Invented name Strength. 125mg/5ml. 250mg/5ml

Transcription

1 Annex I List of the names, pharmaceutical forms, strengths of the medicinal products, route of administration, marketing authorisation holders in the Member States

2 Member State (EU/EEA) Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Content (concentration) Austria Austria Austria Austria Austria Belgium Belgium GlaxoSmithKline Pharma GmbH, Albert Schweitzer- Gasse 6, A-1140 Wien AUSTRIA GlaxoSmithKline Pharma GmbH, Albert Schweitzer- Gasse 6, A-1140 Wien AUSTRIA GlaxoSmithKline Pharma GmbH, Albert Schweitzer- Gasse 6, A-1140 Wien AUSTRIA GlaxoSmithKline Pharma GmbH, Albert Schweitzer- Gasse 6, A-1140 Wien AUSTRIA GlaxoSmithKline Pharma GmbH, Albert Schweitzer- Gasse 6, A-1140 Wien AUSTRIA GlaxoSmithKline s.a. / n.v. Rue du Tilleul Genval BELGIUM GlaxoSmithKline s.a. / n.v. Rue du Tilleul Genval BELGIUM Zinnat 125 mg/5 ml Granulat zur Herstellung einer zum Einnehmen Zinnat 250 mg - Granulat Zinnat 250 mg/5 ml Granulat zur Herstellung einer zum Einnehmen Zinnat 250 mg - Filmtabletten Zinnat 500 mg - Filmtabletten Zinnat 250mg Granules N/A 250mg Film-coated Tablets N/A 500mg Film-coated Tablets N/A Zinnat 250mg Film-coated Tablets N/A Page 2

3 Member State (EU/EEA) Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Content (concentration) Belgium Bulgaria Bulgaria Bulgaria Bulgaria Cyprus Cyprus GlaxoSmithKline s.a. / n.v. Rue du Tilleul Genval BELGIUM GlaxoSmithKline EOOD, Ivan Vazov complex, Dimitar Manov Str., bld 10, 1408 Sofia, BULGARIA Glaxo Group Ltd., Greenford road, Greenford, Middlesex, UB6 0NN, UNITED KINGDOM GlaxoSmithKline EOOD, Ivan Vazov complex, Dimitar Manov Str., bld 10, 1408 Sofia, BULGARIA GlaxoSmithKline EOOD, Ivan Vazov complex, Dimitar Manov Str., bld 10, 1408 Sofia, BULGARIA Glaxo Group Limited Berkeley Avenue Greenford Middlesex UB6 0NN UNITED KINGDOM Glaxo Group Limited Berkeley Avenue Greenford Middlesex UB6 0NN UNITED KINGDOM Zinnat 500mg Film-coated Tablets N/A Zinnat Zinnat Zinnat 250mg Film-coated Tablets N/A Zinnat 500mg Film-coated Tablets N/A Zinnat Zinnat 250mg Film-coated Tablets N/A Page 3

4 Member State (EU/EEA) Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Content (concentration) Cyprus Czech Republic Czech Republic Czech Republic Czech Republic Czech Republic Glaxo Group Limited Berkeley Avenue Greenford Middlesex UB6 0NN UNITED KINGDOM Glaxo Group Ltd., Glaxo Welcome House, Berkeley Avenue, Greenford, Middlesex UB6 0NN ENGLAND Glaxo Group Ltd., Glaxo Welcome House, Berkeley Avenue, Greenford, Middlesex UB6 0NN ENGLAND Glaxo Group Ltd., Glaxo Welcome House, Berkeley Avenue, Greenford, Middlesex UB6 0NN ENGLAND Glaxo Group Ltd., Glaxo Welcome House, Berkeley Avenue, Greenford, Middlesex UB6 0NN ENGLAND Glaxo Group Ltd., Glaxo Welcome House, Berkeley Avenue, Greenford, Middlesex UB6 0NN ENGLAND Zinnat 500mg Film-coated Tablets N/A Zinnat 125 mg Zinnat 250 mg Zinnat 125 mg 125mg Film-coated Tablets N/A Zinnat 250 mg 250mg Film-coated Tablets N/A Zinnat 500 mg 500mg Film-coated Tablets N/A Page 4

5 Member State (EU/EEA) Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Content (concentration) Denmark Denmark Denmark Denmark Estonia Estonia GlaxoSmithKline Pharma A/S Nykaer 68, 2605 Broendby DENMARK GlaxoSmithKline Pharma A/S Nykaer 68, 2605 Broendby DENMARK GlaxoSmithKline Pharma A/S Nykaer 68, 2605 Broendby DENMARK GlaxoSmithKline Pharma A/S Nykaer 68, 2605 Broendby DENMARK Glaxo Group Ltd. Glaxo Wellcome House, Berkeley Avenue, Greenford, Middlesex, UB6 0NN UNITED KINGDOM Glaxo Group Ltd. Glaxo Wellcome House, Berkeley Avenue, Greenford, Middlesex, UB6 0NN UNITED KINGDOM Zinnat (25mg/ml) Zinnat 125mg Film-coated Tablets N/A Zinnat 250mg Film-coated Tablets N/A Zinnat 500mg Film-coated Tablets N/A Zinnat 25mg/1ml 25mg/1ml Zinnat 250mg Film-coated Tablet N/A Page 5

6 Member State (EU/EEA) Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Content (concentration) Estonia Finland Finland Finland France France France Glaxo Group Ltd. Glaxo Wellcome House, Berkeley Avenue, Greenford, Middlesex, UB6 0NN UNITED KINGDOM GlaxoSmithKline Oy P.O.Box 24 (Piispansilta 9 A), FI Espoo, FINLAND Glaxo Operations UK Ltd, Glaxo Wellcome House, Berkeley Avenue, Greenford, Middlesex UB6 0NN, UNITED KINGDOM Glaxo Operations UK Ltd, Glaxo Wellcome House, Berkeley Avenue, Greenford, Middlesex UB6 0NN, UNITED KINGDOM Laboratoire GlaxoSmithKline 100, route de Versailles Marly-le-Roi Cedex FRANCE Laboratoire GlaxoSmithKline 100, route de Versailles Marly-le-Roi Cedex FRANCE Laboratoire GlaxoSmithKline 100, route de Versailles Marly-le-Roi Cedex FRANCE Zinnat 500mg Film-coated Tablet N/A Zinnat 50mg/ml Zinnat 125mg Film-coated Tablets N/A Zinnat 250mg Film-coated Tablets N/A Zinnat 125 mg/5 ml Enfants et Nourrissons N/A Zinnat 125mg Film-coated Tablets N/A Zinnat 250mg Film-coated Tablets N/A Page 6

7 Member State (EU/EEA) Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Content (concentration) France France Germany Germany Germany Germany Germany Germany Laboratoire GlaxoSmithKline 100, route de Versailles Marly-le-Roi Cedex FRANCE Laboratoire GlaxoSmithKline 100, route de Versailles Marly-le-Roi Cedex FRANCE GlaxoSmithKline GmbH & Co. KG, Theresienhöhe München GERMANY GlaxoSmithKline GmbH & Co. KG, Theresienhöhe München GERMANY GlaxoSmithKline GmbH & Co. KG, Theresienhöhe München GERMANY GlaxoSmithKline GmbH & Co. KG, Theresienhöhe München GERMANY GlaxoSmithKline GmbH & Co. KG, Theresienhöhe München GERMANY GlaxoSmithKline GmbH & Co. KG, Theresienhöhe München GERMANY Zinnat 500mg Film-coated Tablets N/A Zinnat 125 mg Enfants et Nourrissons Zinnat -Trockensaft 125mg (25mg/ml) in sachet N/A Zinnat 125mg Film-coated Tablets N/A Zinnat 250mg Film-coated Tablets N/A Zinnat 500mg Film-coated Tablets N/A Elobact 125mg Dosier-Brief Elobact Trockensaft 125mg N/A Page 7

8 Member State (EU/EEA) Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Content (concentration) Germany Germany Germany Germany Greece Greece Greece Hungary Hungary GlaxoSmithKline GmbH & Co. KG, Theresienhöhe München GERMANY GlaxoSmithKline GmbH & Co. KG, Theresienhöhe München GERMANY GlaxoSmithKline GmbH & Co. KG, Theresienhöhe München GERMANY GlaxoSmithKline GmbH & Co. KG, Theresienhöhe München GERMANY GlaxoSmithKline a.e.b.e, Leof. Kifissias 266, Halandri, Athens GREECE GlaxoSmithKline a.e.b.e, Leof. Kifissias 266, Halandri, Athens GREECE GlaxoSmithKline a.e.b.e, Leof. Kifissias 266, Halandri, Athens GREECE GlaxoSmithKline Kft Bp, Csörsz u. 43. HUNGARY GlaxoSmithKline Kft Bp, Csörsz u. 43. HUNGARY Elobact 250mg Dosier-Brief 250mg Elobact 125mg Film-coated Tablets N/A Elobact 250mg Film-coated Tablets N/A Elobact 500mg Film-coated Tablets N/A Zinadol N/A Zinadol 250mg Film-coated Tablets N/A Zinadol 500mg Film-coated Tablets N/A Zinnat Zinnat 125mg Film-coated Tablets N/A Page 8

9 Member State (EU/EEA) Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Content (concentration) Hungary Hungary Iceland Iceland Ireland Ireland Ireland GlaxoSmithKline Kft Bp, Csörsz u. 43. HUNGARY GlaxoSmithKline Kft Bp, Csörsz u. 43. HUNGARY GlaxoSmithKline ehf. Thverholt Reykjavík. ICELAND GlaxoSmithKline ehf. Thverholt Reykjavík. ICELAND GlaxoSmithKline (Ireland) Limited Stonemasons Way, Rathfarnham, Dublin 16 IRELAND GlaxoSmithKline (Ireland) Limited Stonemasons Way, Rathfarnham, Dublin 16 IRELAND GlaxoSmithKline (Ireland) Limited Stonemasons Way, Rathfarnham, Dublin 16 IRELAND Zinnat 250mg Film-coated Tablets N/A Zinnat 500mg Film-coated Tablets N/A Zinnat (25mg/ml) Zinnat 250mg Film-coated Tablets N/A Zinnat Zinnat Zinnat 125mg Film-coated Tablets N/A Page 9

10 Member State (EU/EEA) Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Content (concentration) Ireland Italy Italy Italy Italy Italy Italy Italy GlaxoSmithKline (Ireland) Limited Stonemasons Way, Rathfarnham, Dublin 16 IRELAND GlaxoSmithKline S.p.A. - Via A. Fleming, Verona ITALY GlaxoSmithKline S.p.A. - Via A. Fleming, Verona ITALY GlaxoSmithKline S.p.A. - Via A. Fleming, Verona ITALY GlaxoSmithKline S.p.A. - Via A. Fleming, Verona ITALY GlaxoSmithKline S.p.A. - Via A. Fleming, Verona ITALY GlaxoSmithKline S.p.A. - Via A. Fleming, Verona ITALY GlaxoSmithKline S.p.A. - Via A. Fleming, Verona ITALY Zinnat 500mg Film-coated Tablets N/A Zinnat Zinnat Zinnat 250mg N/A Zinnat 250mg Film-coated Tablets N/A Zinnat 500mg Film-coated Tablets N/A Zoref Zoref Page 10

11 Member State (EU/EEA) Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Content (concentration) Italy Italy Italy Italy Italy Italy GlaxoSmithKline S.p.A. - Via A. Fleming, Verona ITALY GlaxoSmithKline S.p.A. - Via A. Fleming, Verona ITALY Malesci Istituto Farmacobiologico S.p.A Via Lungo l Ema 7, Bagno A Ripoli Firenze ITALY Malesci Istituto Farmacobiologico S.p.A Via Lungo l Ema 7, Bagno A Ripoli Firenze ITALY Malesci Istituto Farmacobiologico S.p.A Via Lungo l Ema 7, Bagno A Ripoli Firenze ITALY Malesci Istituto Farmacobiologico S.p.A Via Lungo l Ema 7, Bagno A Ripoli Firenze ITALY Zoref 250mg Film-coated Tablets N/A Zoref 500mg Film-coated Tablets N/A Oraxim Oraxim Oraxim 250 mg N/A Oraxim 250mg Film-coated Tablets N/A Page 11

12 Member State (EU/EEA) Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Content (concentration) Italy Latvia Latvia Latvia Lithuania Lithuania Lithuania Malesci Istituto Farmacobiologico S.p.A Via Lungo l Ema 7, Bagno A Ripoli Firenze ITALY GlaxoSmithKline Latvia SIA, Bruņinieku 5, Rīga, LV-1001 LATVIA GlaxoSmithKline Latvia SIA, Bruņinieku 5, Rīga, LV-1001 LATVIA GlaxoSmithKline Latvia SIA,Bruņinieku 5, Rīga, LV-1001 LATVIA UAB GlaxoSmithKline Lietuva, A. Goštauto g. 40A, LT Vilnius, LITHUANIA UAB GlaxoSmithKline Lietuva, A. Goštauto g. 40A, LT Vilnius, LITHUANIA UAB GlaxoSmithKline Lietuva, A. Goštauto g. 40A, LT Vilnius, LITHUANIA Oraxim 500mg Film-coated Tablets N/A Zinnat 25 mg/ml granulas iekšķīgi lietojamas suspensijas pagatavošanai Zinnat 250 mg apvalkotās tabletes Zinnat 500 mg apvalkotās tabletes Zinnat (25mg/ml) 250mg Film-coated Tablets N/A 500mg Film-coated Tablets N/A Zinnat 125mg Film-coated Tablets N/A Zinnat 250mg Film-coated Tablets N/A Page 12

13 Member State (EU/EEA) Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Content (concentration) Lithuania UAB GlaxoSmithKline Lietuva, A. Goštauto g. 40A, LT Vilnius, LITHUANIA Zinnat 500mg Film-coated Tablets N/A Luxembourg GLAXOSMITHKLINE PHARMACEUTICALS SA 2-4-6, AVENUE PASCAL B-1330 WAVRE Zinnat Luxembourg GLAXOSMITHKLINE PHARMACEUTICALS SA 2-4-6, AVENUE PASCAL B-1330 WAVRE Zinnat 250mg N/A Luxembourg GLAXOSMITHKLINE PHARMACEUTICALS SA 2-4-6, AVENUE PASCAL B-1330 WAVRE Zinnat Luxembourg Luxembourg GLAXOSMITHKLINE PHARMACEUTICALS SA 2-4-6, AVENUE PASCAL B-1330 WAVRE / GLAXOSMITHKLINE PHARMACEUTICALS SA 2-4-6, AVENUE PASCAL B-1330 WAVRE Zinnat 125mg Film-coated Tablets N/A Zinnat 250mg Film-coated Tablets N/A Page 13

14 Member State (EU/EEA) Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Content (concentration) Luxembourg GLAXOSMITHKLINE PHARMACEUTICALS SA 2-4-6, AVENUE PASCAL B-1330 WAVRE Zinnat 500mg Film-coated Tablets N/A Malta Malta Malta Malta Netherlands Netherlands GlaxoSmithKline (Ireland) Ltd. Stonemasons Way, Rathfarnham, Dublin 16 IRELAND GlaxoSmithKline (Ireland) Ltd. Stonemasons Way, Rathfarnham, Dublin 16 IRELAND Glaxo Wellcome UK Limited Glaxo Wellcome House Berkeley avenue Greenford, Middlesex United Kingdom UB6 0NN GlaxoSmithKline (Ireland) Ltd. Stonemasons Way, Rathfarnham, Dublin 16 IRELAND Glaxo Smith Kline B.V. Huis ter Heideweg LZ ZEIST NETHERLANDS Glaxo Smith Kline B.V. Huis ter Heideweg LZ ZEIST NETHERLANDS Zinnat Zinnat Zinnat 250mg Film-coated Tablets N/A Zinnat 500mg Film-coated Tablets N/A Zinnat Zinnat 125mg Film-coated Tablets N/A Page 14

15 Member State (EU/EEA) Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Content (concentration) Netherlands Netherlands Poland Poland Poland Poland Glaxo Smith Kline B.V. Huis ter Heideweg LZ ZEIST NETHERLANDS Glaxo Smith Kline B.V. Huis ter Heideweg LZ ZEIST NETHERLANDS GlaxoSmithKline Export Ltd 980 Great West Road Brentford, Middlesex, TW8 9GS UNITED KINGDOM GlaxoSmithKline Export Ltd 980 Great West Road Brentford, Middlesex, TW8 9GS UNITED KINGDOM GlaxoSmithKline Export Ltd 980 Great West Road Brentford, Middlesex, TW8 9GS UNITED KINGDOM GlaxoSmithKline Export Ltd 980 Great West Road Brentford, Middlesex, TW8 9GS UNITED KINGDOM Zinnat 250mg Film-coated Tablets N/A Zinnat 500mg Film-coated Tablets N/A Zinnat Zinnat Zinnat 250mg N/A Zinnat 125mg Film-coated Tablets N/A Page 15

16 Member State (EU/EEA) Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Content (concentration) Poland Poland Portugal Portugal Portugal GlaxoSmithKline Export Ltd 980 Great West Road Brentford, Middlesex, TW8 9GS UNITED KINGDOM GlaxoSmithKline Export Ltd 980 Great West Road Brentford, Middlesex, TW8 9GS UNITED KINGDOM Instituto Luso-Fármaco, Lda. Rua Dr António Loureiro Borges nº3 Arquiparque Miraflores Algés PORTUGAL Instituto Luso-Fármaco, Lda. Rua Dr António Loureiro Borges nº3 Arquiparque Miraflores Algés PORTUGAL Instituto Luso-Fármaco, Lda. Rua Dr António Loureiro Borges nº3 Arquiparque Miraflores Algés PORTUGAL Zinnat 250mg Film-coated Tablets N/A Zinnat 500mg Film-coated Tablets N/A Zipos Zipos Zipos 250mg Film-coated Tablets N/A Page 16

17 Member State (EU/EEA) Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Content (concentration) Portugal Portugal Portugal Portugal Portugal Instituto Luso-Fármaco, Lda. Rua Dr António Loureiro Borges nº3 Arquiparque Miraflores Algés PORTUGAL GlaxoWellcome Farmacêutica Lda Rua Dr António Loureiro Borges nº3 Arquiparque Miraflores Algés PORTUGAL GlaxoWellcome Farmacêutica Lda Rua Dr António Loureiro Borges nº3 Arquiparque Miraflores Algés PORTUGAL GlaxoWellcome Farmacêutica Lda Rua Dr António Loureiro Borges nº3 Arquiparque Miraflores Algés PORTUGAL GlaxoWellcome Farmacêutica Lda Rua Dr António Loureiro Borges nº3 Arquiparque Miraflores Algés PORTUGAL Zipos 500mg Film-coated Tablets N/A Zoref Zoref Zoref 250mg Film-coated Tablets N/A Zoref 500mg Film-coated Tablets N/A Page 17

18 Member State (EU/EEA) Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Content (concentration) Romania Romania Romania Romania Slovakia Slovakia Glaxo Wellcome UK Limited, Glaxo Wellcome House, Berkeley Avenue, Greenford, Middlesex, UB6 0NN, UNITED KINGDOM Glaxo Wellcome UK Limited, Glaxo Wellcome House, Berkeley Avenue, Greenford, Middlesex, UB6 0NN, UNITED KINGDOM Glaxo Wellcome UK Limited, Glaxo Wellcome House, Berkeley Avenue, Greenford, Middlesex, UB6 0NN, UNITED KINGDOM Glaxo Wellcome UK Limited, Glaxo Wellcome House, Berkeley Avenue, Greenford, Middlesex, UB6 0NN, UNITED KINGDOM GlaxoSmithKline Slovakia s.r.o., Galvaniho7/A, Bratislava Slovak Republic GlaxoSmithKline Slovakia s.r.o., Galvaniho7/A, Bratislava Slovak Republic Zinnat Granules for Zinnat 125mg Film-coated Tablets N/A Zinnat 250mg Film-coated Tablets N/A Zinnat 500mg Film-coated Tablets N/A Zinnat 125 mg/5 ml Zinnat 250 mg/5 ml Page 18

19 Member State (EU/EEA) Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Content (concentration) Slovakia Slovakia Slovakia Slovenia Slovenia Slovenia Slovenia Spain GlaxoSmithKline Slovakia s.r.o., Galvaniho7/A, Bratislava Slovak Republic GlaxoSmithKline Slovakia s.r.o., Galvaniho7/A, Bratislava Slovak Republic GlaxoSmithKline Slovakia s.r.o., Galvaniho7/A, Bratislava Slovak Republic GSK d.o.o., Ljubljana Cvetkova ulica 29 SI-1000 Ljubljana SLOVENIA GSK d.o.o., Ljubljana Cvetkova ulica 29 SI-1000 Ljubljana SLOVENIA GSK d.o.o., Ljubljana Cvetkova ulica 29 SI-1000 Ljubljana SLOVENIA GSK d.o.o., Ljubljana Cvetkova ulica 29 SI-1000 Ljubljana SLOVENIA GlaxoSmithKline, S.A. Parque Tecnológico de Madrid C/Severo Ochoa, Tres Cantos (Madrid) SPAIN Zinnat 125 mg 125mg Film-coated Tablet N/A Zinnat 250 mg 250mg Film-coated Tablets N/A Zinnat 500 mg 500mg Film-coated Tablets N/A Zinnat 125 mg/5 ml zrnca za peroralno suspenzijo Zinnat 250 mg/5 ml zrnca za peroralno suspenzijo Zinnat 250 mg filmsko obložene tablete Zinnat 500 mg filmsko obložene tablete ZINNAT 125 mg granulado para suspensión oral en sobres 250mg Film-coated Tablets N/A 500mg Film-coated Tablets N/A 125mg N/A Page 19

20 Member State (EU/EEA) Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Content (concentration) Spain GlaxoSmithKline, S.A. Parque Tecnológico de Madrid C/Severo Ochoa, Tres Cantos (Madrid) SPAIN GlaxoSmithKline, S.A. ZINNAT 125 mg/ 5 ml granulado para suspensión oral en frasco Spain Spain Spain Spain Parque Tecnológico de Madrid C/Severo Ochoa, Tres Cantos (Madrid) SPAIN GlaxoSmithKline, S.A. Parque Tecnológico de Madrid C/Severo Ochoa, Tres Cantos (Madrid) SPAIN GlaxoSmithKline, S.A. Parque Tecnológico de Madrid C/Severo Ochoa, Tres Cantos (Madrid) SPAIN GlaxoSmithKline, S.A. Parque Tecnológico de Madrid C/Severo Ochoa, Tres Cantos (Madrid) SPAIN ZINNAT 250 mg granulado para suspensión oral en sobres ZINNAT 250 mg/ 5 ml granulado para suspensión oral en frasco ZINNAT 500 mg granulado para suspensión oral en sobres ZINNAT 125 mg comprimidos recubiertos con película 250mg 500mg N/A N/A 125mg Film-coated Tablets N/A Page 20

21 Member State (EU/EEA) Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Content (concentration) Spain Spain Spain Spain Spain GlaxoSmithKline, S.A. Parque Tecnológico de Madrid C/Severo Ochoa, Tres Cantos (Madrid) SPAIN GlaxoSmithKline, S.A. Parque Tecnológico de Madrid C/Severo Ochoa, Tres Cantos (Madrid) SPAIN GlaxoSmithKline, S.A. Parque Tecnológico de Madrid C/Severo Ochoa, Tres Cantos (Madrid) SPAIN GlaxoSmithKline, S.A. Parque Tecnológico de Madrid C/Severo Ochoa, Tres Cantos (Madrid) SPAIN GlaxoSmithKline, S.A. Parque Tecnológico de Madrid C/Severo Ochoa, Tres Cantos (Madrid) SPAIN ZINNAT 250 mg comprimidos recubiertos con película ZINNAT 500 mg comprimidos recubiertos con película SELAN 125 mg sobres SELAN 125 mg suspensión extemporánea SELAN 250 mg suspensión extemporánea 250mg Film-coated Tablets N/A 500mg Film-coated Tablets N/A 125mg N/A Page 21

22 Member State (EU/EEA) Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Content (concentration) Spain Spain Spain Spain Spain GlaxoSmithKline, S.A. Parque Tecnológico de Madrid C/Severo Ochoa, Tres Cantos (Madrid) SPAIN GlaxoSmithKline, S.A. Parque Tecnológico de Madrid C/Severo Ochoa, Tres Cantos (Madrid) SPAIN GlaxoSmithKline, S.A. Parque Tecnológico de Madrid C/Severo Ochoa, Tres Cantos (Madrid) SPAIN GlaxoSmithKline, S.A. Parque Tecnológico de Madrid C/Severo Ochoa, Tres Cantos (Madrid) SPAIN Wellcome Farmacéutica, S.A. Parque Tecnológico de Madrid C/Severo Ochoa, Tres Cantos (Madrid) SPAIN SELAN 500 mg sobres SELAN 125 mg comprimidos SELAN 250 mg comprimidos SELAN 500 mg comprimidos NIVADOR 125 mg/5 ml granulado para suspensión oral en frasco 500mg N/A 125mg Film-coated Tablets N/A 250mg Film-coated Tablets N/A 500mg Film-coated Tablets N/A 125mg N/A Page 22

23 Member State (EU/EEA) Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Content (concentration) Spain Spain Spain Spain Spain Spain Wellcome Farmacéutica, S.A..- Parque Tecnológico de MadridC/Severo Ochoa, Tres Cantos (Madrid) SPAIN Wellcome Farmacéutica, S.A. P.T.M.- C/Severo Ochoa, Tres Cantos (Madrid) SPAIN Wellcome Farmacéutica, S.A. P.T.M.- C/Severo Ochoa, Tres Cantos (Madrid) SPAIN Wellcome Farmacéutica, S.A. P.T.M.- C/Severo Ochoa, Tres Cantos (Madrid) SPAIN Wellcome Farmacéutica, S.A. P.T.M.- C/Severo Ochoa, Tres Cantos (Madrid) SPAIN Wellcome Farmacéutica, S.A. P.T.M.- C/Severo Ochoa, Tres Cantos (Madrid) SPAIN NIVADOR 125 mg/5 ml granulado para suspensión oral en frasco NIVADOR 250 mg granulado para suspensión oral en sobres NIVADOR 250 mg/5 ml granulado para suspensión oral en frasco NIVADOR 500 mg granulado para suspensión oral en sobres NIVADOR 250 mg comprimidos recubiertos con película NIVADOR 500 mg comprimidos recubiertos con película 250mg 500mg N/A N/A 250mg Film-coated Tablets N/A 500mg Film-coated Tablets N/A Page 23

24 Member State (EU/EEA) Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Content (concentration) Spain Spain Spain Spain Sweden Allen Farmacéutica, S.A. Parque Tecnológico de Madrid C/ Severo Ochoa, Tres Cantos (Madrid) SPAIN Allen Farmacéutica, S.A. Parque Tecnológico de Madrid C/ Severo Ochoa, Tres Cantos (Madrid) SPAIN Allen Farmacéutica, S.A. Parque Tecnológico de Madrid C/ Severo Ochoa, Tres Cantos (Madrid) SPAIN Allen Farmacéutica, S.A. Parque Tecnológico de Madrid C/ Severo Ochoa, Tres Cantos (Madrid) SPAIN GlaxoSmithKline AB Box Solna SWEDEN Cefuroxima Allen 250 mg comprimidos recubiertos con película EFG Cefuroxima Allen 500 mg comprimidos recubiertos con película EFG Cefuroxima Solasma 250 mg comprimidos recubiertos con película EFG Cefuroxima Solasma 500 mg comprimidos recubiertos con película EFG Zinnat 250 mg Film-coated Tablets N/A 500 mg Film-coated Tablets N/A 250 mg Film-coated Tablets N/A 500 mg Film-coated Tablets N/A 25mg/ml N/A Page 24

25 Member State (EU/EEA) Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Content (concentration) Sweden United Kingdom United Kingdom United Kingdom United Kingdom United Kingdom GlaxoSmithKline AB Box Solna SWEDEN Glaxo Wellcome UK Ltd, Stockley Park West, Uxbridge, Middlesex, UB11 1BT Glaxo Wellcome UK Ltd, Stockley Park West, Uxbridge, Middlesex, UB11 1BT Glaxo Wellcome UK Ltd, Stockley Park West, Uxbridge, Middlesex, UB11 1BT Glaxo Wellcome UK Ltd, Stockley Park West, Uxbridge, Middlesex, UB11 1BT Glaxo Wellcome UK Ltd, Stockley Park West, Uxbridge, Middlesex, UB11 1BT Zinnat 250mg Film-coated Tablets N/A Zinnat Zinnat Zinnat 125mg Film-coated Tablets N/A Zinnat 250mg Film-coated Tablets N/A Zinnat 500mg Film-coated Tablets N/A Page 25

26 Annex II Scientific conclusions and grounds for the variation to the terms of the Marketing Authorisations Page 26

27 Scientific conclusions Overall summary of the scientific evaluation of Zinnat and associated names (see Annex I) Zinnat contains cefuroxime axetil which is an oral pro-drug of cefuroxime, a second generation cephalosporin antibacterial agent. Cefuroxime exerts a bactericidal action by inhibiting bacterial enzymes necessary for cell-wall synthesis (peptidoglycan synthesis), thereby causing cell death. Zinnat was first approved in Europe in the late 1980 s and is available as oral formulations. Zinnat was included in the list of products for Summary of Product Characteristics (SmPC) harmonisation, due to the divergent national decisions taken by Member States concerning the authorisation of the abovementioned product. A referral under Article 30(2) of Directive 2001/83/EC was therefore triggered to resolve these divergences and thus harmonise the Product Information (PI) across the EU. Section Therapeutic indications The CHMP noted the large degree of divergences in the nationally approved indications and therefore reviewed the available data supporting each indvidual indication. Acute streptococcal tonsillitis and pharyngitis Having reviewed the submitted data, including studies by Aujard, 1995, Gooch, 1993 and Scholz, 2004, as well as studies by the German Society for Paediatric Infectious Diseases and an open, parallel group MAH-sponsored study conducted in general practice centres in the UK, France and Germany in 1989, the CHMP considered that the data supported the proposed indication. Acute bacterial sinusitis The CHMP noted that acute bacterial sinusitis is difficult to differentiate from the much more common viral sinusitis and that antibacterial treatment is often not warranted. However, having reviewed the submitted data, including studies by Kristo, 2005, Falagas, 2008, Zervos, 2003 as well as a Cochrane systematic review conducted by Ahovuo-Saloranta, 2008, a meta-anlysis by Young, 2008 and a systematic review by Ip, 2005, the CHMP considered the proposed indication to be acceptable. Acute otitis media Based on the submitted data, including studies by Hoberman, 2011, Tähtinen, 2011, Pessey, 1999, Gooch, 1996, McLinn, 1994, McLinn, 1990, Schwarz, 1991, Brodie, 1990 and Pichichero, 1990, the CHMP considered the proposed indication to be acceptable. Community acquired pneumonia The CHMP reviewed all available data and also noted that less susceptible pathogens cannot be managed by using higher doses of cefuroxime axetil than the maximum daily dose of 500 mg, due to the toxic degradation products of cefuroxime axetil and a lack of safety data. Having reviewed the minimum inhibitory concentrations (MIC) distributions for common respiratory pathogens such as penicillin-intermediate S. pneumoniae, H. influenzae and M.catarrhalis (Bulitta et al, 2009), the CHMP considered that the changes in MIC distributions over the last decades have impacted the suitability of cefuroxime axetil in this indication. The CHMP considered that no suitable dosing regimen could be identified to provide adequate coverage for less susceptible pathogens which have MIC up to 1 mg/l. The CHMP therefore concluded that cefuroxime axetil is not an appropriate agent for the empirical treatment of community acquired pneumonia and recommends the removal of this indication. Acute exacerbations of chronic bronchitis Having reviewed the submitted clinical documentation, which consisted of four adequately designed relatively large (>300 patients) double-blinded, comparative studies, the CHMP considered the proposed indication to be acceptable. Urinary tract infections The CHMP noted that no studies were provided to support the indication urethritis and therefore recommends the removal of this indication. Having reviewed the available data, the CHMP agreed that cefuroxime can be a valuable treatment option in the indications pyelonephritis and cystitis, including in children and pregnant women and therefore considered these indications acceptable. Page 27

28 Gonorrhoea The CHMP considered that treatment with cefuroxime axetil might not curtail further transmission of the infection. The CHMP also noted that the 2009 European Guideline on the Diagnosis and Treatment of Gonorrhoea in Adults does not include cefuroxime on the list of antibiotics recommended in this indication, due to its suboptimal pharmacokinetic and pharmacodynamic (PK/PD) characteristics which may lead to worse effectiveness and to the selection of the resistant bacteria strains (Aison et al, 2004). Based on the available data, the CHMP concluded that cefuroxime axetil is not suitable in the treatment of uncomplicated gonorrhoea (urethritis and cervicitis) and therefore recommends the removal of the proposed indication. Skin and soft tissue infections The CHMP noted that the bacterial species most frequently involved in skin and soft tissue infections (i.e. staphylococci and streptococci) are sensitive to cefuroxime. Based on the available data, including one double blind study and several supporting studies, the CHMP concluded that there is sufficient data in support of the indication uncomplicated skin and soft tissue infections. Lyme disease The CHMP reviewed the data from five randomised controlled studies, two of which included patients aged >12 years (Nadelman 1995; Lugar 1995), one which included patients aged >15 years (Cerar 2010), one study including children aged < 15 years (Arnez 1995) and one study including children aged between 6 months - 12 years. Based on the submitted study data, the CHMP considered the indication for the treatment of early Lyme disease to be acceptable. In conclusion, the CHMP adopted the following harmonised indications and wording for Section 4.1: Zinnat is indicated for the treatment of the infections listed below in adults and children from the age of 3 months (see sections 4.4 and 5.1). Acute streptococcal tonsillitis and pharyngitis. Acute bacterial sinusitis. Acute otitis media. Acute exacerbations of chronic bronchitis. Cystitis. Pyelonephritis. Uncomplicated skin and soft tissue infections. Treatment of early Lyme disease. Consideration should be given to official guidance on the appropriate use of antibacterial agents. Section Posology and method of administration The CHMP noted the large degree of divergences in the nationally approved posologies and recommendations and therefore reviewed the available data to support a harmonised Section 4.2. The CHMP considered that the available clinical and PK/PD data confirm that a twice daily regimen of cefuroxime axetil is an effective dosage and that the use of cefuroxime axetil given three times daily is unsupported by the clinical and safety data. The CHMP reviewed the dosage recommendations for each individual indication and agreed that infections suspected or proven to be due to less susceptible bacterial species (such as penicillin intermediate S. pneumonia, M. catarrhalis and H. influenzae) should be treated with 500 mg administered every 12 hours. For the cystitis indication, the CHMP recommended an adult dosing regimen of 250 mg BID, to ensure adequate urinary concentrations of cefuroxime and thus the eradication of the key uropathogens implicated. In children, the CHMP similarly recommended a dosage of 15 mg/kg BID (250 mg twice daily up to 500 mg daily) for the cystitis indication. For Lyme disease, the CHMP considered that the existing clinical data supported treatment for 14 days, with a range of 10 to 21 days (European Union Concerted Action on Lyme Borreliosis, 2010), in adults and in paediatric patients. For the paediatric population, the CHMP agreed that the dosage should be 15 mg/kg twice daily, to a maximum of 250 mg twice daily. The section on paediatric patients was revised extensively, including a revision of the table of dosing recommendations for children below 40 kg to describe dosage and duration per indication as well as the dosing calculations depending on the patient s body mass. The CHMP also agreed on a cut-off age, stating that there is no experience of using Zinnat in children under the age of 3 months. In conclusion, the CHMP adopted harmonised posology recommendations for adults and children. Page 28

29 The CHMP inserted a statement advising that the cefuroxime axetil suspension formulation is not bioequivalent to the tablet formulation and are not substitutable on a milligram-per-milligram basis, due to differences in bioavailability and the time-concentration curve. The CHMP removed the option of parenteral-to-oral sequential therapy for all patients,, due to the significant reduction in exposure to the active drug when switching to the oral formulation. Regarding patients with renal impairment, the CHMP reviewed the data and concluded that the proposed dosing guidelines in patients with renal impairment were acceptable. Regarding patients with hepatic impairment, the CHMP noted that there is no available data. In conclusion, the CHMP adopted a harmonised wording for Section 4.2. Minor divergences in other sections of SmPC, labelling and package leaflet The CHMP also adopted a harmonised wording for the remaining sections of the Zinnat SmPC and brought the labelling and the package leaflet in line with the adopted harmonised SmPC. Grounds for amendment of the summary of product characteristics, labelling and package leaflet The basis for this referral procedure was a harmonisation of the summary of product characteristics, labelling and package leaflet. Having considered the data submitted by the Marketing Authorisation Holder, the rapporteur and co-rapporteur assessment reports and the scientific discussions within the Committee, the CHMP was of the opinion that the benefit-risk ratio of Zinnat and associated names is favourable. Whereas The committee considered the referral under Article 30 of Directive 2001/83/EC, The committee considered the identified divergences for Zinnat and associated names regarding the therapeutic indications and the posology and method of administration sections, as well as in the remaining sections of the SmPC, The committee reviewed the data submitted by the MAH, including data from clinical trials, published literature and other clinical documentation, justifying the proposed harmonisation of the product information; The committee agreed the harmonisation of the summary of product characteristic, labelling and package leaflet proposed by the marketing authorisation holders, the CHMP has recommended the variation to the terms of the marketing authorisations for which the summary of product characteristics, labelling and package leaflet are set out in Annex III for Zinnat and associated names (see Annex I). Page 29

30 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. Page 30

31 SUMMARY OF PRODUCT CHARACTERISTICS Page 31

32 1. NAME OF THE MEDICINAL PRODUCT Zinnat and associated names (see Annex I) 125 mg film-coated tablets Zinnat and associated names (see Annex I) 250 mg film-coated tablets Zinnat and associated names (see Annex I) 500 mg film-coated tablets Zinnat and associated names (see Annex I) 125 mg/5 ml granules for oral suspension Zinnat and associated names (see Annex I) 250 mg/5 ml granules for oral suspension Zinnat and associated names (see Annex I) 125 mg granules for oral suspension Zinnat and associated names (see Annex I) 250 mg granules for oral suspension Zinnat and associated names (see Annex I) 500 mg granules for oral suspension [See Annex I - To be completed nationally] 2. QUALITATIVE AND QUANTITATIVE COMPOSITION 3. PHARMACEUTICAL FORM 125 mg, 250 mg, 500 mg film-coated tablets Film-coated tablet (tablet) 125 mg/5 ml, 250 mg/5 ml granules for oral suspension Granules for oral suspension 125 mg, 250 mg, 500 mg granules for oral suspension Granules for oral suspension 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Zinnat is indicated for the treatment of the infections listed below in adults and children from the age of 3 months (see sections 4.4 and 5.1). Acute streptococcal tonsillitis and pharyngitis. Acute bacterial sinusitis. Acute otitis media. Acute exacerbations of chronic bronchitis. Cystitis. Pyelonephritis. Uncomplicated skin and soft tissue infections. Treatment of early Lyme disease. Consideration should be given to official guidance on the appropriate use of antibacterial agents. Page 32

33 4.2 Posology and method of administration Posology The usual course of therapy is seven days (may range from five to ten days). Table 1. Adults and children ( 40 kg) Indication Dosage Acute tonsillitis and pharyngitis, acute bacterial 250 mg twice daily sinusitis Acute otitis media 500 mg twice daily Acute exacerbations of chronic bronchitis 500 mg twice daily Cystitis 250 mg twice daily Pyelonephritis 250 mg twice daily Uncomplicated skin and soft tissue infections 250 mg twice daily Lyme disease 500 mg twice daily for 14 days (range of 10 to 21 days) Table 2. Children (<40 kg) Indication Acute tonsillitis and pharyngitis, acute bacterial sinusitis Children aged two years or older with otitis media or, where appropriate, with more severe infections Cystitis Pyelonephritis Uncomplicated skin and soft tissue infections Lyme disease Dosage 10 mg/kg twice daily to a maximum of 125 mg twice daily 15 mg/kg twice daily to a maximum of 250 mg twice daily 15 mg/kg twice daily to a maximum of 250 mg twice daily 15 mg/kg twice daily to a maximum of 250 mg twice daily for 10 to 14 days 15 mg/kg twice daily to a maximum of 250 mg twice daily 15 mg/kg twice daily to a maximum of 250 mg twice daily for 14 days (10 to 21 days) There is no experience of using Zinnat in children under the age of 3 months. Cefuroxime axetil tablets and cefuroxime axetil granules for oral suspension are not bioequivalent and are not substitutable on a milligram-per-milligram basis (see section 5.2). 125 mg/5 ml, 250 mg/5 ml granules for oral suspension In infants (from the age of 3 months) and children with a body mass of less than 40 kg, it may be preferable to adjust dosage according to weight or age. The dose in infants and children 3 months to 18 years is 10 mg/kg twice daily for most infections, to a maximum of 250 mg daily. In otitis media or more severe infections the recommended dose is 15 mg/kg twice daily to a maximum of 500 mg daily. The following two tables, divided by age group, serve as a guideline for simplified administration, e.g measuring spoon (5 ml), for the 125 mg/5 ml or the 250 mg/5 ml multi-dose suspension if provided, and 125 mg or 250 mg single dose sachets. Table mg/kg dosage for most infections Page 33

34 Age Dose (mg) twice daily Volume per dose (ml) No. of sachets per dose 125 mg 250 mg 125 mg 250 mg 3 to 6 months 40 to months to 2 years 60 to to to 18 years Table mg/kg dosage for otitis media and more serious infections Age Dose (mg) twice daily Volume per dose (ml) No. of sachets per dose 125 mg 250 mg 125 mg 250 mg 3 to 6 months 60 to months to 2 90 to to (125 mg) - years 2 to 18 years 180 to to to 5 2 (250 mg) 1 (250 mg) Renal impairment The safety and efficacy of cefuroxime axetil in patients with renal failure have not been established. Cefuroxime is primarily excreted by the kidneys. In patients with markedly impaired renal function it is recommended that the dosage of cefuroxime should be reduced to compensate for its slower excretion. Cefuroxime is effectively removed by dialysis. Table 5. Recommended doses for Zinnat in renal impairment Creatinine clearance T 1/2 (hrs) Recommended dosage 30 ml/min/1.73 m no dose adjustment necessary (standard dose of 125 mg to 500 mg given twice daily) ml/min/1.73 m standard individual dose given every 24 hours <10 ml/min/1.73 m standard individual dose given every 48 hours Patients on haemodialysis 2 4 a further standard individual dose should be given at the end of each dialysis Hepatic impairment There are no data available for patients with hepatic impairment. Since cefuroxime is primarily eliminated by the kidney, the presence of hepatic dysfunction is expected to have no effect on the pharmacokinetics of cefuroxime. Method of administration 125 mg, 250 mg, 500 mg film-coated tablets Zinnat tablets should be taken after food for optimum absorption. Zinnat tablets should not be crushed and are therefore unsuitable for treatment of patients who cannot swallow tablets. In children Zinnat oral suspension may be used. Page 34

35 125 mg/5 ml, 250 mg/5 ml granules for oral suspension and 125 mg, 250 mg, 500 mg granules for oral suspension For optimal absorption cefuroxime axetil suspension should be taken with food. For instructions on reconstitution of the medicinal product before administration, see section Contraindications Hypersensitivity to cefuroxime or to any of the excipients listed in section 6.1. Patients with known hypersensitivity to cephalosporin antibiotics. History of severe hypersensitivity (e.g. anaphylactic reaction) to any other type of betalactam antibacterial agent (penicillins, monobactams and carbapenems). 4.4 Special warnings and precautions for use Hypersensitivity reactions Special care is indicated in patients who have experienced an allergic reaction to penicillins or other betalactam antibiotics because there is a risk of cross-sensitivity. As with all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions have been reported. In case of severe hypersensitivity reactions, treatment with cefuroxime must be discontinued immediately and adequate emergency measures must be initiated. Before beginning treatment, it should be established whether the patient has a history of severe hypersensitivity reactions to cefuroxime, to other cephalosporins or to any other type of beta-lactam agent. Caution should be used if cefuroxime is given to patients with a history of non-severe hypersensitivity to other beta-lactam agents. Jarisch-Herxheimer reaction The Jarisch-Herxheimer reaction has been seen following cefuroxime axetil treatment of Lyme disease. It results directly from the bactericidal activity of cefuroxime axetil on the causative bacteria of Lyme disease, the spirochaete Borrelia burgdorferi. Patients should be reassured that this is a common and usually self-limiting consequence of antibiotic treatment of Lyme disease (see section 4.8). Overgrowth of non-susceptible microorganisms As with other antibiotics, use of cefuroxime axetil may result in the overgrowth of Candida. Prolonged use may also result in the overgrowth of other non-susceptible microorganisms (e.g. enterococci and Clostridium difficile), which may require interruption of treatment (see section 4.8). Antibacterial agent associated pseudomembranous colitis have been reported with nearly all antibacterial agents, including cefuroxime and may range in severity from mild to life threatening. This diagnosis should be considered in patients with diarrhoea during or subsequent to the administration of cefuroxime (see section 4.8). Discontinuation of therapy with cefuroxime and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given (see section 4.8). Interference with diagnostic tests Page 35

36 The development of a positive Coomb s Test associated with the use of cefuroxime may interfere with cross matching of blood (see section 4.8). As a false negative result may occur in the ferricyanide test, it is recommended that either the glucose oxidase or hexokinase methods are used to determine blood/plasma glucose levels in patients receiving cefuroxime axetil. Important information about excipients 125 mg, 250 mg, 500 mg film-coated tablets Zinnat tablets contain parabens which may cause allergic reactions (possibly delayed). 125 mg/5 ml, 250 mg/5 ml granules for oral suspension and 125 mg, 250 mg, 500 mg granules for oral suspension The sucrose content of cefuroxime axetil suspension and granules should be taken into account when treating diabetic patients and appropriate advice provided. 125 mg/5 ml granules for oral suspension Contains 3 g of sucrose per 5 ml dose 250 mg/5 ml granules for oral suspension Contains 2.3 g of sucrose per 5 ml dose 125 mg granules for oral suspension Contains 3 g of sucrose per unit dose 250 mg granules for oral suspension Contains 6.1 g of sucrose per unit dose 500 mg granules for oral suspension Contains 12.2 g of sucrose per unit dose Cefuroxime axetil suspension contains aspartame, which is a source of phenylalanine and so should be used with caution in patients with phenylketonuria. 4.5 Interaction with other medicinal products and other forms of interaction Drugs which reduce gastric acidity may result in a lower bioavailability of cefuroxime axetil compared with that of the fasting state and tend to cancel the effect of enhanced absorption after food. Cefuroxime axetil may affect the gut flora, leading to lower oestrogen reabsorption and reduced efficacy of combined oral contraceptives. Cefuroxime is excreted by glomerular filtration and tubular secretion. Concomitant use of probenicid is not recommended. Concurrent administration of probenecid significantly increases the peak concentration, area under the serum concentration time curve and elimination half-life of cefuroxime. Concomitant use with oral anticoagulants may give rise to increased INR. 4.6 Fertility, pregnancy and lactation Pregnancy Page 36

37 There are limited data from the use of cefuroxime in pregnant women. Studies in animals have shown no harmful effects on pregnancy, embryonal or foetal development, parturition or postnatal development. Zinnat should be prescribed to pregnant women only if the benefit outweighs the risk. Breastfeeding Cefuroxime is excreted in human milk in small quantities. Adverse effects at therapeutic doses are not expected, although a risk of diarrhoea and fungus infection of the mucous membranes cannot be excluded. Breastfeeding might have to be discontinued due to these effects. The possibility of sensitisation should be taken into account. Cefuroxime should only be used during breastfeeding after benefit/risk assessment by the physician in charge. Fertility There are no data on the effects of cefuroxime axetil on fertility in humans. Reproductive studies in animals have shown no effects on fertility. 4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed. However, as this medicine may cause dizziness, patients should be warned to be cautious when driving or operating machinery. 4.8 Undesirable effects The most common adverse reactions are Candida overgrowth, eosinophilia, headache, dizziness, gastrointestinal disturbances and transient rise in liver enzymes. The frequency categories assigned to the adverse reactions below are estimates, as for most reactions suitable data (for example from placebo-controlled studies) for calculating incidence were not available. In addition the incidence of adverse reactions associated with cefuroxime axetil may vary according to the indication. Data from large clinical studies were used to determine the frequency of very common to rare undesirable effects. The frequencies assigned to all other undesirable effects (i.e. those occurring at <1/10,000) were mainly determined using post-marketing data and refer to a reporting rate rather than true frequency. Placebo-controlled trial data were not available. Where incidences have been calculated from clinical trial data, these were based on drug-related (investigator assessed) data. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Treatment related adverse reactions, all grades, are listed below by MedDRA body system organ class, frequency and grade of severity. The following convention has been utilised for the classification of frequency: 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 and not known (cannot be estimated from the available data). System organ class Infections and infestations Common Uncommon Not known Candida overgrowth Clostridium difficile overgrowth Blood and lymphatic system disorders Immune system eosinophilia positive Coomb s test, thrombocytopenia, leukopenia (sometimes profound) haemolytic anaemia drug fever, serum sickness, Page 37

38 disorders Nervous system disorders headache, dizziness anaphylaxis, Jarisch-Herxheimer reaction Gastrointestinal disorders Hepatobiliary disorders Skin and subcutaneous tissue disorders diarrhoea, nausea, abdominal pain transient increases of hepatic enzyme levels vomiting skin rashes pseudomembranous colitis jaundice (predominantly cholestatic), hepatitis urticaria, pruritus, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (exanthematic necrolysis) (see Immune system disorders), angioneurotic oedema Description of selected adverse reactions Cephalosporins as a class tend to be absorbed onto the surface of red cells membranes and react with antibodies directed against the drug to produce a positive Coombs test (which can interfere with crossmatching of blood) and very rarely haemolytic anaemia. Transient rises in serum liver enzymes have been observed which are usually reversible. Paediatric population The safety profile for cefuroxime axetil in children is consistent with the profile in adults. 4.9 Overdose Overdose can lead to neurological sequelae including encephalopathy, convulsions and coma. Symptoms of overdose can occur if the dose is not reduced appropriately in patients with renal impairment (see sections 4.2 and 4.4). Serum levels of cefuroxime can be reduced by haemodialysis and peritoneal dialysis. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: antibacterials for systemic use, second-generation cephalosporins, ATC code: J01DC02 Mechanism of action Cefuroxime axetil undergoes hydrolysis by esterase enzymes to the active antibiotic, cefuroxime. Cefuroxime inhibits bacterial cell wall synthesis following attachment to penicillin binding proteins (PBPs). This results in the interruption of cell wall (peptidoglycan) biosynthesis, which leads to bacterial cell lysis and death. Mechanism of resistance Page 38