ANNEX I - European Commission · Carenox 10 mg Retardtabletten : 10 mg . Prolonged-release tablet :...

ANNEX I

List of the names, pharmaceutical forms, strengths of the medicinal products, routes of administration, marketing authorisation holders in the member states (EU/EEA)

1

Member State (EU/EEA)

Marketing Authorisation Holder Invented name Strength Pharmaceutical form Route of

administration

AT - Austria

betapharm Arzneimittel GmbH Kobelweg 95 86156 Augsburg Germany

Carenox 10 mg Retardtabletten 10 mg Prolonged-release tablet Oral use

AT - Austria


Carenox 5 mg Retardtabletten 5 mg Prolonged-release tablet Oral use

AT - Austria


Merlodon 20 mg Retardtabletten

20 mg Prolonged-release tablet Oral use

AT - Austria




AT - Austria




AT - Austria




AT - Austria




AT - Austria

Ethypharm 21, rue St. Mathieu (Z.I.) F- 78550 Houdan 194 Bureaux de la Colline - Bâtiment D, 92213 Saint-Cloud CEDEX France

M - dolor retard 10 mg - Kapseln 10 mg Prolonged-release capsule, hard Oral use

AT - Austria



2



administration

AT - Austria



AT - Austria



AT - Austria


M - dolor retard 60 mg - Kapseln

60 mg Prolonged-release capsule, hard Oral use

AT - Austria

G. L. Pharma GmbH Schloßplatz 1 8502 Lannach Austria

Vendal retard 10 mg - Filmtabletten


AT - Austria




AT - Austria




AT - Austria




AT - Austria




3



administration

AT - Austria

GlaxoSmithKline Pharma GmbH Albert-Schweitzer-Gasse 6 1140 Wien Austria

Kapanol CSR 100 mg - Kapseln 100 mg Prolonged-release capsule, hard Oral use

AT - Austria

GlaxoSmithKline Pharma GmbH Albert-Schweitzer-Gasse 6 1140 Wien Austria

Kapanol CSR 50 mg - Kapseln 50 mg Prolonged-release capsule, hard Oral use

AT - Austria

Hexal Pharma GmbH Stella-Klein-Löw-Weg 17 1020 Wien Austria

Oxycodon Hexal 10 mg - Retardtabletten


AT - Austria




AT - Austria




AT - Austria




AT - Austria




AT - Austria

Janssen - Cilag Pharma GmbH Vorgartenstraße 206b 1020 Wien Austria

Jurnista 16 mg - Retardtabletten


AT - Austria




AT - Austria


Jurnista 4 mg - Retardtabletten 4 mg Prolonged-release tablet Oral use

4



administration

AT - Austria




AT - Austria


Jurnista 8 mg - Retardtabletten 8 mg Prolonged-release tablet Oral use

AT - Austria


Compensan retard 100 mg - Filmtabletten


AT - Austria




AT - Austria




AT - Austria

Lannacher Heilmittel GmbH Schloßplatz 1 8502 Lannach Austria

Morphinhydrochlorid Lannacher retard 10 mg - Filmtabletten


AT - Austria




AT - Austria




AT - Austria




AT - Austria




5



administration

AT - Austria

Mundipharma GmbH Apollogasse 16-18 1070 Wien Austria

Hydal retard 16 mg - Kapseln 16 mg Prolonged-release capsule, hard Oral use

AT - Austria



AT - Austria



AT - Austria



AT - Austria



AT - Austria


Hydal Uno retard 12 mg - Kapseln


AT - Austria




AT - Austria




AT - Austria




AT - Austria


Mundidol retard 10 mg - Filmtabletten


6



administration

AT - Austria




AT - Austria




AT - Austria




AT - Austria




AT - Austria


Mundidol Uno retard 120 mg - Kapseln


AT - Austria




AT - Austria




AT - Austria




AT - Austria


OxyContin retard 10 mg Filmtabletten


AT - Austria




7



administration

AT - Austria




AT - Austria




AT - Austria




AT - Austria


Substitol retard 120 mg - Kapseln


AT - Austria


Substitol retard 200 mg - Kapseln


AT - Austria


Targin 10 mg/5 mg Retardtabletten

10 mg/5 mg Prolonged-release tablet Oral use

AT - Austria




AT - Austria




AT - Austria


Targin 5 mg/2,5 mg Retardtabletten

5 mg/2,5 mg Prolonged-release tablet Oral use

AT - Austria

Pharmachemie B.V. Swensweg 5, P.O. Box 552 2003 RN Haarlem Netherlands

Relimal 200 mg Retardtabletten 200 mg Prolonged-release tablet Oral use

8



administration

AT - Austria

Ratiopharm Arzneimittel Vertriebs-GmbH Albert-Schweitzer Gasse 3 1140 Wien Austria

Hydromorphon ratiopharm 16 mg Retardtabletten


AT - Austria




AT - Austria




AT - Austria




AT - Austria


Oxycodon-HCl-ratiopharm 5 mg Retardtabletten


AT - Austria




AT - Austria




AT - Austria




9



administration

AT - Austria




AT - Austria

Stada Arzneimittel GmbH Muthgasse 36 1190 Wien Austria

Oxycodon-HCl STADA 10 mg Retardtabletten


AT - Austria




AT - Austria




AT - Austria




AT - Austria




AT - Austria

Yes Pharmaceutical Development Services GmbH Bahnstraße 42-46 61381 Friedrichsdorf Germany

Maridolor 20 mg Retardtabletten


AT - Austria




AT - Austria




10



administration

AT - Austria


Oxycodon-HCl "YES" 10 mg Retardtabletten


AT - Austria


Oxycodon-HCl "YES" 5 mg Retardtabletten


BE - Belgium

DOCPHARMA N.V. Ambachtenlaan 13H 3001 Leuven Belgium

DOC MORFINE 10 MG 10mg Prolonged-release tablet Oral use

BE - Belgium


DOC MORFINE 100 MG 100 mg Prolonged-release tablet Oral use

BE - Belgium



BE - Belgium



BE - Belgium

Ethypharm 21, rue St. Mathieu (Z.I.) F- 78550 Houdan 194 Bureaux de la Colline - Bâtiment D, 92213 Saint-Cloud cedex France

ETHYPHARM MORPHINE SULPHATE 10 MG 10 mg Prolonged-release capsule, hard Oral use

BE - Belgium


ETHYPHARM MORPHINE SULPHATE 100 MG


11



administration

BE - Belgium



BE - Belgium



BE - Belgium


OPIDUR 120MG 120 mg Prolonged-release capsule, hard Oral use

BE - Belgium



BE - Belgium



BE - Belgium



12



administration

BE - Belgium



BE - Belgium

GLAXOSMITHKLINE S.A. Rue Du Tilleul 13 1332 Genval Belgium

KAPANOL 100 MG 100 mg Prolonged-release capsule, hard Oral use

BE - Belgium



BE - Belgium



BE - Belgium

I.P.S. (INTERN.PHARMAC.SERVICES)NV Garden Square, Gebouw C Laarstraat 16 2610 Wilrijk Belgium

MORPHISIN 10 10 mg Modified-release tablet Oral use

BE - Belgium



BE - Belgium



13



administration

BE - Belgium



BE - Belgium

MUNDIPHARMA CVA-SCA Schaliënhoevedreef 20H 2800 Mechelen Belgium

MS CONTIN 10 MG 10 mg Prolonged-release tablet Oral use

BE - Belgium


MS CONTIN 100MG 100 mg Prolonged-release tablet Oral use

BE - Belgium



BE - Belgium



BE - Belgium



BE - Belgium



BE - Belgium



BE - Belgium


MS DIRECT 10 MG EX SEVREDOL

10 mg Film-coated tablet Oral use

14



administration

BE - Belgium


MS DIRECT 20 MG EX SEVREDOL

20 mg Film-coated tablet Oral use

BE - Belgium


OXYCONTIN 10 MG 10 mg Prolonged-release tablet Oral use

BE - Belgium



BE - Belgium



BE - Belgium



BE - Belgium



BE - Belgium



BE - Belgium



BE - Belgium



BE - Belgium



15



administration

BE - Belgium



BE - Belgium


TARGINACT 10 MG/5 MG 10.5 mg Prolonged-release tablet Oral use

BE - Belgium


TARGINACT 20 MG/10 MG 21 mg Prolonged-release tablet Oral use

BE - Belgium


TARGINACT 40MG/20MG 42 mg Prolonged-release tablet Oral use

BE - Belgium


TARGINACT 5MG/2,5MG 5.25 mg Prolonged-release tablet Oral use

BE - Belgium


PALLADONE IMMEDIATE RELEASE 1,3 MG

1.3 mg Capsule, hard Oral use

BE - Belgium


PALLADONE IMMEDIATE RELEASE 2,6 MG

2.6 mg Capsule, hard Oral use

BE - Belgium


PALLADONE SLOW RELEASE 16 MG*


BE - Belgium


PALLADONE SLOW RELEASE 24 MG*


BE - Belgium


PALLADONE SLOW RELEASE 4 MG


16



administration

BE - Belgium


PALLADONE SLOW RELEASE 8 MG


BE - Belgium

SANDOZ N.V. Telecom Gardens Medialaan 40 1800 Vilvoorde Belgium

OXYCODON SANDOZ 10 MG 10 mg Prolonged-release tablet Oral use

BE - Belgium



BE - Belgium



BE - Belgium



BE - Belgium



BE - Belgium



BE - Belgium

TEVA PHARMA BELGIUM Laarstraat 16 2610 Wilrijk Belgium

MORPHINE TEVA 10 MG 10 mg Modified-release tablet Oral use

17



administration

BE - Belgium



BE - Belgium



BE - Belgium



BG - Bulgaria

Mundipharma Ges.m.b.H. Apollogasse 16-18, Postfach 83 1072 Vienna Austria

MST-Continus 10 mg Modified-release tablet Oral use

BG - Bulgaria



BG - Bulgaria



BG - Bulgaria



BG - Bulgaria


OxyContin 10 mg Modified-release tablet Oral use

BG - Bulgaria



BG - Bulgaria



18



administration

BG - Bulgaria



BG - Bulgaria


Substitol 120 mg Prolonged-release capsule Oral use

BG - Bulgaria


Substitol 200 mg Prolonged-release capsule Oral use

BG - Bulgaria

Nycomed Danmark A/S Langebjerg 1 DK-4000 Roskilde Denmark

Doltard 10 mg Prolonged-release tablet Oral use

BG - Bulgaria



BG - Bulgaria



BG - Bulgaria



BG - Bulgaria

Тева Фармасютикълс България ЕООД, ул. "Н.В.Гогол" 15, ет.1 1124 София България

Morphine Teva 10 mg Prolonged-release tablet Oral use

BG - Bulgaria



BG - Bulgaria



19



administration

BG - Bulgaria



CY - Cyprus

Mundipharma Pharmaceuticals Ltd 13 Othellos street, P.O.Box 23661 1685 Lefkosia Cyprus

MST CONTINUS PR TABLETS 100mg

100mg Prolonged-release tablet Oral use

CY - Cyprus




CY - Cyprus




CY - Cyprus




CY - Cyprus


OXYCONTIN PR TABLETS 10mg 10mg Prolonged-release tablet Oral use

CY - Cyprus



CY - Cyprus



CY - Cyprus



CY - Cyprus



20



administration

CZ - Czech Republic

MUNDIPHARMA Ges.m.b.H Apollogasse 16-18 A-1070 Viena Austria

MST Continus 100 mg 100 mg Modified-release tablet Oral use

CZ - Czech Republic



CZ - Czech Republic



CZ - Czech Republic


OxyContin 10mg 10 mg prolonged-release tablet Oral use

CZ - Czech Republic



CZ - Czech Republic



CZ - Czech Republic



CZ - Czech Republic

MUNDIPHARMA Ges.m.b.H Apollogasse 16-18, A-1070 Viena, Austria


DE - Germany

1 A Pharma GmbH Keltenring 1 + 3 D-82041 Oberhaching Germany

Oxycodonhydrochlorid - 1 A Pharma 10 mg Retardtabletten


DE - Germany




21



administration

DE - Germany




DE - Germany

AbZ-Pharma GmbH Dr. Georg-Spohn-Str. 7 D-89143 Blaubeuren Germany

Morphinsulfat AbZ 10 mg Retardtabletten


DE - Germany




DE - Germany




DE - Germany




DE - Germany

AbZ-Pharma GmbH Dr.Georg-Spohn-Str. 7 D-89143 Blaubeuren Germany

Oxycodon-HCl AbZ 10 mg Retardtabletten


DE - Germany




DE - Germany




DE - Germany




DE - Germany




22



administration

DE - Germany

ACINO AG Am Windfeld 35 D-83714 Miesbach Germany

Oxycodonhydrochlorid Acino 10 mg Retardtabletten


DE - Germany




DE - Germany




DE - Germany




DE - Germany




DE - Germany

Actavis Deutschland GmbH & Co. KG Elisabeth-Selbert-Str. 1 D-40764 Langenfeld Germany

MORPHIN-PUREN 10 mg retard 10 mg Prolonged-release tablet Oral use

DE - Germany


MORPHIN-PUREN 100 mg retard


DE - Germany



DE - Germany



DE - Germany

ALIUD PHARMA GmbH Gottlieb-Daimler-STr. 19 D-89150 Laichingen Germany

Hydromorphon-AL 16 mg Retardtabletten


23



administration

DE - Germany




DE - Germany




DE - Germany




DE - Germany

ALIUD PHARMA GmbH Gottlieb-Daimler-Str. 19 D-89150 Laichingen Germany

Morphin AL 10 retard 10 mg Prolonged-release tablet Oral use

DE - Germany



DE - Germany



DE - Germany



DE - Germany


Oxycodon-HCl AL 10 mg Retardtabletten


DE - Germany




DE - Germany




24



administration

DE - Germany




DE - Germany




DE - Germany

AWD.pharma GmbH & Co. KG Wasastr. 50 D-01445 Radebeul Germany

Morphin AWD 10 mg retard 10 mg Prolonged-release tablet Oral use

DE - Germany



DE - Germany



DE - Germany



DE - Germany

AWD.pharma GmbH & Co.KG Wasastr. 50 D-01445 Radebeul Germany

Hydromorphon-AWD 16 mg Retardtabletten


DE - Germany




DE - Germany




DE - Germany




25



administration

DE - Germany

betapharm Arzneimittel GmbH Kobelweg 95 D-86156 Augsburg Germany

M-beta 10 10 mg Prolonged-release tablet Oral use

DE - Germany



DE - Germany



DE - Germany



DE - Germany


Oxycodon-HCl beta 10 mg Retardtabletten


DE - Germany




DE - Germany




DE - Germany




DE - Germany




DE - Germany




26



administration

DE - Germany




DE - Germany

CT Arzneimittel GmbH Lengeder Str., 42 a D-13407 Berlin Germany

Morphinsulfat-CT 10 mg Retardtabletten


DE - Germany




DE - Germany




DE - Germany




DE - Germany

CT Arzneimittel GmbH Lengeder Str. 42 a D-13407 Berlin Germany

Oxycodon-HCl-CT 10 mg Retardtabletten


DE - Germany




DE - Germany




DE - Germany




DE - Germany




27



administration

DE - Germany

GlaxoSmithKline GmbH & Co. KG Theresienhöhe 11 D-80339 München Germany

Kapanol 100mg 100 mg Prolonged-release capsule, hard Oral use

DE - Germany



DE - Germany



DE - Germany

Grünenthal GmbH Zieglerstr. 6 D-52078 Aachen Germany

M-long 100mg 100 mg Prolonged-release capsule, hard Oral use

DE - Germany



DE - Germany



DE - Germany



DE - Germany


Morphin Grünenthal 10 mg 10 mg Prolonged-release tablet Oral use

DE - Germany



DE - Germany



28



administration

DE - Germany



DE - Germany

GRY-Pharma GmbH Wasastr. 50 D-01445 Radebeul Germany

Morphinsulfat-GRY 10 mg Retardtabletten


DE - Germany




DE - Germany




DE - Germany




DE - Germany




DE - Germany

Heumann Pharma GmbH & Co. Generica KG Südwestpark 50 D-90449 Nürnberg Germany

Morphin 10 retard Heumann 10 mg Prolonged-release tablet Oral use

DE - Germany



DE - Germany



29



administration

DE - Germany



DE - Germany

HEXAL AG Industriestr. 25 D-83607 Holzkirchen Germany

Hydromorphon-HEXAL retard 16 mg Retardtabletten


DE - Germany




DE - Germany




DE - Germany




DE - Germany


Kancodal HEXAL 10 mg Retardtabletten


DE - Germany


Kancodal HEXAL 20 mg Retardtabletten


DE - Germany


Morphin HEXAL 100mg Retardkapseln


DE - Germany


Morphin HEXAL 100mg Retardtabletten


DE - Germany




30



administration

DE - Germany




DE - Germany




DE - Germany




DE - Germany




DE - Germany




DE - Germany


Oxyco HEXAL 10 mg Retardtabletten


DE - Germany


Oxyco HEXAL 20 mg Retardtabletten


DE - Germany


Oxycodon-HCl HEXAL 10 mg Retardtabletten


DE - Germany




DE - Germany




31



administration

DE - Germany




DE - Germany




DE - Germany




DE - Germany


Oxycodonhydrochloridl HEXAL 5 mg Retardtabletten


DE - Germany

Janssen-Cilag GmbH Johnson & Johnson Platz 1 D-41470 Neuss Germany

JURNISTA 16 mg Retardtabletten


DE - Germany




DE - Germany


JURNISTA 4 mg Retardtabletten 4 mg Prolonged-release tablet Oral use

DE - Germany




DE - Germany


JURNISTA 8 mg Retardtabletten 8 mg Prolonged-release tablet Oral use

DE - Germany

Juta Pharma GmbH Gutenbergstr. 13 D-24941 Flensburg Germany

Morphanton 100mg Retardtabletten


32



administration

DE - Germany




DE - Germany




DE - Germany




DE - Germany

Krewel Meuselbach GmbH Krewelstr. 2 D-53783 Eitorf Germany

Morphin-HCl Krewel 10 mg Retardtabletten


DE - Germany




DE - Germany




DE - Germany




DE - Germany




DE - Germany

medac Gesellschaft für klinische Spezialpräparate mbH Fehlandtstr. 3 D-20354 Hamburg Germany

Capros 1 x täglich 120 mg Hartkapseln, retardiert


33



administration

DE - Germany




DE - Germany




DE - Germany




DE - Germany


Capros 100mg 100 mg Prolonged-release capsule, hard Oral use

DE - Germany



DE - Germany



DE - Germany



DE - Germany

Mundipharma GmbH Mundipharma Str. 2 D-65549 Limburg Germany

MST 10 mg Mundipharma 10 mg Prolonged-release tablet Oral use

34



administration

DE - Germany



DE - Germany



DE - Germany



DE - Germany



DE - Germany


MST Continus 100mg 100 mg Prolonged-release capsule, hard Oral use

DE - Germany



DE - Germany



DE - Germany



DE - Germany


MSTW 10 mg Krugmann 10 mg Prolonged-release tablet Oral use

DE - Germany



35



administration

DE - Germany



DE - Germany



DE - Germany



DE - Germany


OXYGESIC 10 mg 10 mg Prolonged-release tablet Oral use

DE - Germany



DE - Germany



DE - Germany



DE - Germany



DE - Germany


OxyContin 10 mg 10 mg Prolonged-release tablet Oral use

DE - Germany



36



administration

DE - Germany



DE - Germany



DE - Germany



DE - Germany


Oxynal 10/5mg Retardtabletten 10 mg 5 mg

Prolonged-release tablet Oral use

DE - Germany


Oxynal 20/10mg Retardtabletten

20 mg 10 mg


DE - Germany


Palladon retard 16 mg 16 mg Prolonged-release capsule, hard Oral use

DE - Germany



DE - Germany



DE - Germany



DE - Germany



10 mg 5,45


37



administration

DE - Germany



10 mg 5,45


DE - Germany



20 mg 10 mg


DE - Germany



40 mg 21,8 mg


DE - Germany


Targin 5 mg/2,5 mg Retardtabletten

5 mg 2,73


DE - Germany

PS Pharma Service GmbH Lise-Meitner-Str. 10 D-40670 Meerbusch Germany

Morphin EINS PS Pharma 10 mg retard


DE - Germany




DE - Germany




DE - Germany




DE - Germany




DE - Germany


Morphin PS Pharma 200 mg retard


38



administration

DE - Germany


Morphin VIER PS Pharma 10 mg retard


DE - Germany




DE - Germany




DE - Germany




DE - Germany


Morphin ZWEI PS Pharma 10 mg retard


DE - Germany




DE - Germany




DE - Germany




DE - Germany




DE - Germany

ratiopharm GmbH Graf-Arco-Str. 3 D-89079 Ulm Germany

Hydromorphon-ratiopharm 16 mg Retardtabletten


39



administration

DE - Germany




DE - Germany




DE - Germany




DE - Germany


Morphin-ratiopharm 10 mg Retardtabletten


DE - Germany




DE - Germany




DE - Germany




DE - Germany




DE - Germany




DE - Germany




40



administration

DE - Germany




DE - Germany




DE - Germany


Oxycodonhydrochlorid-ratiopharm 10 mg Retardtabletten


DE - Germany




DE - Germany




DE - Germany




DE - Germany




DE - Germany




DE - Germany

Sandoz Pharmaceuticals GmbH Raiffeisenstr. 11 D-83607 Holzkirchen Germany

Morph Sandoz 100mg Retardtabletten


DE - Germany




41



administration

DE - Germany




DE - Germany




DE - Germany


Oxycodon-HCl Sandoz 10 mg Retardtabletten


DE - Germany




DE - Germany




DE - Germany




DE - Germany




DE - Germany




DE - Germany


Oxycodon-HCl Sandoz 10 mg 10 mg Prolonged-release tablet Oral use

DE - Germany

Stadapharm GmbH Stadastr. 2-18 D-61118 Bad Vilbel Germany

Hydromorphon-Stada 16 mg Retardtabletten


42



administration

DE - Germany




DE - Germany




DE - Germany




DE - Germany

Stadapharm GmbH Stadastr. 2 - 18 D-61118 Bad Vilbel Germany

M-Stada 10 mg Retardtabletten 10 mg Prolonged-release tablet Oral use

DE - Germany


M-Stada 100 mg Retardtabletten


DE - Germany


M-Stada 200 mg Retardtabletten


DE - Germany



DE - Germany



DE - Germany




DE - Germany




43



administration

DE - Germany




DE - Germany




DE - Germany




DK - Denmark

Acino AG Am Windfeld 35 DE-83714 Miesbach Germany

Oxycodonhydrochlorid "Acino" 5 mg Prolonged release tablet Oral use

DK - Denmark



DK - Denmark



DK - Denmark



DK - Denmark



DK - Denmark

Ethypharm 17-21, rue St. Mathieu (Z.I.) F- 78550 Houdan 194 Bureaux de la Colline - Bâtiment D 92213 Saint-Cloud cedex France

Ethirfin 20 mg Prolonged-release capsule Oral use

44



administration

DK - Denmark



DK - Denmark



DK - Denmark



DK - Denmark



DK - Denmark


Morphinsulfat "Ethypharm" 20 mg Prolonged-release capsule, hard Oral use

DK - Denmark



45



administration

DK - Denmark



DK - Denmark



DK - Denmark



DK - Denmark


Zomorph 20 mg Prolonged-release capsule, hard Oral use

DK - Denmark



DK - Denmark



46



administration

DK - Denmark



DK - Denmark



DK - Denmark

HEXAL A/S Kanalholmen 8-12 DK 2650 Hvidovre Denmark

Oxycodonhydrochlorid "Hexal" 5 mg Prolonged-release tablet Oral use

DK - Denmark



DK - Denmark



DK - Denmark



DK - Denmark



DK - Denmark

Janssen-Cilag A/S (TIBOTEC) Hammerbakken 19 DK-3460 Birkerød Denmark

Jurnista 4 mg Prolonged release tablet Oral use

DK - Denmark



47



administration

DK - Denmark



DK - Denmark



DK - Denmark



DK - Denmark


Fidestor 4 mg Prolonged release tablet Oral use

DK - Denmark



DK - Denmark



DK - Denmark



DK - Denmark



DK - Denmark


Spanzar 4 mg Prolonged release tablet Oral use

DK - Denmark



48



administration

DK - Denmark



DK - Denmark



DK - Denmark



DK - Denmark

Lannacher Heilmittel Ges.m.b.H. Schlossplatz 1 A-8502 Lannach Austria

Depolan 10 mg Prolonged release tablet Oral use

DK - Denmark



DK - Denmark



DK - Denmark



DK - Denmark



DK - Denmark

Norpharma A/S Slotsmarken 15 DK-2970 Hørsholm Denmark

OxyContin 80 mg Prolonged-release tablet Oral use

DK - Denmark



49



administration

DK – Denmark



DK - Denmark



DK - Denmark



DK - Denmark



DK - Denmark



DK - Denmark



DK - Denmark



DK - Denmark



DK - Denmark


Palladon 4 mg Prolonges release capsule, hard Oral use

DK - Denmark



50



administration

DK - Denmark



DK - Denmark



DK - Denmark


Targin 5 + 2,5 mg Prolonged-release tablet Oral use

DK - Denmark


Targin 10 + 5 mg Prolonged-release tablet Oral use

DK - Denmark



DK - Denmark



DK - Denmark

Nycomed Danmark ApS Langebjerg 1 DK-4000 Roskilde Denmark


DK - Denmark



DK - Denmark



DK - Denmark



51



administration

DK - Denmark

Pfizer ApS Lautrupvang 8 DK-2750 Ballerup Denmark

Contalgin 5 mg Prolonged-release tablet Oral use

DK - Denmark



DK - Denmark



DK - Denmark



DK - Denmark



DK - Denmark



DK - Denmark


Contalgin 20 mg Prolonged-release granules, for oral suspension

Oral use

DK - Denmark



Oral use

DK - Denmark



Oral use

DK - Denmark



Oral use

52



administration

DK - Denmark



Oral use

DK - Denmark


Contalgin Uno 30 mg Prolonged-release capsule Oral use

DK - Denmark



DK - Denmark



DK - Denmark



DK - Denmark



DK - Denmark



DK - Denmark

Ratiopharm GmbH Graf-Arco-Strasse 3 DE-89079 Ulm Germany

Oxycodonhydrochlorid "ratiopharm"


DK - Denmark




DK - Denmark




53



administration

DK - Denmark




DK - Denmark




DK - Denmark

Sandoz A/S Edvard Thomsens Vej 14 DK-2300 København S Denmark

Oxicos 5 mg Prolonged-release tablet Oral use

DK - Denmark



DK - Denmark



DK - Denmark


Oxycodonhydrochlorid "1A Farma"


DK - Denmark




DK - Denmark




DK - Denmark

Teva Denmark A/S Parallelvej 10 DK-2800 Kongens Lyngby Denmark

Malfin 10 mg Prolonged-release tablet Oral use

DK - Denmark



54



administration

DK - Denmark



DK - Denmark



DK - Denmark



EL-Greece

LAVIPHARM HELLAS AE Agias Marinas Str. Paiania Attikis 19002 Greece

MORFICONTIN 10 mg Prolonged release tablet Oral use

EL-Greece



EL-Greece



EL-Greece



EL-Greece



EL-Greece



EL-Greece



55



administration

EL-Greece


MORFICONTIN 5 mg Modified release tablet Oral use

EL-Greece


MORFICONTIN 15 mg Modified release tablet Oral use

EL-Greece

MUNDIPHARMA GMBH GERMANY Mundipharma Strasse 2 POSTFACH 1350 D-620 Limbirg D-6270 Germany

OXYCONTIN 10 mg Prolonged-release tablet Oral use

EL-Greece



EL-Greece



EL-Greece



EL-Greece

P.N.G. GEROLYMATOS ΑΕΒΕ 13 Asklipiou Str. 145 68, Kryoneri Athens Greece

MONGOL 10 mg Modified-release capsule Oral use

EL-Greece



EL-Greece



56



administration

EL-Greece



EL-Greece


MONGOL 200 mg Prolonged-release capsule Oral use

ES - Spain

ARCHIMEDES PHARMA IBERICA S.L. C/ Jorge Juan 139 Madrid Spain

ZOMORPH10 MG Cápsulas 10mg Prolonged-release capsule Oral use

ES - Spain


ZOMORPH100 mg Cápsulas 100mg Prolonged-release capsule Oral use

ES - Spain



ES - Spain



ES - Spain

JANSSEN-CILAG S.A.Pº de Las Doce Estrellas, 5 – 7 28042 MADRID Spain

JURNISTA 64mg Prolonged-release tablet Oral use

ES - Spain



ES - Spain



ES - Spain



57



administration

ES - Spain



ES - Spain

LANNACHER HEILMITTEL GES.M.G.H.Schlobplatz, 1 Lannach A-9502 Austria

MORFINA LANNACHER 10 MG 10 mg coated tablet Oral use

ES - Spain


MORFINA LANNACHER 100 MG 100mg coated tablet Oral use

ES - Spain


MORFINA LANNACHER 200 MG Comprimidos

200 mg coated tablet Oral use

ES - Spain



ES - Spain



ES - Spain

MUNDIPHARMA PHARMACEUTICALS S.L.Edificio Alvento (Torre D) Vía de los Poblados, 1 28033 Madrid Spain

MST 10 CONTINUS 10mg Prolonged-release tablet Oral use

ES - Spain



ES - Spain


MST 15 CONTINUS 15 mg Prolonged-release tablet Oral use

58



administration

ES - Spain



ES - Spain



ES - Spain



ES - Spain



ES - Spain

MUNDIPHARMA PHARMACEUTICALS S.L.Edificio Alvento (Torre D) Vía de los Poblados, 1 28033 MADRID Spain

OXYCONTIN 10 mg comprimidos de liberación modificada


ES - Spain




ES - Spain




ES - Spain


OXYCONTIN 5 mg comprimidos de liberación prolongada


59



administration

ES - Spain


OXYCONTIN 80 mg comprimidos de liberacion modificada


ES - Spain


PALLADONE CONTINUS 4mg Prolonged-release capsule Oral use

ES - Spain



ES - Spain



ES - Spain



ET - Estonia

Johnson & Johnson UAB Gelezinio Vilko g. 18A LT-08104 Vilnius Lithuania


ET - Estonia



ET - Estonia



ET - Estonia



60



administration

ET - Estonia



ET - Estonia

LANNACHER HEILMITTEL GmbH Schlossplatz 1 A-8502 Lannach Austria

VENDAL RETARD 10 MG 10mg Prolonged-release tablet Oral use

ET - Estonia



ET - Estonia



ET - Estonia



ET - Estonia



ET - Estonia

MUNDIPHARMA Ges.m.b.H. Apollogasse 16-18 A-1072 Wien Austria

MST CONTINUS 30 MG 30mg Prolonged-release granules for oral suspension

Oral use

ET - Estonia


MXL 120 MG 120mg Prolonged-release capsule, hard Oral use

ET - Estonia


MXL 30 MG 30mg Prolonged-release capsule, hard Oral use

ET - Estonia


OXYCONTIN 10 MG 10mg Prolonged-release tablet Oral use

61



administration

ET - Estonia



ET - Estonia



ET - Estonia



ET - Estonia

Nycomed Sefa AS Jaama 55B 63308 Põlva Estonia

DOLTARD 30mg Prolonged-release tablet Oral use

ET - Estonia

Nycomed Sefa AS Jaama 55B 63308 Põlva Estonia

DOLTARD 60mg Prolonged-release tablet Oral use

FI - Finland

Hexal A/S Kanalholmen 8-12 2650 HVIDOVRE Denmark

Oxycodone Hexal 20 mg Prolonged-release tablet Oral use

FI - Finland



FI - Finland



FI - Finland

Lannacher Heilmittel Ges.m.b.H. Schlossplatz 1 8502 Lannach Austria

Depolan 10 mg Prolonged-release tablet Oral use

FI - Finland



62


100 mg

Marketing Authorisation Holder

Prolonged-release tablet

Invented name

Oral use

Strength Pharmaceutical form

FI - Finland

Route of administration

Lannacher Heilmittel Ges.m.b.H.

FI - Finland



FI - Finland


Depolan

Schlossplatz 1 8502 Lannach Austria


FI - Finland

Mundipharma Oy Rajatorpantie 41 B 01640 Vantaa Finland

Docontin Unotard 30 mg Prolonged-release capsule Oral use

FI - Finland



FI - Finland



FI - Finland



FI - Finland



FI - Finland



FI - Finland


Dolcontin 20 mg Modified-release granules for oral suspension

Oral use

63



administration

FI - Finland



Oral use

FI - Finland



Oral use

FI - Finland



Oral use

FI - Finland



Oral use

FI - Finland


Dolcontin 10 mg Prolonged-release tablet Oral use

FI - Finland



FI - Finland



FI - Finland



FI - Finland



FI - Finland


Oxycontin 5 mg Prolonged-release tablet Oral use

64



administration

FI - Finland



FI - Finland



FI - Finland



FI - Finland



FI - Finland



FI - Finland



FI - Finland



FI - Finland



FI - Finland



FI - Finland


Palladon 4 mg Prolonged-release capsule, hard Oral use

65



administration

FI - Finland



FI - Finland



FI - Finland



FI - Finland


Targiniq 10 mg/ 5 mg Prolonged-release tablet Oral use

FI - Finland



FI - Finland



FI - Finland


Targiniq 5 mg/ 2,5 mg Prolonged-release tablet Oral use

FI - Finland

ratiopharm GmbH Graf-Arco-Strasse 3 89079 ULM Germany

Oxycodone ratiopharm 5 mg Prolonged-release tablet Oral use

FI - Finland



FI - Finland



66



administration

FI - Finland



FI - Finland



FI - Finland

Sandoz A/S C. F. Tietgens Boulevard 40 5220 ODENSE SØ Denmark

Oxycodone Hydrocloride Sandoz


FR - France

ARCHIMEDES PHARMA FRANCE SARL 12 rue du Sergent Bobillot 92400 Courbevoie France

ZOMORPH L.P. 120 mg, gélule à libération prolongée


FR - France




FR - France




FR - France




FR - France




FR - France

BRISTOL - MYERS SQUIBB 3, rue Joseph Monier 92500 Rueil-Malmaison France

SKENAN L.P. 10 mg, microgranules à libération prolongée en gélule

10 mg Prolonged-release micropillules in hard capsule

Oral use

FR - France




Oral use

67



administration

FR - France




Oral use

FR - France




Oral use

FR - France




Oral use

FR - France

ETHYPHARM 194, Bureaux de la Colline -Bâtiment D 92213 Saint-Cloud Cedex France

SULFATE DE MORPHINE ETHYPHARM L.P. 10 mg, gélule à libération prolongée


FR - France




FR - France




FR - France




FR - France


SULFATE DE MORPHINE ETHYPHARM LP 200 mg, gélule à libération prolongée


FR - France

Laboratoire GLAXOSMITHKLINE 100, route de Versailles 78163 Marly-le-Roi Cedex France

KAPANOL L.P. 100 mg, gélule à libération prolongée


FR - France




68



administration

FR - France




FR - France

Laboratoires STADA ARZNEIMITTEL AG Stada Strasse 2-18 Postfach 1260 61118 Bad Vilbel - Dortelweil Germany

MORPHINE STADA L.P. 10 mg, comprimé pelliculé à libération prolongée

10 mg Prolonged-release film-coated tablet

Oral use

FR - France




Oral use

FR - France




Oral use

FR - France




Oral use

FR - France




Oral use

FR - France

MUNDIPHARMA 2, rue du Docteur Lombard 92130 Issy-les-Moulineaux France

MOSCONTIN 10 mg, comprimé enrobé à libération prolongée

10 mg Prolonged-release coated tablet Oral use

FR - France




FR - France


MOSCONTIN 15 mg, comprimé pelliculé à libération prolongée


Oral use

69



administration

FR - France




FR - France


MOSCONTIN 5 mg, comprimé pelliculé à liberation prolongée


Oral use

FR - France




FR - France


MOSCONTIN L.P. 200 mg, comprimé pelliculé à libération prolongée


Oral use

FR - France


OXYCONTIN L.P. 5 mg, comprimé pelliculé à libération prolongée


Oral use

FR - France


OXYCONTIN LP 10 mg, comprimé pelliculé à libération prolongée


Oral use

FR - France




Oral use

FR - France




Oral use

FR - France




Oral use

FR - France




Oral use

70



administration

FR - France




Oral use

FR - France




Oral use

FR - France




Oral use

FR - France




Oral use

FR - France


SOPHIDONE L.P. 16 mg, gélule à libération prolongée


FR - France




FR - France




FR - France




FR - France


TARGINACT 10 mg/5 mg, comprimé à libération prolongée

10 mg/5 mg prolonged-release tablet Oral use

FR - France




71



administration

FR - France




FR - France


TARGINACT 5 mg/2,5 mg, comprimé à libération prolongée

5 mg/2,5 mg prolonged-release tablet Oral use

FR - France

NAPP Laboratories Limited Cambridge Science Park Milton Road CB4 4GW Cambridge United Kingdom

PALLADONE L.P. 16 mg, gélule à libération prolongée


FR - France




FR - France




FR - France




HU - Hungary

EGIS Gyógyszergyár nyrt. Keresztúri út 30-38. 1106, Budapest Hungary

M-ESLON 30mg Prolonged-release capsule, hard Oral use

HU - Hungary

EGIS Gyógyszergyár nyrt. Keresztúri út 30-38., 1106, Budapest Hungary


HU - Hungary



72



administration

HU - Hungary



HU - Hungary Janssen-Cilag Kft. H-2045 Törökbálint, Tó Park Hungary

Jurnista 4mg Prolonged-release tablet Oral use









HU - Hungary

Mundipharma Ges.m.b.H. Apollogasse 16-18., A-1072 Vienna Austria

MST Continus 10mg Prolonged-release film coated tablet

Oral use

HU - Hungary


MST Continus 30mg Prolonged-release tablet Oral use

HU - Hungary



HU - Hungary



HU - Hungary


Oxycontin 10mg Prolonged-release film coated tablet

Oral use

73



administration

HU - Hungary



Oral use

HU - Hungary



Oral use

HU - Hungary



Oral use

HU - Hungary


Palladone-SR 4mg Prolonged-release capsule Oral use

HU - Hungary



HU - Hungary



HU - Hungary



HU - Hungary


Palladone-XL 12mg Prolonged-release capsule Oral use

HU - Hungary



HU - Hungary



74



administration

HU - Hungary



IE - Ireland

Ethypharm 21, rue St. Mathieu (Z.I.) F- 78550 Houdan 194 Bureaux de la Colline - Bâtiment D 92213 Saint-Cloud cedex France

ETHIRFIN 120 mg prolonged-release capsules, hard 120 mg Prolonged-release capsule Oral use

IE - Ireland



IE - Ireland



IE - Ireland


ETHIRFIN 40 mg prolonged-release capsules, hard

40 mg Prolonged-release capsule Oral use

IE - Ireland



IE - Ireland

Napp Pharmaceuticals Ltd. Cambridge Science Park, Milton Road Cambridge CB4 0GW United Kingdom

MST CONTINUS 10 MG PROLONGED-RELEASE TABLETS


75



administration

IE - Ireland




IE - Ireland




IE - Ireland




IE - Ireland




IE - Ireland




IE - Ireland




IE - Ireland


MST CONTINUS suspension 100 mg

100 mg Prolonged-release granules Oral use

IE - Ireland




IE - Ireland




IE - Ireland




76



administration

IE - Ireland




IE - Ireland


Oxycontin 10 mg Prolonged-release tablets


IE - Ireland




IE - Ireland




IE - Ireland




IE - Ireland




IE - Ireland


Palladone SR Capsules 16 mg 16 mg Prolonged-release capsule Oral use

IE - Ireland



IE - Ireland



IE - Ireland



77



administration

IE - Ireland


Palladone SR Capsules 8mg 8 mg Prolonged-release capsule Oral use

IE - Ireland


Targin 10mg/5 mg Prolonged-release tablets

10mg/5mg Prolonged-release tablet Oral use

IE - Ireland




IE - Ireland




IE - Ireland


Targin 5mg/2.5 mg Prolonged-release tablets

5mg/2.5 mg Prolonged-release tablet Oral use

IE - Ireland Rowex Ltd. Bantry, Co.Cork Ireland

DANCEX SR 10 mg Prolonged-release tablets









Oxydon 10 mg Prolonged-release tablets











78



administration




IE - Ireland

Napp Pharmaceuticals Limited Cambridge Science Park, Milton Road Cambridge, CB4 0GW United Kingdom

OxyContin 60 mg prolonged release tablets

60mg Prolonged release tablet Oral use

IE - Ireland




IE - Ireland




IE - Ireland




IE - Ireland




IS - Iceland

Ethypharm 194 Bureaux de la Colline Batiment D 92213 Saint-Cloud Cedex France

Oxycodone Ethypharm 10 mg Prolonged-release capsule, hard Oral use

IS - Iceland



IS - Iceland



79



administration

IS - Iceland



IS - Iceland

Norpharma Slotsmarken 15 2970 Hørsholm Denmark


IS - Iceland



IS - Iceland



IS - Iceland



IS - Iceland



IS - Iceland



IS - Iceland



IS - Iceland



IS - Iceland



80



administration

IS - Iceland


Targin 5/2.5 mg Prolonged-release tablet Oral use

IS - Iceland


Targin 10/5 mg Prolonged-release tablet Oral use

IS - Iceland



IS - Iceland



IS - Iceland

Pfizer Aps Lautrupsvang 8 2750 Ballerud Denmark


IS - Iceland



IS - Iceland



IS - Iceland



IS - Iceland



IS - Iceland



81



administration

IS - Iceland


Contalgin Uno 30 mg Prolonged-release capsule, hard Oral use

IS - Iceland



IS - Iceland



IS - Iceland



IS - Iceland



IS - Iceland



IT - Italy

Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.p.A. Viale Amelia 70 00181 Roma Italy

ETHIRFIN 20 mg Prolonged-release capsule, hard Oral use

IT - Italy



IT - Italy



IT - Italy



82



administration

IT - Italy



IT - Italy


TWICE 10 mg Prolonged-release capsule, hard Oral use

IT - Italy



IT - Italy



IT - Italy



IT - Italy

BRUNO FARMACEUTICI S.P.A. Via delle Ande, 15 00100 Roma Italy

UNIMORF 20 mg Prolonged-release capsule, hard Oral use

IT - Italy



IT - Italy



IT - Italy



IT - Italy



83



administration

IT - Italy


SKENAN 10 mg Prolonged-release capsule Oral use

IT - Italy



IT - Italy



IT - Italy



IT - Italy

JANSSEN-CILAG SpA Via M. Buonarroti, 23 20093 Cologno Monzese (MI) Italy

JURNISTA 4 mg Prolonged-release tablet Oral use

IT - Italy



IT - Italy



IT - Italy



84



administration

IT - Italy



IT - Italy

Mundipharma Pharmaceuticals Srl Via G. Serbelloni, 4 20122 Milano Italy

MS CONTIN 10 mg Prolonged-release tablet Oral use

IT - Italy



IT - Italy



IT - Italy



IT - Italy



IT - Italy


MS CONTIN 20 mg Controlled release granules for oral suspension

Oral use

IT - Italy



Oral use

IT - Italy



Oral use

IT - Italy



Oral use

85



administration

IT - Italy



Oral use

IT - Italy



IT - Italy



IT - Italy



IT - Italy



IT - Italy



LT - Lithuania

Lannacher Heilmittel Ges. m . b. H Schlossplatz 1 8502 Lannach Austria

Vendal retard 10 mg Prolonged-release tablet Oral use

LT - Lithuania



LT - Lithuania



LT - Lithuania



86



administration

LT - Lithuania



LT - Lithuania



LT - Lithuania



LU - Luxembourg

Ethypharm 21, rue St. Mathieu (Z.I.) F- 78550 Houdan France

Morphine Sulfate LP Ethypharm 200mg Prolonged-release capsule, hard Oral use

LU - Luxembourg


Zomorph L.P. 40mg Prolonged-release capsule, soft Oral use

LU - Luxembourg



LU - Luxembourg



LU - Luxembourg



LU - Luxembourg

Mundipharma C.V.A. Schalienhoevedreef 20H B- 2800 Mechelen Belgium

Palladone Slow Release 4mg Capsule Oral use

LU - Luxembourg



87



administration

LU - Luxembourg



LU - Luxembourg



LU - Luxembourg


Targinact-10/15 10/5mg prolonged-release tablet Oral use

LU - Luxembourg


Targinact-20/10 20/10mg prolonged-release tablet Oral use

LV - Latvia

Lannacher Heilmittel Ges.mbH Schloβplatz 1 A-8502, Lannach Austria

Vendal retard 10 mg prolonged-release tablets


LV - Latvia




LV - Latvia




LV - Latvia




LV - Latvia

MUNDIPHARMA Ges.m.b.H. Apollogasse 16-18 A-1072 Viena Austria



LV - Latvia




88



administration

LV - Latvia




LV - Latvia




LV - Latvia

Nycomed Danmark ApS Langebjerg 1 DK – 4000 Roskilde Denmark

Doltard 30 mg prolonged-release tablets


LV - Latvia

Nycomed Danmark ApS Langebjerg 1 DK – 4000 Roskilde Denmark

Doltard 60 mg prolonged-release tablets

60 mg prolonged-release tablet Oral use

MT - Malta

Napp Pharmaceuticals Ltd Cambridge Science Park Milton Road Cambridge CB4 0GW United Kingdom

MST CONTINUS 10 mg tablets 10mg Prolonged-release tablet Oral use

MT - Malta


MST CONTINUS 30 mg tablets 30mg Prolonged-release tablet Oral use

MT - Malta


MST CONTINUS 60mg tablets 60mg Prolonged-release tablet Oral use

NL - Netherlands

Apothecon B.V. Nijverheidsweg 3 NL-3771 ME Barneveld The Netherlands

Morfine HCl retard 10 A, tabletten met verlengde afgifte 10 mg


NL - Netherlands




89



administration

NL - Netherlands




NL - Netherlands




NL - Netherlands




NL - Netherlands

Centrafarm Services BV Nieuwe Donk 9 NL-4879 AC Etten-Leur The Netherlands

Morfine HCl retard CF 10 mg, tabletten met gereguleerde afgifte

10 mg Modified-release tablet Oral use

NL - Netherlands




NL - Netherlands




NL - Netherlands




NL - Netherlands




NL - Netherlands

GlaxoSmithKline B.V. Huis ter Heideweg 62 NL-3705 LZ Zeist The Netherlands

Kapanol 100, capsules met gereguleerde afgifte 20 mg


NL - Netherlands

GlaxoSmithKline B.V. Huis ter Heideweg 62 NL-3705 LZ Zeist The Netherlands



90


Marketing Authorisation Holder

NL - Netherlands

Invented name

GlaxoSmithKline B.V.

Strength

Huis ter Heideweg 62

Pharmaceutical form

NL-3705 LZ Zeist

Route of administration

The Netherlands



NL - Netherlands

Laboratoires UPSA (Rueil Malmaison), 128, Rue Danton FR-92500 Rueil Malmaison France

Skenan SR 10 mg, capsules met gereguleerde afgifte

10 mg Modified-release capsule Oral use

NL - Netherlands




NL - Netherlands




NL - Netherlands




NL - Netherlands




NL - Netherlands

Mundipharma Pharmaceuticals B.V. De Weil 20 NL-3871 MV Hoevelaken The Netherlands

MS Contin 10 mg, tabletten met gereguleerde afgifte


NL - Netherlands




NL - Netherlands




NL - Netherlands




91



administration

NL - Netherlands




NL - Netherlands




NL - Netherlands




NL - Netherlands


OxyContin 10 mg, tabletten met gereguleerde afgifte

10 mg Modified release tablet Oral use

NL - Netherlands




NL - Netherlands




NL - Netherlands




NL - Netherlands




NL - Netherlands


Palladon-SR capsule 16 mg, capsules met verlengde afgifte

16 mg Prolonged release capsule Oral use

NL - Netherlands




92



administration

NL - Netherlands




NL - Netherlands




NL - Netherlands




NL - Netherlands


Targinact 10 mg/ 5 mg, tabletten met verlengde afgifte

10 and 5 mg Prolonged release tablet Oral use

NL - Netherlands




NL - Netherlands




NL - Netherlands


Targinact 5 mg/ 2,5 mg, tabletten met verlengde afgifte

5 and 2.5 mg Prolonged release tablet Oral use

NL - Netherlands

Pharmachemie BV Swensweg 5 NL-2031 GA Haarlem The Netherlands

Morfinesulfaat retard 10 PCH, tabletten met gereguleerde afgifte 10 mg


NL - Netherlands




NL - Netherlands




93



administration

NL - Netherlands




NL - Netherlands

Ratiopharm Nederland B.V. Ronde Tocht 11 NL-1507 CC Zaandam Florapark 4 2012 HK Haarlem The Netherlands

Oxycodon HCl ratiopharm 10 mg, tabletten met verlengde afgifte

10 mg Prolonged release tablet Oral use

NL - Netherlands




NL - Netherlands




NL - Netherlands




NL - Netherlands




NL - Netherlands

Sandoz B.V. Veluwezoom 22 NL-1327 AH Almere The Netherlands

Oxycodon HCl Sandoz 10 mg, tabletten met verlengde afgifte


NL - Netherlands




NL - Netherlands




94



administration

NL - Netherlands




NL - Netherlands




NL - Netherlands


Oxycodon HCl Sandoz retard 10 mg, tabletten met verlengde afgifte


NL - Netherlands




NL - Netherlands




NO - Norway

Hexal A/S Kanalholmen 8-12 DK-2650 Hvidovre Denmark

Oxycodone Hexal 20 mg Prolonged release tablet Oral use

NO - Norway



NO - Norway



NO - Norway



NO - Norway



95



administration

NO - Norway

Mundipharma As Vollsveien 13c 1366 Lysaker Norway


NO - Norway



NO - Norway



NO - Norway



NO - Norway



NO - Norway


PALLADON 4 mg Prolonged-release capsule, hard Oral use

NO - Norway



NO - Norway



NO - Norway



NO - Norway


PALLADON 1,3 mg capsule, hard Oral use

96



administration

NO - Norway


PALLADON 2,6 mg capsule, hard Oral use

NO - Norway


Targiniq 5 mg/2,5 mg Prolonged-release tablet Oral use

NO - Norway


Targiniq 40 mg/20 mg Prolonged-release tablet Oral use

NO - Norway



NO - Norway



NO - Norway

Pfizer As Postboks 3 1324 Lysaker Norway

DOLCONTIN 20 mg/dose Prolonged-release granules for oral suspension

Oral use

NO - Norway


DOLCONTIN 5 mg Prolonged-release tablet Oral use

NO - Norway



NO - Norway



NO - Norway



97



administration

NO - Norway



NO - Norway



NO - Norway

Ratiopharm GmbH Graf-Arco-Strasse 3 89070 Ulm Germany


NO - Norway



NO - Norway



NO - Norway



NO - Norway



NO - Norway

Sandoz A/S C.F. Tietgens Boulevard 40 DK-5220 Odense SØ Danmark

Oxycodone Sandoz 5 mg Prolonged release tablet Oral use

NO - Norway



NO - Norway



98



administration

PL - Poland

G.L. Pharma GmbH Schloβplatz 1 A-8502 Lannach Austria

Vendal retard 10 mg Prolonged-release film-coated tablet

Oral use

PL - Poland



Oral use

PL - Poland



Oral use

PL - Poland



Oral use

PL - Poland



Oral use

PL - Poland

Molteni Farmaceutici Polska Sp. z o.o. 3 Obroncow Modlina St. 30-733, Cracow Poland

Oramorph O.D. 20 20 mg Prolonged-release capsule, hard Oral use

PL - Poland



PL - Poland



PL - Poland



PL - Poland


Oramorph O.D.120 120 mg Prolonged-release capsule, hard Oral use

99



administration

PL - Poland

Mundipharma Ges.m.b.H Apollogase 16-18 A-1072 Wien Austria

Palladone-XL 12mg 12 mg Prolonged-release capsule, hard Oral use

PL - Poland



PL - Poland



PL - Poland



PL - Poland

Norpharma A/S Slotsmarken 15 2970 Hørsholm Denmark

MST Continus 10 mg Modified-release film-coated tablet

Oral use

PL - Poland



Oral use

PL - Poland



Oral use

PL - Poland



Oral use

PL - Poland



Oral use

PL - Poland



100



administration

PL - Poland



PL - Poland



PL - Poland



PL - Poland



PL - Poland Nycomed Pharma Sp. z o.o. Al. Jerozoimskie 146A 02-305 Warsaw, Poland








PT - Portugal

Grünenthal, S.A. Rua Alfredo da Silva, 16 2610-016 Amadora Portugal

Grumorph 10 mg Prolonged-release capsule Oral use

PT - Portugal



PT - Portugal



101



administration

PT - Portugal



PT - Portugal

Janssen-Cilag Farmacêutica, Lda. Estrada Consiglieri Pedroso, 69 A - Queluz de Baixo 2734-503 Barcarena Portugal

Jurnista 8 mg Prolonged-release tablet Oral use

PT - Portugal



PT - Portugal



PT - Portugal



PT - Portugal



PT - Portugal

Mundipharma Farmacêutica, Lda. Praça Duque de Saldanha, 1 - 6º - Edifício Atrium Saldanha, 1050-094 São Jorge de Arroios – Lisboa Portugal

Mst 1 10 mg Prolonged-release tablet Oral use

PT - Portugal



102



administration

PT - Portugal



PT - Portugal



PT - Portugal



PT - Portugal

Mundipharma GmbH Mundipharma Strasse 2 D-65549, Limburg Germany


PT - Portugal



PT - Portugal



PT - Portugal



PT - Portugal



PT - Portugal


Targin 9 mg + 4.5 mg


103



administration

PT - Portugal


Targin 18 mg + 9 mg Prolonged-release tablet Oral use

PT - Portugal


Targin 36 mg + 18 mg


PT - Portugal


Targin 4.5 mg + 2.25 mg


RO - Romania


VENDAL RETARD 10 mg, comprimate cu eliberare prelungită


RO - Romania




RO - Romania




RO - Romania




RO - Romania


MST CONTINUS 10 mg, comprimate cu eliberare modificată


RO - Romania




RO - Romania




104



administration

RO - Romania


MST CONTINUS 30 mg, comprimate fcu eliberare modificată


RO - Romania




RO - Romania


OXYCONTIN 10 mg, comprimate cu eliberare modificată


RO - Romania




RO - Romania




RO - Romania




SE - Sweden



SE - Sweden



SE - Sweden



SE - Sweden



105



administration

SE - Sweden



SE - Sweden Lannacher Heilmittel Ges.m.b.H., Schlossplatz 1 8502 Lannach Austria











Oxycodone Lannacher 5 mg Prolonged-release tablet Oral use









SE - Sweden

Mundipharma AB Mölndalsvägen 30 B 412 63 Göteborg Sweden


106



administration

SE - Sweden



SE - Sweden



SE - Sweden



SE - Sweden



SE - Sweden



SE - Sweden



SE - Sweden



SE - Sweden



SE - Sweden



SE - Sweden


Targiniq 40 mg/20mg Prolonged-release tablet Oral use

107



administration

SE - Sweden


Targiniq 5 mg/2,5mg Prolonged-release tablet Oral use

SE - Sweden



SE - Sweden



SE - Sweden Pfizer AB 191 90 Sollentuna Sweden


Oral use



Oral use



Oral use



Oral use











108



administration




Dolcontin Unotard 30 mg Prolonged-release capsule, hard Oral use











SE - Sweden

ratiopharm GmbH Graf-Arco-Strasse 3 DE-89079 Ulm Germany


SE - Sweden



SE - Sweden



SE - Sweden



SE - Sweden



109



administration

SE - Sweden


Oxycodone Sandoz 5 mg Prolonged-release tablet Oral use

SE - Sweden



SE - Sweden



SI - Slovenia


M-eslon 10 mg trde kapsule s podaljšanim sproščanjem


SI - Slovenia


M-eslon 100 mg trde kapsule s podaljšanim sproščanjem 100 mg Prolonged-release capsule, hard Oral use

SI - Slovenia



SI - Slovenia



SI - Slovenia

Johnson & Johnson d.o.o. Šmartinska 53 SI- 1000 Ljubljana Slovenia

JURNISTA 16 mg tablete s podaljšanim sproščanjem


110



administration

SI - Slovenia




SI - Slovenia




SI - Slovenia




SI - Slovenia




SI - Slovenia

LEK farmacevtska družba d.d. Verovškova 57 SI-1000 Ljubljana Slovenia

Carexil 10 mg tablete s podaljšanim sproščanjem


SI - Slovenia




SI - Slovenia




SI - Slovenia

LEK farmacevtska družba d.d., Verovškova 57 SI-1000 Ljubljana Slovenia

Oksikodon Lek 10 mg tablete s podaljšanim sproščanjem


SI - Slovenia




SI - Slovenia




111



administration

SI - Slovenia




SI - Slovenia




SI - Slovenia

Medis, d.o.o. Brnčičeva 1 SI-1001 Ljubljana Slovenia

MST Continus 10 mg filmsko obložene tablete s podaljšanim sproščanjem

10 mg film-coated prolonged-release capsule, hard

Oral use

SI - Slovenia




Oral use

SI - Slovenia




Oral use

SI - Slovenia




Oral use

SI - Slovenia


OxyContin 10 mg filmsko obložene tablete s podaljšanim sproščanjem


SI - Slovenia




SI - Slovenia




SI - Slovenia




112



administration

SI - Slovenia


PALLADONE 16 mg trde kapsule s podaljšanim sproščanjem


SI - Slovenia




SI - Slovenia




SI - Slovenia




SI - Slovenia




SI - Slovenia


SUBSTITOL 120 mg trde kapsule s podaljšanim sproščanjem


SI - Slovenia


SUBSTITOL 200 mg trde kapsule s podaljšanim sproščanjem


SK - Slovakia

Johnson & Johnson s.r.o. Plynárenská 7/B Bratislava 82478 Slovak Republic

Jurnista 16 mg tablety s predĺženým uvoľňovaním


SK - Slovakia




SK - Slovakia




113



administration

SK - Slovakia




SK - Slovakia




SK - Slovakia

Lannacher Heilmittel Ges.m.b.H. Schlossplatz 1, 8502 Lannach Austria

Oxypro 10 mg tablety s predĺženým uvoľňovaním


SK - Slovakia




SK - Slovakia




SK - Slovakia




SK - Slovakia




SK - Slovakia

Mundipharma Ges.m.b.H. Apollogasse 16-18 A-1072 Vienna Austria


SK - Slovakia



SK - Slovakia



114



administration

SK - Slovakia



SK - Slovakia


OxyContin 10 mg 10 mg Modified-release tablet Oral use

SK - Slovakia



SK - Slovakia



SK - Slovakia



SK - Slovakia


PALLADONE - SR capsules 16 mg


SK - Slovakia


PALLADONE - SR capsules 2 mg 2 mg Prolonged-release capsule, hard Oral use

SK - Slovakia



SK - Slovakia



SK - Slovakia

Sandoz Pharmaceuticals d.d., Verovškova 57 1000 Ljubljana Slovenia

Oxykodón Sandoz 20 mg tablety s predĺženým uvoľňovaním


115



administration

SK - Slovakia




SK - Slovakia




SK - Slovakia


Oxykosan 10 mg tablety s predĺženým uvoľňovaním


SK - Slovakia


Oxykosan 20 mg tablety s predĺženým uvoľňovaním


SK - Slovakia

YES Pharmaceutical Devel. Services GmbH Bahnstrasse 42-46 D-61381, Friedrichsdorf Germany

Oxykodón YES 10 mg tablety s predĺženým uvoľňovaním


SK - Slovakia




SK - Slovakia




SK - Slovakia




SK - Slovakia




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administration

UK - United Kingdom


ZOMORPH 100MG 100 mg Modified-release capsule Oral use

UK - United Kingdom



UK - United Kingdom



UK - United Kingdom



UK - United Kingdom


ZOMORPH CAPSULES 10MG 10 mg Modified-release capsule Oral use

UK - United Kingdom


ZOMORPH CAPSULES XL 120MG PROLONGED-RELEASE CAPSULES


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administration

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UK - United Kingdom




UK - United Kingdom




UK - United Kingdom




UK - United Kingdom

NAPP PHARMACEUTICALS LIMITED Cambridge Science Park, Milton Road Cambridge CB4 0GW United Kingdom

MST CONTINUS SUSPENSION 100MG


UK - United Kingdom




UK - United Kingdom




UK - United Kingdom




118



administration

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UK - United Kingdom


MST CONTINUS TABLETS 100MG


UK - United Kingdom


MST CONTINUS TABLETS 10MG 10 mg Prolonged-release tablet Oral use

UK - United Kingdom



UK - United Kingdom


MST CONTINUS TABLETS 200MG


UK - United Kingdom



UK - United Kingdom



UK - United Kingdom



UK - United Kingdom


MXL 120MG PROLONGED RELEASE CAPSULES


UK - United Kingdom




119



administration

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UK - United Kingdom




UK - United Kingdom




UK - United Kingdom




UK - United Kingdom

NAPP PHARMACEUTICALS LIMITED Cambridge Science Park, Milton Road, Cambridge CB4 0GW United Kingdom

LONGTEC 10 MG FILM-COATED, PROLONGED RELEASE TABLETS


UK - United Kingdom




UK - United Kingdom




UK - United Kingdom




UK - United Kingdom




UK - United Kingdom


OXYCONTIN 10MG FILM-COATED, PROLONGED RELEASE TABLETS


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administration

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UK - United Kingdom




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UK - United Kingdom




UK - United Kingdom


PALLADONE SR CAPSULES 16MG


UK - United Kingdom


PALLADONE SR CAPSULES 24MG


UK - United Kingdom


PALLADONE SR CAPSULES 2MG 2 mg Modified-release capsule Oral use

UK - United Kingdom



UK - United Kingdom



UK - United Kingdom


TARGINACT 10 MG/5 MG PROLONGED-RELEASE TABLETS

10 mg + 5mg Prolonged-release tablet Oral use

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administration

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20 mg +10 mg


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40 mg +20 mg


UK - United Kingdom


TARGINACT 5 MG/2.5 MG PROLONGED-RELEASE TABLETS

5 mg +2.5 mg Prolonged-release tablet Oral use

UK - United Kingdom

RATIOPHARM GMBH Graf-Arco Strasse 3 Ulm, D-89079 Germany

CANDOX 10MG PROLONGED-RELEASE TABLETS


UK - United Kingdom


CANDOX 20 MG PROLONGED-RELEASE TABLETS


UK - United Kingdom




UK - United Kingdom


CANDOX 5MG PROLONGED-RELEASE TABLETS


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SANDOZ LIMITED 37 Woolmer Way, Borden Hampshire GU35 9QE United Kingdom

CAREXIL 10MG PROLONGED-RELEASE TABLETS


UK - United Kingdom




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administration

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CONTIROXIN 10 MG PROLONGED-RELEASE TABLETS


UK - United Kingdom




UK - United Kingdom




UK - United Kingdom




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Teva Uk Limited Brampton Road, Hampden Park, Eastbourne, E Sussex BN22 9AG United Kingdom

FILNARINE SR 100MG PROLONGED RELEASE TABLETS


UK - United Kingdom




UK - United Kingdom




UK - United Kingdom




123

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administration

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UK - United Kingdom

WAYMADE PLC Sovereign House, Miles Gray Road, Basildon, Essex SS14 3FR United Kingdom

MORPHGESIC SR 100MG TABLETS


UK - United Kingdom




UK - United Kingdom




UK - United Kingdom




ANNEX II

Scientific conclusions and grounds for suspension/amendment of the summaries of product characteristics, package leaflets and labelling presented by the European Medicines Agency

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Scientific conclusions

Overall summary of the scientific evaluation of modified-release oral opioid products in the level III of the WHO scale for the management of pain (intense sustained pain resistant to previous medications) (see Annex I)

1. Introduction

On 18 September 2009, the European Commission triggered a referral under Article 31 of Directive 2001/83/EC, as amended. In the context of marketing authorisation procedures for oxycodone-containing products, possible differences in the safety profile of the originator and generic products had been raised concerning the interaction with alcohol. The CHMP was then asked by the European Commission to determine whether there is a need to take specific measures to deal with the consequences of the interaction between strong-opioid modified-release oral products and alcohol. Therefore, the European Commission requested the CHMP to give its opinion on whether the marketing authorisations for authorised modified-release oral medicinal products of the WHO level III scale for the management of pain (intense sustained pain resistant to previous medications) (containing morphine, oxycodone, fentanyl and hydromorphone) should be maintained, varied, suspended or withdrawn. Modified-release products are complex dosage forms designed to release drugs in a controlled manner to achieve desired efficacy and safety profiles. If, however, the modified-release system is influenced by an external factor or substance (such as alcohol), it is possible that a large quantity of the active substance is released in a short timeframe so that it resembles an immediate-release dosage form. This effect is known as ‘dose-dumping’. In order to assess the potential for dose-dumping of each product, MAHs of products in the level III of the WHO scale for the management of severe pain were asked to submit data on their products. Level III of the WHO scale includes fentanyl, hydromorphone, morphine and oxycodone, however no oral modified-release products containing fentanyl are currently authorised in the EU, as due to a marked first pass effect, oral administration of fentanyl is not feasible.

2. Quality issues

Dissolution data was submitted for two different controlled release systems of hydromorphone, four different controlled release systems of oxycodone, and seven different controlled release systems containing morphine. From the products tested, fifty percent of the formulations were found to be affected by alcohol solutions in vitro. The effect of alcohol on the dissolution rate was mild in most cases, except for one morphine formulation (morphine once-daily capsules). This morphine formulation with polymethacrylate- triethylcitrate coating as modified-release mechanism has been identified as a product where dose dumping might occur when taken together with alcohol. The in vitro data showed a release of 80% of the drug within 15 minutes in 20% of alcohol solution. The polymethacrylate-triethylcitrate based formulation is highly sensitive to alcohol with its modified release properties being destroyed shortly after exposure, making it resemble an immediate release formulation. A product containing hydromorphone and a prolonged release system consisting of ammonio methacrylate co-polymer type B (Eudragit RS) also suffered a significant effect of high concentrations of alcohol on in vitro dissolution. This product has never been marketed. The remaining systems were not significantly affected by alcohol.

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3. Clinical issues

For most of the products assessed, only in vitro data was submitted. In a limited number of cases, the MAH has also presented the results of in vivo studies and/or a review of adverse event reports which may have been related to the concomitant use of alcohol. In vivo studies conducted with a hydromorphone formulation based on ammonio methacrylate co-polymer type B (Eudragit RS) confirmed the existing in vitro data suggesting that alcohol affects the formulation. Another study conducted with a hydromorphone formulation based on cellulose acetate 398-10 and Macrogol 3350 formulation confirmed the conclusions of the in vitro studies that the effect of coadministered alcohol on PK parameters is rather limited. The results of the only study with a morphine product (ethylcellulose N-50, methacrylic acid copolymer type C, polyethylene glycol 6000 and diethyl phthalate formulation) indicate that a relatively high quantity of alcohol has almost no effect in vivo. A low number of cases of interaction between alcohol and opioid products have been reported, most reports involved intentional overdose or abuse in conjunction with other products and some were fatal. Given the type of products and patient population involved, it is acknowledged that underreporting is considerable. Alcohol use is common in patients with chronic pain due to the fact that it reduces pain perception. In the scientific literature, drinking alcohol is referred as a coping mechanism to deal with the stress associated with pain. This may be further aggravated by the fact that many patients with chronic pain will also suffer from depression. Concurrent depression and pain have a much greater impact than either disorder alone and, in patients with pain, depression is associated to more pain sites, greater pain intensity, longer duration of pain, and greater likelihood of poor treatment response (Bair, J et al., Psychosom Med. 2008 October; 70(8): 890-897). The association between pain and drinking was evaluated by Brennan et al in a cohort of 401 elderly with different drinking behavior (Brennan, Addiction. 2005; 100(6): 777-86). Both problem drinkers and non-problem drinkers were included. Both problem drinkers as non-problem drinkers reported to use alcohol to manage pain, although in the latter group to less extent (see figure 1). Pain at baseline was a significant predictive factor for alcohol use in the 3-years follow-up period.

Source; Brennan et al., Addiction 2005; 100 : 777-86

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While it may be argued that patients may use less alcohol as a self-medication strategy if they are sufficiently treated with analgesics like opioids, the results of a recently published Danish Health survey (Ekholm et al. Eur J Pain 2009; 13: 606-12) reveal a different pattern of behavior. In this study, subjects were interviewed about their number of alcohol consumptions of the last week and frequency of binge drinking in the last month (5292 responders). About 20% of the responders reported chronic pain (>6 months). The association between chronic pain and alcohol use is summarized in the table below.

Patients being treated with opioids tend to drink less alcohol than patients who do not use opioids at all. However, a significant percentage of the patients with chronic pain who uses opioids still reports high alcohol intake (10.8%) and binge drinking at least once a month (22.3%), despite existing warnings.

4. Benefit-Risk balance

Having considered all the data submitted, it can be concluded that the large majority of modified-release oral opioid products in the European Union do not exhibit a clinically significant interaction with alcohol. While a pharmacodynamic interaction with alcohol may occur irrespective of the formulation, in most cases a pharmacokinetic interaction will not be clinically significant so as to warrant measures beyond the proposed wording for the product information. Fifty-percent of the formulations assessed are affected by alcohol solutions in vitro, but in most cases, the effect of alcohol on the dissolution rate is mild. The exception is one morphine formulation using polymethacrylate-triethylcitrate coating as modified-release mechanism, for which dose dumping might occur when taken together with alcohol. The dissolution profile of this product (80% dissolved substance within 15 min in 20% alcohol) is beyond the limit of the Ph. Eur. for conventional-release products (NLT 75% dissolved active substance within 45 minutes). In addition, as the medicinal product based on this release-mechanism is intended for once a day dosing, the content of morphine is high and therefore the risk of adverse events following dose-dumping is also higher. A significant effect was observed also in a hydromorphone once a day formulation which is not marketed in the EU.

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In light of the existing data, including published data on the use of alcohol in patients treated with opioids, the Committee is of the opinion that the current warnings and contraindications are not sufficient to protect patients from the significant alcohol interaction observed with the polymethacrylate- triethylcitrate formulation. The Committee is also of the opinion that further minimisations measures would not adequately address the concern. Therefore, patients taking this particular formulation are exposed to a significantly greater risk of developing serious adverse reactions such as respiratory depression and death. For all other strong-opioid modified release oral products in the European market (formulations not containing polymethacrylate-triethylcitrate), no significant risk of dose-dumping due to alcohol use was identified. However, for all of these products, a pharmacodynamic interaction may occur and should be mentioned in the Product information of all products in a consistent manner. While most products already contain warnings and references to this interaction in the SPC, the wording should be harmonised to ensure the same level of awareness. The assessment within this procedure provided an overview of the modified-release systems used in the European Union in oral opioid products. Not all MAHs of modified-release oral opioid products in the level III of the WHO scale for the management of pain in the European market submitted data, and so it can not be guaranteed that all products approved in the EU have been assessed. The National Competent Authorities should therefore determine, based on the modified-release mechanism of the products approved in their Member State, the appropriate actions to be taken for individual products.

5. Re-examination procedure

Following the CHMP Opinion of 22 July 2010, one MAH submitted detailed grounds for the re-examination of the opinion. The MAH expressed the view that: 1. The CHMP had not addressed the issue of the additional risk to patients posed by modified release

formulations of opioids which exhibit a greater vulnerability to alcohol compared with the reference product, whilst conferring no additional patient benefit.

2. The Opinion did not take account of the earlier advice of its own working parties, namely the EWP

and QWP, which had been requested by the CMD(h); nor did it provide any proper reasons for discounting that advice.

3. The CHMP’s conclusions were arbitrary. Firstly, the Opinion does not provide any information

regarding the acceptance criteria to be applied in relation to the clinical significance of pharmacokinetic interactions with alcohol. Secondly, the CHMP’s approach to alcohol interaction is inconsistent with its approach to food interactions.

4. The Opinion was not properly reasoned. In particular, assumptions were made about the behaviour

of some formulations based solely on the excipients; in this respect the CHMP did not take into account the evidence provided in the Oral Hearing on 23 June 2010 that such assumptions are flawed.

Further to the request from the MAH, the CHMP convened an Ad-Hoc Expert meeting including experts on technology/formulation science, pharmacokinetics and clinical/medical practice in order to deliver answers on a consultative basis to specific questions in relation to the grounds for re-examination. Having assessed the detailed grounds for re-examination provided by the MAH, the rapporteurs assessment reports, the conclusions from the ad hoc expert meeting together with the MAH’s expressed concerns on the conclusions of the ad hoc expert meeting and all the information submitted during the referral procedure, the CHMP discussed each one of the grounds submitted:

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1. The CHMP had not addressed the issue of the additional risk to patients posed by modified

release formulations of opioids which exhibit a greater vulnerability to alcohol compared with the reference product, whilst conferring no additional patient benefit.

The issue of additional risk to patients was addressed by CHMP in its initial opinion, and as a consequence a recommendation was adopted to suspend and reformulate the formulations where the interaction was of such magnitude that the products essentially resemble an immediate release formulation (while containing the opioid dose appropriate for a modified release formulation). In this context, the fact that the product is meant for use once or twice a day may be of importance given the higher dose usually contained in once a day formulations. In addition, the CHMP agreed on the inclusion for all other products in the European market of a pharmacodynamic warning. This is justified on the basis that a pharmacodynamic interaction between opioid products and alcohol may occur irrespective of the formulation. The Committee also discussed the possibility of the introduction of a pharmacokinetic warning in those cases where some degree of additional formulation interaction could be suspected. In this respect, it was noted that the in vitro - in vivo correlation is unclear in most cases, and therefore it would be inappropriate to assume a pharmacokinetic interaction. This is clearly demonstrated by the existing data for one specific product for which the in vitro interaction is significant but where the pharmacokinetic parameters did not differ significantly among subjects taking the product with water or with alcohol (ethylcellulose N-50, methacrylic acid copolymer type C, polyethylene glycol 6000 and diethyl phthalate product). The Committee also reflected on the usefulness for prescribers and patients of a pharmacokinetic warning in the Product Information referring to the in vitro data. Considering that the proposed pharmacodynamic warning already advises against concomitant use with alcohol, considering also the limitations of the in vitro data and difficulties in its interpretation by prescribers, the majority of the Committee was of the opinion that the addition of a pharmacokinetic interaction warning based on a description of the in vitro data would not favour the clarity of the message to patients and prescribers regarding the need to avoid concomitant use with alcohol. 2. The Opinion did not take account of the earlier advice of its own working parties, namely

the EWP and QWP, which had been requested by the CMD(h); nor did it provide any proper reasons for discounting that advice.

When adopting its 22 July 2010 opinion on this procedure, CHMP was fully aware of the positions of the different working parties. The advice of the QWP was that formulations should, if possible, be developed such that a physicochemical incompatibility with alcohol is avoided. Where not possible, the QWP recommended the inclusion of differential wording in the Product Information. The question of what could be considered as a clinical significant interaction with alcohol was left for the EWP to consider. The advice of the EWP was to consider the worst case scenario, including gastric residence times of 1-2 to hours and potential exposure to high concentrations of alcohol. As a consequence, where accelerated drug release is seen, the EWP’s recommendation was for label warnings and risk management strategies to be considered. In its detailed grounds for re-examination the MAH referred to statistical analysis confirming different behaviours in the presence of alcohol for a generic and its originator product. This aspect is outside the scope of this procedure and it does not provide any relevant information to the issue at stake. More than confirming that the generic and originator are bioequivalent, in this review it is important to consider whether the observed in vitro effect constitutes an unacceptable risk for patients. In its assessment, the Committee took into consideration data submitted for the different timepoints. An important interaction following alcohol consumption becomes progressively less likely with time due to dilution effect by gastric secretions and saliva, and gastric emptying. This is demonstrated by measurements of gastric-duodenal ethanol levels after consumption of alcohol in healthy volunteers. Gastric ethanol concentrations dropped rapidly after the consumption of alcohol by 70% in 10 min (Levitt et all, Am J Physiol Gastrointest Liver Physiol 273:951-957, 1997). With food the gastric emptying of alcohol is delayed, but still significant (50-60% in 1 hour, Levitt, 1997, and Cortot et al, Digestive Diseases and Sciences 1986; 31:343-48).

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3. The CHMP’s conclusions were arbitrary. Firstly, the Opinion does not provide any

information regarding the acceptance criteria to be applied in relation to the clinical significance of pharmacokinetic interactions with alcohol. Secondly, the CHMP’s approach to alcohol interaction is inconsistent with its approach to food interactions.

The Opinion does not provide information on the acceptance criteria to be applied in relation to the clinical significance of pharmacokinetic interactions because there are currently no standard acceptance criteria to be applied in this context. Further to that, the IVIV correlation is, at present time, uncertain for most products. It follows from the above that data presented on the in vitro effects of alcohol on the dissolution profile of these products are not necessarily a reliable predictor of in vivo behaviour and therefore recommendations such as suspension and reformulation of products should only be adopted for products for which the in vitro interaction is of such magnitude that the products are considered to pose serious risks to the patients. In its detailed grounds for re-examination, the MAH referred to a competitor product in which the release of oxycodone is accelerated in the presence of alcohol as an example of a potentially clinically meaningful interaction. According to the data on a competitor product presented by the MAH requesting re-examination, this product starts to exhibit accelerated release of the active substance after approximately 30 min of exposition to alcohol, and is claimed to release 76.5% of the oxycodone dose within one hour of exposure to concentrations of alcohol around 24%. A product with this dissolution profile cannot be considered to behave as an immediate release formulation. A similar dissolution study from 2007 however, showed that at 60 minutes the dissolution rate of the reference product (considered by the MAH to be a safe product) in the absence of alcohol was actually higher that the dissolution rate of the competing product presented when exposed to 20% alcohol. It is of note that, in the data presented by the MAH for this competitor product, the most pronounced effect of alcohol is not at the highest alcohol concentrations tested (40%), but between 28%-32%. This further illustrates the limitations of the data presented. From all the above mentioned considerations, including the limitations of the existing data and the current status of scientific knowledge, it follows that general recommendations for acceptance criteria to be applied in relation to the clinical significance of pharmacokinetic interactions with alcohol can not be determined by the Committee at this time. The MAH further considered, in its grounds for re-examination, that the CHMP opinion was inconsistent in its approach regarding alcohol versus food interactions. It is well known that food can have an effect on the pharmacokinetic parameters of medicinal products. It is important to note in this regard that the effects of food related interactions are measured in vivo, and therefore the data on food effect reflects, as accurately as possible, the real extent of the interaction. Food related interactions are taken into consideration and reflected in the SPC and package leaflet for the benefit of patients and prescribers. For alcohol, the majority of the data available relates to in vitro testing only, and therefore cannot be assumed, for the reasons previously explained, to be directly reproduced in vivo. Considering that the proposed pharmacodynamic warning already advises against concomitant use with alcohol, considering also the limitations of the in vitro data and difficulties in its interpretation by prescribers, the majority of the Committee was of the opinion that the addition of a pharmacokinetic interaction warning based on a description of the in vitro data would not favour the clarity of the message to patients and prescribers regarding the need to avoid concomitant use with alcohol. It is therefore concluded that the approach is not inconsistent, firstly because in the case of alcohol, a recommendation not to take the product with alcohol will always exist regardless of the formulation. Secondly, because unlike alcohol, SPC information on food interactions will reflect in vivo studies and therefore have clear added value for the prescriber and the patient.

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4. The Opinion was not properly reasoned. In particular, assumptions were made about the

behaviour of some formulations based solely on the excipients; in this respect the CHMP did not take into account the evidence provided in the Oral Hearing on 23 June 2010 that such assumptions are flawed.

The anticipated increase in dissolution rate observed for modified-release products is a result of the modified release system being rendered unstable in the presence of alcohol. This will be related to the specificities of each formulation, namely the physical characteristics of the excipients and the manufacturing process. It is however clear that, in the cases where the highest degree of in vitro interaction was observed, the high alcohol solubility of the excipients provided a clear explanation for the observation. The MAH mentioned in his grounds for re-examination a paper by Smith at al (In vitro dissolution of oral modified-release tablets and capsules in ethanolic media, International Journal of Pharmaceutics 398 (2010) 93-96) to illustrate that formulations should not be assumed to be unaffected by alcohol without data being evaluated. In its initial Opinion, the CHMP did not conclude that the formulations analysed were unaffected by alcohol. It is clearly stated in the Opinion that 50% of the formulations were found to be affected by alcohol in vitro. The question under discussion is, however, whether the magnitude of the interaction is such that it can be assumed to have clinical significance and represent a significant risk for the patient. It should be noted that, while the authors of the above mentioned paper go on to conclude that ‘in vitro dissolution may provide evidence regarding the ruggedness of formulations to ingested alcohol’, no recommendations are issued to specific products given that ‘…further research is needed to understand the relationship between dosage form, product formulation and configuration and drug release in the presence of ethanol.’ The CHMP having assessed all the detailed grounds for re-examination and argumentation presented by the MAH and having considered the views of the Rapporteurs, the scientific discussion within the Committee and the conclusions of the ad hoc expert group as well as the concerns raised by the MAH in this respect, concluded that products with a polymethacrylate-triethylcitrate coating are harmful under the normal conditions of use and that, for the remaining products, the Product Information should be amended to include a warning and recommendation for avoiding concomitant use with alcohol. The Committee is therefore of the opinion that its 22 July 2010 opinion should be maintained.

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Grounds for amendment of the summaries of product characteristics, package leaflets and labelling

Whereas The Committee considered the procedure under Article 31 of Directive 2001/83/EC, as amended

for modified-release oral opioid products in the level III of the WHO scale for the management of pain (intense sustained pain resistant to previous medications) on the EU market,

The Committee considered all the available data submitted by the MAHs,

The Committee considered that a pharmacodynamic interaction between opioid products and alcohol may occur irrespective of the formulation,

The Committee considered that, based on the published literature, a significant percentage of the patient population using these products does not abstain from alcohol consumption despite the existing warnings and contraindications,

The Committee considered that products without a polymethacrylate-triethylcitrate coating as modified-release mechanism do not suggest a significant interaction with alcohol considered to be harmful under normal conditions of use,

The Committee considered, however, that as a pharmacodynamic interaction with alcohol may occur, the product information of the above mentioned products should describe in a clear and harmonised manner the pharmacodynamic interaction between opioid products and alcohol,

The Committee therefore recommended the amendment of the Marketing Authorisation for which the relevant sections of the Summary of Product Characteristics and Package Leaflet are set out in Annex III. As not all medicinal products concerned by this review submitted data, the National Competent Authorities should ensure, based on the modified-release mechanism of the products approved in each Member State, that the appropriate actions are taken for individual products.

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Grounds for suspension of the marketing authorisation

Whereas The Committee considered the procedure under Article 31 of Directive 2001/83/EC, as amended

for modified-release oral opioid products in the level III of the WHO scale for the management of pain (intense sustained pain resistant to previous medications),

The Committee considered all the available data submitted by the MAHs,

The Committee noted that a pharmacodynamic interaction between opioid products and alcohol may occur irrespective of the formulation,

In addition, the Committee considered that the dissolution profile of products containing a polymethacrylate-triethylcitrate coating as modified-release mechanism is significantly affected in the presence of alcohol, leading to an uncontrolled rapid release of the majority of the active substance, and therefore the product exhibits a significant interaction with alcohol with potentially significant clinical effects (e.g. respiratory depression and death),

The Committee, based on the published literature, considered that a significant percentage of the patient population using these products does not abstain from alcohol consumption despite the existing warnings and contraindications, and that therefore the existing risk minimisation measures do not adequately address the concern,

The Committee is also of the opinion that further risk minimisation measures would not adequately address the concern,

The Committee therefore considered that patients exposed to the above mentioned products and concomitant intake of alcohol are at significantly greater risk of developing serious adverse reactions such as respiratory depression and death,

The Committee took the view that modified-release oral opioid products in the level III of the

WHO scale for the management of pain containing a polymethacrylate-triethylcitrate coating as modified-release mechanism are harmful under the normal conditions of use in accordance with article 116 of Directive 2001/83/EC, as amended.

Consequently, the CHMP has recommended the suspension of the marketing authorisation for modified-release oral opioid products in the level III of the WHO scale for the management of pain containing a polymethacrylate-triethylcitrate coating as modified-release mechanism (see annex I). For the suspension to be lifted, the Marketing Authorisation Holders need to provide evidence that the product has been reformulated, that it exhibits an acceptable release profile with the same quality, safety and efficacy profile of the currently authorised formulation but without the clinically significant interaction with alcohol. The new formulation must be approved by the National Competent Authorities of the concerned Member States (see Annex IV).

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Annex III

Relevant Sections of the Summary of Product Characteristics, Package Leaflet and labelling

Amendments to be included in the relevant sections of the Summary of Products Characteristics, Package Leaflet and labelling

Applicable to all products except those containing a polymethacrylate-triethylcitrate coating as modified-release mechanism. For products having warnings regarding the interaction with alcohol, the existing wording in the SPC and package leaflet should be replaced by the wording below. For products not having warnings regarding the interaction with alcohol in the currently approved SPC and package leaflet, the below wording should be added.

Summary of Product Characteristics

4.4 Special warnings and precautions for use

[…] Concomitant use of alcohol and {product name} may increase the undesirable effects of {product name}; concomitant use should be avoided. […]

4.5 Interaction with other medicinal products and other forms of interaction

[…] Alcohol may enhance the pharmacodynamic effects of {product name}; concomitant use should be avoided. […]

Package Leaflet

Section 2 – Before you take {product name}

[…] Drinking alcohol whilst taking {product name} may make you feel more sleepy or increase the risk of serious side effects such as shallow breathing with a risk of stopping breathing, and loss of consciousness. It is recommended not to drink alcohol while you’re taking {product name}. […]

Labelling

Any existing warnings on the interaction with alcohol should be deleted.

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Annex IV

Conditions for lifting the suspension

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Only applicable to products containing a polymethacrylate-triethylcitrate coating as modified-release mechanism For the suspension to be lifted the Marketing Authorisation Holders would need to provide the National Competent Authorities with the following: Evidence that the product has been reformulated, that it exhibits an acceptable release profile with the same quality, safety and efficacy profile of the currently authorised formulation but without the clinically significant interaction with alcohol. The new formulation must be approved by the National Competent Authorities of the concerned Member States.

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