Annex I List of the names, pharmaceutical form, strengths of the medicinal products, route of administration, marketing authorisation holders in the Member States 1
Member State EU/EEA Austria Austria Austria Austria Belgium Belgium Belgium Belgium Bulgaria Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Pfizer Corporation Austria Ges.m.b.H. Floridsdorfer Hauptstrasse 1 A - 1210 Wien Austria Pfizer Corporation Austria Ges.m.b.H. Floridsdorfer Hauptstrasse 1 A - 1210 Wien Austria Pfizer Corporation Austria Ges.m.b.H. Floridsdorfer Hauptstrasse 1 A - 1210 Wien Austria Pfizer Corporation Austria Ges.m.b.H. Floridsdorfer Hauptstrasse 1 A - 1210 Wien Austria Pfizer SA Boulevard de la Plaine 17 B-1050 Brussels Belgium Pfizer SA Boulevard de la Plaine 17 B-1050 Brussels Belgium Pfizer SA Boulevard de la Plaine 17 B-1050 Brussels Belgium Pfizer SA Boulevard de la Plaine 17 B-1050 Brussels Belgium Pfizer Europe MA EEIG, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom Sortis 10 mg - Filmtabletten Sortis 20 mg - Filmtabletten Sortis 40 mg - Filmtabletten Sortis 80 mg - Filmtabletten 10mg Film-coated tablet Oral use 20mg Film-coated tablet Oral use 40mg Film-coated tablet Oral use 80mg Film-coated tablet Oral use Lipitor 10mg Film-coated tablet Oral use Lipitor 20mg Film-coated tablet Oral use Lipitor 40mg Film-coated tablet Oral use Lipitor 80mg Film-coated tablet Oral use Sortis 10mg Film-coated tablet Oral use 2
Member State EU/EEA Bulgaria Bulgaria Bulgaria Cyprus Cyprus Cyprus Czech Republic Czech Republic Marketing Authorisation Holder Pfizer Europe MA EEIG, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom Pfizer Europe MA EEIG, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom Pfizer Europe MA EEIG, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom Pfizer Hellas A. E. 243, Messoghion Ave., 154 51 Νeo Psychiko, Athens Greece Pfizer Hellas A. E. 243, Messoghion Ave., 154 51 Νeo Psychiko, Athens Greece Pfizer Hellas A. E. 243, Messoghion Ave., 154 51 Νeo Psychiko, Athens Greece Pfizer. s r.o Stroupežnického 17 150 00 Prague 5 Czech Republic Pfizer. s r.o Stroupežnického 17 150 00 Prague 5 Czech Republic Invented name Strength Pharmaceutical Form Route of administration Sortis 20mg Film-coated tablet Oral use Sortis 40mg Film-coated tablet Oral use Sortis 80mg Film-coated tablet Oral use Lipitor 10mg Film-coated tablet Oral use Lipitor 20mg Film-coated tablet Oral use Lipitor 40mg Film-coated tablet Oral use Sortis 10mg Film-coated tablet Oral use Sortis 20mg Film-coated tablet Oral use 3
Member State EU/EEA Czech Republic Czech Republic Denmark Denmark Denmark Denmark Estonia Estonia Marketing Authorisation Holder Pfizer. s r.o Stroupežnického 17 150 00 Prague 5 Czech Republic Pfizer. s r.o Stroupežnického 17 150 00 Prague 5 Czech Republic Pfizer ApS Lautrupvang 8 2750 Ballerup Denmark Pfizer ApS Lautrupvang 8 2750 Ballerup Denmark Pfizer ApS Lautrupvang 8 2750 Ballerup Denmark Pfizer ApS Lautrupvang 8 2750 Ballerup Denmark Pfizer Europe MA EEIG, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom Pfizer Europe MA EEIG, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom Invented name Strength Pharmaceutical Form Route of administration Sortis 40mg Film-coated tablet Oral use Sortis 80mg Film-coated tablet Oral use Zarator 10mg Film-coated tablet Oral use Zarator 20mg Film-coated tablet Oral use Zarator 40mg Film-coated tablet Oral use Zarator 80mg Film-coated tablet Oral use Sortis 10mg Film-coated tablet Oral use Sortis 20mg Film-coated tablet Oral use 4
Member State EU/EEA Estonia Estonia Finland Finland Finland Finland Finland Finland Marketing Authorisation Holder Pfizer Europe MA EEIG, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom Pfizer Europe MA EEIG, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom Pfizer Oy Tietokuja 4 00330 Helsinki Finland Pfizer Oy Tietokuja 4 00330 Helsinki Finland Pfizer Oy Tietokuja 4 00330 Helsinki Finland Pfizer Oy Tietokuja 4 00330 Helsinki Finland Pfizer Oy Tietokuja 4 00330 Helsinki Finland Pfizer Oy Tietokuja 4 00330 Helsinki Finland Invented name Strength Pharmaceutical Form Route of administration Sortis 40mg Film-coated tablet Oral use Sortis 80 mg 80mg Film-coated tablet Oral use Lipitor 10mg Film-coated tablet Oral use Lipitor 20mg Film-coated tablet Oral use Lipitor 40mg Film-coated tablet Oral use Lipitor 80mg Film-coated tablet Oral use Orbeos 10mg Film-coated tablet Oral use Orbeos 20mg Film-coated tablet Oral use 5
Member State EU/EEA Finland Finland France France France France Germany Germany Marketing Authorisation Holder Pfizer Oy Tietokuja 4 00330 Helsinki Finland Pfizer Oy Tietokuja 4 00330 Helsinki Finland Pfizer Holding France 23-25 Avenue du Docteur Lannelongue 75668 Paris Cedex 14 France Pfizer Holding France 23-25 Avenue du Docteur Lannelongue 75668 Paris Cedex 14 France Pfizer Holding France 23-25 Avenue du Docteur Lannelongue 75668 Paris Cedex 14 France Pfizer Holding France 23-25 Avenue du Docteur Lannelongue 75668 Paris Cedex 14 France Pfizer Pharma GmbH Linkstraße 10 10785 Berlin Germany Pfizer Pharma GmbH Linkstraße 10 10785 Berlin Germany Invented name Strength Pharmaceutical Form Route of administration Orbeos 40mg Film-coated tablet Oral use Orbeos 80mg Film-coated tablet Oral use Tahor 10mg Film-coated tablet Oral use Tahor 20mg Film-coated tablet Oral use Tahor 40mg Film-coated tablet Oral use Tahor 80mg Film-coated tablet Oral use Sortis 10 mg 10mg Film-coated tablet Oral use Sortis 20 mg 20mg Film-coated tablet Oral use 6
Member State EU/EEA Germany Germany Germany Germany Germany Germany Germany Germany Germany Marketing Authorisation Holder Pfizer Pharma GmbH Linkstraße 10 10785 Berlin Germany Pfizer Pharma GmbH Linkstraße 10 10785 Berlin Germany Pfizer Pharma GmbH Linkstraße 10 10785 Berlin Germany Pfizer Pharma GmbH Linkstraße 10 10785 Berlin Germany Pfizer Pharma GmbH Linkstraße 10 10785 Berlin Germany Pfizer Pharma GmbH Linkstraße 10 10785 Berlin Germany Pfizer Pharma GmbH Linkstraße 10 10785 Berlin Germany Pfizer Pharma GmbH Linkstraße 10 10785 Berlin Germany Pfizer Pharma GmbH Linkstraße 10 10785 Berlin Germany Invented name Strength Pharmaceutical Form Route of administration Sortis 40 mg 40mg Film-coated tablet Oral use Sortis 80 mg 80mg Film-coated tablet Oral use Liprimar 10 mg 10mg Film-coated tablet Oral use Liprimar 20 mg 20mg Film-coated tablet Oral use Liprimar 40 mg 40mg Film-coated tablet Oral use Liprimar 80 mg 80mg Film-coated tablet Oral use Atorvastatin Pfizer 10 mg Atorvastatin Pfizer 20 mg Atorvastatin Pfizer 40 mg 10mg Film-coated tablet Oral use 20mg Film-coated tablet Oral use 40mg Film-coated tablet Oral use 7
Member State EU/EEA Germany Greece Greece Greece Greece Greece Greece Greece Marketing Authorisation Holder Pfizer Pharma GmbH Linkstraße 10 10785 Berlin Germany Pfizer Hellas A. E. 243, Messoghion Ave., 154 51 Νeo Psychiko, Athens Greece Pfizer Hellas A. E. 243, Messoghion Ave., 154 51 Νeo Psychiko, Athens Greece Pfizer Hellas A. E. 243, Messoghion Ave., 154 51 Νeo Psychiko, Athens Greece Pfizer Hellas A. E. 243, Messoghion Ave., 154 51 Νeo Psychiko, Athens Greece WIN MEDICA Ltd 41 Papadiamantopoulou Street 115 28 Ilisia, Athens Greece WIN MEDICA Ltd 41 Papadiamantopoulou Street 115 28 Ilisia, Athens Greece WIN MEDICA Ltd 41 Papadiamantopoulou Street 115 28 Ilisia, Athens Greece Invented name Strength Pharmaceutical Form Route of administration Atorvastatin Pfizer 80 mg 80mg Film-coated tablet Oral use Lipitor 10mg Film-coated tablet Oral use Lipitor 20mg Film-coated tablet Oral use Lipitor 40mg Film-coated tablet Oral use Lipitor 80mg Film-coated tablet Oral use Zarator 10mg Film-coated tablet Oral use Zarator 20mg Film-coated tablet Oral use Zarator 40mg Film-coated tablet Oral use 8
Member State EU/EEA Greece Greece Greece Hungary Hungary Hungary Hungary Hungary Marketing Authorisation Holder Pfizer Hellas A. E. 243, Messoghion Ave., 154 51 Νeo Psychiko, Athens, Greece Pfizer Hellas A. E. 243, Messoghion Ave., 154 51 Νeo Psychiko, Athens, Greece Pfizer Hellas A. E. 243, Messoghion Ave., 154 51 Νeo Psychiko, Athens, Greece Pfizer KFT, 1123 Budapest, Alkotás u. 53. MOM Park "F" Ép. Hungary Pfizer KFT, 1123 Budapest, Alkotás u. 53. MOM Park "F" Ép. Hungary Pfizer KFT, 1123 Budapest, Alkotás u. 53. MOM Park "F" Ép. Hungary Pfizer KFT, 1123 Budapest, Alkotás u. 53. MOM Park "F" Ép. Hungary C.P. Pharma Gyógyszerkereskedelmi Kft. 2040 Budaörs Vasút u. 11., Hungary Invented name Strength Pharmaceutical Form Route of administration Edovin 10mg Film-coated tablet Oral use Edovin 20mg Film-coated tablet Oral use Edovin 40mg Film-coated tablet Oral use Sortis 10mg Film-coated tablet Oral use Sortis 20mg Film-coated tablet Oral use Sortis 40mg Film-coated tablet Oral use Sortis 80mg Film-coated tablet Oral use Obradon 10mg Film-coated tablet Oral use 9
Member State EU/EEA Hungary Hungary Hungary Iceland Iceland Iceland Iceland Ireland Marketing Authorisation Holder C.P. Pharma Gyógyszerkereskedelmi Kft. 2040 Budaörs Vasút u. 11. Hungary C.P. Pharma Gyógyszerkereskedelmi Kft. 2040 Budaörs Vasút u. 11. Hungary C.P. Pharma Gyógyszerkereskedelmi Kft. 2040 Budaörs Vasút u. 11. Hungary Pfizer ApS Lautrupvang 8 2750 Ballerup Denmark Pfizer ApS Lautrupvang 8 2750 Ballerup Denmark Pfizer ApS Lautrupvang 8 2750 Ballerup Denmark Pfizer ApS Lautrupvang 8 2750 Ballerup Denmark Pfizer Ireland Pharmaceuticals, Pottery Road, Dun Laoghaire, Co Dublin Ireland Invented name Strength Pharmaceutical Form Route of administration Obradon 20mg Film-coated tablet Oral use Obradon 40mg Film-coated tablet Oral use Obradon 80mg Film-coated tablet Oral use Zarator 10mg Film-coated tablet Oral use Zarator 20mg Film-coated tablet Oral use Zarator 40mg Film-coated tablet Oral use Zarator 80mg Film-coated tablet Oral use Lipitor 10mg Film-coated tablet Oral use 10
Member State EU/EEA Ireland Ireland Ireland Marketing Authorisation Holder Pfizer Ireland Pharmaceuticals, Pottery Road, Dun Laoghaire, Co Dublin Ireland Pfizer Ireland Pharmaceuticals, Pottery Road, Dun Laoghaire, Co Dublin Ireland Pfizer Ireland Pharmaceuticals, Pottery Road, Dun Laoghaire, Co Dublin Ireland Pfizer Italia S.r.l. Via Isonzo, 71 04100 Latina Pfizer Italia S.r.l. Via Isonzo, 71 04100 Latina Pfizer Italia S.r.l. Via Isonzo, 71 04100 Latina Pfizer Italia S.r.l. Via Isonzo, 71 04100 Latina Bioindustria Farmaceutici S.r.l Via Isonzo, 71 04100 Latina Bioindustria Farmaceutici S.r.l Via Isonzo, 71 04100 Latina Invented name Strength Pharmaceutical Form Route of administration Lipitor 20mg Film-coated tablet Oral use Lipitor 40mg Film-coated tablet Oral use Lipitor 80mg Film-coated tablet Oral use Xarator 10mg Film-coated tablet Oral use Xarator 20mg Film-coated tablet Oral use Xarator 40mg Film-coated tablet Oral use Xarator 80mg Film-coated tablet Oral use Lipitor 10mg Film-coated tablet Oral use Lipitor 20mg Film-coated tablet Oral use 11
Member State EU/EEA Marketing Authorisation Holder Bioindustria Farmaceutici S.r.l Via Isonzo, 71 04100 Latina Bioindustria Farmaceutici S.r.l Via Isonzo, 71 04100 Latina Pfizer Italia S.r.l. Via Isonzo, 71 04100 Latina Pfizer Italia S.r.l. Via Isonzo, 71 04100 Latina Pfizer Italia S.r.l. Via Isonzo, 71 04100 Latina Pfizer Italia S.r.l. Via Isonzo, 71 04100 Latina Laboratori Guidotti S.p.A. Via Livornese 897 - La Vettola 56122 Pisa Laboratori Guidotti S.p.A. Via Livornese 897 - La Vettola 56122 Pisa Invented name Strength Pharmaceutical Form Route of administration Lipitor 40mg Film-coated tablet Oral use Lipitor 80mg Film-coated tablet Oral use Torvast 10mg Film-coated tablet Oral use Torvast 20mg Film-coated tablet Oral use Torvast 40mg Film-coated tablet Oral use Torvast 80mg Film-coated tablet Oral use Totalip 10mg Film-coated tablet Oral use Totalip 20mg Film-coated tablet Oral use 12
Member State EU/EEA Latvia Latvia Latvia Latvia Lithuania Lithuania Marketing Authorisation Holder Laboratori Guidotti S.p.A. Via Livornese 897 - La Vettola 56122 Pisa Laboratori Guidotti S.p.A. Via Livornese 897 - La Vettola 56122 Pisa Pfizer Limited Ramsgate Road, Sandwich Kent CT13 9NJ United Kingdom Pfizer Limited Ramsgate Road, Sandwich Kent CT13 9NJ United Kingdom Pfizer Limited Ramsgate Road, Sandwich Kent CT13 9NJ United Kingdom Pfizer Limited Ramsgate Road, Sandwich Kent CT13 9NJ United Kingdom Pfizer Limited Ramsgate Road, Sandwich Kent CT13 9NJ United Kingdom Pfizer Limited Ramsgate Road, Sandwich Kent CT13 9NJ United Kingdom Invented name Strength Pharmaceutical Form Route of administration Totalip 40mg Film-coated tablet Oral use Totalip 80mg Film-coated tablet Oral use Sortis 10mg Film-coated tablet Oral use Sortis 20mg Film-coated tablet Oral use Sortis 40mg Film-coated tablet Oral use Sortis 80mg Film-coated tablet Oral use Sortis 10mg Film-coated tablet Oral use Sortis 20mg Film-coated tablet Oral use 13
Member State EU/EEA Lithuania Lithuania Luxembourg Luxembourg Luxembourg Luxembourg Malta Malta Malta Marketing Authorisation Holder Pfizer Limited Ramsgate Road, Sandwich Kent CT13 9NJ United Kingdom Pfizer Limited Ramsgate Road, Sandwich Kent CT13 9NJ United Kingdom Pfizer SA Boulevard de la Plaine 17 B-1050 Brussels Belgium Pfizer SA Boulevard de la Plaine 17 B-1050 Brussels Belgium Pfizer SA Boulevard de la Plaine 17 B-1050 Brussels Belgium Pfizer SA Boulevard de la Plaine 17 B-1050 Brussels Belgium Pfizer Hellas S.A. 243, Messoghion Ave., 154 51 Νeo Psychiko, Athens, Greece Pfizer Hellas S.A. 243, Messoghion Ave., 154 51 Νeo Psychiko, Athens, Greece Pfizer Hellas S.A. 243, Messoghion Ave., 154 51 Νeo Psychiko, Athens, Greece Invented name Strength Pharmaceutical Form Route of administration Sortis 40mg Film-coated tablet Oral use Sortis 80mg Film-coated tablet Oral use Lipitor 10mg Film-coated tablet Oral use Lipitor 20mg Film-coated tablet Oral use Lipitor 40mg Film-coated tablet Oral use Lipitor 80mg Film-coated tablet Oral use Lipitor 10mg Film-coated tablet Oral use Lipitor 20mg Film-coated tablet Oral use Lipitor 40mg Film-coated tablet Oral use 14
Member State EU/EEA Malta Netherlands Netherlands Netherlands Netherlands Norway Norway Norway Norway Marketing Authorisation Holder Pfizer Hellas S.A. 243, Messoghion Ave., 154 51 Νeo Psychiko, Athens, Greece Pfizer bv Rivium Westlaan 142 2909 LD Capelle a/d IJssel The Netherlands Pfizer bv Rivium Westlaan 142 2909 LD Capelle a/d IJssel The Netherlands Pfizer bv Rivium Westlaan 142 2909 LD Capelle a/d IJssel The Netherlands Pfizer bv Rivium Westlaan 142 2909 LD Capelle a/d IJssel The Netherlands Pfizer AS Pb. 3 1324 Lysaker Norway Pfizer AS Pb. 3 1324 Lysaker Norway Pfizer AS Pb. 3 1324 Lysaker Norway Pfizer AS Pb. 3 1324 Lysaker Norway Invented name Strength Pharmaceutical Form Route of administration Lipitor 80mg Film-coated tablet Oral use Lipitor 10 10mg Film-coated tablet Oral use Lipitor 20 20mg Film-coated tablet Oral use Lipitor 40 40mg Film-coated tablet Oral use Lipitor 80 80mg Film-coated tablet Oral use Lipitor 10mg Film-coated tablet Oral use Lipitor 20mg Film-coated tablet Oral use Lipitor 40mg Film-coated tablet Oral use Lipitor 80mg Film-coated tablet Oral use 15
Member State EU/EEA Poland Poland Poland Poland Portugal Portugal Portugal Portugal Marketing Authorisation Holder Pfizer Europe MA EEIG, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom Pfizer Europe MA EEIG, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom Pfizer Europe MA EEIG, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom Pfizer Polska Sp.z o.o.ul. Rzymowskiego 28 02-697 Warszawa Poland Laboratorios Pfizer, Lda. Lagoas Park, Edifício 10 2740-271 Porto Salvo Portugal Laboratorios Pfizer, Lda. Lagoas Park, Edifício 10 2740-271 Porto Salvo Portugal Laboratorios Pfizer, Lda. Lagoas Park, Edifício 10 2740-271 Porto Salvo Portugal Laboratorios Pfizer, Lda. Lagoas Park, Edifício 10 2740-271 Porto Salvo Portugal Invented name Strength Pharmaceutical Form Route of administration Sortis 10 10mg Film-coated tablet Oral use Sortis 20 20mg Film-coated tablet Oral use Sortis 40 40mg Film-coated tablet Oral use Sortis 80 80 mg Film-coated tablet Oral use Zarator 10mg Film-coated tablet Oral use Zarator 20mg Film-coated tablet Oral use Zarator 40mg Film-coated tablet Oral use Zarator 80 mg Film-coated tablet Oral use 16
Member State EU/EEA Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Portugal Portugal Portugal Portugal Portugal Portugal Portugal Parke-Davis - Produtos Farmaceuticos Lda. Lagoas Park, Edifício 10 2740-271 Porto Salvo Portugal Parke-Davis - Produtos Farmaceuticos Lda. Lagoas Park, Edifício 10 2740-271 Porto Salvo Portugal Parke-Davis - Produtos Farmaceuticos Lda. Lagoas Park, Edifício 10 2740-271 Porto Salvo Portugal Parke-Davis - Produtos Farmaceuticos Lda. Lagoas Park, Edifício 10 2740-271 Porto Salvo Portugal Farmogene - Produtos Farmacêuticos, Lda Lagoas Park, Edifício 10 2740-271 Porto Salvo Portugal Farmogene - Produtos Farmacêuticos, Lda Lagoas Park, Edifício 10 2740-271 Porto Salvo Portugal Farmogene - Produtos Farmacêuticos, Lda Lagoas Park, Edifício 10 2740-271 Porto Salvo Portugal Atorvastatina Parke- Davis Atorvastatina Parke- Davis Atorvastatina Parke- Davis Atorvastatina Parke- Davis 10mg Film-coated tablet Oral use 20mg Film-coated tablet Oral use 40mg Film-coated tablet Oral use 80 mg Film-coated tablet Oral use Texzor 10mg Film-coated tablet Oral use Texzor 20mg Film-coated tablet Oral use Texzor 40mg Film-coated tablet Oral use 17
Member State EU/EEA Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Portugal Romania Romania Romania Romania Slovak Republic Slovak Republic Farmogene - Produtos Farmacêuticos, Lda Lagoas Park, Edifício 10 2740-271 Porto Salvo Portugal Pfizer Europe MA EEIG Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom Pfizer Europe MA EEIG Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom Pfizer Europe MA EEIG Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom Pfizer Europe MA EEIG Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom Pfizer Europe MA EEIG Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom Pfizer Europe MA EEIG Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom Texzor 80 mg Film-coated tablet Oral use Sortis 10mg Film-coated tablet Oral use Sortis 20mg Film-coated tablet Oral use Sortis 40mg Film-coated tablet Oral use Sortis 80 mg Film-coated tablet Oral use Sortis 10mg Film-coated tablet Oral use Sortis 20mg Film-coated tablet Oral use 18
Member State EU/EEA Slovak Republic Slovak Republic Slovenia Slovenia Slovenia Slovenia Marketing Authorisation Holder Pfizer Europe MA EEIG Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom Pfizer Europe MA EEIG Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom Pfizer Luxembourg SARL 51, Avenue J. F. Kennedy L-1855 Luxembourg Luxembourg Pfizer Luxembourg SARL 51, Avenue J. F. Kennedy L-1855 Luxembourg Luxembourg Pfizer Luxembourg SARL 51, Avenue J. F. Kennedy L-1855 Luxembourg Luxembourg Pfizer Luxembourg SARL 51, Avenue J. F. Kennedy L-1855 Luxembourg Luxembourg Parke Davis. S.L. Avda. de Europa 20B Parque Empresarial la Moraleja 28108 Alcobendas, (Madrid) Parke Davis. S.L. Avda. de Europa 20B Parque Empresarial la Moraleja 28108 Alcobendas, (Madrid) Invented name Strength Pharmaceutical Form Route of administration Sortis 40mg Film-coated tablet Oral use Sortis 80 mg Film-coated tablet Oral use Sortis 10 mg filmsko obložene tablete Sortis 20 mg filmsko obložene tablete Sortis 40 mg filmsko obložene tablete Sortis 80 mg filmsko obložene tablete Zarator 10 mg comprimidos recubiertos con película Zarator 20 mg comprimidos recubiertos con película 10mg Film-coated tablet Oral use 20mg Film-coated tablet Oral use 40mg Film-coated tablet Oral use 80 mg Film-coated tablet Oral use 10mg Film-coated tablet Oral use 20mg Film-coated tablet Oral use 19
Member State EU/EEA Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Parke Davis. S.L. Avda. de Europa 20B Parque Empresarial la Moraleja 28108 Alcobendas, (Madrid) Parke Davis. S.L. Avda. de Europa 20B Parque Empresarial la Moraleja 28108 Alcobendas, (Madrid) Pfizer, S.A. Avda. de Europa 20B Parque Empresarial la Moraleja 28108 Alcobendas, (Madrid) Pfizer, S.A. Avda. de Europa 20B Parque Empresarial la Moraleja 28108 Alcobendas, (Madrid) Pfizer, S.A. Avda. de Europa 20B Parque Empresarial la Moraleja 28108 Alcobendas, (Madrid) Pfizer, S.A. Avda. de Europa 20B Parque Empresarial la Moraleja 28108 Alcobendas, (Madrid) Nostrum Farma, S.A., Avda. de Europa 20B Parque Empresarial la Moraleja 28108 Alcobendas, (Madrid) Zarator 40 mg comprimidos recubiertos con película Zarator 80 mg comprimidos recubiertos con película Cardyl 10 mg comprimidos recubiertos con película Cardyl 20 mg comprimidos recubiertos con película Cardyl 40 mg comprimidos recubiertos con película Cardyl 80 mg comprimidos recubiertos con película Atorvastatina Nostrum 10 mg comprimidos recubiertos con película 40mg Film-coated tablet Oral use 80 mg Film-coated tablet Oral use 10mg Film-coated tablet Oral use 20mg Film-coated tablet Oral use 40mg Film-coated tablet Oral use 80 mg Film-coated tablet Oral use 10mg Film-coated tablet Oral use 20
Member State EU/EEA Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Nostrum Farma, S.A., Avda. de Europa 20B Parque Empresarial la Moraleja 28108 Alcobendas, (Madrid) Nostrum Farma, S.A., Avda. de Europa 20B Parque Empresarial la Moraleja 28108 Alcobendas, (Madrid) Nostrum Farma, S.A., Avda. de Europa 20B Parque Empresarial la Moraleja 28108 Alcobendas, (Madrid) PHARMACIA GRUPO PFIZER, S.L. Avda. de Europa 20B Parque Empresarial la Moraleja 28108 Alcobendas, (Madrid) PHARMACIA GRUPO PFIZER, S.L..Avda. de Europa 20B Parque Empresarial la Moraleja 28108 Alcobendas, (Madrid) PHARMACIA GRUPO PFIZER, S.L. Avda. de Europa 20B Parque Empresarial la Moraleja 28108 Alcobendas, (Madrid) PHARMACIA GRUPO PFIZER, S.L. Avda. de Europa 20B Parque Empresarial la Moraleja 28108 Alcobendas, (Madrid) Atorvastatina Nostrum 20 mg comprimidos recubiertos con película Atorvastatina Nostrum 40 mg comprimidos recubiertos con película Atorvastatina Nostrum 80 mg comprimidos recubiertos con película Atorvastatina Pharmacia 10 mg comprimidos recubiertos con película Atorvastatina Pharmacia 20 mg comprimidos recubiertos con película Atorvastatina Pharmacia 40 mg comprimidos recubiertos con película Atorvastatina Pharmacia 80 mg comprimidos recubiertos con película 20mg Film-coated tablet Oral use 40mg Film-coated tablet Oral use 80 mg Film-coated tablet Oral use 10mg Film-coated tablet Oral use 20mg Film-coated tablet Oral use 40mg Film-coated tablet Oral use 80 mg Film-coated tablet Oral use 21
Member State EU/EEA Sweden Sweden Sweden Sweden United Kingdom United Kingdom Marketing Authorisation Holder Almirall S.A. General Mitre, 151 08022 - Barcelona Almirall S.A. General Mitre, 151 08022 - Barcelona Almirall S.A. General Mitre, 151 08022 - Barcelona Almirall S.A. General Mitre, 151 08022 - Barcelona Pfizer AB 191 90 Sollentuna Sweden Pfizer AB 191 90 Sollentuna Sweden Pfizer AB 191 90 Sollentuna Sweden Pfizer AB 191 90 Sollentuna Sweden Pfizer Ireland Pharmaceuticals, Pottery Road Dun Laoghaire, Co Dublin Ireland Pfizer Ireland Pharmaceuticals, Pottery Road Dun Laoghaire, Co Dublin Ireland Invented name Strength Pharmaceutical Form Route of administration Prevencor 10 mg comprimidos recubiertos con película Prevencor 20 mg comprimidos recubiertos con película Prevencor 40 mg comprimidos recubiertos con película Prevencor 80 mg comprimidos recubiertos con película 10mg Film-coated tablet Oral use 20mg Film-coated tablet Oral use 40mg Film-coated tablet Oral use 80 mg Film-coated tablet Oral use Lipitor 10mg Film-coated tablet Oral use Lipitor 20mg Film-coated tablet Oral use Lipitor 40mg Film-coated tablet Oral use Lipitor 80 mg Film-coated tablet Oral use Lipitor 10mg Film-coated tablet Oral use Lipitor 20mg Film-coated tablet Oral use 22
Member State EU/EEA Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration United Kingdom United Kingdom Pfizer Ireland Pharmaceuticals, Pottery Road Dun Laoghaire, Co Dublin Ireland Pfizer Ireland Pharmaceuticals, Pottery Road Dun Laoghaire, Co Dublin Ireland Lipitor 40mg Film-coated tablet Oral use Lipitor 80 mg Film-coated tablet Oral use 23
Annex II Scientific conclusions and grounds for amendment of the summary of product characteristics, labelling and package leaflet presented by the European Medicines Agency 24
Scientific conclusions Overall summary of the scientific evaluation of Lipitor and associated names (see Annex I) Quality issues Variations to the drug product - atorvastatin calcium, small, round film-coated tablets - are comprehensively documented and the amendments proposed regarding the harmonisation are considered acceptable by the CHMP. The proposal for changes to the large, oval tablets is also considered to be acceptable. Efficacy and safety issues Clinical particulars Section 4.1 Therapeutic Indications Hypercholesterolemia The MAH s proposal regarding hypercholesterolaemia indications were mostly supported except for the proposal to include the wording that: Lipitor also raises HDL-cholesterol and lowers the LDL/HDL and total cholesterol/hdl ratios. This was not endorsed by the CHMP due to the fact that low HDL-levels is not accepted as a surrogate marker for cardiovascular disease. The following wording was agreed by the CHMP: Hypercholesterolaemia {PRODUCT NAME} is indicated as an adjunct to diet for reduction of elevated total cholesterol (total- C), LDL-cholesterol (LDL-C), apolipoprotein B, and triglycerides in patients with primary hypercholesterolaemia including familial hypercholesterolaemia (heterozygous variant) or combined (mixed) hyperlipidaemia (Corresponding to Types IIa and IIb of the Fredrickson classification) when response to diet and other nonpharmacological measures is inadequate. {PRODUCT NAME} is also indicated to reduce total-c and LDL-C in patients with homozygous familial hypercholesterolaemia as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are unavailable. Prevention of cardiovascular disease The proposed SmPC changes were based on data from the Anglo-Scandinavian Cardiac Outcomes Trial Lipid-Lowering Arm (ASCOT-LLA), and the Collaborative Atorvastatin Diabetes Study (CARDS). The similarities between the two clinical trials as well as the timing of completion of the studies allowed for a joint review in support of an indication for atorvastatin in the prevention of cardiovascular disease. The indication proposed by the MAH for the prevention of cardiovascular disease is in line with the wording agreed upon by the CHMP on 20-23 March 2006 (CHMP/76062/2006) during the Article 6(12) referral. The following wording was agreed by the CHMP: Prevention of cardiovascular disease Prevention of cardiovascular events in patients estimated to have a high risk for a first cardiovascular event (see section 5.1), as an adjunct to correction of other risk factors. Section 4.2 - Posology and method of administration No differences are made in dosing recommendations for the treatment of hypercholesterolaemia related to the starting dose regimen and the dose titration in 4 week intervals. For the hypercholesterolaemia indication, the MAH proposes removing the additional text around guidelines. As current guidelines for lipid lowering therapy are subject to constant change, the CHMP agreed that it would not seem to be helpful to fix such an advice in the informative texts. 25
For the indication relating to the prevention of cardiovascular disease, the dosing information is taken from the MRP SmPC. Regarding the time of medication intake and meals, the information is taken from the MRP SmPC, where it is recommended that each daily dose is given all at once, and at any time of the day, with or without food. The following wording was agreed by the CHMP: Posology The patient should be placed on a standard cholesterol-lowering diet before receiving {PRODUCT NAME} and should continue on this diet during treatment with {PRODUCT NAME}. The dose should be individualised according to baseline LDL-C levels, the goal of therapy, and patient response. The usual starting dose is 10 mg once a day. Adjustment of dose should be made at intervals of 4 weeks or more. The maximum dose is 80 mg once a day. Primary hypercholesterolaemia and combined (mixed) hyperlipidaemia The majority of patients are controlled with {PRODUCT NAME} 10 mg once a day. A therapeutic response is evident within 2 weeks, and the maximum therapeutic response is usually achieved within 4 weeks. The response is maintained during chronic therapy. Heterozygous familial hypercholesterolaemia Patients should be started with {PRODUCT NAME} 10 mg daily. Doses should be individualised and adjusted every 4 weeks to 40 mg daily. Thereafter, either the dose may be increased to a maximum of 80 mg daily or a bile acid sequestrant may be combined with 40 mg atorvastatin once daily. Homozygous familial hypercholesterolaemia Only limited data are available (see section 5.1). The dose of atorvastatin in patients with homozygous familial hypercholesterolemia is 10 to 80 mg daily (see section 5.1). Atorvastatin should be used as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) in these patients or if such treatments are unavailable. Prevention of cardiovascular disease In the primary prevention trials the dose was 10 mg/day. Higher doses may be necessary in order to attain (LDL-) cholesterol levels according to current guidelines Method of administration {PRODUCT NAME} is for oral administration. Each daily dose of atorvastatin is given all at once and may be given at any time of day with or without food. Regarding special populations: - The information derived from a compassionate use study in the homozygous familial hypercholesterolemia patient population has been moved to section 5.1 as suggested by the CHMP. - A review of the MAH s clinical trial data did not reveal a muscle safety concern in the renal impairment population and a review of the medical literature suggested that statins can be used safely in patients with chronic kidney disease (CKD). The MAH considered it important that physicians be aware of the potential increased risk in this population and monitor these patients for skeletal muscle effects, and a cross-reference to section 4.4 has been added referring to precautionary information regarding patient history of renal impairment as a potential risk factor for development of rhabdomyolysis and recommending closer monitoring for muscle symptoms. 26
- The MAH has followed the request by the CHMP to include a recommendation for caution for patients with hepatic impairment in section 4.2, with cross references to sections 4.4 and 5.2 of the harmonised SmPC. - Paediatric information currently exists in the Member States, and this has been harmonised and included. The following wording was agreed by the CHMP: Renal impairment No adjustment of dose is required (see section 4.4). Hepatic impairment {PRODUCT NAME} should be used with caution in patients with hepatic impairment (see sections 4.4 and 5.2). {PRODUCT NAME} is contraindicated in patients with active liver disease (see section 4.3). Use in the elderly Efficacy and safety in patients older than 70 using recommended doses are similar to those seen in the general population. Paediatric use Paediatric use should only be carried out by specialists. Experience in paediatrics is limited to a small number of patients (age 4-17 years) with severe dyslipidemias, such as homozygous familial hypercholesterolemia. The recommended starting dose in this population is 10 mg of atorvastatin per day. The dose may be increased to 80 mg daily, according to the response and tolerability. Developmental safety data in this population have not been evaluated. Information regarding Concomitant treatment with other medications has been included in section 4.5. Section 4.3 - Contra-indications Myopathy has not been included in the list of contraindications since no contraindication regarding myopathy was agreed for previous Art 30 procedures for pravastatin, simvastatin and fluvastatin. The CHMP agreed with the MAH s proposal. A contraindication in patients during pregnancy, while breast-feeding and in women of child-bearing potential not using appropriate contraceptive measures was included. Contraindications with regard to drug interactions were not included in this section as it is addressed in section 4.5. The following wording was agreed by the CHMP: {PRODUCT NAME} is contraindicated in patients: - with hypersensitivity to the active substance or to any of the excipients of this medicinal product - with active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal - during pregnancy, while breast-feeding and in women of child-bearing potential not using appropriate contraceptive measures (see section 4.6). Section 4.4 - Special warnings and precautions for use The list of clinically relevant CYP3A4-inhibitors or transporter inhibitors has been made more general including inhibitors for which there is no interaction data available but where significant interaction could be assumed, since an increased risk can be expected for all potent CYP3A4 or OATP1B1 inhibitors. Lower starting doses of atorvastatin for potent CYP3A4 inhibitors and lower maximum doses of atorvastatin for both potent and moderate CYP3A4 inhibitors have been recommended as requested by the CHMP. The temporary suspension of atorvastatin during fusidic acid therapy has been included in line with the Type II MRP variation (DE/H/0109/001-004/II/094). As requested by the CHMP the reference to nefazodone as a concomitant treatment was removed. 27
Section 4.5- Interaction with other medicinal products and other forms of interaction For pharmacokinetic interactions, introductory information has been retained in the text, whilst the interaction information as well as the corresponding clinical recommendation such as cut-off values for special dosage recommendations or other recommendations has been included. The four cut-off ranges as proposed by the MAH take into account the dose proportional increase in AUC exposure over the 10-80 mg atorvastatin dose range and the available strengths (10, 20, 40, and 80 mg) of atorvastatin tablets. The MAH has provided satisfactory justification for the proposed atorvastatin dosing recommendations associated with the specific fold-increases of atorvastatin exposure during coadministration with the interacting drugs. Lower starting doses of atorvastatin for potent CYP3A4 inhibitors and lower maximum doses of atorvastatin for both potent and moderate CYP3A4 inhibitors have been recommended as requested by the CHMP. The information in Section 4.5 (text and table formats) has been rearranged such that drug interactions are now grouped under either Effect of co-administered drugs on atorvastatin or Effect of atorvastatin on co-administered drugs. As requested by the CHMP, the MAH has included mechanistic information and extrapolations. Section 4.6 - Pregnancy and lactation The MAH proposes the inclusion of the contraindication in patients during pregnancy, while breastfeeding and in women of childbearing potential not using appropriate contraceptive measures with a cross reference to section 4.3 of the SmPC. The information that rare reports of congenital anomalies have been received following exposure to HMG-CoA reductase inhibitors has been included. There is no evidence to support a particular timeframe by which to discontinue atorvastatin treatment prior to conception. Hence, the MAH has not included this wording in the proposed harmonised SmPC. Section 4.7 - Effects on ability to drive and use machines The majority of markets currently have the proposed harmonised wording, which is in line with the SmPC guideline dated September 2009. The harmonized text is identical to the current approved MRP SPC. Section 4.8 - Undesirable effects The MAH conducted a review of the pooled data from the 17 completed placebo-controlled clinical trials in the atorvastatin clinical trial database as of June 24, 2008, when the review was initiated. The pooled dataset included a total of 16,066 patients, treated for a median period of 53 weeks. Discontinuation due to adverse reactions occurred in 5.2% of patients on atorvastatin compared to 4.0% of the patients on placebo. Data were reviewed for all doses combined (10-80mg) vs placebo, and adverse events were grouped by categories of organ systems. The adverse events in the database were all mapped to MedDRA dictionary terms. This review identified a number of new adverse events that have been added to the atorvastatin CDS and hence also to the SmPC, as well as some changes to the frequencies of existing adverse events. The MAH agreed to relocate the specified ADRs to their primary MedDRA SOC as requested by the CHMP. Changes to the wording of certain terms as well as justifications for retaining some others were accepted by the CHMP. Following agreement of the Statin Class wording by the PhVWP in November 2009, the agreed text has been included. As "insomnia" and "nightmares" have already been included in the SmPC and "memory loss" is found as "amnesia", additional terms were not considered to be necessary by the MAH, in order to fulfill the PhVWP Statin Class wording, and this proposal was accepted by the CHMP. The remaining undesirable effects mentioned in the PhVWP Statin Class wording have also been included. Section 4.9 Overdose The MAH has used the MRP SmPC text as the proposed harmonised SmPC text as the overdose wording across the Member State SmPCs is essentially identical to the current MRP SmPC text. 5. PHARMACOLOGICAL PROPERTIES Section 5.1 - Pharmacodynamic properties Summaries of the studies investigating the effect of atorvastatin on Atherosclerosis (REVERSAL study), Acute Coronary Syndrome (MIRACL trial), the Prevention of Cardiovascular Disease (ASCOT-LLA and CARDS trials), Recurrent Stroke (SPARCL study) were included. Information from the compassionateuse study in the homozygous familial hypercholesterolaemia patient population has also been included 28
in this section. Information on paediatric studies has not been included in this procedure as the Art 29 paediatric referral has no bearing on this Art 30 harmonisation referral. The procedures are independent and no data will be brought into one or the other procedure. Section 5.2 - Pharmacokinetic properties The MAH has used the MRP text as the harmonised SmPC including the proposed harmonised wording for special populations such as the elderly, paediatrics, gender differences, patients with renal and hepatic insufficiency and SLOC1B1 polymorphism (and its effects on atorvastatin exposure) have been included. Pharmacokinetic data in the paediatric population are not available. Section 5.3 - Preclinical safety data There is evidence from animal studies that HMG-CoA reductase inhibitors may influence the development of embryos or foetuses. In line with the SmPC guidance, dated September 2009, brief and qualitative statement covering the nonclinical safety profile of atorvastatin have been included. Grounds for amendment of the summary of product characteristics, labelling and package leaflet Variations to the drug product - atorvastatin calcium, small, round film-coated tablets - are comprehensively documented and the amendments proposed regarding the harmonisation are considered acceptable by the CHMP. The main areas of disharmony which were addressed by the MAH related to the indication, posology, special warnings and precaution for use, interaction with other medicinal products, pregnancy and lactation, undesirable effects, pharmacodynamic properties, pharmacokinetic properties and preclinical safety data. The MAH has submitted supporting data and arguments relating to these main areas, which have been assessed and considered acceptable by the CHMP. The resulting harmonised SPC, labelling and package leaflet was agreed by the CHMP. Whereas the scope of the referral was the harmonisation of the summary of products characteristics, labelling and package leaflet the summary of products characteristic, labelling and package leaflet proposed by the marketing authorisation holders have been assessed based on the documentation submitted and the scientific discussion within the Committee the CHMP has recommended the amendment of the marketing authorisations for which the summary of product characteristics, labelling and package leaflet are set out in Annex III for Lipitor and associated names (see Annex I). 29
Annex III Summary of product characteristics, labelling and package leaflet Note: This SPC, labelling and packages leaflet is the version valid at the time of Commission decision. After the Commission decision the Member State competent authorities, in liaison with the reference Member State, will update the product information as required. Therefore, this SPC, labelling and package leaflet may not necessarily represent the current text. 30
SUMMARY OF PRODUCT CHARACTERISTICS 31
1. NAME OF THE MEDICINAL PRODUCT LIPITOR and associated names (see Annex I) 10 mg film-coated tablets LIPITOR and associated names (see Annex I) 20 mg film-coated tablets LIPITOR and associated names (see Annex I) 40 mg film-coated tablets LIPITOR and associated names (see Annex I) 80 mg film-coated tablets [See Annex I - To be completed nationally] 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each film-coated tablet contains 10 mg atorvastatin (as atorvastatin calcium trihydrate). Each film-coated tablet contains 20 mg atorvastatin (as atorvastatin calcium trihydrate). Each film-coated tablet contains 40 mg atorvastatin (as atorvastatin calcium trihydrate). Each film-coated tablet contains 80 mg atorvastatin (as atorvastatin calcium trihydrate). Excipients: [To be completed nationally] For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet. [To be completed nationally] 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Hypercholesterolaemia {PRODUCT NAME} is indicated as an adjunct to diet for reduction of elevated total cholesterol (total-c), LDL-cholesterol (LDL-C), apolipoprotein B, and triglycerides in patients with primary hypercholesterolaemia including familial hypercholesterolaemia (heterozygous variant) or combined (mixed) hyperlipidaemia (Corresponding to Types IIa and IIb of the Fredrickson classification) when response to diet and other nonpharmacological measures is inadequate. {PRODUCT NAME} is also indicated to reduce total-c and LDL-C in patients with homozygous familial hypercholesterolaemia as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are unavailable. Prevention of cardiovascular disease Prevention of cardiovascular events in patients estimated to have a high risk for a first cardiovascular event (see section 5.1), as an adjunct to correction of other risk factors. 32
4.2 Posology and method of administration Posology The patient should be placed on a standard cholesterol-lowering diet before receiving {PRODUCT NAME} and should continue on this diet during treatment with {PRODUCT NAME}. The dose should be individualised according to baseline LDL-C levels, the goal of therapy, and patient response. The usual starting dose is 10 mg once a day. Adjustment of dose should be made at intervals of 4 weeks or more. The maximum dose is 80 mg once a day. Primary hypercholesterolaemia and combined (mixed) hyperlipidaemia The majority of patients are controlled with {PRODUCT NAME} 10 mg once a day. A therapeutic response is evident within 2 weeks, and the maximum therapeutic response is usually achieved within 4 weeks. The response is maintained during chronic therapy. Heterozygous familial hypercholesterolaemia Patients should be started with {PRODUCT NAME} 10 mg daily. Doses should be individualised and adjusted every 4 weeks to 40 mg daily. Thereafter, either the dose may be increased to a maximum of 80 mg daily or a bile acid sequestrant may be combined with 40 mg atorvastatin once daily. Homozygous familial hypercholesterolaemia Only limited data are available (see section 5.1). The dose of atorvastatin in patients with homozygous familial hypercholesterolemia is 10 to 80 mg daily (see section 5.1). Atorvastatin should be used as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) in these patients or if such treatments are unavailable. Prevention of cardiovascular disease In the primary prevention trials the dose was 10 mg/day. Higher doses may be necessary in order to attain (LDL-) cholesterol levels according to current guidelines. Renal impairment No adjustment of dose is required (see section 4.4). Hepatic impairment {PRODUCT NAME} should be used with caution in patients with hepatic impairment (see sections 4.4 and 5.2). {PRODUCT NAME} is contraindicated in patients with active liver disease (see section 4.3). Use in the elderly Efficacy and safety in patients older than 70 using recommended doses are similar to those seen in the general population. 33
Paediatric use Paediatric use should only be carried out by specialists. Experience in paediatrics is limited to a small number of patients (age 4-17 years) with severe dyslipidemias, such as homozygous familial hypercholesterolemia. The recommended starting dose in this population is 10 mg of atorvastatin per day. The dose may be increased to 80 mg daily, according to the response and tolerability. Developmental safety data in this population have not been evaluated. Method of administration {PRODUCT NAME} is for oral administration. Each daily dose of atorvastatin is given all at once and may be given at any time of day with or without food. 4.3 Contraindications {PRODUCT NAME} is contraindicated in patients: with hypersensitivity to the active substance or to any of the excipients of this medicinal product with active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal during pregnancy, while breast-feeding and in women of child-bearing potential not using appropriate contraceptive measures (see section 4.6). 4.4 Special warnings and precautions for use Liver effects Liver function tests should be performed before the initiation of treatment and periodically thereafter. Patients who develop any signs or symptoms suggestive of liver injury should have liver function tests performed. Patients who develop increased transaminase levels should be monitored until the abnormality(ies) resolve. Should an increase in transaminases of greater than 3 times the upper limit of normal (ULN) persist, reduction of dose or withdrawal of {PRODUCT NAME} is recommended (see section 4.8). {PRODUCT NAME} should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) In a post-hoc analysis of stroke subtypes in patients without coronary heart disease (CHD) who had a recent stroke or transient ischemic attack (TIA) there was a higher incidence of hemorrhagic stroke in patients initiated on atorvastatin 80 mg compared to placebo. The increased risk was particularly noted in patients with prior hemorrhagic stroke or lacunar infarct at study entry. For patients with prior hemorrhagic stroke or lacunar infarct, the balance of risks and benefits of atorvastatin 80 mg is uncertain, and the potential risk of hemorrhagic stroke should be carefully considered before initiating treatment (see section 5.1). Skeletal muscle effects Atorvastatin, like other HMG-CoA reductase inhibitors, may in rare occasions affect the skeletal muscle and cause myalgia, myositis, and myopathy that may progress to rhabdomyolysis, a potentially lifethreatening condition characterised by markedly elevated creatine kinase (CK) levels (> 10 times ULN), myoglobinaemia and myoglobinuria which may lead to renal failure. 34
Before the treatment Atorvastatin should be prescribed with caution in patients with pre-disposing factors for rhabdomyolysis. A CK level should be measured before starting statin treatment in the following situations: Renal impairment Hypothyroidism Personal or familial history of hereditary muscular disorders Previous history of muscular toxicity with a statin or fibrate Previous history of liver disease and/or where substantial quantities of alcohol are consumed In elderly (age > 70 years), the necessity of such measurement should be considered, according to the presence of other predisposing factors for rhabdomyolysis Situations where an increase in plasma levels may occur, such as interactions (see section 4.5) and special populations including genetic subpopulations (see section 5.2) In such situations, the risk of treatment should be considered in relation to possible benefit, and clinical monitoring is recommended. If CK levels are significantly elevated (> 5 times ULN) at baseline, treatment should not be started. Creatine kinase measurement Creatine kinase (CK) should not be measured following strenuous exercise or in the presence of any plausible alternative cause of CK increase as this makes value interpretation difficult. If CK levels are significantly elevated at baseline (> 5 times ULN), levels should be remeasured within 5 to 7 days later to confirm the results. Whilst on treatment Patients must be asked to promptly report muscle pain, cramps, or weakness especially if accompanied by malaise or fever. If such symptoms occur whilst a patient is receiving treatment with atorvastatin, their CK levels should be measured. If these levels are found to be significantly elevated (> 5 times ULN), treatment should be stopped. If muscular symptoms are severe and cause daily discomfort, even if the CK levels are elevated to 5 x ULN, treatment discontinuation should be considered. If symptoms resolve and CK levels return to normal, then re-introduction of atorvastatin or introduction of an alternative statin may be considered at the lowest dose and with close monitoring. Atorvastatin must be discontinued if clinically significant elevation of CK levels (> 10 x ULN) occur, or if rhabdomyolysis is diagnosed or suspected. Concomitant treatment with other medicinal products Risk of rhabdomyolysis is increased when atorvastatin is administered concomitantly with certain medicinal products that may increase the plasma concentration of atorvastatin such as potent inhibitors of CYP3A4 or transport proteins (e.g. ciclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc). The risk of myopathy may also be increased with the concomitant use of gemfibrozil and other fibric acid derivates, erythromycin, niacin and ezetimibe. If possible, alternative (non-interacting) therapies should be considered instead of these medicinal products. In cases where co-administration of these medicinal products with atorvastatin is necessary, the benefit and the risk of concurrent treatment should be carefully considered. When patients are receiving medicinal products that increase the plasma concentration of atorvastatin, a lower maximum dose of atorvastatin is recommended. In addition, in the case of potent CYP3A4 inhibitors, a lower starting dose 35