annex i list of the invented names, pharmaceutical forms...

Annex I

List of the invented names, pharmaceutical forms, strengths of the medicinal products, routes of administration, marketing authorisation

holders in the member states

1

Member State

EU/EEA Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration

Austria

S.Med Handels GmbH Zachgasse1, Vienna AT-1220 Austria

BufloMed 'S.Med' 300 mg Filmtabletten

300 mg film-coated tablet oral use

Austria

S.Med Handels GmbH Zachgasse1, Vienna AT-1220 Austria

BufloMed 'S.Med' retard 600 mg Filmtabletten

600 mg prolonged-release tablet oral use

Belgium

Amdipharm Limited Temple Chambers 3 Burlington Road Dublin 4 Ireland

Loftyl 150 mg coated tablet oral use

Belgium

Amdipharm Limited Temple Chambers 3 Burlington Road Dublin 4 Ireland

Loftyl 50 mg/5 ml solution for injection intramuscular and intravenous use

Cyprus

MEDOCHEMIE LTD, 1-10 Constantinoupoleos street P.O.Box 51409 3505 Lemesos Cyprus

Ikelan solution for injection or infusion 50mg/5ml

50mg/5ml injection Intramuscular and intravenous use

France

BIOGARAN 15, boulevard Charles de Gaulle 92700 COLOMBES FRANCE

BUFLOMEDIL BIOGARAN 150 mg, comprimé pelliculé

150 mg Film-coated tablet oral use

2

France

QUALIMED 117, allée des Parcs 69800 SAINT-PRIEST France

BUFLOMEDIL QUALIMED 150 mg, comprimé pelliculé


France

TEVA SANTE Le Palatin 1, 1 cours du Triangle 92936 PARIS LA DEFENSE CEDEX France

BUFLOMEDIL TEVA 150 mg, comprimé pelliculé


France

ACTAVIS France La Boursidière Centre d'Affaires 92357 LE PLESSIS ROBINSON France

BUFLOMEDIL ACTAVIS 150 mg, comprimé

150 mg Tablet oral use

France

AMDIPHARM LTD Temple Chambers 3 Burlington Road DUBLIN 4 IRELAND

LOFTYL 50 mg/5 ml, solution injectable 50 mg/5 ml Solution for injection

Intramuscular and intravenous use

France AMDIPHARM LTD Temple Chambers 3, Burlington Road DUBLIN 4 IRELAND

LOFTYL 150 mg, comprimé pelliculé 150 mg Film-coated tablet oral use

France ARROW GENERIQUES 26, avenue Tony Garnier 69007 LYON FRANCE

BUFLOMEDIL ARROW 150 mg, comprimé 150 mg Tablet oral use

France

CEPHALON FRANCE 20, rue Charles Martigny 94700 MAISONS-ALFORT FRANCE

FONZYLANE 150 mg, comprimé pelliculé 150 mg Film-coated tablet oral use

3

France

CRISTERS 22 quai Gallieni 92150 SURESNES FRANCE

BUFLOMEDIL CRISTERS 150 mg, comprimé


France

EG LABO - LABORATOIRES EUROGENERICS "Le Quintet" - bâtiment A 12, rue Danjou 92517 BOULOGNE BILLANCOURT Cedex FRANCE

BUFLOMEDIL EG 150 mg, comprimé pelliculé


France

LABORATOIRE RATIOPHARM 19, boulevard Paul Vaillant Couturier 94200 IVRY SUR SEINE France

BUFLOMEDIL RATIOPHARM 150 mg, comprimé pelliculé


France

MYLAN SAS 117, allée des Parcs 69800 SAINT-PRIEST France

BUFLOMEDIL MYLAN 150 mg, comprimé pelliculé


France

RANBAXY PHARMACIE GENERIQUES 11-15 Quai Dion Bouton 92800 PUTEAUX France

BUFLOMEDIL RPG 150 mg, comprimé pelliculé


France

RANBAXY PHARMACIE GENERIQUES 11-15 Quai Dion Bouton 92800 PUTEAUX France

BUFLOMEDIL RPG 150 mg, comprimé


France

SANDOZ 49, avenue Georges Pompidou 92300 LEVALLOIS-PERRET France

BUFLOMEDIL SANDOZ 150 mg, comprimé


4

France

ZYDUS FRANCE 25, rue des Peupliers ZAC Les Hautes Pâtures - Parc d’Activités des Peupliers 92000 NANTERRE France

BUFLOMEDIL ZYDUS 150 mg, comprimé 150 mg Tablet oral use

Germany Amdipharm Limited Temple Chamcers, 3 Burlington Road IRL- DUBLIN 4 Irland

Bufedil long Retardtabletten

600 mg Prolonged-release tablet oral use

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

Buflomedil AbZ, 600 mg Retardtabletten


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

Buflo-Puren 300 300 mg Film-coated tablet oral use

Germany

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

BUFLO-Puren 600 retard 600mg Prolonged-release tablet oral use

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

Buflomedil-CT 150mg Filmtabletten 150 mg Film-coated tablet oral use


Buflomedil-CT 300mg Filmtabletten 300 mg Film-coated tablet oral use

5


Buflomedil-CT 50mg/5ml Ampullen 50mg / 5ml

Solution for injection, solution for infusion

Intravenous and intramuscular use


Buflomedil-CT 600mg Retardtabletten


Germany

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

Buflomedil-ratiopharm 300 mg Filmtabletten


Germany

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

Buflomedil-ratiopharm 600 mg Retardtabletten


Germany

Riemser Arzneimittel AG An der Wiek 7 D-17493 Greifswald - Insel Riems Germany

Complamin Buflomedil 600 mg retard


Germany

Riemser Arzneimittel AG An der Wiek 7 D-17493 Greifswald - Insel Riems Germany

Complamin Buflomedil Injekt 50mg / 5ml Solution for injection

intravenous and intramuscular use

Germany

Sanofi-Aventis Deutschland GmbH Industriepark Höchst, Gebäude K703 D-65926 Frankfurt am Main Germany

Defluina peri 300 mg Film-coated tablet oral use

6

Germany

Sanofi-Aventis Deutschland GmbH Industriepark Höchst, Gebäude K703 D-65926 Frankfurt am Main Germany

Deflunia peri mite 150 mg Film-coated tablet oral use

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

Buflomedil Stada 150mg Filmtabletten


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

Buflomedil Stada 300mg Filmtabletten


Greece

BROS LTD AYGIS AND GALINIS 15 KIFISSIA ATHENS 14564 Greece

THIOCODIN 150MG/TAB COATED TABLET oral use

Greece

BROS LTD AYGIS AND GALINIS 15 KIFISSIA ATHENS 14564 Greece

THIOCODIN 300MG/TAB COATED TABLET oral use

Greece

AMDIPHARM LIMITED, IRELAND Temple Chambers 3 Burlington Road Dublin 4 Ireland

LOFTYL 150MG/TAB FILM COATED TABLET oral use

Greece


LOFTYL 300MG/TAB FILM COATED TABLET oral use

7

Greece


LOFTYL 150MG/ML ORAL DROPS SOLUTION oral use

Greece


LOFTYL 50MG/5ML SOLUTION FOR INJECTION

INTRAVENOUS INFUSION, INTRAVENOUS INJECTION, INTRAMUSCULAR

Greece


LOFTYL 600MG/TAB CONTROLLED RELEASE TABLET

oral use

Greece

BIOSPRAY ABEE 18TH KM MARATHONOS AVENUE PALLINI Athens 15344 Greece

BOTAMIRAL 300MG/TAB FILM COATED TABLET oral use

Greece

FARAN ABEE PRODUCTION AND DISTRIBUTION OF MEDICINES ACHAIAS AND TRIZOINIAS NEA KIFISSIA Athens 14564 Greece

VANOGEL 150MG/ML ORAL DROPS SOLUTION oral use

Greece

FARAN ABEE PRODUCTION AND DISTRIBUTION OF MEDICINES ACHAIAS AND TRIZOINIAS NEA KIFISSIA 14565 Greece

VANOGEL 300MG/TAB FILM COATED TABLET oral use

Greece

HELP ABEE VALAORITOU 10, METAMORFOSI ATTIKIS 144 52 Greece

VARDOLIN 150MG/ML ORAL DROPS SOLUTION oral use

8

Greece


VARDOLIN 150MG/TAB FILM COATED TABLET oral use

Greece


VARDOLIN 300MG/TAB FILM COATED TABLET oral use

Greece


VARDOLIN 600MG/TAB CONTROLLED RELEASE TABLET

oral use

Greece

NORMA HELLAS S.A. MENANDROU 54 ATHENS 10431 Greece

FLUBIR 150MG/TAB FILM COATED TABLET oral use

Greece

NORMA HELLAS S.A. MENANDROU 54 ATHENS 10432 Greece

FLUBIR 300MG/TAB FILM COATED TABLET oral use

Greece

RAFARM A.E.B.E. KORINTHOU 12, NEO PSYCHIKO 15451 Greece

ZELIAN 150MG/TAB FILM COATED TABLET oral use

Greece

RAFARM A.E.B.E. KORINTHOU 12, NEO PSYCHIKO 15451 Greece

ZELIAN 300MG/TAB FILM COATED TABLET oral use

9

Greece

BIOSTAM KAL. MPOUGA AND CO DIAKRIAS 6 ZOGRAFOU 157 73 Athens Greece

CHLOROFARM-S 300MG/TAB FILM COATED TABLET oral use

Greece

ANFARM HELLAS PERIKLEOUS 53-57 ATHENS 105 60 Greece

BLADIRON 300MG/TAB FILM COATED TABLET oral use

Greece

ANFARM HELLAS PERIKLEOUS 53-57 ATHENS 105 60 Greece

BLADIRON 150MG/ML ORAL DROPS SOLUTION oral use

Greece

A. NIKOLAKOPOULOS AND CO GALATSIOU AVENUE 115, ATHENS 11146 Greece

IRRODAN RETARD 600MG/TAB SUSTAINED RELEASE TABLET

oral use

Greece

MEDICHROM S.A. 6Km MARKOPOULOU-KOROPI AVENUE MARKOPOPULO MESOGEIWN 19003 Greece

BUFLODIL 300MG/TAB FILM COATED TABLET oral use

Greece

ELPEN SA PHARMACEUTICAL INDUSTRY MARATHONOS AVENUE 95 PIKERMI ATTIKIS 19009 Greece

PENPURIN 150MG/TAB FILM COATED TABLET oral use

Greece


PENPURIN 300MG/TAB FILM COATED TABLET oral use

10

Greece


PENPURIN 150MG/ML ORAL DROPS SOLUTION oral use

Greece


PENPURIN 600MG/TAB CONTROLLED RELEASE TABLET

oral use

Greece

VIOFAR LTD ETHNIKIS ANTISTASEOS AND TRIFYLLIAS ACHARNES 13671 Greece

SULODIL 300MG/TAB FILM COATED TABLET oral use

Greece

VIOFAR LTD ETHNIKIS ANTISTASEOS AND TRIFYLLIAS ACHARNES 13672 Greece

SULODIL 600MG/TAB CONTROLLED RELEASE TABLET oral use

Italy

AMDIPHARM LTD Temple Chambers, 3 Burlington Road, Dublin 4 IRELAND

LOFTYL 150 mg/ml oral drop, solution oral use

Italy


LOFTYL 10 mg/ml solution for injection intramuscular and intravenous use

Italy


LOFTYL 300 mg/10 ml oral solution oral use

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Italy


LOFTYL 600 mg prolonged-release tablet oral use

Italy


LOFTYL 300 mg tablet oral use

Italy

BIOMEDICA FOSCAMA GROUP SpA Via della Giuliana 73 00195 Roma Italy

IRRODAN 10 mg/ml solution for injection intramuscular and intravenous use

Italy


IRRODAN 150 mg/ml oral drop, solution oral use

Italy


IRRODAN 300 mg tablet oral use

Italy

LABORATORIO FARMACEUTICO C.T. S.r.l. - Strada Solaro n. 75-77 - Villa Sayonara - Sanremo - 18038 IMPERIA Italy

BUFLOCIT 300 mg capsule, hard oral use

Italy


BUFLOCIT 150 mg capsule, hard oral use

12

Italy


BUFLOCIT 600 mg prolonged-release tablet oral use

Luxembourg AMDIPHARM LIMITED 3, TEMPLE CHAMBERS IRL DUBLIN

Loftyl 50mg solution for injection Intramuscular and intravenous use

Luxembourg

Amdipharm Limited Temple Chambers, 3 Burlington Road Dublin 4 Ireland

Loftyl 150mg tablets oral use

Portugal

Amdipharm Limited Temple Chambers - 3, Burlington Road Dublin 4 Ireland

Loftyl 300 300 mg Coated tablet oral use

Portugal


Loftyl Forte 600 mg Prolonged-release tablet oral use

Netherlands


Loftyl 150 mg tablets oral use

Spain


LOFTON 150 mg comprimidos recubiertos

150mg coated tablet oral use

13

14

Spain


LOFTON 150 mg/ml gotas orales en solución

150mg/ml oral drops solution oral use

Poland

ICN Polfa Rezszów S.A. Przemysłowa 2 35-959 Rzeszów, Poland Office in Warsaw: ul. Marynarska 15 02-674 Warszawa, Poland

Buvasodil 150 mg film coated tablets oral use

Poland

ICN Polfa Rezszów S.A. Przemysłowa 2 35-959 Rzeszów, Poland Office in Warsaw: ul. Marynarska 15 02-674 Warszawa, Poland

Buvasodil 300 mg film coated tablets oral use

Annex II

Scientific conclusions and grounds for the suspension of the marketing and use of the products presented by the EMA

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Scientific conclusions Overall summary of the scientific evaluation of buflomedil-containing medicinal products (see Annex I) Buflomedil is an α1-, α2-adrenolytic agent with vasoactive and haemorheologic properties, improving the blood flow in the microcirculation as well as tissue oxygenation. Buflomedil-containing medicines are authorised and marketed in 12 EU countries by national procedures and were first authorised in France in 1974. Buflomedil is currently approved in France in the treatment of ”symptomatic peripheral arterial occlusive disease (PAOD Stage II) symptoms”. The approved maximum daily dose in patients with normal renal function is 600 mg and 300 mg in patients with renal impairment. Usage of buflomedil according to these conditions is considered to be under normal conditions of use. France previously conducted two pharmacovigilance and toxicovigilance investigations following reports of nervous system and cardiac serious adverse events (SAEs) associated with the use of buflomedil. In these enquires, the reported nervous system SAEs consisted mainly of convulsions, myoclonia and status epilepticus while the cardiac SAEs consisted mainly of tachycardia, hypotension, ventricular rhythm disorders and cardiac arrest. Following these enquiries, France took a number of national regulatory actions to minimise the risk of adverse events associated with buflomedil. In December 2010, a further French benefit-risk evaluation of buflomedil was carried out, following which the French National Competent Authority suspended all French Marketing Authorisations for buflomedil-containing products. As a result, a procedure under Article 107 of Directive 2001/83/EC, as amended was automatically initiated. The procedure started during the February 2011 CHMP meeting.

Discussion on safety

The CHMP noted a review of French Eudravigilance data analysing spontaneous reports associated with treatment with buflomedil, to identify cases where cardiac and neurological reactions occurred under normal therapeutic doses (i.e. maximum of 600 mg daily for the oral tablet formulation). The CHMP also considered a review of the individual case safety reports (ICSR) database conducted by the MAH, to identify cases of cardiological or neurological adverse events under normal conditions of use, i.e. cases where the dose did not exceed the maximum daily dose of 600mg, cases with accidental overdoses or cases including patients with known renal impairment requiring dose adjustment. The CHMP also examined a review of all available individual case safety data related to buflomedil, conducted by the MAH, based on post-marketing safety data from Abbott Laboratories’ global safety database and Amdipharm’s safety database, published medical literature (worldwide) and from a number of other sources, including Toxicology/Poison Control Centres and Regulatory Authorities.

Serious cardiovascular and neurological adverse events under normal conditions of use

The EudraVigilance review identified 74 cases of adverse events associated with buflomedil, with a total of 35 cases recording cardiac adverse and 39 cases recording neurological adverse events. From these cases, a total of 12 cases were identified in which patients were treated within the maximum therapeutic range (i.e. up to 600 mg daily) of buflomedil. There were 6 cases of cardiovascular and 6 cases of neurological serious adverse events. Although the 12 cases were complicated by underlying clinical conditions and other concomitant medications, the CHMP considered them to confirm the risk of serious adverse events associated with the use of buflomedil under normal conditions of use. The MAH review of the ICSR database identified 33 cases involving the use of a maximum daily dose of 600 mg. From these, a total of 21 cases of neurological adverse events were retrieved. One patient experienced convulsions after taking two 300 mg tablets at the same time instead of two tablets BID. The CHMP was of the opinion that this data showed the risks associated with buflomedil in view of its narrow therapeutic margin. In addition, 32 cardiological adverse events were retrieved; the most frequent reactions were tachycardia, hypertension, flushing and hypotension.

Serious cardiovascular and neurological adverse events in elderly patients and patients with renal impairment

The MAH review of the ICSR database identified 5 cases with known dosage occurring in elderly patients for whom dosage adjustment was required. The reported ADRs were mainly related to serious neurological and cardiovascular ADRs. In addition to these 5 cases, a further two cases related to renal impairment were identified, where the dose was unknown. In addition, review of all available individual case safety data related to buflomedil identified 28 cases of overdoses in elderly patients (over 65

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years of age). In 70% of the cases, the dose of buflomedil received by the patients was inappropriate because of underlying renal failure. The CHMP also noted the two French pharmacovigilance enquiries covering the period 1998 to 2004 and 2006 to 2009. These reported 188 and 26 patients respectively who experienced AEs. The mean age was 70.2 and 71.6 years, respectively.

Safety of the injectable formulations of buflomedil

The CHMP also carried out a separate assessment of the safety of the parenteral formulations of buflomedil, which are used in the hospital setting for the treatment of severe chronic ischaemia of the lower limbs. The CHMP noted that of the 24 reported cases (about 5% of all adverse drug reactions recorded in the MAH database), a majority (13 out of 24) were cases of accidental overdose. While acknowledging the iatrogenic nature of the reported cases, the CHMP considered that these cases provide supportive evidence of the cardiovascular and neurological risks of buflomedil, as adverse events were noted in patients administered twice the daily dosage, which suggests that the risks are associated with overdoses of relatively small magnitudes. According to the approved indication, the injection formulation of buflomedil is used to initiate PAOD therapy, to be followed by a switch to oral therapy. As a result, when addressing the risk-benefit of buflomedil under normal conditions for use, the CHMP assumed a switch to oral formulations and therefore considered that the risk/benefit of buflomedil injectable needs to be considered within the overall discussion of the risk-benefit of buflomedil.

Overall conclusions on safety

In summary, the CHMP concluded that the use of buflomedil is associated with a number of serious cardiological (mainly tachycardia, hypotension, ventricular rhythm disorders and cardiac arrest) and neurological (mainly convulsions, myoclonia and status epilepticus) adverse events, which occur under normal conditions of use, particularly in elderly patients, who are predominantly the patient population relevant to the approved indication. These risks are compounded by the fact that buflomedil is a substance with a narrow therapeutic index and that buflomedil treatment requires dose-adaptation to adjust for renal function. If dose-adaptation is not done correctly, this leads to serious and life-threatening toxicity. This is of particular concern as patients with peripheral vascular disease are inherently likely to experience decreased renal function due to the nature of their condition.

Risk minimisation measures

Following a European PSUR assessment and a full benefit-risk assessment completed by the MAH in January 2010, the MAH proposed a number of measures to address the identified concerns. Various indications previously registered across the EU were deleted and the indication was restricted to the Symptomatic treatment of chronic peripheral vascular disease (stage 2) (intermittent claudication), bringing it in line with the French SmPC. The need to consider renal function was also introduced. The CHMP acknowledged that variations to implement the European harmonisation of the SmPC are still ongoing in some countries but noted that the RMP proposed by Amdipharm in May 2010 was largely equivalent to the RMPs already implemented in France. The CHMP also noted the pharmacovigilance and toxicovigilance data which show no improvement of the safety profile of buflomedil despite the implementation of the RMP in France in 2006; instead, a two fold increase of misuse compared to the previous period was observed. The CHMP concluded that due to the similarities between the proposed RMMs and the ones implemented in France, it is possible to conclude on the effectiveness of the proposed RMMs, despite the lack of implementation in all member states and that these measures are inadequate to prevent the occurrence of serious adverse events with buflomedil.

Thalès observational drug utilisation study

The CHMP also noted the results of the Thalès observational drug utilisation study, including 300 000 patients and conducted to assess the impact of the RMMs implemented in France on prescription patterns. The study compared a reference period of 6 months before the 2006 French evaluation with two 6-months evaluation periods following the implementation of the resulting RMMs and the circulation of a DHPC. The study showed that about 30% of patients with renal failure still receive an excessive dose, although it was noted that this had decreased from 75% prior to the DHPC. The CHMP was of the opinion that despite this reduction, the percentage of patients at risk remained unacceptably high. In addition, the CHMP observed with concern that an initial assessment of renal function was only carried out in 20% of patients and that measurements of creatinine clearance were only performed in 17% of patients, despite the SmPC recommendations. The CHMP concluded that the

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impact of the implemented measures was very weak and that the expected impact of the proposed measures was insufficient to adequately address the identified risks observed with buflomedil. Following an oral explanation held in July 2011, the MAH was requested to propose further risk minimisation measures and asked whether a restricted population could be identified. The CHMP noted the proposed additional revisions to the SmPC, restricting the population by further narrowing the PAOD indication and revising the wording of the contraindication in severe renal impairment in order to improve compliance to prescribing in the event of renal insufficiency. The CHMP also noted the MAH proposal to reduce the pack size, to minimise the consequences of an intentional overdose. The CHMP noted that the MAH did not propose to withdraw the 300 mg tablets formulation. The CHMP considered the proposal for a website dedicated to buflomedil to be unlikely to significantly improve the awareness of prescribers, as previous communication tools already implemented in France were insufficient to improve compliance with indications and renal monitoring. Regarding the proposed additional pharmacovigilance activities, the CHMP was of the opinion that signal detection is no longer a priority, given that the risks associated with buflomedil are now identified and confirmed. Having assessed the totality of the risk minimisation measures proposed by the MAH, the CHMP concluded that given the high risk with buflomedil, notably in patients with impaired renal function and in elderly patients, no measures could be identified to reduce the risks associated with buflomedil to an acceptable level.

Overall summary on safety and on risk minimisation measures

With regards to safety, the CHMP concluded that the use of buflomedil is associated with a number of serious cardiological (mainly tachycardia, hypotension, ventricular rhythm disorders and cardiac arrest) and neurological (mainly convulsions, myoclonia and status epilepticus) adverse events, which occur under normal conditions of use, particularly in elderly patients, who are predominantly the patient population relevant to the approved indication. These risks are compounded by the fact that buflomedil is a substance with a narrow therapeutic index and that buflomedil treatment requires dose-adaptation to adjust for renal function. If dose-adaptation is not done correctly, this leads to serious and life-threatening toxicity. This is of particular concern as patients with peripheral vascular disease are inherently likely to experience decreased renal function due to the nature of their condition.

Regarding risk minimisation measures, the CHMP noted the MAH proposals but considered that these are unlikely to be sufficient to prevent the occurrence of serious cardiac and neurological adverse events under normal conditions of use nor reduce the well identified risks of accidental overdoses and non-compliance with renal function monitoring associated with the use of buflomedil to an acceptable level. The CHMP noted that according to the French experience (including the results of the Thalès study and the publication by Bruhat et al.), cases of non-compliance with the recommended dose, non-adjustment of dose in patients with renal impairment and lack of monitoring of renal function persist, resulting in cases of serious adverse events, which is unacceptable for a product for which the only benefit is a limited level of efficacy in the lower limb peripheral vascular disease indication. As the Risk Management Plan (RMP) proposed in the scope of this Article 107 procedure is equivalent to the French RMP implemented in 2006, the CHMP was therefore of the opinion that it is possible to conclude on the effectiveness of the proposed RMMs, despite the lack of implementation in all member states.

Having assessed the risk minimisation measures proposed by the MAH, the CHMP concluded that given the high risk with buflomedil, notably in patients with advanced vascular disease and/or diabetes and metabolic syndrome, in patients with impaired renal function and in elderly patients, no adequate or sufficient measures could be identified to reduce the risks associated with buflomedil to an acceptable level.

Discussion on efficacy

The CHMP noted the efficacy data submitted by the MAH, including the relatively recent large placebo–controlled LIMB (Limbs International Medicinal Buflomedil) study. Regarding the LIMB study, the results indicated a trend of a decrease in symptoms (symptomatic deterioration of PAOD, amputations) although there was an increase in cardiovascular events (MI, stroke, CV deaths). However, the CHMP noted that the analysis did not demonstrate statistical significance and that the results therefore did not allow to conclude on a statistically significant reduction in the combined primary endpoint compared to placebo. Overall, the CHMP considered the clinical data submitted in support of the efficacy of buflomedil to be limited. Consequently, while the efficacy remains largely unchanged since the granting of the initial MA, the CHMP was of the opinion that the available evidence is not supportive of a significant clinical efficacy of buflomedil on cardiovascular events and on walking distance.

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Overall benefit-risk assessment

With regards to safety, the CHMP concluded that the use of buflomedil is associated with a number of serious cardiological (mainly tachycardia, hypotension, ventricular rhythm disorders and cardiac arrest) and neurological (mainly convulsions, myoclonia and status epilepticus) adverse events, which occur under normal conditions of use, particularly in elderly patients, who are predominantly the patient population relevant to the approved indication. These risks are compounded by the fact that buflomedil is a substance with a narrow therapeutic index and that buflomedil treatment requires dose-adaptation to adjust for renal function. If dose-adaptation is not done correctly, this leads to serious and life-threatening toxicity. This is of particular concern as patients with peripheral vascular disease are inherently likely to experience decreased renal function due to the nature of their condition. The concerns regarding the rapid deterioration of renal function in these patients, requiring regular and frequent monitoring were also reiterated. The CHMP assessed the impact of the risk minimisation measures previously implemented in France, consisting mainly of revisions to the SmPC and communication and noted the proposed extension of these measures to other member states. However, the CHMP considered that the risk minimisation measures proposed by the MAH are unlikely to reduce the serious cardiac and neurological adverse events associated with the use of buflomedil to a clinically acceptable level. In addition, the CHMP noted the evidence of limited clinical efficacy of buflomedil, as demonstrated in recent clinical trials. In conclusion, taking into account the serious cardiac and neurological adverse events associated with the use of buflomedil-containing medicinal products under normal conditions of use, the evidence of limited clinical efficacy which is insufficient to compensate for the risks associated with the use of buflomedil and the established concerns regarding the effectiveness of the risk minimisation measures, the CHMP considered that the risk-benefit balance of buflomedil-containing medicinal products is not positive under normal conditions of use. Grounds for the suspension of the Marketing Authorisations Whereas The Committee considered that a number of serious cardiac and neurological adverse events have

been reported with the use of buflomedil under normal conditions of use, particularly in elderly patients.

The Committee considered that in this context, the narrow therapeutic index of buflomedil is of

major concern, as patients with peripheral vascular disease treated with buflomedil are inherently likely to experience decreased renal function, due to the nature of their condition.

The Committee raised concerns regarding the rapid deterioration of renal function in patients with

peripheral vascular disease, requiring regular and frequent monitoring. The Committee considered, based on the assessment of the impact of risk minimisation measures

already implemented in some Member States and on the published literature, that the risk minimisation measures proposed by the Marketing Authorisation Holder would not be able to adequately reduce the risks of serious adverse events to a clinically acceptable level.

The Committee considered that buflomedil-containing medicinal products showed only limited

clinical efficacy in the symptomatic treatment of chronic peripheral vascular disease. The Committee therefore concluded, in view of the available data, that the risks of serious cardiac

and neurological adverse events associated with the use of buflomedil-containing medicinal products in the symptomatic treatment of chronic peripheral vascular disease, under normal conditions of use, outweigh the limited benefits.

The Committee therefore considered that the risk-benefit balance of buflomedil-containing

medicinal products is not positive under normal conditions of use. Consequently, the CHMP recommended to the European Commission the suspension of the Marketing Authorisations of buflomedil-containing medicinal products listed in Annex I of the Opinion in all

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concerned EU Member States. This opinion supersedes the opinion on temporary measures adopted on 4 July 2011. For the lifting of the suspension, the Marketing Authorisation Holders should provide convincing data to identify a population in which the benefits of buflomedil clearly outweigh its identified risks (see Annex III).

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Annex III

Conditions for lifting the suspension

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For the suspension to be lifted the Marketing Authorisation Holders would need to provide the National Competent Authorities with the following: Convincing data to identify a patient population in which the benefits of buflomedil clearly outweigh its identified risks.

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