Fibrinogen Sealants

Annex I

List of the names, pharmaceutical forms, strengths of the medicinal products, routes of administration, marketing authorisation holders in the member states

Artiss and associated names; Tisseel and associated names; Tissucol and associated names

Member State Marketing Authorisation Invented name Strength Pharmaceutical Route of (in EEA) Holder Name Form administration

Austria Baxter AG ARTISS – Lösungen Fibrinogen: 91 mg/ml Solution for sealant Epilesional use Industriestraße 67 für einen Aprotinin: 3000 KIU/ml 1221 Vienna Gewebekleber Thrombin: 4 IU/ml Austria Calcium chloride: 40 μmol/ml Austria Baxter AG ARTISS LYO – Fibrinogen: 91 mg/ml Powder and solvent Epilesional use Industriestraße 67 Pulver und Aprotinin: 3000 KIE/ml for sealant 1221 Vienna Lösungsmittel für Thrombin: 4 IU/ml Austria einen Calcium chloride: 40 μmol/ml Gewebekleber Austria Baxter AG Tisseel - Lösungen Fibrinogen: 91 mg/ml Solution for sealant Epilesional use Industriestraße 67 für einen Aprotinin: 3000 KIU/ml 1221 Vienna Gewebekleber Thrombin: 500 IU/ml Austria Calcium chloride: 40 μmol/ml Austria Baxter AG Tisseel Lyo - Pulver Fibrinogen: 91 mg/ml Powder and solvent Epilesional use Industriestraße 67 und Lösungsmittel Aprotinin: 3000 KIU/ml for sealant 1221 Vienna für einen Thrombin: 500 IU/ml Austria Gewebekleber Calcium chloride: 40 μmol/ml Belgium Baxter SA Artiss Fibrinogen: 91 mg/ml Solution for sealant Epilesional use Boulevard René Aprotinin: 3000 KIU/ml Branquart 80 Thrombin: 4 IU/ml 7860 Lessines Calcium chloride: 40 μmol/ml Belgium Belgium Baxter AG Tissucol Duo 500 Syringe TISSUCOL-APROTININ: Total Solution for sealant Epilesional use Industriestraße 67 Proteins 100-130 mg/ml; 1221 Vienna clottable protein 75-115 mg/ml, of which Austria fibrinogen 70-110 mg/ml and plasmatic fibronectin 2-9 mg/ml: Factor XIII 10-50 UI/ml; Plasminogen 0.04-0.12 mg/ml; Aprotinin 3000 UIK/ml (1.67 UPE/ml); Syringe THROMBIN-CALCIUM CHLORIDE: Proteins 50mg/ml; Thrombin 500 UI/ml; calcium chloride 40 µmol/ml

Member State Marketing Authorisation Invented name Strength Pharmaceutical Route of (in EEA) Holder Name Form administration

Belgium Baxter AG Tissucol Kit Bottle 1: Total Proteins 100-130 mg/ml; Powder and solvent Epilesional use Industriestraße 67 dont clottable protein 75-115 mg/ml, for sealant 1221 Vienna Factor XIII 10-50 UI/ml; Plasminogen Austria 0.04-0.12 mg/ml; Bottle 2: Aprotinin bovine 3000 UIK/ml (1.67 UPE/ml); Bottle 3: Human Thrombin 500 IU/ml; Proteins 50mg/ml; Bottle 4: Human Thrombin 4 UI/ml; Proteins 50mg/ml; Bottle 5: calcium chloride 40 µmol/ml Belgium Baxter AG Tissucol S/D Human fibrinogen (clottable protein): Solution for sealant Epilesional use Industriestraße 67 72-110 mg/ml 1221 Vienna Factor XIII ≤ 10 UI/ml Austria Aprotinin: 3000 UIK/ml Human Thrombin: 500 UI/ml Calcium chloride: 40 μmol/ml Belgium Baxter AG Tissucol S/D Kit Human fibrinogen (clottable protein): Powder and solvent Epilesional use Industriestraße 67 72-110 mg/ml for sealant 1221 Vienna Factor XIII ≤ 10 UI/ml Austria Aprotinin: 3000 UIK/ml Human Thrombin: 500 UI/ml Calcium chloride: 40 μmol/ml Bulgaria Baxter d.o.o. Artiss solution for Human fibrinogen 91 mg/ml Solution for sealant Epilesional use Zelezna cesta 18 sealant frozen Aprotinin 3000 KIU/ml 1000 Ljubljana Human Thrombin 4 IU/ml Slovenia Calcium Chloride 40 µmol/ml

Bulgaria Baxter d.o.o. Tisseel Lyo powders Human fibrinogen 91 mg/ml Powder and solvent Epilesional use Zelezna cesta 18 and solvents for Aprotinin 3000 KIU/ml for sealant 1000 Ljubljana sealant Human Thrombin 4 IU/ml Slovenia Calcium Chloride 40 µmol/ml

Bulgaria Baxter d.o.o. Tisseel solutions for Human fibrinogen 72-110 mg/ml Solution for sealant Epilesional use Zelezna cesta 18 sealant Aprotinin 3000 KIU/ml 1000 Ljubljana Human Thrombin 500 IU/ml Slovenia Calcium Chloride 40 µmol/ml

Member State Marketing Authorisation Invented name Strength Pharmaceutical Route of (in EEA) Holder Name Form administration

Czech Republic Baxter Czech spol. s r.o. Artiss Fibrinogen: 91 mg/ml Solution for sealant Epilesional use Karla Engliše 3201/6 Aprotinin: 3000 KIU/ml 150 00 Praha 5 Thrombin: 4 IU/ml Czech Republic Calcium chloride: 40 μmol/ml Czech Republic Baxter Czech spol. s r.o. Tisseel Fibrinogen: 91 mg/ml Solution for sealant Epilesional use Karla Engliše 3201/6 Aprotinin: 3000 KIU/ml 150 00 Praha 5 Thrombin: 500 IU/ml Czech Republic Calcium chloride: 40 μmol/ml Czech Republic Baxter Czech spol. s r.o. Tisseel Lyo Fibrinogen: 91 mg/ml Powder and solvent Epilesional use Karla Engliše 3201/6 Aprotinin: 3000 KIU/ml for sealant 150 00 Praha 5 Thrombin: 500 IU/ml Czech Republic Calcium chloride: 40 μmol/ml Denmark Baxter A/S Artiss Fibrinogen: 91 mg/ml Solution for sealant Intralesional use Gydevang 43 Aprotinin: 3000 KIU/ml DK-3450 Allerød Thrombin: 4 IU/ml Denmark Calcium chloride: 40 μmol/ml Denmark Baxter AG Tisseel Duo Quick Fibrinogen 90mg/ml Solution for sealant Intralesional use Industriestraße 67 Fibronectin 6mg/ml 1221 Vienna Aprotinin 3000KIE/ml Austria Coagulation Factor XIII 30IE/ml Plasminogen 80 μg/ml Thrombin human 500 IE/ml Calcium Chloride Dihydrate 40 μg/ml Denmark Baxter A/S Tissel Fibrinogen: 91 mg/ml Solution for sealant Intralesional use Gydevang 43 Aprotinin: 3000 KIU/ml DK-3450 Allerød Thrombin: 500 IU/ml Denmark Calcium chloride: 40 μmol/ml Finland Baxter Oy, Artiss Fibrinogen: 91 mg/ml Solution for sealant Topical PL 119, Aprotinin: 3000 KIU/ml 00181 Helsinki Thrombin: 4 IU/ml Finland Calcium chloride: 40 μmol/ml

Member State Marketing Authorisation Invented name Strength Pharmaceutical Route of (in EEA) Holder Name Form administration

Finland Baxter AG Tisseel Fibrinogen 72-110 mg/ml Solution for sealant Topical Industriestraße 67 Factor XIII coagulationis humanus 10 1221 Vienna IU/ml Austria Aprotinin: 3000 KIU/ml Thrombin: 500 IU/ml Calcium chloride: 40 μmol/ml Finland Baxter AG Tisseel duo quick Plasmaproteinum humanum 100-130 Solution for sealant Topical Industriestraße 67 mg/ml: Fibrinogen 90mg/ml 1221 Vienna Plasmafibrinonectinum 5,5mg/ml Austria Factor XIII coagulationis humanus 30 IU/ml Aprotinin 1,67 Ph.Eur.U./ml Coagulation Factor XIII 30IE/ml Plasminogen 80 μg/ml Thrombin human 500 IE/ml plasmaproteinum humanum 50mg/ml Calcium Chloride Dihydrate 40 μg/ml France BAXTER SAS ARTISS solution Fibrinogen 91 mg/ml Solution for sealant Epilesional use 6 Avenue Louis Pasteur for sealant Aprotinin: 3000 KIE/ml 78310 MAUREPAS Thrombin: 4 IU/ml FRANCE Calcium chloride: 40 μmol/ml

France BAXTER SAS TISSUCOL KIT 1st Component: Powder, solution and Epilesional use 6 Avenue Louis Pasteur Fibrinogen human 90,00 mg /ml solvent for sealant 78310 MAUREPAS Factor XIII : 10,00 UI/ml FRANCE Fibronectin : 5,50 mg/ml Plasminogen : 0,08 mg/ml Aprotinin 3000,0 UIK*** /ml

2nd Component: Thrombin 500 UI/ml Germany Baxter Deutschland GmbH Artiss Fibrinogen: 91 mg/ml Solution for sealant Epilesional use Edisonstr. 4 Aprotinin: 3000 KIU/ml D-85716 Unterschleißheim Thrombin: 4 IU/ml Germany Calcium chloride: 40 μmol/ml

Member State Marketing Authorisation Invented name Strength Pharmaceutical Route of (in EEA) Holder Name Form administration

Germany Baxter Deutschland GmbH Tissucol-Duo S Component 1 Powder and solvent Epilesional use Edisonstr. 4 0,5 ml/1ml/2 ml Fibrinogen:70-110 mg/ml for sealant D-85716 Unterschleißheim Immuno Coagulation factor XIII: 10-50 I.E./ml Germany Plasmafibronectin: 2-9 mg/ml Aprotinin (bovin): 3000 KIE/ml

Component 2 Thrombin (human) 500 I.E./ml Calcium chloride: 5,88 mg/ml Germany Baxter Deutschland GmbH Tissucol-Kit Component 1: Powder and solvent Epilesional use Edisonstr. 4 1,0/2,0/5,0 Fibrinogen: 70 - 110 mg/ml for sealant D-85716 Unterschleißheim Immuno Plasmafibronectin: 2 - 9 mg/ml Germany Coagulation factor XIII: 10 - 50 I.E/ml Aprotininsolution: 3000 KIE/ml

Component 2: Thrombin S lyophilized: 500 I.E/ml Thrombin L lyophilized: 4 I.E/ml Calcium chloride: 5,88 mg/ml Greece BAXTER HELLAS LTD ARTISS Fibrinogen: 91 mg/ml Solution for sealant Epilesional use 3 Metsovou str, Aprotinin: 3000 KIU/ml 14121-N Irakleio, Thrombin: 4 IU/ml Athens Calcium chloride: 40 µmol/ml Greece Greece BAXTER HELLAS LTD TISSEEL Fibrinogen: 91 mg/ml Solution for sealant Epilesional use 3 Metsovou str, Aprotinin: 3000 KIU/ml 14121-N Irakleio, Thrombin: 500 IU/ml Athens Calcium chloride: 40 µmol/ml Greece

Greece BAXTER HELLAS LTD TISSEEL LYO Fibrinogen: 91 mg/ml Powder and solvent Epilesional use 3 Metsovou str, Aprotinin: 3000 KIU/ml for sealant 14121-N Irakleio, Thrombin: 500 IU/ml Athens Calcium chloride: 40 µmol/ml Greece

Member State Marketing Authorisation Invented name Strength Pharmaceutical Route of (in EEA) Holder Name Form administration

Hungary Baxter Hungary Kft. TISSEEL LYO por és Fibrinogen: 91 mg/ml Powder and solvent Epilesional use Népfürdő u. 22. IX. em. oldószer Aprotinin: 3000 KIU/ml for sealant 1138 Budapest szövetragasztóhoz Thrombin: 500 IU/ml Hungary Calcium chloride: 40 μmol/ml Hungary Baxter AG TISSUCOL Kit 1,0 1st Component: Powder and solvent Epilesional use Industriestraße 67 kétkomponensű Total Protein 100-130 mg; for sealant 1221 Vienna fibrinragasztó Clottable protein: 75-115 mg, Austria thereof Fibrinogen 70-110 mg; Plasma Fibronectin 2-9 mg; Factor XIII 10-50 UI; Plasminogen 0.04-0.12 mg; Aprotinin 3000 KIU;

2nd Component: Thrombin 500 IU or Thrombin 4 UI; Calcium Chlorid Dihydrate 5.88 mg Hungary Baxter AG TISSUCOL Kit 2,0 1st Component: Powder and solvent Epilesional use Industriestraße 67 kétkomponensű Total Protein 200-260 mg; for sealant 1221 Vienna fibrinragasztó Clottable protein: 150-230 mg, Austria thereof Fibrinogen 140-220 mg; Plasma Fibronectin 4-18 mg; Factor XIII 20-100 UI; Plasminogen 0.08-0.24 mg; Aprotinin 6000 KIU;

2nd Component: Thrombin 1000 IU or Thrombin 8 UI; Calcium Chlorid Dihydrate 11.76 mg

Member State Marketing Authorisation Invented name Strength Pharmaceutical Route of (in EEA) Holder Name Form administration

Hungary Baxter AG TISSUCOL Kit 5,0 1st Component: Powder and solvent Epilesional use Industriestraße 67 kétkomponensű Total Protein 500-650 mg; for sealant 1221 Vienna fibrinragasztó Clottable protein: 375-575 mg, Austria thereof Fibrinogen 350-550 mg; Plasma Fibronectin 10-45 mg; Factor XIII 50-250 UI; Plasminogen 0.2-0.6 mg; Aprotinin 15000 KIU;

2nd Component: Thrombin 2500 IU or Thrombin 20 UI; Calcium Chlorid Dihydrate 29.4 mg Iceland Baxter Medical AB, Artiss Human Fibrinogen 91 mg/ml Solution for sealant Epilesional use Isafjordstgatan 30B Aprotinum INN 3000 KIU/ml (bovine) P.O. Box 63 Human Thrombin 4 ae^3/ml 164 94 Kista, Calcium Chloride 40 micromol/ml Sweden Iceland Baxter AG TISSEEL Human Fibrinogen 91 gm/ml Solution for sealant Epilesional use Industriestraße 67 Human Factor XIII 10 IU/ml 1221 Vienna Bovine Aprotinin 3000 IU/ml Austria Human Thrombin 500 IU/ml Calcium Chloride 40 micromol/ml Iceland Baxter AG Tisseel Duo Quick Tisseel solution Per ml - Solution for sealant Epilesional use Industriestraße 67 Fibrinogen 90 mg 1221 Vienna Fibronectin 5,5 mg Austria Factor XIII 30 a.e Aprotinin (bovel) 3000 KIU Plasminogen 80 microgram Thrombin solution per ml Human thrombin 500 ae Calcium chloridum 40 micromol

Member State Marketing Authorisation Invented name Strength Pharmaceutical Route of (in EEA) Holder Name Form administration

Ireland Baxter Healthcare Limited, Artiss solutions for Human Fibrinogen: 72-110 mg/ml Solution for sealant Epilesional use Caxton Way, sealant, deep Aprotinin: 3000 KIU/ml Thetford, frozen Human Thrombin: 4 IU/ml Norfork Calcium Chloride: 40 μmol/ml IP24 3SE, United Kingdom Ireland Baxter Healthcare Limited, Tiseel Ready to use Human Fibrinogen: 72/110 mg/ml Solution for sealant Epilesional use Caxton Way, Solutions for Aprotinin: 3000 KIU/ml Thetford, Sealant Human Thrombin: 500 IU/ml Norfork Calcium Chloride: 40 μmol/ml IP24 3SE, United Kingdom Ireland Baxter Healthcare Limited, TISSEEL Lyo Human Fibrinogen: 72/110 mg/ml Powder and solvent Epilesional use Caxton Way, Aprotinin:3000 KIU/ml for sealant Thetford, Human Thrombin: 500 IU/ml Norfork Calcium Chloride: 40 μmol/ml IP24 3SE, United Kingdom Italy Baxter S.p.A. ARTISS Fibrinogen: 91 mg/ml Solution for sealant Epilesional use Piazzale dell'Industria, 20 Aprotinin: 3000 KIU/ml 00144 Roma Thrombin: 4 IU/ml Italy Calcium Chloride: 40 μmol/ml Italy Baxter AG TISSEEL Fibrinogen: 91 mg/ml Solution for sealant Epilesional use Industriestraße 67 Aprotinin: 3000 KIU 1221 Vienna Thrombin: 500 UI/ML Austria Calcium Chloride: 40 MMO LI/L Factor XIII ≤ 10 UI/ml Luxembourg Baxter SA Artiss Fibrinogen: 91 mg/ml Solution for sealant Epilesional use Boulevard René Aprotinin: 3000 KIU/ml Branquart 80 Thrombin: 4 IU/ml 7860 Lessines Calcium chloride: 40 μmol/ml Belgium

Member State Marketing Authorisation Invented name Strength Pharmaceutical Route of (in EEA) Holder Name Form administration

Luxembourg Baxter AG Tissucol S/D Kit Fibrinogene humain (proteines Powder and solvent Epilesional use Industriestraße 67 coagulables) 72-110 mg/ml for sealant 1221 Vienna Facteur XIII ≤ 10 UI/ml Austria Aprotinine 3000 UIK/ml Thrombine humaine 500 UI/ml Chlorure de calcium 40 μmol/ml Malta Baxter Healthcare Limited, TISSEEL KIT 2.0 Fibrinogen: 70-110mg/ml Powder and solvent Cutaneous Use Caxton Way, ml, Two- Plasmafibronectin (CIG): 2-9mg/ml for sealant Thetford, Component Fibrin Factor XIII: 10-50 U/ml Norfork IP24 3SE, Sealant Plasminogen: 0.04 - 0.12mg/ml United Kingdom Malta Baxter Healthcare Limited, TISSEEL Lyo, Two- Fibrinogen: 72-110mg/ml Powder and solvent Cutaneous Use Caxton Way, Component Fibrin Aprotinin: 3000KIU/ml for sealant Thetford, Sealant Thrombin: 500 IU/ml in 45-55mg total Norfork IP24 3SE, protein United Kingdom Calcium chloride: 40 µmol/ml Norway Baxter AS, Artiss Human Fibrinogen: 91mg1/ ml Solution for sealant Epilesional use Gjerdrumsvei 11, Aprotinin: 3000 KIU2/ml 0484 Oslo, Human Thrombin: 4IU3/ml Norway Calcium Chloride:40μmol/ml Norway Baxter AS, Tisseel Human Fibrinogen: 91 mg1/ml Solution for sealant Epilesional use Gjerdrumsvei 11, Aprotinin: 3000 KIU2/ml 0484 Oslo, Human Thrombin: 500 IU3/ml Norway Calcium Chloride: 40 µmol/ml Norway Baxter AS, Tisseel Human Fibrinogen: 91 mg1/ml Powder and solvent Epilesional use Gjerdrumsvei 11, Aprotinin: 3000 KIU2/ml for sealant 0484 Oslo, Human Thrombin: 500 IU3/ml Norway Calcium Chloride: 40 µmol/ml Poland Baxter Polska Sp. z o.o. Artiss Fibrinogen: 91 mg/ml Solution for sealant Epilesional use ul. Kruczkowskiego 8 Aprotinin: 3000 KIU/ml 00-380 Warzawa Thrombin: 4 IU/ml Poland Calcium chloride: 40 µmol/ml

Member State Marketing Authorisation Invented name Strength Pharmaceutical Route of (in EEA) Holder Name Form administration

Poland Baxter Polska Sp. z o.o. Tisseel Fibrinogen: 91 mg/ml Solution for sealant Epilesional use ul. Kruczkowskiego 8 Aprotinin: 3000 KIU/ml 00-380 Warzawa Thrombin: 500 IU/ml Poland Calcium chloride: 40 µmol/ml Poland Baxter Polska Sp. z o.o. Tisseel Lyo Fibrinogen: 91 mg/ml Powder and solvent Epilesional use ul. Kruczkowskiego 8 Aprotinin: 3000 KIU/ml for sealant 00-380 Warzawa Thrombin: 500 IU/ml Poland Calcium chloride: 40 µmol/ml Portugal Baxter Médico-Farmacêutica, Artiss Human fibrinogen: 91 mg/ml Solvent for sealant Epilesional use Lda. Aprotinin: 3000 KUI2/ml Zona Industrial da Abrunheira Human thrombin: 4 UI3/ml - Edifício 10 - Sintra Business Calcium chloride: 40 mmol/ml Park 2710-089 Sintra Portugal Portugal Baxter Médico-Farmacêutica, Tisseel Human fibrinogen: 72-110 mg/ml Sealant Epilesional use Lda. Factor xiii: ≤10 UI Zona Industrial da Abrunheira Aprotinin: 3000 KU12/ml - Edifício 10 - Sintra Business Human thrombin: 500 UI3/ml Park Calcium chloride: 40 micromol/ml 2710-089 Sintra Portugal Portugal Baxter Médico-Farmacêutica, Tisseellyo Human fibrinogen (72-110 mg/ml) Powder and solvent Epilesional use Lda. Factor xiii (≤10 UI) for sealant Zona Industrial da Abrunheira Aprotinin (3000 KUI2/ml) - Edifício 10 - Sintra Business Human thrombin (500 UI3/ml) Park Calcium chloride (40micromol/ml) 2710-089 Sintra Portugal Spain BAXTER, S.L. ARTISS soluciones Fibrinogen: 91 mg/ml Solution for sealant Intralesional use Polígono Industrial Sector 14 para adhesivo Aprotinin: 3000 KIU/ml Pouet de Camilo, 2 tisular Thrombin: 4 IU/ml 46394 Ribarroja del Turia Ultracongeladas Calcium chloride: 40 μmol/ml Valencia Spain

Member State Marketing Authorisation Invented name Strength Pharmaceutical Route of (in EEA) Holder Name Form administration

Spain BAXTER, S.L. TISSUCOL DUO 2,0 Syringe TISSUCOL-APROTININ: Total Solution for sealant Epilesional use Polígono Industrial Sector 14 ml Proteins 100-130 mg/ml; Pouet de Camilo, 2 clottable protein 75-115 mg/ml, of which 46394 Ribarroja del Turia fibrinogen 70-110 mg/ml and plasmatic Valencia fibronectin 2-9 mg/ml: Factor XIII 10-50 Spain UI/ml; Plasminogen 0.04-0.12 mg/ml; Aprotinin 3000 UIK/ml (1.67 UPE/ml); Syringe THROMBIN-CALCIUM CHLORIDE: Proteins 50mg/ml; Thrombin 500 UI/ml; calcium chloride 40 µmol/ml

Spain BAXTER, S.L. TISSUCOL DUO 5,0 Syringe TISSUCOL-APROTININ: Total Solution for sealant Epilesional use Polígono Industrial Sector 14 ml Proteins 100-130 mg/ml; Pouet de Camilo, 2 clottable protein 75-115 mg/ml, of which 46394 Ribarroja del Turia fibrinogen 70-110 mg/ml and plasmatic Valencia fibronectin 2-9 mg/ml: Factor XIII 10-50 Spain UI/ml; Plasminogen 0.04-0.12 mg/ml; Aprotinin 3000 UIK/ml (1.67 UPE/ml); Syringe THROMBIN-CALCIUM CHLORIDE: Proteins 50mg/ml; Thrombin 500 UI/ml; calcium chloride 40 µmol/ml Sweden Baxter Medical AB, Artiss Fibrinogen: 91 mg/ml Solution for sealant Epilesional use Isafjordstgatan 30B Aprotinin: 3000 KIU/ml P.O. Box 63 Thrombin: 4 IU/ml 164 94 Kista, Calcium chloride: 40 μmol/ml Sweden Sweden Baxter AG Tisseel Fibrinogen: 91 mg/ml Solution for sealant Epilesional use Industriestraße 67 Aprotinin: 3000 KIU/ml A- 1221 Vienna Thrombin: 500 IU/ml Austria Calcium chloride: 40 µmol/ml Factor XIII: 10 IU/ml

Member State Marketing Authorisation Invented name Strength Pharmaceutical Route of (in EEA) Holder Name Form administration

Sweden Baxter AG Tisseel Duo Quick Fibrinogen: 90 mg/ml Solution for sealant Epilesional use Industriestraße 67 Aprotinin: 3000 KIU/ml A- 1221 Vienna Thrombin: 500 IU/ml Austria Calcium chloride: 40 µmol/ml Factor XIII: 30 IU/ml Plasminogen: 0,08 mg/ml Fibronectin: 5,5 mg/ml The Netherlands Baxter B.V. ARTISS, Fibrinogen: 91 mg/ml Solution for sealant Epilesional use Kobaltweg 49, Utrecht oplossingen voor Aprotinin: 3000 KIU/ml 3542 CE weefsellijm (RVG Thrombin: 4 IU/ml The Netherlands 100631) Calcium chloride: 40 μmol/ml

The Netherlands Baxter AG Tisseel (RVG Fibrinogen: 91 mg/ml Solution for sealant Epilesional use Industriestraße 67 35050/1/2) Aprotinin (synthetic): 3000 KIU/ml A- 1221 Vienna Thrombin: 500 IU/ml Austria Calcium chloride: 40 µmol/ml Factor XIII: ≤ 10 IU/ml The Netherlands Baxter AG Tissucol Duo (RVG Fibrinogen: 70 - 110 mg/ml Solution for sealant Epilesional use Industriestraße 67 17099) Fibronectine 2 - 9 mg/ml A- 1221 Vienna Thrombin: 500 IU/ml Austria Calcium chloride: 40 µmol/ml Factor XIII: 10-50 IU/ml Aprotinine (bovine): 3000 KIU/ml The Netherlands Baxter AG Tissucol, Kit (RVG Fibrinogen: 70 - 110 mg/ml Powder and solvent Epilesional use Industriestraße 67 17100/1/2/3) Fibronectine 2 - 9 mg/ml for sealant A- 1221 Vienna Thrombin: 500 IU/ml Austria Calcium chloride: 40 µmol/ml Factor XIII: 10 - 50 IU/ml Aprotinine (bovine): 3000 KIU/ml United Kingdom Baxter Healthcare Limited, Artiss, solution for Human fibrinogen: 110mg/ml Solution for sealant Epilesional use Caxton Way, sealant deep frozen Aprotinin: 3750KIU/ml Thetford, Human thrombin: 6.5IU/ml Norfork IP24 3SE, Calcium chloride: 44mcmol/ml United Kingdom

Member State Marketing Authorisation Invented name Strength Pharmaceutical Route of (in EEA) Holder Name Form administration

United Kingdom Baxter Healthcare Limited, Tisseel Lyo Two- Fibrinogen: 75mg Powder for sealant Epilesional use Caxton Way, component Fibrin Human thrombin: 500 IU and Solution for Thetford, Sealant Aprotinin: 3000KIU sealant Norfork IP24 3SE, Calcium chloride: 40 mcmol/ml United Kingdom United Kingdom Baxter Healthcare Limited, Tisseel Ready to Human fibrinogen: 110mg/ml Solution for sealant Epilesional use Caxton Way, use Solutions for Aprotinin: 3000KU/ml Thetford, Sealant Human thrombin: 500 iu/ml Norfork IP24 3SE, Calcium chloride: 40mcmol/ml United Kingdom

Beriplast and associated names

Member State Marketing Authorisation Invented name Strength Pharmaceutical Route of Holder Name Form administration (in EEA)

Austria CSL Behring GmbH Beriplast P Combi- Fibrinogen: 90 mg/ml Powder and solvent Epilesional use Emil-von-Behring-Straße 76 Set Pulver und Coagulation factor XIII: 60 U/ml for sealant D-35041 Marburg Lösungsmittel für Aprotinin: 1000 KIU = 0,56 EPU Germany einen Thrombin: 500 IU /ml Gewebekleber Calcium chloride (dihydrate): 5,9 mg/ml France CSL Behring GmbH BERIPLAST P 0.5 Fibrinogen: 90 mg/ml Powder and solvent Epilesional use Emil-von-Behring-Straße 76 ml, 1 ml, 3 ml, Coagulation factor XIII: 60 U/ml for sealant D-35041 Marburg powders and Aprotinin: 1000 KIU = 0,56 EPU Germany solvents for sealant Thrombin: 500 IU /ml Combi-Set Calcium chloride (dihydrate): 5,9 mg/ml

Germany CSL Behring GmbH Beriplast P Combi- Combi-Set 1: Powder and solvent Epilesional use Emil-von-Behring-Straße 76 Set 0,5ml/1ml/3ml Fibrinogen: 90 mg/ml for sealant D-35041 Marburg Coagulation factor XIII: 60 U/ml Germany Aprotinin: 1000 KIU/ml=0.56 PEU/ml

Combi-Set 2: Thrombin: 500 IU/ml Calcium chloride: 5,9 mg/ml

Member State Marketing Authorisation Invented name Strength Pharmaceutical Route of Holder Name Form administration (in EEA)

Greece CSL BEHRING BERIPLAST P Fibrinogen: 90 mg/ml Powder and solvent Epilesional use 5 Hadjiyianni Mexi str, Factor XIII: 60 U/ml for sealant 11528-Athens Aprotinin: 1000 UIC/ml Greece Thrombin: 500 UI/ml Calcium chloride dihydrate: 5,9 mg/ml Greece CSL BEHRING BERIPLAST P Fibrinogen: 90 mg/ml Powder and solvent Epilesional use 5 Hadjiyianni Mexi str, Factor XIII: 60 U/ml for sealant 11528-Athens Aprotinin: 1000 UIC/ml Greece Thrombin: 500 UI/ml Calcium chloride dihydrate: 5,9 mg/ml Greece CSL BEHRING BERIPLAST P Fibrinogen: 90 mg/ml Powder and solvent Epilesional use 5 Hadjiyianni Mexi str, Factor XIII: 60 U/ml for sealant 11528-Athens Aprotinin: 1000 UIC/ml Greece Thrombin: 500 UI/ml Calcium chloride dihydrate: 5,9 mg/ml Hungary CSL Behring GmbH BERIPLAST P Combi-Set 1: Powder and solvent Epilesional use Emil-von-Behring-Straße 76 COMBI-SET 1 ml fibrinogen: 90 mg/ml for sealant D-35041 Marburg szövetragasztó coagulation factor XIII: 60 U/ml Germany készlet aprotinin: 1000 KIU/ml=0.56 PEU/ml

Combi-Set 2: thrombin: 500 IU/ml

Hungary CSL Behring GmbH BERIPLAST P Combi-Set 1: Powder and solvent Epilesional use Emil-von-Behring-Straße 76 COMBI-SET 3 ml fibrinogen: 90 mg/ml for sealant D-35041 Marburg szövetragasztó coagulation factor XIII: 60 U/ml Germany készlet aprotinin: 1000 KIU/ml=0.56 PEU/ml

Combi-Set 2: thrombin: 500 IU/ml Italy CSL Behring GmbH BERIPLAST P Fibrinogen: 90 mg/ml Powder and solvent Epilesional use Emil-von-Behring-Straße 76 Factor XIII: 60 U/ml for sealant D-35041 Marburg Aprotinin: 1000 KIU/ml Germany Thrombin: 500 IU/ml Calcium Chloride: 5.9 mg/ml

Member State Marketing Authorisation Invented name Strength Pharmaceutical Route of Holder Name Form administration (in EEA)

The Netherlands CSL Behring GmbH, Beriplast P Combi- Fibrinogen: 90 mg/ml Powder and solvent Epilesional use Emil-von-Behring-Strasse 76 Set, weefsellijm - Aprotinin (bovine): 1000 KIU/ml for sealant 35041 Marburg 26655/6/7 Thrombin: 500 IU/ml Germany Calcium chloride: 5,9 mg/ml Factor XIII: 60 U/ml Slovak Republic CSL Behring GmbH, Beriplast P Combi- Human fibrinogen: 90 mg Powder and solvent Epilesional use Emil-von-Behring-Strasse 76 Set 0,5 ml, Coagulation factor XIII: 60 UI for tissue sealant 35041 Marburg Beriplast P Combi- Aprotinin: 1000 KUI Germany Set 1 ml, Trombin: 7,6 mg Beriplast P Combi- Calcium chloride: 5,9 mg Set 3 ml Slovenia CSL Behring GmbH, Beriplast P Combi- Human fibrinogen: 90 mg/ml Powder and solvent Epilesional use Emil-von-Behring-Strasse 76 Set 1 ml prašek in Coagulation factor XIII: 60 e/ml for tissue sealant 35041 Marburg vehikel za lepilo za Aprotinin: 1000 EIK/ml Germany tkiva Thrombin: 7,6 mg/ml Calcium chloride: 5,9 mg/ml Slovenia CSL Behring GmbH, Beriplast P Combi- Human fibrinogen: 90 mg/ml Powder and solvent Epilesional use Emil-von-Behring-Strasse 76 Set 3 ml prašek in Coagulation factor XIII: 60 e/ml for tissue sealant 35041 Marburg vehikel za lepilo za Aprotinin: 1000 EIK/ml Germany tkiva Thrombin: 7,6 mg/ml Calcium chloride: 5,9 mg/ml Spain CSL Behring GmbH, BERIPLAST P Fibrinogen: 90 mg/ml Powder and solvent Epilesional use Emil-von-Behring-Strasse 76 COMBI-SET 0,5 ml Coagulation factor XIII: 60 U/ml for sealant 35041 Marburg Aprotinin: 1000 KIU = 0,56 EPU Germany Thrombin: 500 IU /ml Calcium chloride (dihydrate): 5,9 mg/ml Spain CSL Behring GmbH, BERIPLAST P Fibrinogen: 90 mg/ml Powder and solvent Epilesional use Emil-von-Behring-Strasse 76 COMBI-SET 1 ml Coagulation factor XIII: 60 U/ml for sealant 35041 Marburg Aprotinin: 1000 KIU = 0,56 EPU Germany Thrombin: 500 IU /ml Calcium chloride (dihydrate): 5,9 mg/ml

Member State Marketing Authorisation Invented name Strength Pharmaceutical Route of Holder Name Form administration (in EEA)

Spain CSL Behring GmbH, BERIPLAST P Fibrinogen: 90 mg/ml Powder and solvent Epilesional use Emil-von-Behring-Strasse 76 COMBI-SET 3 ml Coagulation factor XIII: 60 U/ml for sealant 35041 Marburg Aprotinin: 1000 KIU = 0,56 EPU Germany Thrombin: 500 IU /ml Calcium chloride (dihydrate): 5,9 mg/ml

Annex II

Scientific conclusions and grounds for variation to the terms of the Marketing Authorisations

Scientific conclusions

Overall summary of the scientific evaluation

Background information

From 2008 until May 2012, a total of eight cases of life-threatening air embolism were associated with the spray application of the fibrin sealants Quixil or Evicel (of which three had a fatal outcome, in one case no product was administered).

Despite risk mitigation activities put in place between August 2010 and early 2011 for Quixil and Evicel, including: 1) a direct healthcare professional communication regarding a change in product labelling, 2) field safety notification for the pressure regulator including change in the instructions for use, and 3) updated customer training programs, two new cases of air embolism (and a third case was received during the referral procedure) have been reported following use of the spray application of Evicel (one non-fatal case in August 2011 and a fatal case in January 2012).

Based on the above, the European Commission initiated a procedure under Article 20 of Regulation (EC) No 726/2004 on 21 May 2012, requesting the CHMP to assess the above concerns and their impact on the benefit-risk for Evicel, to give its opinion on measures necessary to ensure the safe and effective use of Evicel and on whether the marketing authorisation for this product should be maintained, varied, suspended or withdrawn. Following this, the UK’s Medicines and Healthcare products Regulatory Agency triggered a procedure under Article 31 on 24 May 2012, requesting the CHMP to carry out the same assessment for the other fibrin sealants available in the EU, i.e. Quixil, Tissucol, Tisseel, Artiss, Beriplast P, and associated names (see Annex I).

The active ingredients for these products vary, with the main difference being the antifibrinolytic component. Beriplast P, Tisseel, Tissucol and Artiss contain aprotinin, whereas Quixil contains tranexamic acid. Tisseel and Tissucol differ in terms of Factor XIII content.

The authorised indications for Tisseel/Tissucol and Beriplast P are the “supportive treatment where standard surgical techniques are insufficient for improvement of haemostasis” and “to promote adhesion/sealing or as suture support”. Artiss is indicated as a tissue glue to adhere/seal subcutaneous tissue in plastic, reconstructive and burn surgery, as a replacement or an adjunct to sutures or staples. In addition, ARTISS is indicated as an adjunct to haemostasis on subcutaneous tissue surfaces.

Fibrin sealants can be applied either by drip or spray method, the choice of method is left to the surgeon depending on the degree and surface area of bleeding expected or encountered and the remoteness of the location of the bleeding surface. When applied by spraying and in order to achieve a sufficiently fine and uniform spray, the syringe containing the fibrin and thrombin components is usually connected to a supply of gas through a pressure regulator.

Although there are instructions in the current product labelling for use regarding the pressure that must be set and the distance from the bleeding tissue that must be maintained during the spray application in order to avoid forcing gas into the vasculature and the risk of air embolism, there is a concern that these instructions are not always being adhered to, leading to a risk of air embolism.

On 15 November 2012, the CHMP concluded the review of Quixil (for which four cases of life- threatening air embolism were reported) and agreed that the benefit-risk balance of Quixil as supportive treatment in surgery where standard surgical techniques are insufficient, for improvement of haemostasis is positive under normal conditions of use, subject to changes to the product information and implementation of risk minimisation measures, including educational materials and training to be provided to users of the product.

The CHMP also concluded the Article 20 review on Evicel. The Committee agreed that the benefit-risk balance of Evicel was positive under normal conditions of use, subject to similar risk minimisation measures (including changes to the Product Information) as for Quixil. This report only reflects the assessment of Tisseel/Tissucol, Artiss and Beriplast P.

Scientific Discussion

With regard to the efficacy of sprayable fibrin sealants, the CHMP assessed the available information, including data submitted by the MAHs. The CHMP also noted that there appears to be evidence for the need to use the combination spray sealants in situations where there is significant blood loss from a wide surface area and the survival of the patient is threatened. The CHMP therefore concluded that the available evidence supports the efficacy and use of fibrinogen-containing sealants in the approved indications.

Risk of air embolism associated with the spray application of fibrin sealants

With regards to safety, the CHMP noted that the main risk with sprayable fibrin sealants is the risk of air embolism, due air entering the vasculature. The CHMP therefore considered that correct administration of sprayable fibrin sealants is essential to reduce this risk and focused its assessment on the identification of measures that would be necessary and adequate to minimise this risk.

The CHMP reviewed all cases of gas embolism reported with the use of sprayable fibrin sealants (including the cases reported with Quixil and Evicel). The analysis of the case reports showed that symptomatic air/gas embolism had occurred only when the instructions for use were not followed; in each of the other cases there was a failure to follow at least one of the current guidelines on administration of spray application of fibrin sealants using pressurised gas:

1. Inappropriate distance from the tissue surface

2. Excessive pressure

3. Use on open vessels or within a highly vascular cavity e.g. bone marrow.

In one of the Quixil cases, the air embolism was caused by using pressurised air to dry the wound area, with a fatal outcome, although no product was administered. The CHMP pointed out that surgeons and surgical staff should be advised on the appropriate means of achieving a tissue surface that is as dry as possible (e.g. intermittent application of compresses, swabs, use of suction devices).

During the Article 31 procedure, the CHMP also noted a new case of gas embolism reported with the use of Evicel during laser prostatectomy. Evicel was sprayed antero-laterally via pressure regulator with N2 (nitrogen) for a single two-second burst at approximately 2½ to 3 centimetres with reduced pressure of 8 (eight) PSI. This case highlights the problems with the application of sprayable fibrin sealants during endoscopic procedures, where it is not always feasible to accurately judge the distance from the target tissue when spraying. As a result, gas embolism may occur even with a reduced pressure.

A single not well documented non-fatal case of a potential air embolism in association with Tisseel was reported in 2009. The patient underwent a surgical procedure for an unknown reason and Tisseel was reported to have been sprayed using the Easyspray pressure regulator to a ‘closure port’ leading to an air embolism. No other details were provided.

An ad-hoc expert advisory group meeting was convened in October 2012 at the request of the CHMP, during which the experts discussed the benefits of sprayable fibrin sealants as well as potential risk

20 minimisation measures, in particular with regard to the risk of air embolism. The experts agreed that sprayable fibrin sealants are recommended when there is a large surface area of surgical bleeding, generally oozing, and that not using sprayable fibrin sealants in these cases would lead to an increased use of other blood products, which would lead to a higher risk of complications. The experts unanimously agreed that the risk of air embolism is not related to the medicinal product itself but to the device design and its misuse in practice. They were of the opinion that CO2 should be used instead of air as a safety precaution because of the markedly lower risk of gas embolism due to the high solubility of CO2 in the blood. Furthermore, the device design should have a specific gas pressure governor to be used with the spray applicator and with a limit not above the maximal optimal pressure recommended. They also recommended that appropriate educational materials and training for healthcare professionals to administer the product correctly (at the recommended distance and pressure for spray application) is required.

Tisseel/Tissucol and Artiss

The MAHs provided responses to a request from the CHMP to discuss the merits and feasibility of any risk minimisation measures which could be introduced in order to improve the benefit/risk of Tisseel, Tissucol and Artiss spray application.

Having considered all available data, the MAH’s responses and the ad-hoc advisory group recommendations, the CHMP identified and agreed upon a number of risk minimisation measures to be implemented by the MAH to reduce the risk of air/gas embolism associated with the spray use of Tisseel, Tissucol and Artiss. However the CHMP noted that to date, only one non-fatal case of air embolism has been reported for these products as compared to the 8 cases of air embolism (including 3 cases with fatal outcome) reported with Quixil and Evicel.

In particular, the MAH was requested to ensure that all users of the spray application are provided with adequate educational material on the correct use of the product and are offered an educational program which teaches the content of the mentioned educational material. In addition, the MAH should ensure that all users of the spray application of those products are provided with labels for the pressure regulator with a symbol that informs about the correct pressure and distance in open surgery. For Tisseel and Tissucol, which are also recommended for use in laparoscopic procedures, a label for the pressure regulator with a symbol that informs about the correct pressure and distance laparoscopic procedures should also be provided.

Artiss is only indicated for subcutaneous use. It is not recommended for use in laparoscopic surgery.

Finally, Tisseel/Tissucol and Artiss should only be sprayed using a pressure regulator that caps the maximum pressure at 2.0 bar in open wound surgery and using a pressure regulator device that deliver a maximum pressure of 1.5 bar and carbon dioxide gas only in minimally invasive/laparoscopic procedures.

Regarding the clinical use of the products, the CHMP was of the opinion, based on the last case of air embolism reported during an endoscopy procedure with Evicel, where the surgeon had limited visibility of the tissue surface, that the use of fibrin sealants with compressed gas should only be considered if it is possible to accurately judge the spraying distance.

Clear instructions to surgeons with regard to the distances and pressures recommended and the pressurised gas to be used should be provided and the use should be restricted to experienced surgeons who have been trained in the use of those products. Appropriate means of achieving a tissue surface that is as dry as possible should be used and changes in blood pressure, pulse, oxygen

21 saturation and end tidal CO2 should be monitored during application of those products by spray because of the possibility of occurrence of air or gas embolism.

Tisseel/Tissucol use different pressure regulators for open surgery (pressurized air) and minimally invasive/laparoscopic procedures (pressurized CO2), respectively. CHMP considered restricting spray application of these products to CO2 gas only. However, technical requirements when limiting spray application to CO2 gas were considered to add uncertainties to the clinical use of those products, e.g. in minimally invasive/laparoscopic surgery where the maximal pressure to be applied is 1.5 bar, the pressure regulator intended for open wound surgery that allows a higher pressure, could be used by mistake, or the handling associated with CO2 cylinders and respective pressure reducing connectors in the operating theatre. The anticipated benefit of mandating CO2 use in open surgery may not outweigh the risks linked to inappropriate use of Tisseel/ Tissucol and Artiss. Considering the limited evidence of risk of air embolism with those specific products (Tisseel/Tissucol and Artiss), CHMP concluded that beyond the above mentioned risk minimisation measures no further actions were deemed justified. Therefore the CHMP agreed that the use of carbon dioxide should not be mandatory for the spray application using a pressure regulator of those products. The CHMP however recommended the inclusion in the Product information of the warning that the risk of gas embolism appears to be higher when fibrin sealants are sprayed using air, as compared to CO2 and cannot be excluded with Tisseel/Tissucol and Artiss when sprayed in open wound surgery. In minimally invasive/laparoscopic procedures (Tisseel/Tissucol), only carbon dioxide gas should be used.

The CHMP recommended changes the Product Information of Tisseel, Tissucol and Artiss accordingly, to ensure the safe and effective use of those products (see Annex III).

The CHMP agreed on a Direct Healthcare Professional Communication (DHPC), to communicate the outcome of the present review. The CHMP agreed that the DHPC should be circulated to all users of those products in Europe, no later than 15 January 2013.

Beriplast P

Beriplast P is not sprayed using automated pressure regulator. It employs manual pressure derived by the syringe applicator and therefore, no gas-assisted spray device is available for Beriplast. An attachment of air feeding lines or other device components to the manual spray tips physically is not possible. The risk of air embolism with this product was therefore considered negligible by the CHMP.

In order to minimise the potential risk of Beriplast P being used with a pressure regulator not recommended for use with this product, the CHMP recommended that the PI of Beriplast be amended to emphasize that Beriplast should only be reconstituted and administered according to the instructions and with the devices as provided with this product. In addition, in line with the changes requested for the other fibrin sealants used by spray, the PI was amended to reflect that appropriate means of achieving a tissue surface that is as dry as possible should be used (see Annex III).

Benefit Risk balance

Tisseel/Tissucol and Artiss

Having considered all the available data, including the MAH responses provided in writing and during oral explanations and the conclusions of the Ad-hoc Expert meeting, the CHMP agreed that the benefit- risk balance of Tisseel, Tissucol and Artiss in their approved indications, is positive under normal conditions of use, subject to the changes to the product information, (see Annex III), together with the agreed risk minimisation measures (see Annex IV) and the agreed Direct Healthcare Professional Communication.

Beriplast P

Having considered all the available data, including the MAH written responses and the conclusions of the Ad-hoc Expert meeting, the CHMP agreed that the benefit-risk balance of Beriplast P as supportive treatment where standard surgical techniques are insufficient for improvement of haemostasis (including endoscopic treatment of bleeding gastro-duodenal ulcer) and as a tissue to promote adhesion/sealing or as suture support, is positive under normal conditions of use, subject to the changes to the product information, (see Annex III).

Grounds for the variation to the terms of the marketing authorisation of Tisseel/Tissucol and Artiss (and associated names)

Whereas

 The Committee considered the procedure under Article 31 of Directive 2001/83/EC fibrinogen- containing solutions for sealant authorised for administration by spray application;

 The Committee reviewed all the data provided by the MAH in writing and in the oral explanation and the outcome of the ad-hoc expert advisory group meeting;

 The Committee considered all the cases of air embolism associated with the use of fibrinogen- sealants by spray application that have been reported and concluded that the reported cases had only occurred when the instructions for use were not followed.

 The Committee agreed on a number of risk minimisation measures, including changes to the product information regarding the use of the product as well as educational materials and training to be provided to users of the product, which adequately addressed the identified risk of air embolism;

 The Committee, as a consequence, concluded that the benefit-risk balance of the spray application of fibrinogen-sealants is positive under normal conditions of use, subject to the agreed risk minimisation measures, including changes to the product information.

Therefore the CHMP recommended the variation to the terms of the Marketing Authorisations for the Tisseel/Tissucol and Artiss medicinal products (and associated names) referred to in Annex I, in accordance to the amendments to the Summary of Product Characteristics and Package Leaflet set out in Annex III and subject to the conditions set out in Annex IV.

Grounds for the variation to the terms of the marketing authorisation of Beriplast P

Whereas

 The Committee considered the procedure under Article 31 of Directive 2001/83/EC fibrinogen- containing solutions for sealant authorised for administration by spray application;

 The Committee reviewed all the data provided by the MAH in writing and the outcome of the ad- hoc expert advisory group meeting;

 The Committee has considered that as no gas-assisted spray device is available for Beriplast and that an attachment of air feeding lines or other device components to the manual spray tips is not possible, the risk of air embolism with Beriplast is negligible;

 The Committee, as a consequence, concluded that the benefit-risk balance of the spray application of Beriplast P is positive under normal conditions of use, subject to changes to the product information.

Therefore the CHMP recommended the variation to the terms of the Marketing Authorisations for the Beriplast P medicinal products (and associated names) referred to in Annex I, in accordance to the amendments to the Summary of Product Characteristics and Package Leaflet set out in Annex III.

Annex III

Amendments to relevant sections of the summary of product characteristics and package leaflet

Tisseel and associated names

A. Summary of Products Characteristics

The following changes should be made to the SmPC of Tisseel and associated names:

4.2 Posology and method of administration

The following text should be added to this section:

“The use of [PRODUCT NAME] is restricted to experienced surgeons who have been trained in the use of [PRODUCT NAME].”

4.2.2 Method and route of administration

This section of the SmPC should include the following wording:

“In order to ensure optimal safe use of [PRODUCT NAME] by spray application the following recommendations should be followed:

In open wound surgery - a pressure regulator device that delivers a maximum pressure of no more than 2.0 bar (28.5 psi) should be used.

In minimally invasive/laparoscopic procedures – a pressure regulator device that delivers a maximum pressure of no more than 1.5 bar (22 psi) and uses carbon dioxide gas only should be used.

Prior to applying [PRODUCT NAME] the surface area of the wound needs to be dried by standard techniques (e.g. intermittent application of compresses, swabs, use of suction devices).

[PRODUCT NAME] should only be reconstituted and administered according to the instructions and with the devices recommended for this product (see section 6.6).

For spray application, see sections 4.4 and 6.6 for specific recommendations on the required pressure and distance from tissue per surgical procedure and length of applicator tips.”

4.4 Special warnings and precautions for use

This section of the SmPC should include the following wording, in bold and underlined format where indicated:

“Apply [PRODUCT NAME] as a thin layer. Excessive clot thickness may negatively interfere with the product’s efficacy and the wound healing process.

Life-threatening/fatal air or gas embolism has occurred with the use of spray devices employing a pressure regulator to administer fibrin sealants. This event appears to be related to the use of the spray device at higher than recommended pressures and/or in close proximity to the tissue surface. The risk appears to be higher when fibrin sealants are sprayed with air, as compared to CO2 and therefore cannot be excluded with [Product Name] when sprayed in open wound surgery.

When applying [PRODUCT NAME] using a spray device, be sure to use a pressure within the pressure range recommended by the spray device manufacturer (see table in section 6.6 for pressures and distances).

[PRODUCT NAME] spray application should only be used if it is possible to accurately judge the spray distance as recommended by the manufacturer. Do not spray closer than the recommended distances.

When spraying [PRODUCT NAME], changes in blood pressure, pulse, oxygen saturation and end tidal CO2 should be monitored because of the possibility of occurrence of air or gas embolism (also see section 4.2).”

6.6 Special precautions for disposal

Spray application

This section of the SmPC should include the following wording, in bold and underlined format where indicated:

“When applying [PRODUCT NAME] using a spray device be sure to use a pressure and a distance from tissue within the ranges recommended by the manufacturer as follows:

Recommended pressure, distance and devices for spray application of [product name] Recommen Pressure ded Recommended Spray set to Applicator tips to Surgery regulator to be distance spray be used be used used from target pressure tissue Tisseel / Artiss n.a. EasySpray Spray Set 1.5-2.0 bar Open wound Tisseel / Artiss 10-15cm (21.5-28.5 Spray Set 10 n.a. EasySpray psi). pack

When spraying the [PRODUCT NAME], changes in blood pressure, pulse, oxygen saturation and end tidal CO2 should be monitored because of the possibility of occurrence of air or gas embolism (see sections 4.2 and 4.4).”

B. Package Leaflet

The following changes should be made to the package leaflet of Tisseel and associated names:

2. Before you use [PRODUCT NAME]

Take special care with [PRODUCT NAME]

This section of the Package Leaflet should include the following wording, in bold and underlined format where indicated:

 “Life-threatening/fatal air or gas embolism (air getting into the blood circulation which can be serious or life-threatening) has occurred very rarely with the use of spray devices employing pressure regulators to administer fibrin sealants. This appears to be related to the use of the spray device at higher than recommended pressures and/or in close proximity to the tissue surface. The risk appears to be higher when fibrin sealants are sprayed with air, as compared to CO2 and therefore cannot be excluded with [Product Name] when sprayed in open wound surgery.  Spray devices and the accessory tip provide instructions for use with recommendations for pressure ranges and to the spraying distance from the tissue surface.  [PRODUCT NAME] should be administered strictly according to the instructions and only with devices recommended for this product.  When spraying [PRODUCT NAME], changes in blood pressure, pulse, oxygen saturation and end tidal CO2 should be monitored for possible occurrence of gas embolism.”

3. How to use [PRODUCT NAME]

This section of the Package Leaflet should include the following wording, in bold and underlined format where indicated:

“The use of [PRODUCT NAME] is restricted to experienced surgeons who have been trained in the use of [PRODUCT NAME]

Prior to applying [PRODUCT NAME] the surface area of the wound needs to be dried by standard techniques (e.g. intermittent application of compresses, swabs, use of suction devices).

When applying [PRODUCT NAME] using a spray device be sure to use a pressure and a distance from the tissue within the range recommended by the manufacturer as follows:

Duplospray MIS Regulator Duplospray MIS Duplospray MIS Applicator 20cm Regulator NIST B11 Duplospray MIS Regulator Duplospray MIS Duplospray MIS Applicator 30cm Laparoscopic Regulator NIST / minimally B11 1.2-1.5 bar n.a. 2 – 5 cm invasive Duplospray MIS (18-22 psi) procedures Regulator Duplospray MIS Duplospray MIS Applicator 40cm Regulator NIST B11 Duplospray MIS Regulator Replaceable tip Duplospray MIS Regulator NIST B11 When spraying the [PRODUCT NAME], changes in blood pressure, pulse, oxygen saturation and end tidal CO2 should be monitored because of the possibility of occurrence of air or gas embolism (see section 2).”

Tissucol and associated names

A. Summary of Products Characteristics

The following changes should be made to the SmPC of Tissucol and associated names:

4.2 Posology and method of administration

The following text should be added to this section:

“The use of [PRODUCT NAME] is restricted to experienced surgeons who have been trained in the use of [PRODUCT NAME].”

4.2.2 Method and route of administration

This section of the SmPC should include the following wording:

“In order to ensure optimal safe use of [PRODUCT NAME] by spray application the following recommendations should be followed:

In open wound surgery - a pressure regulator device that delivers a maximum pressure of no more than 2.0 bar (28.5 psi) should be used.

In minimally invasive/laparoscopic procedures – a pressure regulator device that delivers a maximum pressure of no more than 1.5 bar (22 psi) and uses carbon dioxide gas only should be used.

Prior to applying [PRODUCT NAME] the surface area of the wound needs to be dried by standard techniques (e.g. intermittent application of compresses, swabs, use of suction devices).

[PRODUCT NAME] should only be reconstituted and administered according to the instructions and with the devices recommended for this product (see section 6.6).

For spray application, see sections 4.4 and 6.6 for specific recommendations on the required pressure and distance from tissue per surgical procedure and length of applicator tips.”

4.4 Special warnings and precautions for use

This section of the SmPC should include the following wording, in bold and underlined format where indicated:

“Apply [PRODUCT NAME] as a thin layer. Excessive clot thickness may negatively interfere with the product’s efficacy and the wound healing process.

[PRODUCT NAME] spray application should only be used if it is possible to accurately judge the spray distance as recommended by the manufacturer. Do not spray closer than the recommended distances.

6.6 Special precautions for disposal

Spray application

This section of the SmPC should include the following wording, in bold and underlined format where indicated:

“When applying [PRODUCT NAME] using a spray device be sure to use a pressure and a distance from tissue within the ranges recommended by the manufacturer as follows:

Recommended pressure, distance and devices for spray application of [product name] Applicator Recommended Spray set Pressure regulator Recommended Surgery tips to be distance from to be used to be used spray pressure used target tissue Duploject 1.5-2.0 bar n.a. Tissomat 10-15cm Spray Set (21.5-28.5 psi). Open wound Tisseel / 1.5-2.0 bar Tissucol n.a. EasySpray 10-15cm (21.5-28.5 psi). Spray Set

Duplospray MIS Duplospray Regulator MIS Applicator Duplospray MIS 20cm Regulator NIST B11 Duplospray MIS Duplospray Regulator MIS Applicator Duplospray MIS Laparoscopic 30cm Regulator NIST / minimally 1.2-1.5 bar (18- n.a. B11 2 – 5 cm invasive 22 psi) Duplospray MIS procedures Duplospray Regulator MIS Applicator Duplospray MIS 40cm Regulator NIST B11 Duplospray MIS Regulator Replaceable Duplospray MIS tip Regulator NIST B11

B. Package Leaflet

The following changes should be made to the package leaflet of Tissucol and associated names:

2. Before you use [PRODUCT NAME]

Take special care with [PRODUCT NAME]

This section of the Package Leaflet should include the following wording, in bold and underlined format where indicated:

3. How to use [PRODUCT NAME]

This section of the Package Leaflet should include the following wording, in bold and underlined format where indicated:

“The use of [PRODUCT NAME] is restricted to experienced surgeons who have been trained in the use of [PRODUCT NAME]

Prior to applying [PRODUCT NAME] the surface area of the wound needs to be dried by standard techniques (e.g. intermittent application of compresses, swabs, use of suction devices).

When applying [PRODUCT NAME] using a spray device be sure to use a pressure and a distance from the tissue within the range recommended by the manufacturer as follows:

Artiss and associated names

A. Summary of Products Characteristics

The following changes should be made to the SmPC of Artiss:

4.2 Posology and method of administration

This wording:

“ARTISS is intended for Hospital Use Only by suitably experienced physicians or surgeons.”

Should be replaced by:

“The use of [PRODUCT NAME] is restricted to experienced surgeons who have been trained in the use of [PRODUCT NAME].”

4.2.2 Method and route of administration

This section of the SmPC should include the following wording:

“For subcutaneous use only. [PRODUCT NAME] is not recommended for laparoscopic surgery.

In order to ensure optimal safe use of [PRODUCT NAME] it should be sprayed using a pressure regulator device that delivers a maximum pressure of up to 2.0 bar (28.5 psi).

Prior to applying [PRODUCT NAME] the surface area of the wound needs to be dried by standard techniques (e.g. intermittent application of compresses, swabs, use of suction devices).

[PRODUCT NAME] should only be reconstituted and administered according to the instructions and with the devices recommended for this product (see section 6.6).

For spray application, see sections 4.4 and 6.6 for specific recommendations on the required pressure and distance from tissue per surgical procedure and length of applicator tips.”

4.4 Special warnings and precautions for use

This section of the SmPC should include the following wording, in bold and underlined format where indicated:

“Apply [PRODUCT NAME] as a thin layer. Excessive clot thickness may negatively interfere with the product’s efficacy and the wound healing process.

Life-threatening air or gas embolism has occurred with the use of spray devices employing a pressure regulator to administer fibrin sealants. This event appears to be related to the use of the spray device at higher than recommended pressures and/or in close proximity to the tissue surface. The risk appears to be higher when fibrin sealants are sprayed with air, as compared to CO2 and therefore cannot be excluded with [PRODUCT NAME].

[PRODUCT NAME] spray application should only be used if it is possible to accurately judge the spray distance as recommended by the manufacturer. Do not spray closer than the recommended distances.

6.6 Special precautions for disposal

Spray application

This section of the SmPC should include the following wording, in bold and underlined format where indicated:

“When applying [PRODUCT NAME] using a spray device be sure to use a pressure and a distance from tissue within the ranges recommended by the manufacturer as follows:

Recommended pressure, distance and devices for spray application of [product name] Recommend Pressure Spray set to be Applicator tips ed distance Recommended regulator to be used to be used from target spray pressure used tissue Tisseel / Artiss Open wound n.a. EasySpray Spray Set 1.5-2.0 bar surgery of Tisseel / Artiss 10 – 15 cm (21.5-28.5 subcutaneou Spray Set 10 n.a. EasySpray psi) s tissue pack

B. Package Leaflet

The following changes should be made to the package leaflet of Artiss and associated names:

2. Before you use [PRODUCT NAME]

Take special care with [PRODUCT NAME]

This section of the Package Leaflet should include the following wording, in bold and underlined format where indicated:

 “[PRODUCT NAME] should not be used in laparoscopic surgery (keyhole surgery).  Life-threatening/fatal air or gas embolism (air getting into the blood circulation which can be serious or life-threatening) has occurred very rarely with the use of spray devices employing pressure regulators to administer fibrin sealants. This appears to be related to the use of the spray device at higher than recommended pressures and/or in close proximity to the tissue surface. The risk appears to be higher when fibrin sealants are sprayed with air, as compared to CO2 and therefore cannot be excluded with [Product Name].  When [PRODUCT NAME] is applied using a spray device, the pressure and spraying distance have to be within the range recommended by the manufacturer. [PRODUCT NAME] should be administered strictly according to the instructions and only with devices recommended for this product.  When spraying [PRODUCT NAME], changes in blood pressure, pulse, oxygen saturation and end tidal CO2 should be monitored for possible occurrence of gas embolism.”

3. How to use [PRODUCT NAME]

This section of the Package Leaflet should include the following wording, in bold and underlined format where indicated:

“The use of [PRODUCT NAME] is restricted to experienced surgeons who have been trained in the use of [PRODUCT NAME].

Prior to applying [PRODUCT NAME] the surface area of the wound needs to be dried by standard techniques (e.g. intermittent application of compresses, swabs, use of suction devices).

When applying [PRODUCT NAME] using a spray device be sure to use a pressure and a distance from the tissue within the range recommended by the manufacturer as follows:

Beriplast P and associated names

A. Summary of Products Characteristics

The following changes should be made to the package leaflet of Beriplast P and associated names:

4.2 Posology and method of administration

The following text should be inserted in this section:

“Prior to applying [PRODUCT NAME] the surface area of the wound needs to be dried by standard techniques (e.g. intermittent application of compresses, swabs, use of suction devices).

[PRODUCT NAME] should only be reconstituted and administered according to the instructions and with the devices as provided with this product.”

6.6 Special precautions for disposal

The following text should be inserted in this section:

“Prior to applying [PRODUCT NAME] the surface area of the wound needs to be dried by standard techniques (e.g. intermittent application of compresses, swabs, use of suction devices).”

B. Package Leaflet

The following changes should be made to the package leaflet of Beriplast P and associated names:

4. Possible side effects

Section 4.2 – Method and route of administration

The following text should be inserted in this section:

“Prior to applying Beriplast the surface area of the wound needs to be dried by standard techniques (e.g. intermittent application of compresses, swabs, use of suction devices).

The product should only be reconstituted and administered according to the instructions and with the devices as provided with this product.”

Section 6.6 – Special precautions for disposal

The following text should be inserted in this section:

“Prior to applying [product name] the surface area of the wound needs to be dried by standard techniques (e.g. intermittent application of compresses, swabs, use of suction devices).”

Information for healthcare professionals

The following text should be inserted in this section:

“Prior to applying Beriplast the surface area of the wound needs to be dried by standard techniques (e.g. intermittent application of compresses, swabs, use of suction devices).

The product should only be reconstituted and administered according to the instructions and with the devices as provided with this product.”

Annex IV

Conditions to the marketing authorisation

Tisseel / Tissucol and associated names

The Marketing Authorisation Holder (MAH) shall submit to the national competent authority, within one month of the European Commission decision on this procedure (EMEA/H/A-31/1337), an EU risk management plan for the products according to the EU Good Vigilance Practices which includes the safety concern of gas embolism.

The MAH shall ensure that, within 10 months of the European Commission decision for this procedure (EMEA/H/C/A31/1337), all users of the spray application of this product are provided with educational material and within 4 months of the European Commission decision for this procedure (EMEA/H/C/A31/1337) all internal personnel are provided with educational material. This material shall inform about the

 risk of life-threatening gas embolism if the product is sprayed incorrectly  correct pressure and distance from tissue depending on kind of surgery (open or laparoscopic)  for laparoscopic surgery restriction to only use if the minimum spray distance of 2cm

(recommended range 2-5cm) can be accurately judged and with CO2 only  requirement to dry the wound using standard techniques (e.g. intermittent application of compresses, swabs, use of suction devices) prior to using the product

 requirement to closely monitor blood pressure, pulse rate, oxygen saturation and end tidal CO2 when spraying the product, for the occurrence of gas embolism.  which regulator(s) should be used, in line with manufacturer recommendations and the SmPC instructions for use

The material shall include the latest Summary of Product Characteristics and the section titled “The following information is intended for medical or healthcare professionals only” of the latest package leaflet.

The MAH shall offer an educational program to all users of the spray application of this product. The program shall teach the content of the mentioned educational material.

The Marketing Authorisation Holder shall agree the exact content and format of the educational material and educational program with the national competent authority.

The MAH shall ensure that, within three months of the European Commission decision on this procedure (EMEA/H/C/A31/1337), all users of the spray application of this product are provided with  labels for the pressure regulator with a symbol that informs about the correct pressures and distances in open and laparoscopic procedures

The MAH should ensure within two years, that the product is used in accordance with the SmPC, with a pressure regulator device that delivers a maximum pressure of no more than 2.0 bar (28.5 psi) in open wound surgery.

The MAH should ensure within two years, that the product is used in accordance with the SmPC, with a pressure regulator device that delivers a maximum pressure of no more than 1.5 bar (22 psi) in minimally invasive/laparoscopic procedures.

Artiss and associated names

The Marketing Authorisation Holder (MAH) shall submit to the national competent authority, within one month of the European Commission decision on this procedure (EMEA/H/A-31/1337), an EU risk management plan for the product according to the EU Good Vigilance Practices which includes the safety concern of gas embolism.

 risk of life-threatening gas embolism if the product is sprayed incorrectly  correct pressure and distance from tissue depending on kind of surgery (open or laparoscopic)  requirement to dry the wound using standard techniques (e.g. intermittent application of compresses, swabs, use of suction devices) prior to using the product

 requirement to closely monitor blood pressure, pulse rate, oxygen saturation and end tidal CO2 when spraying the product, for the occurrence of gas embolism.  which regulator should be used, in line with manufacturer recommendations and the SmPC instructions for use  restriction to open wound subcutaneous surgery only

The MAH shall offer an educational program to all users of the spray application of this product. The program shall teach the content of the mentioned educational material.

The Marketing Authorisation Holder shall agree the exact content and format of the educational material and educational program with the national competent authority.

The MAH should ensure within two years, that the product is used in accordance with the SmPC, with a pressure regulator device that delivers a maximum pressure of no more than 2.0 bar (28.5 psi).