other active substances The absorption of posaconazole, erlotinib, ketoconazol and itraconazol is significantly reduced and thus clinical efficacy may be impaired. For posaconazol and erlotinib concomitant use should be avoided. Active substances metabolised by CYP2C19 Omeprazole is a moderate inhibitor of CYP2C19, the major omeprazole metabolising enzyme. Thus, the metabolism of concomitant active substances also metabolised by CYP2C19, may be decreased and the systemic exposure to these substances increased. Examples of such drugs are R-warfarin and other vitamin K antagonists, cilostazol, diazepam and phenytoin. Cilostazol Omeprazole, given in doses of 40 mg to healthy subjects in a cross-over study, increased Cmax and AUC for cilostazol by 18% and 26% respectively, and one of its active metabolites by 29% and 69% respectively. Phenytoin Monitoring phenytoin plasma concentration is recommended during the first two weeks after initiating omeprazole treatment and, if a phenytoin dose adjustment is made, monitoring and a further dose adjustment should occur upon ending omeprazole treatment. Unknown mechanism Saquinavir Concomitant administration of omeprazole with saquinavir/ritonavir resulted in increased plasma levels up to approximately 70% for saquinavir associated with good tolerability in HIV-infected patients. Tacrolimus Concomitant administration of omeprazole has been reported to increase the serum levels of tacrolimus. A reinforced monitoring of tacrolimus concentrations as well as renal function (creatinine clearance) should be performed, and dosage of tacrolimus adjusted if needed. Effects of other active substances on the pharmacokinetics of omeprazole Inhibitors CYP2C19 and/or CYP3A4 Since omeprazole is metabolised by CYP2C19 and CYP3A4, active substances known to inhibit CYP2C19 or CYP3A4 (such as clarithromycin and voriconazole) may lead to increased omeprazole serum levels by decreasing omeprazole’s rate of metabolism. Concomitant voriconazole treatment resulted in more than doubling of the omeprazole exposure. As high doses of omeprazole have been well-tolerated adjustment of the omeprazole dose is not generally required. However, dose adjustment should be considered in patients with severe hepatic impairment and if long-term treatment is indicated. Inducers of CYP2C19 and/or CYP3A4 Active substances known to induce CYP2C19 or CYP3A4 or both (such as rifampicin and St John’s wort) may lead to decreased omeprazole serum levels by increasing omeprazole’s rate of metabolism. 4.6 Pregnancy and lactation

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Results from three prospective epidemiological studies (more than 1000 exposed outcomes) indicate no adverse effects of omeprazole on pregnancy or on the health of the foetus/newborn child. Omeprazole can be used during pregnancy. Omeprazole is excreted in breast milk but is not likely to influence the child when therapeutic doses are used. 4.7 Effects on ability to drive and use machines Losec is not likely to affect the ability to drive or 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 machinery. 4.8 Undesirable effects The most common side effects (1-10% of patients) are headache, abdominal pain, constipation, diarrhoea, flatulence and nausea/vomiting. The following adverse drug reactions have been identified or suspected in the clinical trials programme for omeprazole and post-marketing. None was found to be dose-related. Adverse reactions listed below are classified according to frequency and System Organ Class (SOC). Frequency categories are defined according to the following convention: 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). SOC/frequency

Adverse reaction

Blood and lymphatic system disorders Rare: Leukopenia, thrombocytopenia Very rare: Agranulocytosis, pancytopenia Immune system disorders Rare: Hypersensitivity reactions e.g. fever, angioedema and anaphylactic

reaction/shock Metabolism and nutrition disorders Rare: Hyponatraemia Very rare: Hypomagnesaemia Psychiatric disorders Uncommon: Insomnia Rare: Agitation, confusion, depression Very rare: Aggression, hallucinations Nervous system disorders Common: Headache Uncommon: Dizziness, paraesthesia, somnolence Rare: Taste disturbance Eye disorders Rare: Blurred vision Ear and labyrinth disorders Uncommon: Vertigo Respiratory, thoracic and mediastinal disorders Rare: Bronchospasm Gastrointestinal disorders Common: Abdominal pain, constipation, diarrhoea, flatulence, nausea/vomiting Rare: Dry mouth, stomatitis, gastrointestinal candidiasis

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Hepatobiliary disorders Uncommon: Increased liver enzymes Rare: Hepatitis with or without jaundice Very rare: Hepatic failure, encephalopathy in patients with pre-existing liver disease Skin and subcutaneous tissue disorders Uncommon: Dermatitis, pruritus, rash, urticaria Rare: Alopecia, photosensitivity Very rare: Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis

(TEN) Musculoskeletal and connective tissue disorders Rare: Arthralgia, myalgia Very rare: Muscular weakness Renal and urinary disorders Rare: Interstitial nephritis Reproductive system and breast disorders Very rare: Gynaecomastia General disorders and administration site conditions Uncommon: Malaise, peripheral oedema Rare: Increased sweating Paediatric population The safety of omeprazole has been assessed in a total of 310 children aged 0 to 16 years with acid-related disease. There are limited long term safety data from 46 children who received maintenance therapy of omeprazole during a clinical study for severe erosive esophagitis for up to 749 days. The adverse event profile was generally the same as for adults in short- as well as in long-term treatment. There are no long term data regarding the effects of omeprazole treatment on puberty and growth. 4.9 Overdose There is limited information available on the effects of overdoses of omeprazole in humans. In the literature, doses of up to 560 mg have been described, and occasional reports have been received when single oral doses have reached up to 2,400 mg omeprazole (120 times the usual recommended clinical dose). Nausea, vomiting, dizziness, abdominal pain, diarrhoea and headache have been reported. Also apathy, depression and confusion have been described in single cases. The symptoms described have been transient, and no serious outcome has been reported. The rate of elimination was unchanged (first order kinetics) with increased doses. Treatment, if needed, is symptomatic. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Proton pump inhibitors, ATC code: A02BC01 Mechanism of action Omeprazole, a racemic mixture of two enantiomers reduces gastric acid secretion through a highly targeted mechanism of action. It is a specific inhibitor of the acid pump in the parietal cell. It is rapidly acting and provides control through reversible inhibition of gastric acid secretion with once daily dosing. Omeprazole is a weak base and is concentrated and converted to the active form in the highly acidic environment of the intracellular canaliculi within the parietal cell, where it inhibits the enzyme

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H+ K+-ATPase - the acid pump. This effect on the final step of the gastric acid formation process is dose-dependent and provides for highly effective inhibition of both basal acid secretion and stimulated acid secretion, irrespective of stimulus. Pharmacodynamic effects All pharmacodynamic effects observed can be explained by the effect of omeprazole on acid secretion. Effect on gastric acid secretion Oral dosing with omeprazole once daily provides for rapid and effective inhibition of daytime and night-time gastric acid secretion with maximum effect being achieved within 4 days of treatment. With omeprazole 20 mg, a mean decrease of at least 80% in 24-hour intragastric acidity is then maintained in duodenal ulcer patients, with the mean decrease in peak acid output after pentagastrin stimulation being about 70% 24 hours after dosing. Oral dosing with omeprazole 20 mg maintains an intragastric pH of ≥ 3 for a mean time of 17 hours of the 24-hour period in duodenal ulcer patients. As a consequence of reduced acid secretion and intragastric acidity, omeprazole dose-dependently reduces/normalizes acid exposure of the esophagus in patients with gastro-esophageal reflux disease. The inhibition of acid secretion is related to the area under the plasma concentration-time curve (AUC) of omeprazole and not to the actual plasma concentration at a given time. No tachyphylaxis has been observed during treatment with omeprazole. Effect on H. pylori H. pylori is associated with peptic ulcer disease, including duodenal and gastric ulcer disease. H. pylori is a major factor in the development of gastritis. H. pylori together with gastric acid are major factors in the development of peptic ulcer disease. H. pylori is a major factor in the development of atrophic gastritis which is associated with an increased risk of developing gastric cancer. Eradication of H. pylori with omeprazole and antimicrobials is associated with, high rates of healing and long-term remission of peptic ulcers. Dual therapies have been tested and found to be less effective than triple therapies. They could, however, be considered in cases where known hypersensitivity precludes use of any triple combination. Other effects related to acid inhibition During long-term treatment gastric glandular cysts have been reported in a somewhat increased frequency. These changes are a physiological consequence of pronounced inhibition of acid secretion, are benign and appear to be reversible. Decreased gastric acidity due to any means including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with acid-reducing drugs may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter. Paediatric use In a non-controlled study in children (1 to 16 years of age) with severe reflux esophagitis, omeprazole at doses of 0.7 to 1.4 mg/kg improved esophagitis level in 90% of the cases and significantly reduced reflux symptoms. In a single-blind study, children aged 0–24 months with clinically diagnosed gastro-esophageal reflux disease were treated with 0.5, 1.0 or 1.5 mg omeprazole/kg. The frequency of vomiting/regurgitation episodes decreased by 50% after 8 weeks of treatment irrespective of the dose.

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Eradication of H. pylori in children A randomised, double blind clinical study (Héliot study) concluded that omeprazole in combination with two antibiotics (amoxicillin and clarithromycin), was safe and effective in the treatment of H. pylori infection in children age 4 years old and above with gastritis: H. pylori eradication rate: 74.2% (23/31 patients) with omeprazole + amoxicillin + clarithromycin versus 9.4% (3/32 patients) with amoxicillin + clarithromycin. However, there was no evidence of any clinical benefit with respect to dyspeptic symptoms. This study does not support any information for children aged less than 4 years. 5.2 Pharmacokinetic properties Absorption Omeprazole and omeprazole magnesium are acid labile and are therefore administered orally as enteric-coated granules in capsules or tablets. Absorption of omeprazole is rapid, with peak plasma levels occurring approximately 1-2 hours after dose. Absorption of omeprazole takes place in the small intestine and is usually completed within 3-6 hours. Concomitant intake of food has no influence on the bioavailability. The systemic availability (bioavailability) from a single oral dose of omeprazole is approximately 40%. After repeated once-daily administration, the bioavailability increases to about 60%. Distribution The apparent volume of distribution in healthy subjects is approximately 0.3 l/kg body weight. Omeprazole is 97% plasma protein bound. Metabolism Omeprazole is completely metabolised by the cytochrome P450 system (CYP). The major part of its metabolism is dependent on the polymorphically expressed CYP2C19, responsible for the formation of hydroxyomeprazole, the major metabolite in plasma. The remaining part is dependent on another specific isoform, CYP3A4, responsible for the formation of omeprazole sulphone. As a consequence of high affinity of omeprazole to CYP2C19, there is a potential for competitive inhibition and metabolic drug-drug interactions with other substrates for CYP2C19. However, due to low affinity to CYP3A4, omeprazole has no potential to inhibit the metabolism of other CYP3A4 substrates. In addition, omeprazole lacks an inhibitory effect on the main CYP enzymes. Approximately 3% of the Caucasian population and 15-20% of Asian populations lack a functional CYP2C19 enzyme and are called poor metabolisers. In such individuals the metabolism of omeprazole is probably mainly catalysed by CYP3A4. After repeated once-daily administration of 20 mg omeprazole, the mean AUC was 5 to 10 times higher in poor metabolisers than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations were also higher, by 3 to 5 times. These findings have no implications for the posology of omeprazole. Excretion The plasma elimination half-life of omeprazole is usually shorter than one hour both after single and repeated oral once-daily dosing. Omeprazole is completely eliminated from plasma between doses with no tendency for accumulation during once-daily administration. Almost 80% of an oral dose of omeprazole is excreted as metabolites in the urine, the remainder in the faeces, primarily originating from bile secretion. The AUC of omeprazole increases with repeated administration. This increase is dose-dependent and results in a non-linear dose-AUC relationship after repeated administration. This time- and dose-dependency is due to a decrease of first pass metabolism and systemic clearance probably caused by an inhibition of the CYP2C19 enzyme by omeprazole and/or its metabolites (e.g. the sulphone). No metabolite has been found to have any effect on gastric acid secretion. Special populations Impaired hepatic function

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The metabolism of omeprazole in patients with liver dysfunction is impaired, resulting in an increased AUC. Omeprazole has not shown any tendency to accumulate with once daily dosing. Impaired renal function The pharmacokinetics of omeprazole, including systemic bioavailability and elimination rate, are unchanged in patients with reduced renal function. Elderly The metabolism rate of omeprazole is somewhat reduced in elderly subjects (75-79 years of age). Paediatric patients During treatment with the recommended doses to children from the age of 1 year, similar plasma concentrations were obtained as compared to adults. In children younger than 6 months, clearance of omeprazole is low due to low capacity to metabolise omeprazole. 5.3 Preclinical safety data Gastric ECL-cell hyperplasia and carcinoids, have been observed in life-long studies in rats treated with omeprazole. These changes are the result of sustained hypergastrinaemia secondary to acid inhibition. Similar findings have been made after treatment with H2-receptor antagonists, proton pump inhibitors and after partial fundectomy. Thus, these changes are not from a direct effect of any individual active substance. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Disodium hydrogen phosphate dihydrate, hydroxypropylcellulose, hydroxypropyl methylcellulose, lactose anhydrous, magnesium stearate, mannitol, methacrylic acid co-polymer, microcrystalline cellulose, macrogol (polyethylene glycol), sodium lauryl sulphate, iron oxide, titanium dioxide, gelatine, printing ink (containing shellac, ammonium hydroxide, potassium hydroxide and black iron oxide) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage Do not store above 30°C.

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Bottle: Keep the container tightly closed in order to protect from moisture. Blister: Store in the original package in order to protect from moisture. 6.5 Nature and contents of container HDPE bottle: with a tight fitting polypropylene screw-cap equipped with a desiccant capsule. 10 mg: 5, 7, 10, 14, 15, 28, 30, 50, 56, 60, 100 capsules; hospital packs of 140, 280 or 700 capsules. 20 mg: 5, 7, 10, 14, 15, 28, 30, 50, 60, 100 capsules; hospital packs of 140, 280 or 700 capsules. 40 mg: 5, 7, 14, 15, 28, 30, 60 capsules; hospital packs of 140, 280 or 700 capsules. Aluminium blister. 10 mg: 7, 14, 15, 28, 30, 35, 50, 56, 84 capsules. 20 mg 7, 14, 15, 28, 30, 50, 60, 84 capsules. 40 mg 7, 14, 15, 28, 30 capsules. Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements. 7. MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] 8. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION [To be completed nationally] 10. DATE OF REVISION OF THE TEXT [To be completed nationally] Detailed information on this product is available on the website of: {name of MS/Agency} [To be completed nationally]

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1. NAME OF THE MEDICINAL PRODUCT Losec and associated names (see Annex I) 10 mg gastro-resistant tablets Losec and associated names (see Annex I) 20 mg gastro-resistant tablets Losec and associated names (see Annex I) 40 mg gastro-resistant tablets [See Annex I - To be completed nationally] 2. QUALITATIVE AND QUANTITATIVE COMPOSITION 10 mg: Each gastro-resistant tablet contains 10.3 mg omeprazole magnesium equivalent to 10 mg omeprazole.. 20 mg: Each gastro-resistant tablet contains 20.6 mg omeprazole magnesium equivalent to 20 mg omeprazole. 40 mg: Each gastro-resistant tablet contains 39–41 mg omeprazole magnesium equivalent to 40 mg omeprazole. Excipient: 10 mg: Each gastro-resistant tablet contains 19–20 mg sucrose. 20 mg: Each gastro-resistant tablet contains 19–20 mg sucrose. 40 mg: Each gastro-resistant tablet contains 39–41 mg sucrose. For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL form Gastro-resistant tablet. Losec 10 mg gastro-resistant tablets: Light-pink, oblong, biconvex, film-coated tablets engraved with or on one side and 10 mg on the other side containing enteric coated pellets. Losec 20 mg gastro-resistant tablets: Pink, oblong, biconvex, film-coated tablets, engraved with or on one side and 20 mg on the other side containing enteric coated pellets. Losec 40 mg gastro-resistant tablets: Dark red-brown, oblong, biconvex, film-coated tablets, engraved with or on one side and 40 mg and a score on the other side containing enteric coated pellets. 4. Clinical particulars 4.1 Therapeutic indications Losec gastro-resistant tablets are indicated for: Adults • Treatment of duodenal ulcers • Prevention of relapse of duodenal ulcers • Treatment of gastric ulcers • Prevention of relapse of gastric ulcers • In combination with appropriate antibiotics, Helicobacter pylori (H. pylori) eradication in peptic

ulcer disease • Treatment of NSAID-associated gastric and duodenal ulcers

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• Prevention of NSAID-associated gastric and duodenal ulcers in patients at risk • Treatment of reflux esophagitis • Long-term management of patients with healed reflux esophagitis • Treatment of symptomatic gastro-esophageal reflux disease • Treatment of Zollinger-Ellison syndrome Paediatric use Children over 1 year of age and ≥ 10 kg • Treatment of reflux esophagitis • Symptomatic treatment of heartburn and acid regurgitation in gastro-esophageal reflux disease Children and adolescents over 4 years of age • In combination with antibiotics in treatment of duodenal ulcer caused by H. pylori 4.2 Posology and method of administration Posology in adults Treatment of duodenal ulcers The recommended dose in patients with an active duodenal ulcer is Losec 20 mg once daily. In most patients healing occurs within two weeks. For those patients who may not be fully healed after the initial course, healing usually occurs during a further two weeks treatment period. In patients with poorly responsive duodenal ulcer Losec 40 mg once daily is recommended and healing is usually achieved within four weeks. Prevention of relapse of duodenal ulcers For the prevention of relapse of duodenal ulcer in H. pylori negative patients or when H. pylori eradication is not possible the recommended dose is Losec 20 mg once daily. In some patients a daily dose of 10 mg may be sufficient. In case of therapy failure, the dose can be increased to 40 mg. Treatment of gastric ulcers The recommended dose is Losec 20 mg once daily. In most patients healing occurs within four weeks. For those patients who may not be fully healed after the initial course, healing usually occurs during a further four weeks treatment period. In patients with poorly responsive gastric ulcer Losec 40 mg once daily is recommended and healing is usually achieved within eight weeks. Prevention of relapse of gastric ulcers For the prevention of relapse in patients with poorly responsive gastric ulcer the recommended dose is Losec 20 mg once daily. If needed the dose can be increased to Losec 40 mg once daily. H. pylori eradication in peptic ulcer disease For the eradication of H. pylori the selection of antibiotics should consider the individual patient’s drug tolerance, and should be undertaken in accordance with national, regional and local resistance patterns and treatment guidelines. • Losec 20 mg + clarithromycin 500 mg + amoxicillin 1,000 mg, each twice daily for one week, or • Losec 20 mg + clarithromycin 250 mg (alternatively 500 mg) + metronidazole 400 mg (or 500 mg

or tinidazole 500 mg), each twice daily for one week, or • Losec 40 mg once daily with amoxicillin 500 mg and metronidazole 400 mg (or 500 mg or

tinidazole 500 mg), both three times a day for one week. In each regimen, if the patient is still H. pylori positive, therapy may be repeated. Treatment of NSAID-associated gastric and duodenal ulcers

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For the treatment of NSAID-associated gastric and duodenal ulcers, the recommended dose is Losec 20 mg once daily. In most patients healing occurs within four weeks. For those patients who may not be fully healed after the initial course, healing usually occurs during a further four weeks treatment period. Prevention of NSAID-associated gastric and duodenal ulcers in patients at risk For the prevention of NSAID associated gastric ulcers or duodenal ulcers in patients at risk (age> 60, previous history of gastric and duodenal ulcers, previous history of upper GI bleeding) the recommended dose is Losec 20 mg once daily. Treatment of reflux esophagitis The recommended dose is Losec 20 mg once daily. In most patients healing occurs within four weeks. For those patients who may not be fully healed after the initial course, healing usually occurs during a further four weeks treatment period. In patients with severe esophagitis Losec 40 mg once daily is recommended and healing is usually achieved within eight weeks. Long-term management of patients with healed reflux esophagitis For the long-term management of patients with healed reflux esophagitis the recommended dose is Losec 10 mg once daily. If needed, the dose can be increased to Losec 20-40 mg once daily. Treatment of symptomatic gastro-esophageal reflux disease The recommended dose is Losec 20 mg daily. Patients may respond adequately to 10 mg daily, and therefore individual dose adjustment should be considered. If symptom control has not been achieved after 4 weeks treatment with Losec 20 mg daily, further investigation is recommended. Treatment of Zollinger-Ellison syndrome In patients with Zollinger-Ellison syndrome the dose should be individually adjusted and treatment continued as long as clinically indicated. The recommended initial dose is Losec 60 mg daily. All patients with severe disease and inadequate response to other therapies have been effectively controlled and more than 90% of the patients maintained on doses of Losec 20–120 mg daily. When dose exceed Losec 80 mg daily, the dose should be divided and given twice daily. Posology in children Children over 1 year of age and ≥ 10 kg Treatment of reflux esophagitis

Symptomatic treatment of heartburn and acid regurgitation in gastro-esophageal reflux disease The posology recommendations are as follows: Age Weight Posology ≥ 1 year of age 10-20 kg 10 mg once daily. The dose can be increased to 20 mg once daily if

needed ≥ 2 years of age

> 20 kg 20 mg once daily. The dose can be increased to 40 mg once daily if needed

Reflux esophagitis: The treatment time is 4–8 weeks. Symptomatic treatment of heartburn and acid regurgitation in gastro-esophageal reflux disease: The treatment time is 2–4 weeks. If symptom control has not been achieved after 2–4 weeks the patient should be investigated further.

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Children and adolescents over 4 years of age Treatment of duodenal ulcer caused by H. pylori When selecting appropriate combination therapy, consideration should be given to official national, regional and local guidance regarding bacterial resistance, duration of treatment (most commonly 7 days but sometimes up to 14 days), and appropriate use of antibacterial agents. The treatment should be supervised by a specialist. The posology recommendations are as follows: Weight Posology 15-30 kg Combination with two antibiotics: Losec 10 mg, amoxicillin 25 mg/kg body weight and

clarithromycin 7.5 mg/kg body weight are all administrated together two times daily for one week

31-40 kg Combination with two antibiotics: Losec 20 mg, amoxicillin 750 mg and clarithromycin 7.5 mg/kg body weight are all administrated two times daily for one week

> 40 kg Combination with two antibiotics: Losec 20 mg, amoxicillin 1 g and clarithromycin 500 mg are all administrated two times daily for one week.

Special populations Impaired renal function Dose adjustment is not needed in patients with impaired renal function (see section 5.2). Impaired hepatic function In patients with impaired hepatic function a daily dose of 10–20 mg may be sufficient (see section 5.2). Elderly (> 65 years old) Dose adjustment is not needed in the elderly (see section 5.2). Method of administration It is recommended to take Losec tablets in the morning, swallowed whole with half a glass of water. The tablets must not be chewed or crushed. For patients with swallowing difficulties and for children who can drink or swallow semi-solid food Patients can break the tablet and disperse it in a spoonful of non-carbonated water and if so wished, mix with some fruit juices or applesauce. Patients should be advised that the dispersion should be taken immediately (or within 30 minutes)and always be stirred just before drinking and rinsed down with half a glass of water. DO NOT USE milk or carbonated water. The enteric-coated pellets must not be chewed. 4.3 Contraindications Hypersensitivity to omeprazole, substituted benzimidazoles or to any of the excipients. Omeprazole like other proton pump inhibitors must not be used concomitantly with nelfinavir (see section 4.5). 4.4 Special warnings and precautions for use In the presence of any alarm symptom (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment may alleviate symptoms and delay diagnosis.

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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; omeprazole 20 mg should not be exceeded. Omeprazole, 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. Omeprazole is a CYP2C19 inhibitor. When starting or ending treatment with omeprazole, the potential for interactions with drugs metabolised through CYP2C19 should be considered. An interaction is observed between clopidogrel and omeprazole (see section 4.5). The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of omeprazole and clopidogrel should be discouraged. Some children with chronic illnesses may require long-term treatment although it is not recommended. Losec gastro-resistant tablets contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter (see section 5.1). As in all long-term treatments, especially when exceeding a treatment period of 1 year, patients should be kept under regular surveillance. 4.5 Interaction with other medicinal products and other forms of interaction Effects of omeprazole on the pharmacokinetics of other active substances Active substances with pH dependent absorption The decreased intragastric acidity during treatment with omeprazole might increase or decrease the absorption of active substances with a gastric pH dependent absorption. Nelfinavir, atazanavir The plasma levels of nelfinavir and atazanavir are decreased in case of co-administration with omeprazole. Concomitant administration of omeprazole with nelfinavir is contraindicated (see section 4.3). Co-administration of omeprazole (40 mg once daily) reduced mean nelvinavir exposure by ca. 40% and the mean exposure of the pharmacologically active metabolite M8 was reduced by ca. 75-90%. The interaction may also involve CYP2C19 inhibition. Concomitant administration of omeprazole with atazanavir is not recommended (see section 4.4). Concomitant administration of omeprazole (40 mg once daily) and atazanavir 300 mg/ritonavir 100 mg to healthy volunteers resulted in a 75% decrease of the atazanavir exposure. Increasing the atazanavir dose to 400 mg did not compensate for the impact of omeprazole on atazanavir exposure. The co-administration of omeprazole (20 mg once daily) with atazanavir 400 mg/ritonavir 100 mg to healthy volunteers resulted in a decrease of approximately 30% in the atazanavir exposure as compared to atazanavir 300 mg/ritonavir 100 mg once daily. Digoxin Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10%. Digoxin toxicity has been rarely reported. However caution should be

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exercised when omeprazole is given at high doses in elderly patients. Therapeutic drug monitoring of digoxin should be then be reinforced. Clopidogrel In a crossover clinical study, clopidogrel (300 mg loading dose followed by 75 mg/day) alone and with omeprazole (80 mg at the same time as clopidogrel) were administered for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and omeprazole were administered together. Mean inhibition of platelet aggregation (IPA) was diminished by 47% (24 hours) and 30% (Day 5) when clopidogrel and omeprazole were administered together. In another study it was shown that administering clopidogrel and omeprazole at different times did not prevent their interaction that is likely to be driven by the inhibitory effect of omeprazole on CYP2C19. Inconsistent data on the clinical implications of this PK/PD interaction in terms of major cardiovascular events have been reported from observational and clinical studies. Other active substances The absorption of posaconazole, erlotinib, ketoconazol and itraconazol is significantly reduced and thus clinical efficacy may be impaired. For posaconazol and erlotinib concomitant use should be avoided. Active substances metabolised by CYP2C19 Omeprazole is a moderate inhibitor of CYP2C19, the major omeprazole metabolising enzyme. Thus, the metabolism of concomitant active substances also metabolised by CYP2C19, may be decreased and the systemic exposure to these substances increased. Examples of such drugs are R-warfarin and other vitamin K antagonists, cilostazol, diazepam and phenytoin. Cilostazol Omeprazole, given in doses of 40 mg to healthy subjects in a cross-over study, increased Cmax and AUC for cilostazol by 18% and 26% respectively, and one of its active metabolites by 29% and 69% respectively. Phenytoin Monitoring phenytoin plasma concentration is recommended during the first two weeks after initiating omeprazole treatment and, if a phenytoin dose adjustment is made, monitoring and a further dose adjustment should occur upon ending omeprazole treatment. Unknown mechanism Saquinavir Concomitant administration of omeprazole with saquinavir/ritonavir resulted in increased plasma levels up to approximately 70% for saquinavir associated with good tolerability in HIV-infected patients. Tacrolimus Concomitant administration of omeprazole has been reported to increase the serum levels of tacrolimus. A reinforced monitoring of tacrolimus concentrations as well as renal function (creatinine clearance) should be performed, and dosage of tacrolimus adjusted if needed. Effects of other active substances on the pharmacokinetics of omeprazole Inhibitors of CYP2C19 and/or CYP3A4 Since omeprazole is metabolised by CYP2C19 and CYP3A4, active substances known to inhibit CYP2C19 or CYP3A4 (such as clarithromycin and voriconazole) may lead to increased omeprazole serum levels by decreasing omeprazole’s rate of metabolism. Concomitant voriconazole treatment resulted in more than doubling of the omeprazole exposure. As high doses of omeprazole have been well-tolerated adjustment of the omeprazole dose is not generally required. However, dose adjustment should be considered in patients with severe hepatic impairment and if long-term treatment is indicated.

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Inducers of CYP2C19 and/or CYP3A4 Active substances known to induce CYP2C19 or CYP3A4 or both (such as rifampicin and St John’s wort) may lead to decreased omeprazole serum levels by increasing omeprazole’s rate of metabolism. 4.6 Pregnancy and lactation Results from three prospective epidemiological studies (more than 1000 exposed outcomes) indicate no adverse effects of omeprazole on pregnancy or on the health of the foetus/newborn child. Omeprazole can be used during pregnancy. Omeprazole is excreted in breast milk but is not likely to influence the child when therapeutic doses are used. 4.7 Effects on ability to drive and use machines Losec is not likely to affect the ability to drive or 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 machinery. 4.8 Undesirable effects The most common side effects (1-10% of patients) are headache, abdominal pain, constipation, diarrhoea, flatulence and nausea/vomiting. The following adverse drug reactions have been identified or suspected in the clinical trials programme for omeprazole and post-marketing. None was found to be dose-related. Adverse reactions listed below are classified according to frequency and System Organ Class (SOC). Frequency categories are defined according to the following convention: 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). SOC/frequency

Adverse reaction


reaction/shock Metabolism and nutrition disorders Rare: Hyponatraemia Very rare: Hypomagnesaemia Psychiatric disorders Uncommon: Insomnia Rare: Agitation, confusion, depression Very rare: Aggression, hallucinations Nervous system disorders Common: Headache Uncommon: Dizziness, paraesthesia, somnolence Rare: Taste disturbance Eye disorders Rare: Blurred vision

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Ear and labyrinth disorders Uncommon: Vertigo Respiratory, thoracic and mediastinal disorders Rare: Bronchospasm Gastrointestinal disorders Common: Abdominal pain, constipation, diarrhoea, flatulence, nausea/vomiting Rare: Dry mouth, stomatitis, gastrointestinal candidiasis Hepatobiliary disorders Uncommon: Increased liver enzymes Rare: Hepatitis with or without jaundice Very rare: Hepatic failure, encephalopathy in patients with pre-existing liver disease Skin and subcutaneous tissue disorders Uncommon: Dermatitis, pruritus, rash, urticaria Rare: Alopecia, photosensitivity Very rare: Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis

(TEN) Musculoskeletal and connective tissue disorders Rare: Arthralgia, myalgia Very rare: Muscular weakness Renal and urinary disorders Rare: Interstitial nephritis Reproductive system and breast disorders Very rare: Gynaecomastia General disorders and administration site conditions Uncommon: Malaise, peripheral oedema Rare: Increased sweating Paediatric population The safety of omeprazole has been assessed in a total of 310 children aged 0 to 16 years with acid-related disease. There are limited long term safety data from 46 children who received maintenance therapy of omeprazole during a clinical study for severe erosive esophagitis for up to 749 days. The adverse event profile was generally the same as for adults in short- as well as in long-term treatment. There are no long term data regarding the effects of omeprazole treatment on puberty and growth. 4.9 Overdose There is limited information available on the effects of overdoses of omeprazole in humans. In the literature, doses of up to 560 mg have been described, and occasional reports have been received when single oral doses have reached up to 2,400 mg omeprazole (120 times the usual recommended clinical dose). Nausea, vomiting, dizziness, abdominal pain, diarrhoea and headache have been reported. Also apathy, depression and confusion have been described in single cases. The symptoms described in connection to omeprazole overdose have been transient, and no serious outcome has been reported. The rate of elimination was unchanged (first order kinetics) with increased doses. Treatment, if needed, is symptomatic. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Proton pump inhibitors, ATC code: A02BC01

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Mechanism of action Omeprazole, a racemic mixture of two enantiomers reduces gastric acid secretion through a highly targeted mechanism of action. It is a specific inhibitor of the acid pump in the parietal cell. It is rapidly acting and provides control through reversible inhibition of gastric acid secretion with once daily dosing. Omeprazole is a weak base and is concentrated and converted to the active form in the highly acidic environment of the intracellular canaliculi within the parietal cell, where it inhibits the enzyme H+ K+-ATPase - the acid pump. This effect on the final step of the gastric acid formation process is dose-dependent and provides for highly effective inhibition of both basal acid secretion and stimulated acid secretion, irrespective of stimulus. Pharmacodynamic effects All pharmacodynamic effects observed can be explained by the effect of omeprazole on acid secretion. Effect on gastric acid secretion Oral dosing with omeprazole once daily provides for rapid and effective inhibition of daytime and night-time gastric acid secretion with maximum effect being achieved within 4 days of treatment. With omeprazole 20 mg, a mean decrease of at least 80% in 24-hour intragastric acidity is then maintained in duodenal ulcer patients, with the mean decrease in peak acid output after pentagastrin stimulation being about 70% 24 hours after dosing. Oral dosing with omeprazole 20 mg maintains an intragastric pH of ≥ 3 for a mean time of 17 hours of the 24-hour period in duodenal ulcer patients. As a consequence of reduced acid secretion and intragastric acidity, omeprazole dose-dependently reduces/normalizes acid exposure of the esophagus in patients with gastro-esophageal reflux disease. The inhibition of acid secretion is related to the area under the plasma concentration-time curve (AUC) of omeprazole and not to the actual plasma concentration at a given time. No tachyphylaxis has been observed during treatment with omeprazole. Effect on H. pylori H. pylori is associated with peptic ulcer disease, including duodenal and gastric ulcer disease. H. pylori is a major factor in the development of gastritis. H. pylori together with gastric acid are major factors in the development of peptic ulcer disease. H. pylori is a major factor in the development of atrophic gastritis which is associated with an increased risk of developing gastric cancer. Eradication of H. pylori with omeprazole and antimicrobials is associated with high rates of healing and long-term remission of peptic ulcers Dual therapies have been tested and found to be less effective than triple therapies. They could, however, be considered in cases where known hypersensitivity precludes use of any triple combination. Other effects related to acid inhibition During long-term treatment gastric glandular cysts have been reported in a somewhat increased frequency. These changes are a physiological consequence of pronounced inhibition of acid secretion, are benign and appear to be reversible. Decreased gastric acidity due to any means including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with acid-reducing drugs may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter.

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Paediatric use In a non-controlled study in children (1 to 16 years of age) with severe reflux esophagitis, omeprazole at doses of 0.7 to 1.4 mg/kg improved esophagitis level in 90% of the cases and significantly reduced reflux symptoms. In a single-blind study, children aged 0–24 months with clinically diagnosed gastro-esophageal reflux disease were treated with 0.5, 1.0 or 1.5 mg omeprazole/kg. The frequency of vomiting/regurgitation episodes decreased by 50% after 8 weeks of treatment irrespective of the dose. Eradication of H. pylori in children A randomised, double blind clinical study (Héliot study) concluded that omeprazole, in combination with two antibiotics (amoxicillin and clarithromycin), was safe and effective in the treatment of H. pylori infection in children age 4 years old and above with gastritis: H. pylori eradication rate: 74.2% (23/31 patients) with omeprazole + amoxicillin + clarithromycin versus 9.4% (3/32 patients) with amoxicillin + clarithromycin. However, there was no evidence of any clinical benefit with respect to dyspeptic symptoms. This study does not support any information for children aged less than 4 years. 5.2 Pharmacokinetic properties Absorption Omeprazole and omeprazole magnesium are acid labile and are therefore administered orally as enteric-coated granules in capsules or tablets. Absorption of omeprazole is rapid, with peak plasma levels occurring approximately 1-2 hours after dose. Absorption of omeprazole takes place in the small intestine and is usually completed within 3-6 hours. Concomitant intake of food has no influence on the bioavailability. The systemic availability (bioavailability) from a single oral dose of omeprazole is approximately 40%. After repeated once-daily administration, the bioavailability increases to about 60%. Distribution The apparent volume of distribution in healthy subjects is approximately 0.3 l/kg body weight. Omeprazole is 97% plasma protein bound. Bioequivalence between Losec capsules and Losec gastro-resistant tablets, based on both area under the omeprazole plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) of omeprazole, has been demonstrated for all doses, 10 mg, 20 mg and 40 mg. Metabolism Omeprazole is completely metabolised by the cytochrome P450 system (CYP). The major part of its metabolism is dependent on the polymorphically expressed CYP2C19, responsible for the formation of hydroxyomeprazole, the major metabolite in plasma. The remaining part is dependent on another specific isoform, CYP3A4, responsible for the formation of omeprazole sulphone. As a consequence of high affinity of omeprazole to CYP2C19, there is a potential for competitive inhibition and metabolic drug-drug interactions with other substrates for CYP2C19. However, due to low affinity to CYP3A4, omeprazole has no potential to inhibit the metabolism of other CYP3A4 substrates. In addition, omeprazole lacks an inhibitory effect on the main CYP enzymes. Approximately 3% of the Caucasian population and 15-20% of Asian populations lack a functional CYP2C19 enzyme and are called poor metabolisers. In such individuals the metabolism of omeprazole is probably mainly catalysed by CYP3A4. After repeated once-daily administration of 20 mg omeprazole, the mean AUC was 5 to 10 times higher in poor metabolisers than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations were also higher, by 3 to 5 times. These findings have no implications for the posology of omeprazole. Excretion The plasma elimination half-life of omeprazole is usually shorter than one hour both after single and repeated oral once-daily dosing. Omeprazole is completely eliminated from plasma between doses with no

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tendency for accumulation during once-daily administration. Almost 80% of an oral dose of omeprazole is excreted as metabolites in the urine, the remainder in the faeces, primarily originating from bile secretion. The AUC of omeprazole increases with repeated administration. This increase is dose-dependent and results in a non-linear dose-AUC relationship after repeated administration. This time- and dose-dependency is due to a decrease of first pass metabolism and systemic clearance probably caused by an inhibition of the CYP2C19 enzyme by omeprazole and/or its metabolites (e.g. the sulphone). No metabolite has been found to have any effect on gastric acid secretion. Special populations Impaired hepatic function The metabolism of omeprazole in patients with liver dysfunction is impaired, resulting in an increased AUC. Omeprazole has not shown any tendency to accumulate with once-daily dosing. Impaired renal function The pharmacokinetics of omeprazole, including systemic bioavailability and elimination rate, are unchanged in patients with reduced renal function. Elderly The metabolism rate of omeprazole is somewhat reduced in elderly subjects (75-79 years of age). Paediatric patients During treatment with the recommended doses to children from the age of 1 year, similar plasma concentrations were obtained as compared to adults. In children younger than 6 months, clearance of omeprazole is low due to low capacity to metabolise omeprazole. 5.3 Preclinical safety data Gastric ECL-cell hyperplasia and carcinoids, have been observed in life-long studies in rats treated with omeprazole. These changes are the result of sustained hypergastrinaemia secondary to acid inhibition. Similar findings have been made after treatment with H2-receptor antagonists, proton pump inhibitors and after partial fundectomy. Thus, these changes are not from a direct effect of any individual active substance. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Microcrystalline cellulose, glyceryl monostearate, hydroxypropylcellulose, hydroxypropyl methylcellulose, magnesium stearate, methacrylic acid co-polymer, sugar spheres, paraffin, macrogol (polyethylene glycol), polysorbate, polyvinylpyrrolidone crosslinked, sodium hydroxide (for pH-adjustment), sodium stearyl fumarate, talc,

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triethyl citrate, iron oxide, titanium dioxide 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage Do not store above 25°C. Bottle: Keep the container tightly closed in order to protect from moisture. Blister: Store in the original package in order to protect from moisture. 6.5 Nature and contents of container HDPE bottle: with a tight fitting polypropylene screw-cap equipped with a desiccant capsule. 10 mg: 7, 14, 15, 28, 30, 50, 100 tablets; hospital pack of 140 tablets. 20 mg: 7, 14, 15, 28, 30, 50, 56, 100 tablets; hospital packs of 140, 200, 280 tablets. 40 mg: 7, 14, 15, 28, 30, 100 tablets. Aluminium blister. 10 mg: 5, 7, 10, 14, 15, 25, 28, 30, 50, 56, 60, 84, 90, 100 tablets; hospital pack of 560 tablets. 20 mg: 5, 7, 14, 15, 25, 28, 30, 50, 56, 60, 84, 90, 98, 100 tablets; hospital pack of, 560 tablets. 40 mg: 5, 7, 14, 15, 28, 30, 50, 56, 60, 100 tablets; hospital pack of 560 tablets. Perforated unit dose blister (hospital pack): 10 mg: 25 x 1, 28 x 1, 50 x 1, 56 x 1 tablets. 20 mg: 25 x 1, 28 x 1, 50 x 1, 56 x 1, 100 x 1 tablets. 40 mg: 25 x 1, 28 x 1, 50 x 1 tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements 7. MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] 8. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

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[To be completed nationally] 10. DATE OF REVISION OF THE TEXT [To be completed nationally] Detailed information on this product is available on the website of: {name of MS/Agency} [To be completed nationally]

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1. NAME OF THE MEDICINAL PRODUCT Losec and associated names (see Annex I) 40 mg powder for solution for infusion [See Annex I - To be completed nationally] 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each vial contains omeprazole sodium 42.6 mg, equivalent to omeprazole 40 mg. After reconstitution, 1 ml contains omeprazole sodium 0.426 mg, equivalent to omeprazole 0.4 mg. For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL form Powder for solution for infusion (Powder for infusion) pH interval in glucose is approximately 8.9-9.5 and in sodium chloride 0.9%, 9.3-10.3 4. Clinical particulars 4.1 Therapeutic indications Losec for intravenous use is indicated as an alternative to oral therapy for the following indications i.e. Adults • Treatment of duodenal ulcers • Prevention of relapse of duodenal ulcers • Treatment of gastric ulcers • Prevention of relapse of gastric ulcers • In combination with appropriate antibiotics, Helicobacter pylori (H. pylori) eradication in peptic

ulcer disease • Treatment of NSAID-associated gastric and duodenal ulcers • Prevention of NSAID-associated gastric and duodenal ulcers in patients at risk • Treatment of reflux esophagitis • Long-term management of patients with healed reflux esophagitis • Treatment of symptomatic gastro-esophageal reflux disease • Treatment of Zollinger-Ellison syndrome 4.2 Posology and method of administration Posology Alternative to oral therapy In patients where the use of oral medicinal products is inappropriate, Losec IV 40 mg once daily is recommended. In patients with Zollinger-Ellison Syndrome the recommended initial dose of Losec given intravenously is 60 mg daily. Higher daily doses may be required and the dose should be adjusted individually. When doses exceed 60 mg daily, the dose should be divided and given twice daily. Losec is to be administered in an intravenous infusion for 20-30 minutes.

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For instructions on reconstitution of the product before administration, see section 6.6. Special populations Impaired renal function Dose adjustment is not needed in patients with impaired renal function. (see section 5.2). Impaired hepatic function In patients with impaired hepatic function a daily dose of 10-20 mg may be sufficient (see section 5.2). Elderly (> 65 years old) Dose adjustment is not needed in the elderly (see section 5.2). Paediatric patients There is limited experience with Losec for intravenous use in children. 4.3 Contraindications Hypersensitivity to omeprazole, substituted benzimidazoles or to any of the excipients. Omeprazole like other proton pump inhibitors (PPIs) should not be used concomitantly with nelfinavir (see section 4.5). 4.4 Special warnings and precautions for use In the presence of any alarm symptoms (eg, significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment may alleviate symptoms and delay diagnosis. 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; omeprazole 20 mg should not be exceeded. Omeprazole, 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. Omeprazole is a CYP2C19 inhibitor. When starting or ending treatment with omeprazole, the potential for interactions with drugs metabolised through CYP2C19 should be considered. An interaction is observed between clopidogrel and omeprazole (see section 4.5). The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of omeprazole and clopidogrel should be discouraged. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter (see section 5.1). As in all long-term treatments, especially when exceeding a treatment period of 1 year, patients should be kept under regular surveillance. 4.5 Interaction with other medicinal products and other forms of interaction Effects of omeprazole on the pharmacokinetics of other active substances Active substances with pH dependent absorption

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The decreased intragastric acidity during treatment with omeprazole might increase or decrease the absorption of active substances with a gastric pH dependent absorption. Nelfinavir, atazanavir The plasma levels of nelfinavir and atazanavir are decreased in case of co-administration with omeprazole. Concomitant administration of omeprazole with nelfinavir is contraindicated (see section 4.3). Co-administration of omeprazole (40 mg once daily) reduced mean nelvinavir exposure by ca. 40% and the mean exposure of the pharmacologically active metabolite M8 was reduced by ca. 75-90%. The interaction may also involve CYP2C19 inhibition. Concomitant administration of omeprazole with atazanavir is not recommended (see section 4.4). Concomitant administration of omeprazole (40 mg once daily) and atazanavir 300 mg/ritonavir 100 mg to healthy volunteers resulted in a 75% decrease of the atazanavir exposure. Increasing the atazanavir dose to 400 mg did not compensate for the impact of omeprazole on atazanavir exposure. The co-administration of omeprazole (20 mg once daily) with atazanavir 400 mg/ritonavir 100 mg to healthy volunteers resulted in a decrease of approximately 30% in the atazanavir exposure as compared to atazanavir 300 mg/ritonavir 100 mg once daily. Digoxin Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10%. Digoxin toxicity has been rarely reported. However caution should be exercised when omeprazole is given at high doses in elderly patients. Therapeutic drug monitoring of digoxin should be then be reinforced. Clopidogrel In a crossover clinical study, clopidogrel (300 mg loading dose followed by 75 mg/day) alone and with omeprazole (80 mg at the same time as clopidogrel) were administered for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and omeprazole were administered together. Mean inhibition of platelet aggregation (IPA) was diminished by 47% (24 hours) and 30% (Day 5) when clopidogrel and omeprazole were administered together. In another study it was shown that administering clopidogrel and omeprazole at different times did not prevent their interaction that is likely to be driven by the inhibitory effect of omeprazole on CYP2C19. Inconsistent data on the clinical implications of this PK/PD interaction in terms of major cardiovascular events have been reported from observational and clinical studies. Other active substances The absorption of posaconazole, erlotinib, ketoconazol and itraconazol is significantly reduced and thus clinical efficacy may be impaired. For posaconazol and erlotinib concomitant use should be avoided. Active substances metabolised by CYP2C19 Omeprazole is a moderate inhibitor of CYP2C19, the major omeprazole metabolising enzyme. Thus, the metabolism of concomitant active substances also metabolised by CYP2C19, may be decreased and the systemic exposure to these substances increased. Examples of such drugs are R-warfarin and other vitamin K antagonists, cilostazol, diazepam and phenytoin. Cilostazol Omeprazole, given in doses of 40 mg to healthy subjects in a cross-over study, increased Cmax and AUC for cilostazol by 18% and 26% respectively, and one of its active metabolites by 29% and 69% respectively. Phenytoin

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Monitoring phenytoin plasma concentration is recommended during the first two weeks after initiating omeprazole treatment and, if a phenytoin dose adjustment is made, monitoring and a further dose adjustment should occur upon ending omeprazole treatment. Unknown mechanism Saquinavir Concomitant administration of omeprazole with saquinavir/ritonavir resulted in increased plasma levels up to approximately 70% for saquinavir associated with good tolerability in HIV-infected patients. Tacrolimus Concomitant administration of omeprazole has been reported to increase the serum levels of tacrolimus. A reinforced monitoring of tacrolimus concentrations as well as renal function (creatinine clearance) should be performed, and dosage of tacrolimus adjusted if needed. Effects of other active substances on the pharmacokinetics of omeprazole Inhibitors of CYP2C19 and/or CYP3A4 Since omeprazole is metabolised by CYP2C19 and CYP3A4, active substances known to inhibit CYP2C19 or CYP3A4 (such as clarithromycin and voriconazole) may lead to increased omeprazole serum levels by decreasing omeprazole’s rate of metabolism. Concomitant voriconazole treatment resulted in more than doubling of the omeprazole exposure. As high doses of omeprazole have been well-tolerated adjustment of the omeprazole dose is not generally required. However, dose adjustment should be considered in patients with severe hepatic impairment and if long-term treatment is indicated. Inducers of CYP2C19 and/or CYP3A4 Active substances known to induce CYP2C19 or CYP3A4 or both (such as rifampicin and St John’s wort) may lead to decreased omeprazole serum levels by increasing omeprazole’s rate of metabolism. 4.6 Pregnancy and lactation Results from three prospective epidemiological studies (more than 1000 exposed outcomes) indicate no adverse effects of omeprazole on pregnancy or on the health of the foetus/newborn child. Omeprazole can be used during pregnancy. Omeprazole is excreted in breast milk but is not likely to influence the child when therapeutic doses are used. 4.7 Effects on ability to drive and use machines Losec is not likely to affect the ability to drive or 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 machinery. 4.8 Undesirable effects The most common side effects (1-10% of patients) are headache, abdominal pain, constipation, diarrhoea, flatulence and nausea/vomiting. The following adverse drug reactions have been identified or suspected in the clinical trials programme for omeprazole and post-marketing. None was found to be dose-related. Adverse reactions listed below are classified according to frequency and System Organ Class (SOC). Frequency categories are defined according to the following convention: Very common (≥ 1/10), Common (≥ 1/100 to < 1/10), Uncommon

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(≥ 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). SOC/frequency

Adverse reaction


reaction/shock Metabolism and nutrition disorders Rare: Hyponatraemia Very rare: Hypomagnesaemia Psychiatric disorders Uncommon: Insomnia Rare: Agitation, confusion, depression Very rare: Aggression, hallucinations Nervous system disorders Common: Headache Uncommon: Dizziness, paraesthesia, somnolence Rare: Taste disturbance Eye disorders Rare: Blurred vision Ear and labyrinth disorders Uncommon: Vertigo Respiratory, thoracic and mediastinal disorders Rare: Bronchospasm Gastrointestinal disorders Common: Abdominal pain, constipation, diarrhoea, flatulence, nausea/vomiting Rare: Dry mouth, stomatitis, gastrointestinal candidiasis Hepatobiliary disorders Uncommon: Increased liver enzymes Rare: Hepatitis with or without jaundice Very rare: Hepatic failure, encephalopathy in patients with pre-existing liver disease Skin and subcutaneous tissue disorders Uncommon: Dermatitis, pruritus, rash, urticaria Rare: Alopecia, photosensitivity Very rare: Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis

(TEN) Musculoskeletal and connective tissue disorders Rare: Arthralgia, myalgia Very rare: Muscular weakness Renal and urinary disorders Rare: Interstitial nephritis Reproductive system and breast disorders Very rare: Gynaecomastia General disorders and administration site conditions Uncommon: Malaise, peripheral oedema Rare: Increased sweating

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Irreversible visual impairment has been reported in isolated cases of critically ill patients who have received omeprazole intravenous injection, especially at high doses, but no causal relationship has been established. 4.9 Overdose There is limited information available on the effects of overdoses of omeprazole in humans. In the literature, doses of up to 560 mg have been described, and occasional reports have been received when single oral doses have reached up to 2,400 mg omeprazole (120 times the usual recommended clinical dose). Nausea, vomiting, dizziness, abdominal pain, diarrhoea and headache have been reported. Also apathy, depression and confusion have been described in single cases. The symptoms described have been transient, and no serious outcome has been reported. The rate of elimination was unchanged (first order kinetics) with increased doses. Treatment, if needed, is symptomatic. Intravenous doses of up to 270 mg on a single day and up to 650 mg over a three-day period have been given in clinical trials without any dose-related adverse reactions. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Proton pump inhibitors, ATC code: A02BC01 Mechanism of action Omeprazole, a racemic mixture of two enantiomers reduces gastric acid secretion through a highly targeted mechanism of action. It is a specific inhibitor of the acid pump in the parietal cell. It is rapidly acting and provides control through reversible inhibition of gastric acid secretion with once-daily dosing. Omeprazole is a weak base and is concentrated and converted to the active form in the highly acidic environment of the intracellular canaliculi within the parietal cell, where it inhibits the enzyme H+,K+-ATPase - the acid pump. This effect on the final step of the gastric acid formation process is dose-dependent and provides for highly effective inhibition of both basal acid secretion and stimulated acid secretion, irrespective of stimulus. Pharmacodynamic effects All pharmacodynamic effects observed can be explained by the effect of omeprazole on acid secretion. Effect on gastric acid secretion Intravenous omeprazole produces a dose dependent inhibition of gastric acid secretion in humans. In order to immediately achieve a similar reduction of intragastric acidity as after repeated dosing with 20 mg orally, a first dose of 40 mg intravenously is recommended. This results in an immediate decrease in intragastric acidity and a mean decrease over 24 hours of approximately 90% for both iv injection and iv infusion. The inhibition of acid secretion is related to the area under the plasma concentration-time curve (AUC) of omeprazole and not to the actual plasma concentration at a given time. No tachyphylaxis has been observed during treatment with omeprazole.

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Effect on H. pylori H. pylori is associated with peptic ulcer disease, including duodenal and gastric ulcer disease. H. pylori is a major factor in the development of gastritis. H. pylori together with gastric acid are major factors in the development of peptic ulcer disease. H. pylori is a major factor in the development of atrophic gastritis which is associated with an increased risk of developing gastric cancer. Eradication of H. pylori with omeprazole and antimicrobials is associated with high rates of healing and long-term remission of peptic ulcers. Other effects related to acid inhibition During long-term treatment gastric glandular cysts have been reported in a somewhat increased frequency. These changes are a physiological consequence of pronounced inhibition of acid secretion, are benign and appear to be reversible. Decreased gastric acidity due to any means including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with acid-reducing drugs may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter. 5.2 Pharmacokinetic properties Distribution The apparent volume of distribution in healthy subjects is approximately 0.3 l/kg body weight. Omeprazole is 97% plasma protein bound. Metabolism Omeprazole is completely metabolised by the cytochrome P450 system (CYP). The major part of its metabolism is dependent on the polymorphically expressed CYP2C19, responsible for the formation of hydroxyomeprazole, the major metabolite in plasma. The remaining part is dependent on another specific isoform, CYP3A4, responsible for the formation of omeprazole sulphone. As a consequence of high affinity of omeprazole to CYP2C19, there is a potential for competitive inhibition and metabolic drug-drug interactions with other substrates for CYP2C19. However, due to low affinity to CYP3A4, omeprazole has no potential to inhibit the metabolism of other CYP3A4 substrates. In addition, omeprazole lacks an inhibitory effect on the main CYP enzymes. Approximately 3% of the Caucasian population and 15–20% of Asian populations lack a functional CYP2C19 enzyme and are called poor metabolisers. In such individuals the metabolism of omeprazole is probably mainly catalysed by CYP3A4. After repeated once-daily administration of 20 mg omeprazole, the mean AUC was 5 to 10 times higher in poor metabolisers than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations were also higher, by 3 to 5 times. These findings have no implications for the posology of omeprazole. Excretion Total plasma clearance is about 30-40 l/h after a single dose. The plasma elimination half-life of omeprazole is usually shorter than one hour both after single and repeated once-daily dosing. Omeprazole is completely eliminated from plasma between doses with no tendency for accumulation during once-daily administration. Almost 80% of a dose of omeprazole is excreted as metabolites in the urine, the remainder in the faeces, primarily originating from bile secretion. The AUC of omeprazole increases with repeated administration. This increase is dose-dependent and results in a non-linear dose-AUC relationship after repeated administration. This time- and dose-dependency is due to a decrease of first pass metabolism and systemic clearance probably caused by an inhibition of the CYP2C19 enzyme by omeprazole and/or its metabolites (e.g. the sulphone). No metabolite has been found to have any effect on gastric acid secretion.

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Special populations Impaired hepatic function The metabolism of omeprazole in patients with liver dysfunction is impaired, resulting in an increased AUC. Omeprazole has not shown any tendency to accumulate with once-daily dosing. Impaired renal function The pharmacokinetics of omeprazole, including systemic bioavailability and elimination rate, are unchanged in patients with reduced renal function. Elderly The metabolism rate of omeprazole is somewhat reduced in elderly subjects (75-79 years of age). 5.3 Preclinical safety data Gastric ECL-cell hyperplasia and carcinoids, have been observed in life-long studies in rats treated with omeprazole. These changes are the result of sustained hypergastrinaemia secondary to acid inhibition. Similar findings have been made after treatment with H2-receptor antagonists, proton pump inhibitors and after partial fundectomy. Thus, these changes are not from a direct effect of any individual active substance. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Disodium edetate, sodium hydroxide (for pH adjustment) 6.2 Incompatibilities This medicinal product should not be mixed with other medicinal products than those mentioned in section 6.6. 6.3 Shelf life Unopened packs: 2 years. Reconstituted solution: Chemical and physical in-use stability has been demonstrated for 12 hours at 25°C after reconstitution with sodium chloride 9 mg/ml (0.9%) solution for infusion and for 6 hours at 25°C after reconstitution with glucose 50 mg/ml (5%) solution for infusion. From a microbiological point of view, the product should be used immediately unless it has been reconstituted under controlled and validated aseptic conditions. 6.4 Special precautions for storage Do not store above 25oC. Keep the vial in the outer carton in order to protect from light. Vials can however be stored exposed to normal indoor light out side the box for up to 24 hours. For storage conditions of the reconstituted medicinal product, see section 6.3.

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6.5 Nature and contents of container Vial of 10 ml made of colourless borosilicate glass, type I. Stopper made of bromobutyl rubber, cap made of aluminium and a plastic polypropylene lid. Pack sizes: Vials 1x40 mg, 5x40 mg, 10x40 mg. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling The entire contents of each vial is to be dissolved in approximately 5 ml and then immediately diluted to 100 ml. Sodium chloride 9 mg/ml (0.9%) solution for infusion or glucose 50 mg/ml (5%) solution for infusion must be used. The stability of omeprazole is influenced by the pH of the solution for infusion, which is why no other solvent or quantities should be used for dilution. Preparation 1. With a syringe draw 5 ml of infusion solution from the 100 ml infusion bottle or bag. 2. Add this volume to the vial with the freeze-dried omeprazole, mix thoroughly making sure all

omeprazole is dissolved. 3. Draw the omeprazole solution back into the syringe. 4. Transfer the solution into the infusion bag or bottle. 5. Repeat steps 1-4 to make sure all omeprazole is transferred from the vial into the infusion bag or

bottle. Alternative preparation for infusions in flexible containers 1. Use a double-ended transfer needle and attach to the injection membrane of the infusion bag.

Connect the other needle-end from the vial with freeze-dried omeprazole. 2. Dissolve the omeprazole substance by pumping the infusion solution back and forward between the

infusion bag and the vial. 3. Make sure all omeprazole is dissolved. The solution for infusion is to be administrered in an intravenous infusion for 20-30 minutes. 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] 8. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION [To be completed nationally] 10. DATE OF REVISION OF THE TEXT

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[To be completed nationally] Detailed information on this product is available on the website of: {name of MS/Agency} [To be completed nationally]

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1. NAME OF THE MEDICINAL PRODUCT Losec and associated names (see Annex I) 40 mg powder and solvent for solution for injection [See Annex I - To be completed nationally] 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each vial of powder for solution for injection contains omeprazole sodium 42.6 mg, equivalent to omeprazole 40 mg. After reconstitution, 1 ml contains omeprazole sodium 4.26 mg, equivalent to omeprazole 4 mg. For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL form Powder and solvent for solution for injection (Powder for injection; and Solvent for injection) pH 8.8 to 9.2 4. Clinical particulars 4.1 Therapeutic indications Losec for intravenous use is indicated as an alternative to oral therapy for the following indications: Adults • Treatment of duodenal ulcers • Prevention of relapse of duodenal ulcers • Treatment of gastric ulcers • Prevention of relapse of gastric ulcers • In combination with appropriate antibiotics, Helicobacter pylori (H. pylori) eradication in peptic

ulcer disease • Treatment of NSAID-associated gastric and duodenal ulcers • Prevention of NSAID-associated gastric and duodenal ulcers in patients at risk • Treatment of reflux esophagitis • Long-term management of patients with healed reflux esophagitis • Treatment of symptomatic gastro-esophageal reflux disease • Treatment of Zollinger-Ellison syndrome 4.2 Posology and method of administration Posology Alternative to oral therapy In patients where the use of oral medicinal products is inappropriate, Losec IV 40 mg once daily is recommended. In patients with Zollinger-Ellison Syndrome the recommended initial dose of Losec given intravenously is 60 mg daily. Higher daily doses may be required and the dose should be adjusted individually. When doses exceed 60 mg daily, the dose should be divided and given twice daily. Losec solution for injection must be given only as an intravenous injection and it must not be added to infusion solutions. After reconstitution the injection should be given slowly over a period of at least

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2.5 minutes at a maximum rate of 4 ml per minute. For instructions on reconstitution of the product before administration, see section 6.6. Special populations Impaired renal function Dose adjustment is not needed in patients with impaired renal function. (see section 5.2). Impaired hepatic function In patients with impaired hepatic function a daily dose of 10-20 mg may be sufficient (see section 5.2). Elderly ( > 65 years old) Dose adjustment is not needed in the elderly (see section 5.2). Paediatric patients There is limited experience with Losec for intravenous use in children. 4.3 Contraindications Hypersensitivity to omeprazole, substituted benzimidazoles or to any of the excipients. Omeprazole like other proton pump inhibitors (PPIs) should not be used concomitantly with nelfinavir (see section 4.5). 4.4 Special warnings and precautions for use In the presence of any alarm symptoms (eg, significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment may alleviate symptoms and delay diagnosis. 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; omeprazole 20 mg should not be exceeded. Omeprazole, 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. Omeprazole is a CYP2C19 inhibitor. When starting or ending treatment with omeprazole, the potential for interactions with drugs metabolised through CYP2C19 should be considered. An interaction is observed between clopidogrel and omeprazole (see section 4.5). The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of omeprazole and clopidogrel should be discouraged. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter (see section 5.1). As in all long-term treatments, especially when exceeding a treatment period of 1 year, patients should be kept under regular surveillance. 4.5 Interaction with other medicinal products and other forms of interaction Effects of omeprazole on the pharmacokinetics of other active substances Active substances with pH dependent absorption

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The decreased intragastric acidity during treatment with omeprazole might increase or decrease the absorption of active substances with a gastric pH dependent absorption. Nelfinavir, atazanavir The plasma levels of nelfinavir and atazanavir are decreased in case of co-administration with omeprazole. Concomitant administration of omeprazole with nelfinavir is contraindicated (see section 4.3). Co-administration of omeprazole (40 mg once daily) reduced mean nelvinavir exposure by ca. 40% and the mean exposure of the pharmacologically active metabolite M8 was reduced by ca. 75-90%. The interaction may also involve CYP2C19 inhibition. Concomitant administration of omeprazole with atazanavir is not recommended (see section 4.4). Concomitant administration of omeprazole (40 mg once daily) and atazanavir 300 mg/ritonavir 100 mg to healthy volunteers resulted in a 75% decrease of the atazanavir exposure. Increasing the atazanavir dose to 400 mg did not compensate for the impact of omeprazole on atazanavir exposure. The co-administration of omeprazole (20 mg once daily) with atazanavir 400 mg/ritonavir 100 mg to healthy volunteers resulted in a decrease of approximately 30% in the atazanavir exposure as compared to atazanavir 300 mg/ritonavir 100 mg once daily. Digoxin Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10%. Digoxin toxicity has been rarely reported. However caution should be exercised when omeprazole is given at high doses in elderly patients. Therapeutic drug monitoring of digoxin should be then be reinforced. Clopidogrel In a crossover clinical study, clopidogrel (300 mg loading dose followed by 75 mg/day) alone and with omeprazole (80 mg at the same time as clopidogrel) were administered for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and omeprazole were administered together. Mean inhibition of platelet aggregation (IPA) was diminished by 47% (24 hours) and 30% (Day 5) when clopidogrel and omeprazole were administered together. In another study it was shown that administering clopidogrel and omeprazole at different times did not prevent their interaction that is likely to be driven by the inhibitory effect of omeprazole on CYP2C19. Inconsistent data on the clinical implications of this PK/PD interaction in terms of major cardiovascular events have been reported from observational and clinical studies. Other active substances The absorption of posaconazole, erlotinib, ketoconazol and itraconazol is significantly reduced and thus clinical efficacy may be impaired. For posaconazol and erlotinib concomitant use should be avoided. Active substances metabolised by CYP2C19 Omeprazole is a moderate inhibitor of CYP2C19, the major omeprazole metabolising enzyme. Thus, the metabolism of concomitant active substances also metabolised by CYP2C19, may be decreased and the systemic exposure to these substances increased. Examples of such drugs are R-warfarin and other vitamin K antagonists, cilostazol, diazepam and phenytoin. Cilostazol Omeprazole, given in doses of 40 mg to healthy subjects in a cross-over study, increased Cmax and AUC for cilostazol by 18% and 26% respectively, and one of its active metabolites by 29% and 69% respectively. Phenytoin

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Monitoring phenytoin plasma concentration is recommended during the first two weeks after initiating omeprazole treatment and, if a phenytoin dose adjustment is made, monitoring and a further dose adjustment should occur upon ending omeprazole treatment. Unknown mechanism Saquinavir Concomitant administration of omeprazole with saquinavir/ritonavir resulted in increased plasma levels up to approximately 70% for saquinavir associated with good tolerability in HIV-infected patients. Tacrolimus Concomitant administration of omeprazole has been reported to increase the serum levels of tacrolimus. A reinforced monitoring of tacrolimus concentrations as well as renal function (creatinine clearance) should be performed, and dosage of tacrolimus adjusted if needed. Effects of other active substances on the pharmacokinetics of omeprazole Inhibitors of CYP2C19 and/or CYP3A4 Since omeprazole is metabolised by CYP2C19 and CYP3A4, active substances known to inhibit CYP2C19 or CYP3A4 (such as clarithromycin and voriconazole) may lead to increased omeprazole serum levels by decreasing omeprazole’s rate of metabolism. Concomitant voriconazole treatment resulted in more than doubling of the omeprazole exposure. As high doses of omeprazole have been well-tolerated adjustment of the omeprazole dose is not generally required. However, dose adjustment should be considered in patients with severe hepatic impairment and if long-term treatment is indicated. Inducers of CYP2C19 and/or CYP3A4 Active substances known to induce CYP2C19 or CYP3A4 or both (such as rifampicin and St John’s wort) may lead to decreased omeprazole serum levels by increasing omeprazole’s rate of metabolism. 4.6 Pregnancy and lactation Results from three prospective epidemiological studies (more than 1000 exposed outcomes) indicate no adverse effects of omeprazole on pregnancy or on the health of the foetus/newborn child. Omeprazole can be used during pregnancy. Omeprazole is excreted in breast milk but is not likely to influence the child when therapeutic doses are used. 4.7 Effects on ability to drive and use machines Losec is not likely to affect the ability to drive or 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 machinery. 4.8 Undesirable effects The most common side effects (1-10% of patients) are headache, abdominal pain, constipation, diarrhoea, flatulence and nausea/vomiting. The following adverse drug reactions have been identified or suspected in the clinical trials programme for omeprazole and post-marketing. None was found to be dose-related. Adverse reactions listed below are classified according to frequency and System Organ Class (SOC). Frequency categories are defined according to the following convention: Very common (≥ 1/10),

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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). SOC/frequency

Adverse reaction


reaction/shock Metabolism and nutrition disorders Rare: Hyponatraemia Very rare: Hypomagnesaemia Psychiatric disorders Uncommon: Insomnia Rare: Agitation, confusion, depression Very rare: Aggression, hallucinations Nervous system disorders Common: Headache Uncommon: Dizziness, paraesthesia, somnolence Rare: Taste disturbance Eye disorders Rare: Blurred vision Ear and labyrinth disorders Uncommon: Vertigo Respiratory, thoracic and mediastinal disorders Rare: Bronchospasm Gastrointestinal disorders Common: Abdominal pain, constipation, diarrhoea, flatulence, nausea/vomiting Rare: Dry mouth, stomatitis, gastrointestinal candidiasis Hepatobiliary disorders Uncommon: Increased liver enzymes Rare: Hepatitis with or without jaundice Very rare: Hepatic failure, encephalopathy in patients with pre-existing liver disease Skin and subcutaneous tissue disorders Uncommon: Dermatitis, pruritus, rash, urticaria Rare: Alopecia, photosensitivity Very rare: Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis

(TEN) Musculoskeletal and connective tissue disorders Rare: Arthralgia, myalgia Very rare: Muscular weakness Renal and urinary disorders Rare: Interstitial nephritis Reproductive system and breast disorders Very rare: Gynaecomastia General disorders and administration site conditions Uncommon: Malaise, peripheral oedema Rare: Increased sweating

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Irreversible visual impairment has been reported in isolated cases of critically ill patients who have received omeprazole intravenous injection, especially at high doses, but no causal relationship has been established. 4.9 Overdose There is limited information available on the effects of overdoses of omeprazole in humans. In the literature, doses of up to 560 mg have been described, and occasional reports have been received when single oral doses have reached up to 2,400 mg omeprazole (120 times the usual recommended clinical dose). Nausea, vomiting, dizziness, abdominal pain, diarrhoea and headache have been reported. Also apathy, depression and confusion have been described in single cases. The symptoms described have been transient, and no serious outcome has been reported. The rate of elimination was unchanged (first order kinetics) with increased doses. Treatment, if needed, is symptomatic. Intravenous doses of up to 270 mg on a single day and up to 650 mg over a three-day period have been given in clinical trials without any dose-related adverse reactions. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Proton pump inhibitors, ATC code: A02BC01 Mechanism of action Omeprazole, a racemic mixture of two enantiomers reduces gastric acid secretion through a highly targeted mechanism of action. It is a specific inhibitor of the acid pump in the parietal cell. It is rapidly acting and provides control through reversible inhibition of gastric acid secretion with once daily dosing. Omeprazole is a weak base and is concentrated and converted to the active form in the highly acidic environment of the intracellular canaliculi within the parietal cell, where it inhibits the enzyme H+,K+-ATPase - the acid pump. This effect on the final step of the gastric acid formation process is dose-dependent and provides for highly effective inhibition of both basal acid secretion and stimulated acid secretion, irrespective of stimulus. Pharmacodynamic effects All pharmacodynamic effects observed can be explained by the effect of omeprazole on acid secretion. Effect on gastric acid secretion Intravenous omeprazole produces a dose dependent inhibition of gastric acid secretion in humans. In order to immediately achieve a similar reduction of intragastric acidity as after repeated dosing with 20 mg orally, a first dose of 40 mg intravenously is recommended. This results in an immediate decrease in intragastric acidity and a mean decrease over 24 hours of approximately 90% for both iv injection and iv infusion. The inhibition of acid secretion is related to the area under the plasma concentration-time curve (AUC) of omeprazole and not to the actual plasma concentration at a given time. No tachyphylaxis has been observed during treatment with omeprazole. Effect on H. pylori

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H. pylori is associated with peptic ulcer disease, including duodenal and gastric ulcer disease. H. pylori is a major factor in the development of gastritis. H. pylori together with gastric acid are major factors in the development of peptic ulcer disease. H. pylori is a major factor in the development of atrophic gastritis which is associated with an increased risk of developing gastric cancer. Eradication of H. pylori with omeprazole and antimicrobials is associated with high rates of healing and long-term remission of peptic ulcers. Other effects related to acid inhibition During long-term treatment gastric glandular cysts have been reported in a somewhat increased frequency. These changes are a physiological consequence of pronounced inhibition of acid secretion, are benign and appear to be reversible. Decreased gastric acidity due to any means including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with acid-reducing drugs may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter. 5.2 Pharmacokinetic properties Distribution The apparent volume of distribution in healthy subjects is approximately 0.3 l/kg body weight. Omeprazole is 97% plasma protein bound. Metabolism Omeprazole is completely metabolised by the cytochrome P450 system (CYP). The major part of its metabolism is dependent on the polymorphically expressed CYP2C19, responsible for the formation of hydroxyomeprazole, the major metabolite in plasma. The remaining part is dependent on another specific isoform, CYP3A4, responsible for the formation of omeprazole sulphone. As a consequence of high affinity of omeprazole to CYP2C19, there is a potential for competitive inhibition and metabolic drug-drug interactions with other substrates for CYP2C19. However, due to low affinity to CYP3A4, omeprazole has no potential to inhibit the metabolism of other CYP3A4 substrates. In addition, omeprazole lacks an inhibitory effect on the main CYP enzymes. Approximately 3% of the Caucasian population and 15-20% of Asian populations lack a functional CYP2C19 enzyme and are called poor metabolisers. In such individuals the metabolism of omeprazole is probably mainly catalysed by CYP3A4. After repeated once-daily administration of 20 mg omeprazole, the mean AUC was 5 to 10 times higher in poor metabolisers than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations were also higher, by 3 to 5 times. These findings have no implications for the posology of omeprazole. Excretion Total plasma clearance is about 30–40 l/h after a single dose. The plasma elimination half-life of omeprazole is usually shorter than one hour both after single and repeated once-daily dosing. Omeprazole is completely eliminated from plasma between doses. Almost 80% of a dose of omeprazole is excreted as metabolites in the urine, the remainder in the faeces, primarily originating from bile secretion. The AUC of omeprazole increases with repeated administration due to a decrease of systemic clearance probably caused by an inhibition of the CYP2C19 enzyme by omeprazole and/or its metabolites (e.g. the sulphone). No metabolite has been found to have any effect on gastric acid secretion.

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Special populations Impaired hepatic function The metabolism of omeprazole in patients with liver dysfunction is impaired, resulting in an increased AUC. Omeprazole has not shown any tendency to accumulate with once-daily dosing. Impaired renal function The pharmacokinetics of omeprazole, including systemic bioavailability and elimination rate, are unchanged in patients with reduced renal function. Elderly The metabolism rate of omeprazole is somewhat reduced in elderly subjects (75-79 years of age). 5.3 Preclinical safety data Gastric ECL-cell hyperplasia and carcinoids, have been observed in life-long studies in rats treated with omeprazole. These changes are the result of sustained hypergastrinaemia secondary to acid inhibition. Similar findings have been made after treatment with H2-receptor antagonists, proton pump inhibitors and after partial fundectomy. Thus, these changes are not from a direct effect of any individual active substance. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Vial of active substance Sodium hydroxide (for pH adjustment) Ampoule of solvent Citric acid monohydrate (for pH adjustment), macrogol 400, water for injection 6.2 Incompatibilities This medicinal product should not be mixed with other medicinal products than those mentioned in section 6.6. 6.3 Shelf life Unopened packs: 2 years. Reconstituted solution: Chemical and physical in-use stability has been demonstrated for 4 hours at 25oC after reconstitution. From a microbiological point of view, the product should be used immediately unless it has been reconstituted under controlled and validated aseptic conditions. 6.4 Special precautions for storage Do not store above 25oC.

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Keep the containers in the outer carton in order to protect from light. Vials can however be stored exposed to normal indoor light out side the box for up to 24 hours. For storage conditions of the reconstituted medicinal product, see section 6.3. 6.5 Nature and contents of container Combination pack (I+II): I: Dry substance in a 10 ml vial made of colourless borosilicate glass, type I. Stopper made of bromobutyl rubber, cap made of aluminium and a plastic polypropylene lid. II: 10 ml solvent in an ampoule (colourless borosilicate glass). Pack sizes: 1x40 mg (I+II), 5x40 mg (I+II) and 10x40 mg (I+II). Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling Losec solution for injection is obtained by dissolving the freeze-dried substance in the accompanying solvent. No other solvent should be used. The stability of omeprazole is influenced by the pH of the solution for injection, which is why no other solvents or quantities should be used for dilution. Improperly prepared solutions can be identified by their yellow to brown discolouration and must not be used. Use only clear, colourless or pale yellowish-brown solutions. Preparation NOTE: Steps 1 to 5 must be performed in immediate sequence: 1. With a syringe draw all of the solvent from the ampoule (10 ml). 2. Add approximately 5 ml of the solvent to the vial with freeze-dried omeprazole. 3. Withdraw as much air as possible from the vial back into the syringe. This will make it easier to

add the remaining solvent. 4. Add the remaining solvent into the vial, make sure the syringe is empty. 5. Rotate and shake the vial to ensure all the freeze-dried omeprazole has dissolved.

Losec solution for injection must be given only as an intravenous injection and it must not be added to infusion solutions. After reconstitution the injection should be given slowly over a period of at least 2.5 minutes at a maximum rate of 4 ml per minute. 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] 8. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION [To be completed nationally]

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10. DATE OF REVISION OF THE TEXT [To be completed nationally] Detailed information on this product is available on the website of: {name of MS/Agency} [To be completed nationally]

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SUMMARY OF PRODUCT CHARACTERISTICS

For medicinal products available without prescription

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1. NAME OF THE MEDICINAL PRODUCT Losec and associated names (see Annex I) 10 mg gastro-resistant tablets Losec and associated names (see Annex I) 20 mg gastro-resistant tablets [See Annex I - To be completed nationally] 2. QUALITATIVE AND QUANTITATIVE COMPOSITION 10 mg: Each gastro-resistant tablet contains 10.3 mg omeprazole magnesium equivalent to 10 mg omeprazole. 20 mg: Each gastro-resistant tablet contains 20.6 mg omeprazole magnesium equivalent to 20 mg omeprazole. Excipient: 10 mg: Each gastro-resistant tablet contains 19–20 mg sucrose. 20 mg: Each gastro-resistant tablet contains 19–20 mg sucrose. For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL form Gastro-resistant tablet. Losec 10 mg gastro-resistant tablets: Light-pink, oblong, biconvex, film-coated tablets engraved with or on one side and 10 mg on the other side containing enteric coated pellets. Losec 20 mg gastro-resistant tablets: Pink, oblong, biconvex, film-coated tablets, engraved with or on one side and 20 mg on the other side containing enteric coated pellets. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Losec gastro-resistant tablets are indicated for the treatment of reflux symptoms (e.g. heartburn, acid regurgitation) in adults 4.2 Posology and method of administration Posology in adults The recommended dose is 20 mg once daily for 14 days. It might be necessary to take the tablets for 2-3 consecutive days to achieve improvement of symptoms. The majority of patients achieve complete relief of heartburn within 7 days. Once complete relief of symptoms has occurred, treatment should be discontinued. Special populations Impaired renal function Dose adjustment is not needed in patients with impaired renal function (see section 5.2).

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Impaired hepatic function Patients with impaired hepatic function should be advised by a doctor before taking Losec (see section 5.2). Elderly (> 65 years old) Dose adjustment is not needed in the elderly (see section 5.2). Method of administration It is recommended to take Losec tablets in the morning, swallowed whole with half a glass of water. The tablets must not be chewed or crushed.

For patients with swallowing difficulties Break the tablet and disperse it in a spoonful of non-carbonated water - if so wished, mix with some fruit juices or applesauce. The dispersion should be taken immediately (or within 30 minutes). The dispersion should always be stirred just before drinking and rinsed down with half a glass of water. DO NOT USE milk or carbonated water. The enteric-coated pellets must not be chewed. 4.3 Contraindications Hypersensitivity to omeprazole, substituted benzimidazoles or to any of the excipients. Omeprazole like other proton pump inhibitors must not be used concomitantly with nelfinavir (see section 4.5). 4.4 Special warnings and precautions for use In the presence of any alarm symptom (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment may alleviate symptoms and delay diagnosis. 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; omeprazole 20 mg should not be exceeded. Omeprazole is a CYP2C19 inhibitor. When starting or ending treatment with omeprazole, the potential for interactions with drugs metabolised through CYP2C19 should be considered. An interaction is observed between clopidogrel and omeprazole (see section 4.5). The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of omeprazole and clopidogrel should be discouraged. Losec gastro-resistant tablets contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter (see section 5.1). Patients with long-term recurrent symptoms of indigestion or heartburn should see their doctor at regular intervals. Especially, patients over 55 years taking any ‘over-the-counter’ (OTC, non-prescription) indigestion or heartburn remedy on a daily basis should inform their pharmacist or doctor. Patients should be instructed to consult a doctor if:

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• They have had previous gastric ulcer or gastrointestinal surgery • They are on continuous symptomatic treatment of indigestion or heartburn for 4 or more weeks • They have jaundice or severe liver disease. • They are aged over 55 years with new or recently changed symptoms. Patients should not take omeprazole as a preventative medication. 4.5 Interaction with other medicinal products and other forms of interaction Effects of omeprazole on the pharmacokinetics of other active substances Active substances with pH dependent absorption The decreased intragastric acidity during treatment with omeprazole might increase or decrease the absorption of active substances with a gastric pH dependent absorption. Nelfinavir, atazanavir The plasma levels of nelfinavir and atazanavir are decreased in case of co-administration with omeprazole. Concomitant administration of omeprazole with nelfinavir is contraindicated (see section 4.3). Co-administration of omeprazole (40 mg once daily) reduced mean nelvinavir exposure by ca. 40% and the mean exposure of the pharmacologically active metabolite M8 was reduced by ca. 75-90%. The interaction may also involve CYP2C19 inhibition. Concomitant administration of omeprazole with atazanavir is not recommended (see section 4.4). Concomitant administration of omeprazole (40 mg once daily) and atazanavir 300 mg/ritonavir 100 mg to healthy volunteers resulted in a 75% decrease of the atazanavir exposure. Increasing the atazanavir dose to 400 mg did not compensate for the impact of omeprazole on atazanavir exposure. The co-administration of omeprazole (20 mg once daily) with atazanavir 400 mg/ritonavir 100 mg to healthy volunteers resulted in a decrease of approximately 30% in the atazanavir exposure as compared to atazanavir 300 mg/ritonavir 100 mg once daily. Digoxin Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10%. Digoxin toxicity has been rarely reported. However caution should be exercised when omeprazole is given at high doses in elderly patients. Therapeutic drug monitoring of digoxin should be then be reinforced. Clopidogrel In a crossover clinical study, clopidogrel (300 mg loading dose followed by 75 mg/day) alone and with omeprazole (80 mg at the same time as clopidogrel) were administered for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and omeprazole were administered together. Mean inhibition of platelet aggregation (IPA) was diminished by 47% (24 hours) and 30% (Day 5) when clopidogrel and omeprazole were administered together. In another study it was shown that administering clopidogrel and omeprazole at different times did not prevent their interaction that is likely to be driven by the inhibitory effect of omeprazole on CYP2C19. Inconsistent data on the clinical implications of this PK/PD interaction in terms of major cardiovascular events have been reported from observational and clinical studies. Other active substances The absorption of posaconazole, erlotinib, ketoconazol and itraconazol is significantly reduced and thus clinical efficacy may be impaired. For posaconazol and erlotinib concomitant use should be avoided.

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Active substances metabolised by CYP2C19 Omeprazole is a moderate inhibitor of CYP2C19, the major omeprazole metabolising enzyme. Thus, the metabolism of concomitant active substances also metabolised by CYP2C19, may be decreased and the systemic exposure to these substances increased. Examples of such drugs are R-warfarin and other vitamin K antagonists, cilostazol, diazepam and phenytoin. Cilostazol Omeprazole, given in doses of 40 mg to healthy subjects in a cross-over study, increased Cmax and AUC for cilostazol by 18% and 26% respectively, and one of its active metabolites by 29% and 69% respectively. Phenytoin Monitoring phenytoin plasma concentration is recommended during the first two weeks after initiating omeprazole treatment and, if a phenytoin dose adjustment is made, monitoring and a further dose adjustment should occur upon ending omeprazole treatment. Unknown mechanism Saquinavir Concomitant administration of omeprazole with saquinavir/ritonavir resulted in increased plasma levels up to approximately 70% for saquinavir associated with good tolerability in HIV-infected patients. Tacrolimus Concomitant administration of omeprazole has been reported to increase the serum levels of tacrolimus. A reinforced monitoring of tacrolimus concentrations as well as renal function (creatinine clearance) should be performed, and dosage of tacrolimus adjusted if needed. Effects of other active substances on the pharmacokinetics of omeprazole Inhibitors of CYP2C19 and/or CYP3A4 Since omeprazole is metabolised by CYP2C19 and CYP3A4, active substances known to inhibit CYP2C19 or CYP3A4 (such as clarithromycin and voriconazole) may lead to increased omeprazole serum levels by decreasing omeprazole’s rate of metabolism. Concomitant voriconazole treatment resulted in more than doubling of the omeprazole exposure. As high doses of omeprazole have been well-tolerated adjustment of the omeprazole dose is not generally required. However, dose adjustment should be considered in patients with severe hepatic impairment and if long-term treatment is indicated. Inducers of CYP2C19 and/or CYP3A4 Active substances known to induce CYP2C19 or CYP3A4 or both (such as rifampicin and St John’s wort) may lead to decreased omeprazole serum levels by increasing omeprazole’s rate of metabolism. 4.6 Pregnancy and lactation Results from three prospective epidemiological studies (more than 1000 exposed outcomes) indicate no adverse effects of omeprazole on pregnancy or on the health of the foetus/newborn child. Omeprazole can be used during pregnancy. Omeprazole is excreted in breast milk but is not likely to influence the child when therapeutic doses are used.

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4.7 Effects on ability to drive and use machines Losec is not likely to affect the ability to drive or 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 machinery. 4.8 Undesirable effects The most common side effects (1-10% of patients) are headache, abdominal pain, constipation, diarrhoea, flatulence and nausea/vomiting. The following adverse drug reactions have been identified or suspected in the clinical trials programme for omeprazole and post-marketing. None was found to be dose-related. Adverse reactions listed below are classified according to frequency and System Organ Class (SOC). Frequency categories are defined according to the following convention: 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). SOC/frequency

Adverse reaction


reaction/shock Metabolism and nutrition disorders Rare: Hyponatraemia Very rare: Hypomagnesaemia Psychiatric disorders Uncommon: Insomnia Rare: Agitation, confusion, depression Very rare: Aggression, hallucinations Nervous system disorders Common: Headache Uncommon: Dizziness, paraesthesia, somnolence Rare: Taste disturbance Eye disorders Rare: Blurred vision Ear and labyrinth disorders Uncommon: Vertigo Respiratory, thoracic and mediastinal disorders Rare: Bronchospasm Gastrointestinal disorders Common: Abdominal pain, constipation, diarrhoea, flatulence, nausea/vomiting Rare: Dry mouth, stomatitis, gastrointestinal candidiasis Hepatobiliary disorders Uncommon: Increased liver enzymes Rare: Hepatitis with or without jaundice Very rare: Hepatic failure, encephalopathy in patients with pre-existing liver disease Skin and subcutaneous tissue disorders Uncommon: Dermatitis, pruritus, rash, urticaria

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Rare: Alopecia, photosensitivity Very rare: Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis

(TEN) Musculoskeletal and connective tissue disorders Rare: Arthralgia, myalgia Very rare: Muscular weakness Renal and urinary disorders Rare: Interstitial nephritis Reproductive system and breast disorders Very rare: Gynaecomastia General disorders and administration site conditions Uncommon: Malaise, peripheral oedema Rare: Increased sweating 4.9 Overdose There is limited information available on the effects of overdoses of omeprazole in humans. In the literature, doses of up to 560 mg have been described, and occasional reports have been received when single oral doses have reached up to 2,400 mg omeprazole (120 times the usual recommended clinical dose). Nausea, vomiting, dizziness, abdominal pain, diarrhoea and headache have been reported. Also apathy, depression and confusion have been described in single cases. The symptoms described in connection to omeprazole overdose have been transient, and no serious outcome has been reported. The rate of elimination was unchanged (first order kinetics) with increased doses. Treatment, if needed, is symptomatic. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Proton pump inhibitors, ATC code: A02BC01 Mechanism of action Omeprazole, a racemic mixture of two enantiomers reduces gastric acid secretion through a highly targeted mechanism of action. It is a specific inhibitor of the acid pump in the parietal cell. It is rapidly acting and provides control through reversible inhibition of gastric acid secretion with once-daily dosing. Omeprazole is a weak base and is concentrated and converted to the active form in the highly acidic environment of the intracellular canaliculi within the parietal cell, where it inhibits the enzyme H+ K+-ATPase - the acid pump. This effect on the final step of the gastric acid formation process is dose-dependent and provides for highly effective inhibition of both basal acid secretion and stimulated acid secretion, irrespective of stimulus. Pharmacodynamic effects All pharmacodynamic effects observed can be explained by the effect of omeprazole on acid secretion. Effect on gastric acid secretion Oral dosing with omeprazole once daily provides for rapid and sustained inhibition of daytime and night-time gastric acid secretion with maximum effect being achieved within 4 days of treatment. With omeprazole 20 mg, a mean decrease of at least 80% in 24-hour intragastric acidity is then maintained in duodenal ulcer patients, with the mean decrease in peak acid output after pentagastrin stimulation being about 70% 24 hours after dosing.

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Oral dosing with omeprazole 20 mg maintains an intragastric pH of ≥ 3 for a mean time of 17 hours of the 24-hour period in duodenal ulcer patients. As a consequence of reduced acid secretion and intragastric acidity, omeprazole dose-dependently reduces/normalizes acid exposure of the esophagus in patients with gastro-esophageal reflux disease. The inhibition of acid secretion is related to the area under the plasma concentration-time curve (AUC) of omeprazole and not to the actual plasma concentration at a given time. No tachyphylaxis has been observed during treatment with omeprazole. Other effects related to acid inhibition During long-term treatment gastric glandular cysts have been reported in a somewhat increased frequency. These changes are a physiological consequence of pronounced inhibition of acid secretion, are benign and appear to be reversible. Decreased gastric acidity due to any means including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with acid-reducing drugs may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter. Omeprazole, 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. 5.2 Pharmacokinetic properties Absorption Omeprazole and omeprazole magnesium are acid labile and are therefore administered orally as enteric-coated granules in capsules or tablets. Absorption of omeprazole is rapid, with peak plasma levels occurring approximately 1-2 hours after dose. Absorption of omeprazole takes place in the small intestine and is usually completed within 3-6 hours. Concomitant intake of food has no influence on the bioavailability. The systemic availability (bioavailability) from a single oral dose of omeprazole is approximately 40%. After repeated once-daily administration, the bioavailability increases to about 60%. Distribution The apparent volume of distribution in healthy subjects is approximately 0.3 l/kg body weight. Omeprazole is 97% plasma protein bound. Metabolism Omeprazole is completely metabolised by the cytochrome P450 system (CYP). The major part of its metabolism is dependent on the polymorphically expressed CYP2C19, responsible for the formation of hydroxyomeprazole, the major metabolite in plasma. The remaining part is dependent on another specific isoform, CYP3A4, responsible for the formation of omeprazole sulphone. As a consequence of high affinity of omeprazole to CYP2C19, there is a potential for competitive inhibition and metabolic drug-drug interactions with other substrates for CYP2C19. However, due to low affinity to CYP3A4, omeprazole has no potential to inhibit the metabolism of other CYP3A4 substrates. In addition, omeprazole lacks an inhibitory effect on the main CYP enzymes. Approximately 3% of the Caucasian population and 15-20% of Asian populations lack a functional CYP2C19 enzyme and are called poor metabolisers. In such individuals the metabolism of omeprazole is probably mainly catalysed by CYP3A4. After repeated once-daily administration of 20 mg omeprazole, the mean AUC was 5 to 10 times higher in poor metabolisers than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations were also higher, by 3 to 5 times. These findings have no implications for the posology of omeprazole.

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Excretion The plasma elimination half-life of omeprazole is usually shorter than one hour both after single and repeated oral once-daily dosing. Omeprazole is completely eliminated from plasma between doses with no tendency for accumulation during once-daily administration. Almost 80% of an oral dose of omeprazole is excreted as metabolites in the urine, the remainder in the faeces, primarily originating from bile secretion. The AUC of omeprazole increases with repeated administration. This increase is dose-dependent and results in a non-linear dose-AUC relationship after repeated administration. This time- and dose-dependency is due to a decrease of first pass metabolism and systemic clearance probably caused by an inhibition of the CYP2C19 enzyme by omeprazole and/or its metabolites (e.g. the sulphone). No metabolite has been found to have any effect on gastric acid secretion. Special populations Impaired hepatic function The metabolism of omeprazole in patients with liver dysfunction is impaired, resulting in an increased AUC. Omeprazole has not shown any tendency to accumulate with once-daily dosing. Impaired renal function The pharmacokinetics of omeprazole, including systemic bioavailability and elimination rate, are unchanged in patients with reduced renal function. Elderly The metabolism rate of omeprazole is somewhat reduced in elderly subjects (75-79 years of age). 5.3 Preclinical safety data Gastric ECL-cell hyperplasia and carcinoids, have been observed in life-long studies in rats treated with omeprazole. These changes are the result of sustained hypergastrinaemia secondary to acid inhibition. Similar findings have been made after treatment with H2-receptor antagonists, proton pump inhibitors and after partial fundectomy. Thus, these changes are not from a direct effect of any individual active substance. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Microcrystalline cellulose, glyceryl monostearate, hydroxypropylcellulose, hydroxypropyl methylcellulose, magnesium stearate, methacrylic acid co-polymer, sugar spheres, paraffin, macrogol (polyethylene glycol), polysorbate, polyvinylpyrrolidone crosslinked, sodium hydroxide (for pH-adjustment), sodium stearyl fumarate, talc, triethyl citrate,

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iron oxide, titanium dioxide 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage Do not store above 25°C. Blister: Store in the original package in order to protect from moisture. 6.5 Nature and contents of container Aluminium blister. 10 mg: 7, 14, 28 tablets 20 mg: 7, 14 tablets Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements 7. MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] 8. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION [To be completed nationally] 10. DATE OF REVISION OF THE TEXT [To be completed nationally]

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LABELLING

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE PACKAGING CARTON FOR BLISTER CARTON FOR BOTTLE BOTTLE LABEL 1. NAME OF THE MEDICINAL PRODUCT Losec and associated names (see Annex I) 10 mg hard capsules Losec and associated names (see Annex I) 20 mg hard capsules Losec and associated names (see Annex I) 40 mg hard capsules [See Annex I - To be completed nationally] omeprazole 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each capsule contains 10 mg omeprazole. Each capsule contains 20 mg omeprazole. Each capsule contains 40 mg omeprazole. 3. LIST OF EXCIPIENTS Contains lactose. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Hard capsules Blister: 7 capsules 14 capsules 15 capsules 28 capsules 30 capsules 35 capsules (10 mg only) 50 capsules (10 mg and 20 mg only) 56 capsules (10 mg only) 60 capsules (20 mg only) 84 capsules (10 mg and 20 mg only) HDPE bottle: 5 capsules 7 capsules 10 capsules (10 mg and 20 mg only) 14 capsules 15 capsules 28 capsules 30 capsules

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50 capsules (10 mg and 20 mg only) 56 capsules (10 mg only) 60 capsules 100 capsules (10 mg and 20 mg only) 140 capsules 280 capsules 700 capsules 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral 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. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Do not store above 30°C. Carton for blister: Store in the original package in order to protect from moisture. Carton for bottle and label: Keep the container tightly closed in order to protect from moisture. 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] 12. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally]

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13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Losec and associated names (see Annex I) 10 mg Losec and associated names (see Annex I) 20 mg Losec and associated names (see Annex I) 40 mg Hospital pack: Justification for not including Braille accepted [To be completed nationally]

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER 1. NAME OF THE MEDICINAL PRODUCT Losec and associated names (see Annex I) 10 mg capsules Losec and associated names (see Annex I) 20 mg capsules Losec and associated names (see Annex I) 40 mg capsules [See Annex I - To be completed nationally] omeprazole 2. NAME OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally]

3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE PACKAGING CARTON FOR BOTTLE CARTON FOR BLISTER WALLET BOTTLE LABEL 1. NAME OF THE MEDICINAL PRODUCT Losec and associated names (see Annex I) 10 mg gastro-resistant tablets Losec and associated names (see Annex I) 20 mg gastro-resistant tablets Losec and associated names (see Annex I) 40 mg gastro-resistant tablets [See Annex I - To be completed nationally] omeprazole 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each gastro-resistant tablet contains 10 mg omeprazole. Each gastro-resistant tablet contains 20 mg omeprazole. Each gastro-resistant tablet contains 40 mg omeprazole. 3. LIST OF EXCIPIENTS Contains sucrose. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Gastro-resistant tablets Blister: 5 tablets 7 tablets 10 tablets (10 mg only) 14 tablets 15 tablets 25 tablets 28 tablets 30 tablets 50 tablets 56 tablets 60 tablets 84 tablets (10 mg and 20 mg only) 90 tablets (10 mg and 20 mg only) 98 tablets (20 mg only) 100 tablets 560 tablets

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Perforated unit dose blister: 25 x 1 tablets 28 x 1 tablets 50 x 1 tablets 56 x 1 tablets (10 mg and 20 mg only) 100 x 1 (20 mg only) HDPE bottle: 7 tablets 14 tablets 15 tablets 28 tablets 30 tablets 50 tablets (10 mg and 20 mg only) 56 tablets (20 mg only) 100 tablets 140 tablets (10 mg and 20 mg only) 200 tablets (20 mg only) 280 tablets (20 mg only) 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral 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. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Do not store above 25°C. Carton for blister and wallet: Store in the original package in order to protect from moisture. Carton for bottle and label: Keep the container tightly closed in order to protect from moisture.

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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] 12. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Losec and associated names (see Annex I) 10 mg Losec and associated names (see Annex I) 20 mg Losec and associated names (see Annex I) 40 mg Hospital pack: Justification for not including Braille accepted [To be completed nationally]

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER 1. NAME OF THE MEDICINAL PRODUCT Losec and associated names (see Annex I) 10 mg gastro-resistant tablets Losec and associated names (see Annex I) 20 mg gastro-resistant tablets Losec and associated names (see Annex I) 40 mg gastro-resistant tablets [See Annex I - To be completed nationally] omeprazole 2. NAME OF THE MARKETING AUTHORISATION HOLDER [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 Losec and associated names (see Annex I) 40 mg powder for solution for infusion [See Annex I - To be completed nationally] omeprazole 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each vial contains omeprazole sodium equivalent to 40 mg omeprazole 3. LIST OF EXCIPIENTS Each vial contains disodium edetate and sodium hydroxide. 4. PHARMACEUTICAL FORM AND CONTENTS 1 vial x40 mg 5 vials x40 mg 10 vials x40 mg 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Intravenous 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. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP

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9. SPECIAL STORAGE CONDITIONS Do not store above 25°C. Store in the original package 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] 12. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Hospital pack: Justification for not including Braille accepted

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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Losec and associated names (see Annex I) 40 mg powder for infusion [See Annex I - To be completed nationally] omeprazole iv 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6. OTHER

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Losec and associated names (see Annex I) 40 mg powder and solvent for solution for injection (I+II) [See Annex I - To be completed nationally] omeprazole 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each vial contains omeprazole sodium equivalent to 40 mg omeprazole 3. LIST OF EXCIPIENTS I. Powder for injection Each vial contains sodium hydroxide. II. Solvent for injection Each ampoule contains citric acid monohydrate, macrogol 400 and water for injection. 4. PHARMACEUTICAL FORM AND CONTENTS 1x40 mg 5x40 mg 10x40 mg 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Intravenous 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. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE

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EXP 9. SPECIAL STORAGE CONDITIONS Do not store above 25°C. Store in the original package 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] 12. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Hospital pack: Justification for not including Braille accepted

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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Losec and associated names (see Annex I) 40 mg powder for injection [See Annex I - To be completed nationally] omeprazole iv 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6. OTHER

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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS AMPOULE 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Solvent for reconstitution of Losec and associated names (see Annex I) solution for injection [See Annex I - To be completed nationally] iv 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 10 ml 6. OTHER

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE PACKAGING OTC CARTON FOR BOTTLE CARTON FOR BLISTER WALLET BOTTLE LABEL 1. NAME OF THE MEDICINAL PRODUCT Losec and associated names (see Annex I) 10 mg gastro-resistant tablets Losec and associated names (see Annex I) 20 mg gastro-resistant tablets [See Annex I - To be completed nationally] omeprazole 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each gastro-resistant tablet contains 10 mg omeprazole. Each gastro-resistant tablet contains 20 mg omeprazole. 3. LIST OF EXCIPIENTS Contains sucrose. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Gastro-resistant tablets Blister: 7 tablets 14 tablets 28 tablets (10 mg only) 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral 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. 7. OTHER SPECIAL WARNING(S), IF NECESSARY

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8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Do not store above 25°C. Carton for blister: Store in the original package in order to protect from moisture. 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] 12. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product not subject to medical prescription. 15. INSTRUCTIONS ON USE For short – term treatment of reflux symptoms (for example, heartburn, acid regurgitation) in adults. Take one 20 mg tablet or two 10 mg tablets once a day for 14 days. Contact your doctor if you are not free from symptoms after this period. Read the package leaflet before use. 16. INFORMATION IN BRAILLE Losec and associated names (see Annex I) 10 mg Losec and associated names (see Annex I) 20 mg

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[To be completed nationally]

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER 1. NAME OF THE MEDICINAL PRODUCT Losec and associated names (see Annex I) 10 mg gastro-resistant tablets Losec and associated names (see Annex I) 20 mg gastro-resistant tablets [See Annex I - To be completed nationally] omeprazole 2. NAME OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally]


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PACKAGE LEAFLETs

For medicinal products available on prescription

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PACKAGE LEAFLET: INFORMATION FOR THE USER

Losec and associated names (see Annex I) 10 mg hard capsules Losec and associated names (see Annex I) 20 mg hard capsules Losec and associated names (see Annex I) 40 mg hard capsules

[See Annex I - To be completed nationally] Omeprazole

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 Losec is and what it is used for 2. Before you take Losec 3. How to take Losec 4. Possible side effects 5. How to store Losec 6. Further information 1. WHAT LOSEC IS AND WHAT IT IS USED FOR Losec contains the active substance omeprazole. It belongs to a group of medicines called ‘proton pump inhibitors’. They work by reducing the amount of acid that your stomach produces. Losec is used to treat the following conditions:

In adults: • ‘Gastro-esophageal reflux disease’ (GERD). This is where acid from the stomach escapes into the

gullet (the tube which connects your throat to your stomach) causing pain, inflammation and heartburn.

• Ulcers in the upper part of the intestine (duodenal ulcer) or stomach (gastric ulcer). • Ulcers which are infected with bacteria called ‘Helicobacter pylori’. If you have this condition,

your doctor may also prescribe antibiotics to treat the infection and allow the ulcer to heal. • Ulcers caused by medicines called NSAIDs (Non-Steroidal Anti-Inflammatory Drugs). Losec can

also be used to stop ulcers from forming if you are taking NSAIDs. • Too much acid in the stomach caused by a growth in the pancreas (Zollinger-Ellison syndrome). In children: Children over 1 year of age and ≥ 10 kg • ‘Gastro-esophageal reflux disease’ (GERD). This is where acid from the stomach escapes into the

gullet (the tube which connects your throat to your stomach) causing pain, inflammation and heartburn. In children, the symptoms of the condition can include the return of stomach contents into the mouth (regurgitation), being sick (vomiting) and poor weight gain.

Children and adolescents over 4 years of age

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• Ulcers which are infected with bacteria called ‘Helicobacter pylori’. If your child has this condition, your doctor may also prescribe antibiotics to treat the infection and allow the ulcer to heal.

2. BEFORE YOU TAKE LOSEC Do not take Losec • if you are allergic (hypersensitive) to omeprazole or any of the other ingredients of Losec. • if you are allergic to medicines containing other proton pump inhibitors (eg pantoprazole,

lansoprazole, rabeprazole, esomeprazole). • if you are taking a medicine containing nelfinavir (used for HIV infection) If you are not sure, talk to your doctor or pharmacist before taking Losec. Take special care with Losec Losec may hide the symptoms of other diseases. Therefore, if any of the following happen to you before you start taking Losec or while you are taking it, talk to your doctor straight away: • You lose a lot of weight for no reason and have problems swallowing. • You get stomach pain or indigestion. • You begin to vomit food or blood. • You pass black stools (blood-stained faeces). • You experience severe or persistent diarrhoea, as omeprazole has been associated with a small

increase in infectious diarrhoea. • You have severe liver problems. If you take Losec 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 Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. This is because Losec can affect the way some medicines work and some medicines can have an effect on Losec. Do not take Losec if you are taking a medicine containing nelfinavir (used to treat HIV infection). Tell your doctor or pharmacist if you are taking any of the following medicines: • Ketoconazole, itraconazole or voriconazole (used to treat infections caused by a fungus) • Digoxin (used to treat heart problems) • Diazepam (used to treat anxiety, relax muscles or in epilepsy) • Phenytoin (used in epilepsy). If you are taking phenytoin, your doctor will need to monitor you

when you start or stop taking Losec • Medicines that are used to thin your blood, such as warfarin or other vitamin K blockers. Your

doctor may need to monitor you when you start or stop taking Losec • Rifampicin (used to treat tuberculosis) • Atazanavir (used to treat HIV infection) • Tacrolimus (in cases of organ transplantation) • St John’s wort (Hypericum perforatum) (used to treat mild depression) • Cilostazol (used to treat intermittent claudication) • Saquinavir (used to treat HIV infection) • Clopidogrel (used to prevent blood clots (thrombi))

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If your doctor has prescribed the antibiotics amoxicillin and clarithromycin as well as Losec to treat ulcers caused by Helicobacter pylori infection, it is very important that you tell your doctor about any other medicines you are taking. Taking Losec with food and drink You can take your capsules with food or on an empty stomach. Pregnancy and breast-feeding Before taking Losec, tell your doctor if you are pregnant or trying to get pregnant. Your doctor will decide whether you can take Losec during this time. Your doctor will decide whether you can take Losec if you are breastfeeding. Driving and using machines Losec is not likely to affect your ability to drive or use any tools or machines. Side effects such as dizziness and visual disturbances may occur (see section 4). If affected, you should not drive or operate machinery. Important information about some of the ingredients of Losec Losec capsules contain lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product. 3. HOW TO TAKE LOSEC Always take Losec exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. Your doctor will tell you how many capsules to take and how long to take them for. This will depend on your condition and how old you are. The usual doses are given below. Adults: To treat symptoms of GERD such as heartburn and acid regurgitation: • If your doctor has found that your food pipe (gullet) has been slightly damaged, the usual dose is

20 mg once a day for 4-8 weeks. Your doctor may tell you to take a dose of 40 mg for a further 8 weeks if your gullet has not yet healed.

• The usual dose once the gullet has healed is 10 mg once a day. • If your gullet has not been damaged, the usual dose is 10 mg once a day. To treat ulcers in the upper part of the intestine (duodenal ulcer): • The usual dose is 20 mg once a day for 2 weeks. Your doctor may tell you to take the same dose for

a further 2 weeks if your ulcer has not yet healed. • If the ulcer do not fully heal, the dose can be increased to 40 mg once a day for 4 weeks. To treat ulcers in the stomach (gastric ulcer): • The usual dose is 20 mg once a day for 4 weeks. Your doctor may tell you to take the same dose for

a further 4 weeks if your ulcer has not yet healed. • If the ulcer do not fully heal, the dose can be increased to 40 mg once a day for 8 weeks.

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To prevent the duodenal and stomach ulcers from coming back: • The usual dose is 10 mg or 20 mg once a day. Your doctor may increase the dose to 40 mg once a

day. To treat duodenal and stomach ulcers caused by NSAIDs (Non-Steroidal Anti-Inflammatory Drugs): • The usual dose is 20 mg once a day for 4–8 weeks. To prevent duodenal and stomach ulcers if you are taking NSAIDs: • The usual dose is 20 mg once a day. To treat ulcers caused by Helicobacter pylori infection and to stop them coming back: • The usual dose is 20 mg Losec twice a day for one week. • Your doctor will also tell you to take two antibiotics among amoxicillin, clarithromycin and

metronidazole. To treat too much acid in the stomach caused by a growth in the pancreas (Zollinger-Ellison syndrome): • The usual dose is 60 mg daily. • Your doctor will adjust the dose depending on your needs and will also decide how long you need

to take the medicine for. Children: To treat symptoms of GERD such as heartburn and acid regurgitation: • Children over 1 year of age and with a body weight of more than 10 kg may take Losec. The dose

for children is based on the child’s weight and the doctor will decide the correct dose. To treat ulcers caused by Helicobacter pylori infection and to stop them coming back: • Children aged over 4 years may take Losec. The dose for children is based on the child’s weight

and the doctor will decide the correct dose. • Your doctor will also prescribe two antibiotics called amoxicillin and clarithromycin for your child. Taking this medicine • It is recommended that you take your capsules in the morning. • You can take your capsules with food or on an empty stomach. • Swallow your capsules whole with half a glass of water. Do not chew or crush the capsules. This is

because the capsules contain coated pellets which stop the medicine from being broken down by the acid in your stomach. It is important not to damage the pellets.

What to do if you or your child have trouble swallowing the capsules • If you or your child have trouble swallowing the capsules:

- Open the capsules and swallow the contents directly with half a glass of water or put the contents into a glass of still (non-fizzy) water, any acidic fruit juice (e.g. apple, orange or pineapple) or apple sauce.

- Always stir the mixture just before drinking it (the mixture will not be clear). Then drink the mixture straight away or within 30 minutes.

- To make sure that you have drunk all of the medicine, rinse the glass very well with half a glass of water and drink it. The solid pieces contain the medicine - do not chew or crush them.

If you take more Losec than you should If you take more Losec than prescribed by your doctor, talk to your doctor or pharmacist straight away.

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If you forget to take Losec If you forget to take a dose, take it as soon as you remember it. However, if it is almost time for your next dose, skip the missed dose. Do not take a double dose to make up for a forgotten dose. 4. POSSIBLE SIDE EFFECTS Like all medicines, Losec can cause side effects, although not everybody gets them. If you notice any of the following rare but serious side effects, stop taking Losec and contact a doctor immediately: • Sudden wheezing, swelling of your lips, tongue and throat or body, rash, fainting or difficulties in

swallowing (severe allergic reaction). • Reddening of the skin with blisters or peeling. There may also be severe blisters and bleeding in the

lips, eyes, mouth, nose and genitals. This could be ‘Stevens-Johnson syndrome’ or ‘toxic epidermal necrolysis’.

• Yellow skin, dark urine and tiredness which can be symptoms of liver problems. Side effects may occur with certain frequencies, which are defined as follows: 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 Other side effects include: Common side effects • Headache. • Effects on your stomach or gut: diarrhoea, stomach pain, constipation, wind (flatulence). • Feeling sick (nausea) or being sick (vomiting). Uncommon side effects • Swelling of the feet and ankles. • Disturbed sleep (insomnia). • Dizziness, tingling feelings such as “pins and needles”, feeling sleepy. • Spinning feeling (vertigo). • Changes in blood tests that check how the liver is working. • Skin rash, lumpy rash (hives) and itchy skin. • Generally feeling unwell and lacking energy. Rare side effects • Blood problems such as a reduced number of white cells or platelets. This can cause weakness,

bruising or make infections more likely. • Allergic reactions, sometimes very severe, including swelling of the lips, tongue and throat, fever,

wheezing. • Low levels of sodium in the blood. This may cause weakness, being sick (vomiting) and cramps. • Feeling agitated, confused or depressed. • Taste changes. • Eyesight problems such as blurred vision. • Suddenly feeling wheezy or short of breath (bronchospasm). • Dry mouth. • An inflammation of the inside of the mouth.

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• An infection called “thrush” which can affect the gut and is caused by a fungus. • Liver problems, including jaundice which can cause yellow skin, dark urine, and tiredness. • Hair loss (alopecia). • Skin rash on exposure to sunshine. • Joint pains (arthralgia) or muscle pains (myalgia). • Severe kidney problems (interstitial nephritis). • Increased sweating. Very rare side effects • Changes in blood count including agranulocytosis (lack of white blood cells). • Aggression. • Seeing, feeling or hearing things that are not there (hallucinations). • Severe liver problems leading to liver failure and inflammation of the brain. • Sudden onset of a severe rash or blistering or peeling skin. This may be associated with a high fever

and joint pains (Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis). • Muscle weakness. • Enlarged breasts in men. • Hypomagnesaemia Losec may in very rare cases affect the white blood cells leading to immune deficiency. If you have an infection with symptoms such as fever with a severely reduced general condition or fever with symptoms of a local infection such as pain in the neck, throat or mouth or difficulties in urinating, you must consult your doctor as soon as possible so that a lack of white blood cells (agranulocytosis) can be ruled out by a blood test. It is important for you to give information about your medicine at this time. Do not be concerned by this list of possible side effects. You may not get any of them. If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. 5. HOW TO STORE LOSEC • Keep out of the reach and sight of children.

• Do not use Losec after the expiry date which is stated on the pack after EXP. The expiry date refers

to the last day of that month.

• Do not store above 30°C.

• Store this blister in the original package or keep the bottle tightly closed in order to protect from moisture.

• 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 Losec contains - The active substance is omeprazole. Losec capsules contain 10 mg, 20 mg or 40 mg of omeprazole. - The other ingredients are disodium hydrogen phosphate dihydrate, hydroxypropylcellulose,

hydroxypropyl methylcellulose, lactose anhydrous, magnesium stearate, mannitol, methacrylic acid co-polymer, microcrystalline cellulose, macrogol (polyethylene glycol), sodium lauryl sulphate,

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iron oxide, titanium dioxide, gelatine, printing ink (containing shellac, ammonium hydroxide, potassium hydroxide and black iron oxide).

What Losec looks like and contents of the pack • Losec 10 mg capsules have a pink body, marked 10 and a pink cap marked A/OS. • Losec 20 mg capsules have a pink body, marked 20 and a reddish-brown cap marked A/OM. • Losec 40 mg capsules have a reddish-brown body marked 40 and a reddish-brown cap marked

A/OL. Pack sizes:

• 10 mg: o HDPE bottles of 5, 7, 10, 14, 15, 28, 30, 50, 56, 60 or 100 capsules; hospital packs of

140, 280 or 700 capsules. o Blisters of 7, 14, 15, 28, 30, 35, 50, 56 and 84 capsules.

• 20 mg:

o HDPE bottles of 5, 7, 10, 14, 15, 28, 30, 50, 60 or 100 capsules; hospital packs of 140, 280 , or 700 capsules.

o Blisters of 7, 14, 15, 28, 30, 50, 60 or 84 capsules.

• 40 mg: o HDPE bottles of 5, 7, 14, 15, 28, 30 or 60 capsules; hospital packs of 140, 280, or 700

capsules. o Blisters of 7, 14, 15, 28 or 30 capsules.

Not all pack sizes may be marketed. Marketing Authorisation Holder and Manufacturer [See Annex I - To be completed nationally] This medicinal product is authorised in the Member States of the EEA under the following names: [See Annex I - To be completed nationally] This leaflet was last approved in {MM/YYYY}. [To be completed nationally]

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Losec and associated names (see Annex I) 10 mg gastro-resistant tablets Losec and associated names (see Annex I) 20 mg gastro-resistant tablets Losec and associated names (see Annex I) 40 mg gastro-resistant tablets


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 Losec is and what it is used for 2. Before you take Losec 3. How to take Losec 4. Possible side effects 5. How to store Losec 6. Further information 1. WHAT LOSEC IS AND WHAT IT IS USED FOR Losec gastro-resistant tablets contains the active substance omeprazole. It belongs to a group of medicines called ‘proton pump inhibitors’. They work by reducing the amount of acid that your stomach produces. Losec is used to treat the following conditions:

In adults: • ‘Gastro-esophageal reflux disease’ (GERD). This is where acid from the stomach escapes into the

gullet (the tube which connects your throat to your stomach) causing pain, inflammation and heartburn.

• Ulcers in the upper part of the intestine (duodenal ulcer) or stomach (gastric ulcer). • Ulcers which are infected with bacteria called ‘Helicobacter pylori’. If you have this condition,

your doctor may also prescribe antibiotics to treat the infection and allow the ulcer to heal. • Ulcers caused by medicines called NSAIDs (Non-Steroidal Anti-Inflammatory Drugs). Losec can

also be used to stop ulcers from forming if you are taking NSAIDs. • Too much acid in the stomach caused by a growth in the pancreas (Zollinger-Ellison syndrome). In children: Children over 1 year of age and ≥ 10 kg • ‘Gastro-esophageal reflux disease’ (GERD). This is where acid from the stomach escapes into the

gullet (the tube which connects your throat to your stomach) causing pain, inflammation and heartburn. In children, the symptoms of the condition can include the return of stomach contents into the mouth (regurgitation), being sick (vomiting) and poor weight gain.

Children and adolescents over 4 years of age

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• Ulcers which are infected with bacteria called ‘Helicobacter pylori’. If your child has this condition, your doctor may also prescribe antibiotics to treat the infection and allow the ulcer to heal.

2. BEFORE YOU TAKE LOSEC Do not take Losec • if you are allergic (hypersensitive) to omeprazole or any of the other ingredients of Losec. • if you are allergic to medicines containing other proton pump inhibitors (e.g. pantoprazole,

lansoprazole, rabeprazole, esomeprazole). • if you are taking a medicine containing nelfinavir (for HIV infection). If you are not sure, talk to your doctor or pharmacist before taking Losec. Take special care with Losec Losec may hide the symptoms of other diseases. Therefore, if any of the following happen to you before you start taking Losec or while you are taking it, talk to your doctor straight away: • You lose a lot of weight for no reason and have problems swallowing. • You get stomach pain or indigestion. • You begin to vomit food or blood. • You pass black stools (blood-stained faeces). • You experience severe or persistent diarrhoea, as omeprazole has been associated with a small

increase in infectious diarrhoea. • You have severe liver problems. If you take Losec 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 Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. This is because Losec can affect the way some medicines work and some medicines can have an effect on Losec. Do not take Losec if you are taking a medicine containing nelfinavir (used to treat HIV infection). Tell your doctor or pharmacist if you are taking any of the following medicines: • Ketoconazole, itraconazole or voriconazole (used to treat infections caused by a fungus). • Digoxin (used to treat heart problems) • Diazepam (used to treat anxiety, relax muscles or in epilepsy). • Phenytoin (used in epilepsy). If you are taking phenytoin, your doctor will need to monitor you


doctor may need to monitor you when you start or stop taking Losec. • Rifampicin (used to treat tuberculosis) • Atazanavir (used to treat HIV infections) • Tacrolimus (in cases of organ transplantation) • St John’s wort (Hypericum perforatum) (used to treat mild depression) • Cilostazol (used to treat intermittent claudication) • Saquinavir (used to treat HIV infection) • Clopidogrel (used to prevent blood clots (thrombi))

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If your doctor has prescribed the antibiotics amoxicillin and clarithromycin as well as Losec to treat ulcers caused by Helicobacter pylori infection, it is very important that you tell your doctor about any other medicines you are taking. Taking Losec with food and drink You can take your tablets with food or on an empty stomach. Pregnancy and breast-feeding Before taking Losec, tell your doctor if you are pregnant or trying to get pregnant. Your doctor will decide whether you can take Losec during this time. Your doctor will decide whether you can take Losec if you are breastfeeding. Driving and using machines Losec is not likely to affect your ability to drive or use any tools or machines. Side effects such as dizziness and visual disturbances may occur (see section 4). If affected, you should not drive or operate machinery. Important information about some of the ingredients of Losec Losec gastro-resistant tablets contain sucrose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product 3. HOW TO TAKE LOSEC Always take Losec exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. Your doctor will tell you how many tablets to take and how long to take them for. This will depend on your condition and how old you are. The usual doses are given below. Adults: To treat symptoms of GERD such as heartburn and acid regurgitation: • If your doctor has found that your food pipe (gullet) has been slightly damaged, the usual dose is

20 mg once a day for 4-8 weeks. Your doctor may tell you to take a dose of 40 mg for a further 8 weeks if your gullet has not yet healed.

• The usual dose once the gullet has healed is 10 mg once a day. • If your gullet has not been damaged, the usual dose is 10 mg once a day. To treat ulcers in the upper part of the intestine (duodenal ulcer): • The usual dose is 20 mg once a day for 2 weeks. Your doctor may tell you to take the same dose for

a further 2 weeks if your ulcer has not yet healed. • If the ulcer do not fully heal, the dose can be increased to 40 mg once a day for 4 weeks. To treat ulcers in the stomach (gastric ulcer): • The usual dose is 20 mg once a day for 4 weeks. Your doctor may tell you to take the same dose for

a further 4 weeks if your ulcer has not yet healed. • If the ulcer do not fully heal, the dose can be increased to 40 mg once a day for 8 weeks.

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To prevent the duodenal and stomach ulcers from coming back: • The usual dose is 10 mg or 20 mg once a day. Your doctor may increase the dose to 40 mg once a

day. To treat duodenal and stomach ulcers caused by NSAIDs (Non-Steroidal Anti-Inflammatory Drugs): • The usual dose is 20 mg once a day for 4 to 8 weeks. To prevent duodenal and stomach ulcers if you are taking NSAIDs: • The usual dose is 20 mg once a day. To treat ulcers caused by Helicobacter pylori infection and to stop them coming back: • The usual dose is 20 mg Losec twice a day for one week. • Your doctor will also tell you to take two antibiotics among amoxicillin, clarithromycin and

metronidazole. To treat too much acid in the stomach caused by a growth in the pancreas (Zollinger-Ellison syndrome): • The usual dose is 60 mg daily. • Your doctor will adjust the dose depending on your needs and will also decide how long you need

to take the medicine for. Children: To treat symptoms of GERD such as heartburn and acid regurgitation: • Children over 1 year of age and with a body weight of more than 10 kg may take Losec. The dose

for children is based on the child’s weight and the doctor will decide the correct dose. To treat ulcers caused by Helicobacter pylori infection and to stop them coming back: • Children aged over 4 years may take Losec. The dose for children is based on the child’s weight

and the doctor will decide the correct dose. • Your doctor will also prescribe two antibiotics called amoxicillin and clarithromycin for your child. Taking this medicine • It is recommended that you take your tablets in the morning. • You can take your tablets with food or on an empty stomach. • Swallow your tablets whole with half a glass of water. Do not chew or crush the tablets. This is

because the tablets contain coated pellets which stop the medicine from being broken down by the acid in your stomach. It is important not to damage the pellets.

What to do if you or your child have trouble swallowing the tablets • If you or your child have trouble swallowing the tablets:

- Break the tablet and disperse it in a spoonful of water (non-fizzy), any acidic fruit juice (e.g. apple, orange or pineapple) or apple sauce.

- Always stir the mixture just before drinking (the mixture will not be clear). Then drink the mixture straight away or within 30 minutes.

- To make sure that you have drunk all of the medicine, rinse the glass very well with half a glass of water and drink it. Do not use milk or fizzy water. The solid pieces contain the medicine - do not chew or crush them.

If you take more Losec than you should If you take more Losec than prescribed by your doctor, talk to your doctor or pharmacist straight away. If you forget to take Losec

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If you forget to take a dose, take it as soon as you remember it. However, if it is almost time for your next dose, skip the missed dose. Do not take a double dose to make up for a forgotten dose. 4. POSSIBLE SIDE EFFECTS Like all medicines, Losec can cause side effects, although not everybody gets them. If you notice any of the following rare but serious side effects, stop taking Losec and contact a doctor immediately: • Sudden wheezing, swelling of your lips, tongue and throat or body, rash, fainting or difficulties in

swallowing (severe allergic reaction). • Reddening of the skin with blisters or peeling. There may also be severe blisters and bleeding in the




wheezing. • Low levels of sodium in the blood. This may cause weakness, being sick (vomiting) and cramps. • Feeling agitated, confused or depressed. • Taste changes. • Eyesight problems such as blurred vision. • Suddenly feeling wheezy or short of breath (bronchospasm). • Dry mouth. • An inflammation of the inside of the mouth. • An infection called “thrush” which can affect the gut and is caused by a fungus.

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• Liver problems, including jaundice which can cause yellow skin, dark urine, and tiredness. • Hair loss (alopecia). • Skin rash on exposure to sunshine. • Joint pains (arthralgia) or muscle pains (myalgia). • Severe kidney problems (interstitial nephritis). • Increased sweating. Very rare side effects • Changes in blood count including agranulocytosis (lack of white blood cells) • Aggression. • Seeing, feeling or hearing things that are not there (hallucinations). • Severe liver problems leading to liver failure and inflammation of the brain. • Sudden onset of a severe rash or blistering or peeling skin. This may be associated with a high fever

and joint pains (Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis) • Muscle weakness. • Enlarged breasts in men. • Hypomagnesaemia Losec may in very rare cases affect the white blood cells leading to immune deficiency. If you have an infection with symptoms such as fever with a severely reduced general condition or fever with symptoms of a local infection such as pain in the neck, throat or mouth or difficulties in urinating, you must consult your doctor as soon as possible so that a lack of white blood cells (agranulocytosis) can be ruled out by a blood test. It is important for you to give information about your medicine at this time. Do not be concerned by this list of possible side effects. You may not get any of them. If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. 5. HOW TO STORE LOSEC • Keep out of the reach and sight of children.

• Do not use Losec after the expiry date which is stated on the outer and inner pack after EXP. The

expiry date refers to the last day of that month.


• Store this blister in the original package or keep the bottle tightly closed in order to protect from moisture.


to dispose of medicines no longer required. These measures will help to protect the environment. 6. FURTHER INFORMATION What Losec contains - The active substance is omeprazole. Losec gastro-resistant tablets contain omeprazole magnesium

corresponding to 10 mg, 20 mg or 40 mg omeprazole. - The other ingredients are microcrystalline cellulose, glyceryl monostearate,

hydroxypropylcellulose, hydroxypropyl methylcellulose, magnesium stearate, methacrylic acid co-polymer, sugar spheres, paraffin, macrogol (polyethylene glycol), polysorbate,

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polyvinylpyrrolidone crosslinked, sodium hydroxide (for pH-adjustment), sodium stearyl fumarate, talc, triethyl citrate, iron oxide, titanium dioxide.

What Losec looks like and contents of the pack • Losec 10 mg gastro-resistant tablets are light-pink with or on one side and 10 mg on the

other side. • Losec 20 mg gastro-resistant tablets are pink with or on one side and 20 mg on the other

side. • Losec 40 mg gastro-resistant tablets are dark red-brown with or on one side and 40 mg on the

other side.

Pack sizes: • 10 mg:

o HDPE bottles of 7, 14, 15, 28, 30, 50, 100 tablets; hospital pack of 140 tablets. o Blisters of 5, 7, 10, 14, 15, 25, 28, 30, 50, 56, 60, 84, 90, 100 tablets; hospital pack of 560

tablets. o Perforated unit dose blisters (hospital packs) of 25 x 1, 28 x 1, 50 x 1, 56 x 1 tablets.

• 20 mg:

o HDPE bottles of 7, 14, 15, 28, 30, 50, 56, 100 tablets; hospital packs of 140 , 200, 280 tablets.

o Blisters of 5, 7, 14, 15, 25, 28, 30, 50, 56, 60, 84, 90, 98, 100 tablets; hospital pack of 560 tablets.

o Perforated unit dose blisters (hospital packs) of 25 x 1, 28 x 1, 50 x 1, 56 x 1, 100 x 1 tablets.

• 40 mg:

o HDPE bottles of 7, 14, 15, 28, 30, 100 tablets. o Blisters of 5, 7, 14, 15, 25, 28, 30, 50, 56, 60, 100 tablets; hospital pack of 560 tablets. o Perforated unit dose blisters (hospital packs) of 25 x 1, 28 x 1, 50 x 1 tablets.


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

Omeprazole

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, nurse 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, nurse or pharmacist. In this leaflet: 1. What Losec is and what it is used for 2. Before Losec is given to you 3. How Losec is given to you 4. Possible side effects 5. How to store Losec 6. Further information 1. WHAT LOSEC IS AND WHAT IT IS USED FOR Losec contains the active substance omeprazole. It belongs to a group of medicines called ‘proton pump inhibitors’. They work by reducing the amount of acid that your stomach produces. Losec powder for solution for infusion can be used as an alternative to oral therapy. 2. BEFORE LOSEC IS GIVEN TO YOU You must not be given Losec

• if you are allergic (hypersensitive) to omeprazole or any of the other ingredients of Losec. • if you are allergic to other proton pump inhibitor medicines (e.g. pantoprazole, lansoprazole,

rabeprazole, esomeprazole). • if you are taking a medicine containing nelfinavir (used for HIV infection).

If you are not sure, talk to your doctor, nurse or pharmacist before you are given this medicine. Take special care with Losec Losec may hide the symptoms of other diseases. Therefore, if any of the following happen to you before you are given Losec or after you are given it, talk to your doctor straight away: • You lose a lot of weight for no reason and have problems swallowing. • You get stomach pain or indigestion. • You begin to vomit food or blood. • You pass black stools (blood-stained faeces). • You experience severe or persistent diarrhoea, as omeprazole has been associated with a small

increase in infectious diarrhoea. • You have severe liver problems. Using other medicines Please tell your doctor, nurse or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. This is because Losec can affect the way some medicines work and some medicines can have an effect on Losec.

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You must not be given Losec if you are taking a medicine containing nelfinavir (used to treat HIV infection). Tell your doctor or pharmacist if you are taking any of the following medicines: • Ketoconazole, itraconazole or voriconazole (used to treat infections caused by a fungus). • Digoxin (used to treat heart problems) • Diazepam (used to treat anxiety, relax muscles or in epilepsy) • Phenytoin (used in epilepsy). If you are taking phenytoin, your doctor will need to monitor you

when you start or stop taking Losec. • Medicines that are used to thin your blood, such as warfarin or other vitamin K blockers. Your

doctor may need to monitor you when you start or stop taking Losec • Rifampicin (used to treat tuberculosis) • Atazanavir (used to treat HIV infection) • Tacrolimus (in cases of organ transplantation) • St John’s wort (Hypericum perforatum) (used to treat mild depression) • Cilostazol (used to treat intermittent claudication) • Saquinavir (used to treat HIV infection) • Clopidogrel (used to prevent blood clots (thrombi)) If your doctor has prescribed the antibiotics amoxicillin and clarithromycin as well as Losec to treat ulcers caused by Helicobacter pylori infection, it is very important that you tell your doctor about any other medicines you are taking. Pregnancy and breast-feeding Before you are given Losec, tell your doctor if you are pregnant or trying to get pregnant. Your doctor will decide whether you can be given Losec during this time. Your doctor will decide whether you can take Losec if you are breastfeeding. Driving and using machines Losec is not likely to affect your ability to drive or use any tools or machines. Side effects such as dizziness and visual disturbances may occur (see section 4). If affected, you should not drive or operate machinery. 3. HOW LOSEC IS GIVEN TO YOU • Losec can be given to adults including the elderly. • There is limited experience with Losec for intravenous use in children. Being given Losec • Losec will be given to you by a doctor who will decide how much you need. • The medicine will be given to you as an infusion into one of your veins. If you are given more Losec than you should If you think you have been given too much Losec, talk to your doctor straight away. 4. POSSIBLE SIDE EFFECTS Like all medicines, Losec can cause side effects, although not everybody gets them.

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If you notice any of the following rare but serious side effects, stop using Losec and contact a doctor immediately: • Sudden wheezing, swelling of your lips, tongue and throat or body, rash, fainting or difficulties to

swallow (severe allergic reaction). • Reddening of the skin with blisters or peeling. There may also be severe blisters and bleeding in the


• Yellow skin, dark urine and tiredness which can be symptoms of liver problems.

Side effects may occur with certain frequencies, which are defined as follows: 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 Other side effects include: Common side effects • Headache. • Effects on your stomach or gut: diarrhoea, stomach pain, constipation, wind (flatulence). • Feeling sick (nausea) or being sick (vomiting). Uncommon side effects • Swelling of the feet and ankles. • Disturbed sleep (insomnia). • Dizziness, tingling feelings such as “pins and needles”, feeling sleepy. • Spinning feeling (vertigo). • Changes in blood tests that check how the liver is working. • Skin rash, lumpy rash (hives) and itchy skin. • Generally feeling unwell and lacking energy. Rare side effects • Blood problems such as a reduced number of white cells or platelets. This can cause weakness,


wheezing. • Low levels of sodium in the blood. This may cause weakness, being sick (vomiting) and cramps. • Feeling agitated, confused or depressed. • Taste changes. • Eyesight problems such as blurred vision. • Suddenly feeling wheezy or short of breath (bronchospasm). • Dry mouth. • An inflammation of the inside of the mouth. • An infection called “thrush” which can affect the gut and is caused by a fungus. • Liver problems, including jaundice which can cause yellow skin, dark urine, and tiredness. • Hair loss (alopecia). • Skin rash on exposure to sunshine. • Joint pains (arthralgia) or muscle pains (myalgia). • Severe kidney problems (interstitial nephritis). • Increased sweating.

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Very rare side effects • Changes in blood count including agranulocytosis (lack of white blood cells). • Aggression. • Seeing, feeling or hearing things that are not there (hallucinations). • Severe liver problems leading to liver failure and inflammation of the brain. • Sudden onset of a severe rash or blistering or peeling skin. This may be associated with a high fever

and joint pains (Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis) • Muscle weakness. • Enlarged breasts in men. • Hypomagnesaemia Irreversible visual impairment has been reported in isolated cases of critically ill patients who have received omeprazole intravenous injection, especially at high doses, but no causal relationship has been established. Losec may in very rare cases affect the white blood cells leading to immune deficiency. If you have an infection with symptoms such as fever with a severely reduced general condition or fever with symptoms of a local infection such as pain in the neck, throat or mouth or difficulties in urinating, you must consult your doctor as soon as possible so that a lack of white blood cells (agranulocytosis) can be ruled out by a blood test. It is important for you to give information about your medicine at this time. Do not be concerned by this list of possible side effects. You may not get any of them. If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. 5. HOW TO STORE LOSEC • Keep out of the reach and sight of children. • Do not use Losec after the expiry date which is stated on the vial and carton after EXP. The expiry

date refers to the last day of that month. • Do not store above 25°C. Store in the original package in order to protect from light. • Shelf life after reconstitution:

Solution for infusion reconstituted with sodium chloride 9 mg/ml (0.9%) should be used within 12 hours after preparation. Solution for infusion reconstituted with glucose 50 mg/ml (5%) should be used within 6 hours after preparation. From a microbiological point of view, the product should be used immediately unless it has been reconstituted under controlled and validated aseptic conditions.


to dispose of medicines no longer required. These measures will help to protect the environment. 6. FURTHER INFORMATION What Losec contains

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- The active substance is omeprazole. Each vial of powder for solution for infusion contains omeprazole sodium equivalent to 40 mg of omeprazole. - The other ingredients are disodium edetate and sodium hydroxide.

What Losec looks like and contents of the pack Losec 40 mg powder for solution for infusion (powder for infusion) comes in a vial. The dry powder in the vial is made into a solution before it is given to you. Pack sizes: Vials 1x40 mg, 5x40 mg and 10x40 mg. Not all pack sizes may be marketed. Marketing Authorisation Holder and Manufacturer [See Annex I - To be completed nationally] This medicinal product is authorised in the Member States of the EEA under the following names: [See Annex I - To be completed nationally] This leaflet was last approved in {MM/YYYY}. [To be completed nationally] ----------------------------------------------------------------------------------------------------------------------------- The following information is intended for medical or healthcare professionals only: The entire contents of each vial is to be dissolved in approximately 5 ml and then immediately diluted to 100 ml. Sodium chloride 9 mg/ml (0.9%) solution for infusion or glucose 50 mg/ml (5%) solution for infusion must be used. The stability of omeprazole is influenced by the pH of the solution for infusion, which is why no other solvent or quantities should be used for dilution. Preparation 1. With a syringe draw 5 ml of infusion solution from the 100 ml infusion bottle or bag. 2. Add this volume to the vial with the freeze-dried omeprazole, mix thoroughly making sure all

omeprazole is dissolved. 3. Draw the omeprazole solution back into the syringe. 4. Transfer the solution into the infusion bag or bottle. 5. Repeat steps 1-4 to make sure all omeprazole is transferred from the vial into the infusion bag or

bottle. Alternative preparation for infusions in flexible containers 1. Use a double-ended transfer needle and attach to the injection membrane of the infusion bag.

Connect the other needle-end from the vial with freeze-dried omeprazole. 2. Dissolve the omeprazole substance by pumping the infusion solution back and forward between the

infusion bag and the vial. 3. Make sure all omeprazole is dissolved. The solution for infusion is to be administrered in an intravenous infusion for 20-30 minutes.

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Losec and associated names (see Annex I) 40 mg powder and solvent for solution for injection


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, nurse 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, nurse or pharmacist. In this leaflet: 1. What Losec is and what it is used for 2. Before Losec is given to you 3. How Losec is given to you 4. Possible side effects 5. How to store Losec 6. Further information 1. WHAT LOSEC IS AND WHAT IT IS USED FOR Losec contains the active substance omeprazole. It belongs to a group of medicines called ‘proton pump inhibitors’. They work by reducing the amount of acid that your stomach produces. Losec powder and solvent for solution for injection can be used as an alternative to oral therapy. 2. BEFORE LOSEC IS GIVEN TO YOU You must not be given Losec • if you are allergic (hypersensitive) to omeprazole or any of the other ingredients of Losec. • if you are allergic to other proton pump inhibitor medicines (e.g. pantoprazole, lansoprazole,

rabeprazole, esomeprazole). • if you are taking a medicine containing nelfinavir (used for HIV infection). If you are not sure, talk to your doctor, nurse or pharmacist before you are given this medicine. Take special care with Losec Losec may hide the symptoms of other diseases. Therefore, if any of the following happen to you before you are given Losec or after you are given it, talk to your doctor straight away: • You lose a lot of weight for no reason and have problems swallowing. • You get stomach pain or indigestion. • You begin to vomit food or blood. • You pass black stools (blood-stained faeces). • You experience severe or persistent diarrhoea, as omeprazole has been associated with a small

increase in infectious diarrhoea. • You have severe liver problems.

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Using other medicines Please tell your doctor, nurse or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. This is because Losec can affect the way some medicines work and some medicines can have an effect on Losec.

You must not be given Losec if you are taking a medicine containing nelfinavir (used to treat HIV infection). Tell your doctor or pharmacist if you are taking any of the following medicines: • Ketoconazole, itraconazole or voriconazole (used to treat infections caused by a fungus). • Digoxin (used to treat heart problems) • Diazepam (used to treat anxiety, relax muscles or in epilepsy). • Phenytoin (used in epilepsy). If you are taking phenytoin, your doctor will need to monitor you


doctor may need to monitor you when you start or stop taking Losec • Rifampicin (used to treat tuberculosis) • Atazanavir (used to treat HIV infection) • Tacrolimus (in cases of organ transplantation) • St John’s wort (Hypericum perforatum) (used to treat mild depression) • Cilostazol (used to treat intermittent claudication) • Saquinavir (used to treat HIV infection) • Clopidogrel (used to prevent blood clots (thrombi)) If your doctor has prescribed the antibiotics amoxicillin and clarithromycin as well as Losec to treat ulcers caused by Helicobacter pylori infection, it is very important that you tell your doctor about any other medicines you are taking. Pregnancy and breast-feeding Before you are given Losec, tell your doctor if you are pregnant or trying to get pregnant. Your doctor will decide whether you can be given Losec during this time. Omeprazole is excreted in breast milk but is not likely to influence the child when therapeutic doses are used. Your doctor will decide whether you can take Losec if you are breastfeeding. Driving and using machines Losec is not likely to affect your ability to drive or use any tools or machines. Side effects such as dizziness and visual disturbances may occur (see section 4). If affected, you should not drive or operate machinery. 3. HOW LOSEC IS GIVEN TO YOU • Losec can be given to adults including the elderly. • There is limited experience with Losec for intravenous use in children. Being given Losec • Losec will be given to you by a doctor who will decide how much you need. • The medicine will be given to you as an injection into one of your veins. If you are given more Losec than you should If you think you have been given too much Losec, talk to your doctor straight away.

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4. POSSIBLE SIDE EFFECTS Like all medicines, Losec can cause side effects, although not everybody gets them. If you notice any of the following rare but serious side effects, stop using Losec and contact a doctor immediately: • Sudden wheezing, swelling of your lips, tongue and throat or body, rash, fainting or difficulties to

swallow (severe allergic reaction). • Reddening of the skin with blisters or peeling. There may also be severe blisters and bleeding in the


• Yellow skin, dark urine and tiredness which can be symptoms of liver problems.

Side effects may occur with certain frequencies, which are defined as follows: 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. Other side effects include: Common side effects • Headache. • Effects on your stomach or gut: diarrhoea, stomach pain, constipation, wind (flatulence). • Feeling sick (nausea) or being sick (vomiting). Uncommon side effects • Swelling of the feet and ankles. • Disturbed sleep (insomnia). • Dizziness, tingling feelings such as “pins and needles”, feeling sleepy. • Spinning feeling (vertigo). • Changes in blood tests that check how the liver is working. • Skin rash, lumpy rash (hives) and itchy skin. • Generally feeling unwell and lacking energy. Rare side effects • Blood problems such as a reduced number of white cells or platelets. This can cause weakness,


wheezing. • Low levels of sodium in the blood. This may cause weakness, being sick (vomiting) and cramps. • Feeling agitated, confused or depressed. • Taste changes. • Eyesight problems such as blurred vision. • Suddenly feeling wheezy or short of breath (bronchospasm). • Dry mouth. • An inflammation of the inside of the mouth. • An infection called “thrush” which can affect the gut and is caused by a fungus. • Liver problems, including jaundice which can cause yellow skin, dark urine, and tiredness. • Hair loss (alopecia). • Skin rash on exposure to sunshine. • Joint pains (arthralgia) or muscle pains (myalgia).

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• Severe kidney problems (interstitial nephritis). • Increased sweating. Very rare side effects • Changes in blood count including agranulocytosis (lack of white blood cells). • Aggression. • Seeing, feeling or hearing things that are not there (hallucinations). • Severe liver problems leading to liver failure and inflammation of the brain. • Sudden onset of a severe rash or blistering or peeling skin. This may be associated with a high fever

and joint pains (Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis). • Muscle weakness. • Enlarged breasts in men. • Hypomagnesaemia Irreversible visual impairment has been reported in isolated cases of critically ill patients who have received Losec intravenous injection, especially at high doses, but no causal relationship has been established. Losec may in very rare cases affect the white blood cells leading to immune deficiency. If you have an infection with symptoms such as fever with a severely reduced general condition or fever with symptoms of a local infection such as pain in the neck, throat or mouth or difficulties in urinating, you must consult your doctor as soon as possible so that a lack of white blood cells (agranulocytosis) can be ruled out by a blood test. It is important for you to give information about your medicine at this time. Do not be concerned by this list of possible side effects. You may not get any of them. If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. 5. HOW TO STORE LOSEC • Keep out of the reach and sight of children. • Do not use Losec after the expiry date which is stated on the label and carton after EXP. The expiry

date refers to the last day of that month. • Do not store above 25°C. Store in the original package in order to protect from light. • Shelf life after reconstitution:

The reconstituted solution should not be stored at temperatures above 25°C and should be used within 4 hours after preparation. From a microbiological point of view, the product should be used immediately unless it has been reconstituted under controlled and validated aseptic conditions.


to dispose of medicines no longer required. These measures will help to protect the environment. 6. FURTHER INFORMATION What Losec contains - The active substance is omeprazole. Each vial of powder for solution for injection contains

omeprazole sodium equivalent to 40 mg of omeprazole. - The other ingredients are:

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Powder for injection: sodium hydroxide (for pH adjustment). Solvent for injection: citric acid monohydrate (for pH adjustment), macrogol 400, and water for

injection. What Losec looks like and contents of the pack Losec 40 mg powder and solvent for solution for injection (Powder for injection; and Solvent for reconstitution of solution for injection) comes in a combination pack consisting of a vial containing dry substance (I) and an ampoule containing solvent (II). The dry powder in the vial is made into a solution before it is given to you. Pack sizes: 1x40 mg(I+II), 5x40 mg(I+II), 10x40 mg (I+II). Not all pack sizes may be marketed. Marketing Authorisation Holder and Manufacturer [See Annex I - To be completed nationally] This medicinal product is authorised in the Member States of the EEA under the following names: [See Annex I - To be completed nationally] This leaflet was last approved in {MM/YYYY}. [To be completed nationally] ----------------------------------------------------------------------------------------------------------------------------- The following information is intended for medical or healthcare professionals only: Losec solution for injection is obtained by dissolving the freeze-dried substance in the accompanying solvent. No other solvent should be used. The stability of omeprazole is influenced by the pH of the solution for injection, which is why no other solvents or quantities should be used for dilution. Improperly prepared solutions can be identified by their yellow to brown discolouration and must not be used. Use only clear, colourless or pale yellowish-brown solutions. Preparation NOTE: Steps 1 to 5 must be performed in immediate sequence: 1. With a syringe draw all of the solvent from the ampoule (10 ml). 2. Add approximately 5 ml of the solvent to the vial with freeze-dried omeprazole. 3. Withdraw as much air as possible from the vial back into the syringe. This will make it easier to

add the remaining solvent. 4. Add the remaining solvent into the vial, make sure the syringe is empty. 5. Rotate and shake the vial to ensure all the freeze-dried omeprazole has dissolved.

Losec solution for injection must be given only as an intravenous injection and it must not be added to infusion solutions. After reconstitution the injection should be given slowly over a period of at least 2.5 minutes at a maximum rate of 4 ml per minute.

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PACKAGE LEAFLET

For medicinal products available without prescription

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Losec and associated names (see Annex I) 10 mg gastro-resistant tablets Losec and associated names (see Annex I) 20 mg gastro-resistant tablets


Read all of this leaflet carefully because it contains important information for you. This medicine is available without prescription. However, you still need to take Losec carefully to get the best results from it. - Keep this leaflet. You may need to read it again. - Ask your pharmacist if you need more information or advice. - You must contact a doctor if your symptoms worsen or do not improve after 14 days. - If any of the side effects gets serious, or if you notice any side effect not listed in this leaflet, please

tell your doctor or pharmacist. In this leaflet: 1. What Losec is and what it is used for 2. Before you take Losec 3. How to take Losec 4. Possible side effects 5. How to store Losec 6. Further information 1. WHAT LOSEC IS AND WHAT IT IS USED FOR Losec gastro-resistant tablets contains the active substance omeprazole. It belongs to a group of medicines called ‘proton pump inhibitors’. They work by reducing the amount of acid that your stomach produces. Losec is used in adults for the short-term treatment of reflux symptoms (for example, heartburn, acid regurgitation). Reflux is the backflow of acid from the stomach into the gullet “foodpipe”, which may become inflamed and painful. This may cause you symptoms such as a painful burning sensation in the chest rising up to the throat (heartburn) and a sour taste in the mouth (acid regurgitation). It might be necessary to take the tablets for 2-3 consecutive days to achieve improvement of symptoms. 2. BEFORE YOU TAKE LOSEC Do not take Losec • if you are allergic (hypersensitive) to omeprazole or any of the other ingredients of Losec. • if you are allergic to medicines containing other proton pump inhibitors (e.g. pantoprazole,

lansoprazole, rabeprazole, esomeprazole). • if you are taking a medicine containing nelfinavir (for HIV infection). If you are not sure, talk to your doctor or pharmacist before taking Losec. Take special care with Losec Do not take Losec for more than 14 days without consulting a doctor. If you do not experience relief, or if you experience a worsening of symptoms, consult your doctor.

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Losec may hide the symptoms of other diseases. Therefore, if any of the following happen to you before you start taking Losec or while you are taking it, talk to your doctor straight away: • You lose a lot of weight for no reason and have problems swallowing. • You get stomach pain or indigestion. • You begin to vomit food or blood. • You pass black stools (blood-stained faeces). • You experience severe or persistent diarrhoea, as omeprazole has been associated with a small

increase in infectious diarrhoea. • You have had previous gastric ulcer or gastrointestinal surgery. • You are on continuous symptomatic treatment of indigestion or heartburn for 4 or more weeks. • You continuously suffer from indigestion or heartburn for 4 or more weeks. • You have jaundice or severe liver disease. • You are aged over 55 years with new or recently changed symptoms. Patients should not take omeprazole as a preventative medication. Taking other medicines Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. This is because Losec can affect the way some medicines work and some medicines can have an effect on Losec. Do not take Losec if you are taking a medicine containing nelfinavir (used to treat HIV infection). You should specifically tell your doctor or pharmacist if you are taking clopidogrel (used to prevent blood clots (thrombi)). Tell your doctor or pharmacist if you are taking any of the following medicines: • Ketoconazole, itraconazole or voriconazole (used to treat infections caused by a fungus). • Digoxin (used to treat heart problems) • Diazepam (used to treat anxiety, relax muscles or in epilepsy). • Phenytoin (used in epilepsy). If you are taking phenytoin, your doctor will need to monitor you

when you start or stop taking Losec. • Medicines that are used to thin your blood, such as warfarin or other vitamin K blockers. Your

doctor may need to monitor you when you start or stop taking Losec. • Rifampicin (used to treat tuberculosis) • Atazanavir (used to treat HIV infection) • Tacrolimus (in cases of organ transplantation) • St John’s wort (Hypericum perforatum) (used to treat mild depression) • Cilostazol (used to treat intermittent claudication) • Saquinavir (used to treat HIV infection) Taking Losec with food and drink You can take your tablets with food or on an empty stomach. Pregnancy and breast-feeding Before taking Losec, tell your doctor or pharmacist if you are pregnant or trying to get pregnant. Your doctor will decide whether you can take Losec during this time. Your doctor will decide whether you can take Losec if you are breastfeeding. Driving and using machines Losec is not likely to affect your ability to drive or use any tools or machines. Side effects such as dizziness and visual disturbances may occur (see section 4). If affected, you should not drive or operate machinery.

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Important information about some of the ingredients of Losec Losec gastro-resistant tablets contain sucrose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product 3. HOW TO TAKE LOSEC Always take Losec exactly as described in this leaflet. You should check with your doctor or pharmacist if you are not sure. The usual dose is one 20 mg tablet or two 10 mg tablets once a day for 14 days. Contact your doctor if you are not free from symptoms after this period. It might be necessary to take the tablets for 2-3 consecutive days to achieve improvement of symptoms. Taking this medicine • It is recommended that you take your tablets in the morning. • You can take your tablets with food or on an empty stomach. • Swallow your tablets whole with half a glass of water. Do not chew or crush the tablets. This is

because the tablets contain coated pellets which stop the medicine from being broken down by the acid in your stomach. It is important not to damage the pellets. These micro-pellets contain the active substance omeprazole and are enteric coated which protects them from being broken down during passage through the stomach. The pellets release the active ingredient in the intestine, where it is absorbed by your body to give an effect.

What to do if you have trouble swallowing the tablets • If you have trouble swallowing the tablets:

- Break the tablet and disperse it in a spoonful of water (non-fizzy), any acidic fruit juice (e.g. apple, orange or pineapple) or apple sauce.

- Always stir the mixture just before drinking (the mixture will not be clear). Then drink the mixture straight away or within 30 minutes.

- To make sure that you have drunk all of the medicine, rinse the glass very well with half a glass of water and drink it. Do not use milk or fizzy water. The solid pieces contain the medicine - do not chew or crush them.

If you take more Losec than you should If you take more Losec than recommended, talk to your doctor or pharmacist straight away. If you forget to take Losec If you forget to take a dose, take it as soon as you remember it. However, if it is almost time for your next dose, skip the missed dose. Do not take a double dose to make up for a forgotten dose. 4. POSSIBLE SIDE EFFECTS Like all medicines, Losec can cause side effects, although not everybody gets them. If you notice any of the following rare but serious side effects, stop taking Losec and contact a doctor immediately: • Sudden wheezing, swelling of your lips, tongue and throat or body, rash, fainting or difficulties in

swallowing (severe allergic reaction).

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• Reddening of the skin with blisters or peeling. There may also be severe blisters and bleeding in the lips, eyes, mouth, nose and genitals. This could be ‘Stevens-Johnson syndrome’ or ‘toxic epidermal necrolysis’.



wheezing. • Low levels of sodium in the blood. This may cause weakness, being sick (vomiting) and cramps. • Feeling agitated, confused or depressed. • Taste changes. • Eyesight problems such as blurred vision. • Suddenly feeling wheezy or short of breath (bronchospasm). • Dry mouth. • An inflammation of the inside of the mouth. • An infection called “thrush” which can affect the gut and is caused by a fungus. • Liver problems, including jaundice which can cause yellow skin, dark urine, and tiredness. • Hair loss (alopecia). • Skin rash on exposure to sunshine. • Joint pains (arthralgia) or muscle pains (myalgia). • Severe kidney problems (interstitial nephritis). • Increased sweating. Very rare side effects • Changes in blood count including agranulocytosis (lack of white blood cells). • Aggression. • Seeing, feeling or hearing things that are not there (hallucinations).

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• Severe liver problems leading to liver failure and inflammation of the brain. • Sudden onset of a severe rash or blistering or peeling skin. This may be associated with a high fever

and joint pains (Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis) • Muscle weakness. • Enlarged breasts in men. • Hypomagnesaemia Losec may in very rare cases affect the white blood cells leading to immune deficiency. If you have an infection with symptoms such as fever with a severely reduced general condition or fever with symptoms of a local infection such as pain in the neck, throat or mouth or difficulties in urinating, you must consult your doctor as soon as possible so that a lack of white blood cells (agranulocytosis) can be ruled out by a blood test. It is important for you to give information about your medicine at this time. Do not be concerned by this list of possible side effects. You may not get any of them. If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. 5. HOW TO STORE LOSEC • Keep out of the reach and sight of children.

• Do not use Losec after the expiry date which is stated on the outer and inner pack after EXP. The

expiry date refers to the last day of that month.


• Store this blister in the original package in order to protect from moisture.

• 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 Losec contains - The active substance is omeprazole. Losec gastro-resistant tablets contain omeprazole magnesium

corresponding to 10 mg or 20 mg omeprazole. - The other ingredients are microcrystalline cellulose, glyceryl monostearate,

hydroxypropylcellulose, hydroxypropyl methylcellulose, magnesium stearate, methacrylic acid co-polymer, sugar spheres, paraffin, macrogol (polyethylene glycol), polysorbate, polyvinylpyrrolidone crosslinked, sodium hydroxide (for pH-adjustment), sodium stearyl fumarate, talc, triethyl citrate, iron oxide, titanium dioxide.

What Losec looks like and contents of the pack • Losec 10 mg gastro-resistant tablets are light-pink with or on one side and 10 mg on the

other side. • Losec 20 mg gastro-resistant tablets are pink with or on one side and 20 mg on the other

side.

Pack sizes: • 10 mg:

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o Blisters of 7, 14, 28 tablets

• 20 mg: o Blisters of 7, 14 tablets


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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:

1. The MAH commits to conduct an epidemiological study on the risk of falls and fractures and to provide the results of this study by Q2 of 2011. The MAH commits to amend the product information as relevant based on the outcome of the study.

2. The MAH commits to respond to the following unresolved quality issues by discussing and

implementing as relevant in the context of an update of the CTD documentation in May 2010.

All formulations

The MAH commits to provide the supporting documents and data regarding the stability of the modification of the drug substance omeprazole magnesium and omeprazole.

The MAH commits to develop and introduce a second identification method for the drug substance omeprazole.

MUPS and capsules

The MAH commits to provide the supporting documents regarding bioequivalence to the biobatch.

The MAH commits to update the dossier according to the various regulations and the EU Directive 2001/83/EC.

The MAH commits to provide stability data for the intermediate/bulk product.

The MAH commits to update the specifications with the test uniformity of dosage units.

MUPS The MAH commits to investigate, justify and introduce the limits for impurities in accordance with the guideline ICH Topic Q3B: Impurities in new Drug Products

MUPS The MAH commits to provide the supporting documents regarding the limits of quantifications of the drug product

Capsules and solution for injection and solution for infusion

The MAH commits to investigate, justify and introduce limits for a number of degradation products.

Solution for injection and solution for infusion

The MAH commits to clarify the activities of the drug product manufacturer.

The MAH commits to provide the supporting documents regarding the shelf-life specification of the finished product.

The MAH commits to provide the supporting documents regarding TSE (Transmissible Spongiform Encephalopathies) safety.

The MAH commits to update the document ’P3-03 Description of Manufacturing Process and Process Controls for Drug Product’

annex i list of the names, pharmaceutical...

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