1

Annex I

List of the names, pharmaceutical form(s), strength(s) of the medicinal product(s), route(s) of administration, marketing authorisation holder(s) in the Member States

2

Member State (in EEA)

Marketing authorisation holder

INN Invented name Strength Pharmaceutical form

Route of administration

Austria Lincoln Medical Ltd Unit 8 Wilton Business Centre Wilton, Salisbury SP2 0AH United Kingdom

Epinephrine Anapen Junior 150 Mikrogramm in 0,3 ml - Injektionslösung (Fertigspritze)

150 Mikrogramm/0,3ml

Solution for injection Intramuscular use

Austria Lincoln Medical Ltd Unit 8 Wilton Business Centre Wilton, Salisbury SP2 0AH United Kingdom

Epinephrine Anapen 300 Mikrogramm in 0,3 ml - Injektionslösung (Fertigspritze)

300 Mikrogramm/0,3ml

Solution for injection Intramuscular use

Austria Lincoln Medical Ltd Unit 8 Wilton Business Centre Wilton, Salisbury SP2 0AH United Kingdom

Epinephrine Anapen 500 Mikrogramm/0,3 ml Injektionslösung in einer Fertigspritze

500 Mikrogramm/0,3ml

Solution for injection Intramuscular use

Austria Meda Pharma GmbH Guglgasse 15 1110 Wien Austria

Epinephrine EpiPen Junior 150 Mikrogramm Injektionslösung in einem Fertigpen

150 Mikrogramm

Solution for injection Intramuscular use

Austria Meda Pharma GmbH Guglgasse 15 1110 Wien Austria

Epinephrine EpiPen 300 Mikrogramm Injektionslösung in einem FertigPen

300 Mikrogramm

Solution for injection Intramuscular use

Austria Alk Abello A/S Boge Alle 6-8 2970 Horsholm Denmark

Epinephrine hydrotartrat

Jext 150 Mikrogramm Injektionslösung in einem Fertigpen

150 Mikrogramm

Solution for injection Intramuscular use

3

Member State (in EEA)

Marketing authorisation holder

INN Invented name Strength Pharmaceutical form

Route of administration

Austria Alk Abello A/S Boge Alle 6-8 2970 Horsholm Denmark

Epinephrine hydrotartrat

Jext 300 Mikrogramm Injektionslösung in einem Fertigpen

300 Mikrogramm

Solution for injection Intramuscular use

Belgium Meda Pharma sa-nv Chaussée de la Hulpe 166 1170 Brussels Belgium

Epinephrine Epipen 300 µg Solution for injection Intramuscular use

Belgium Meda Pharma sa-nv Chaussée de la Hulpe 166 1170 Brussels Belgium

Epinephrine Epipen junior 150 µg Solution for injection Intramuscular use

Belgium ALK-Abello Boge Alle 6-8 2970 Horsholm Denmark

Epinephrine Bitartrate

Jext 150 µg Solution for injection Intramuscular use

Belgium ALK-Abello Boge Alle 6-8 2970 Horsholm Denmark

Epinephrine Bitartrate

Jext 300 µg Solution for injection Intramuscular use

Bulgaria Lincoln Medical Ltd Unit 8 Wilton Business Centre Wilton, Salisbury SP2 0AH United Kingdom

Adrenaline Anapen Junior 150 mcg/0,3 ml

Solution for injection Intramuscular use

4

Member State (in EEA)

Marketing authorisation holder

INN Invented name Strength Pharmaceutical form

Route of administration

Bulgaria Lincoln Medical Ltd Unit 8 Wilton Business Centre Wilton, Salisbury SP2 0AH United Kingdom

Adrenaline Anapen 300 mcg/0,3 ml

Solution for injection Intramuscular use

Bulgaria MEDA Pharma GmbH & Co. KG Benzstr. 1 + Bad Homburg 61352 Germany

Adrenaline EpiPen Jr. 150 mcg/0,3 ml

Solution for injection Intramuscular use

Bulgaria MEDA Pharma GmbH & Co. KG Benzstr. 1 + Bad Homburg 61352 Germany

Adrenaline EpiPen 300 mcg/0,3 ml

Solution for injection Intramuscular use

Croatia Medical Intertrade d.o.o. Dr. Franje Tuđmana 3 Sveta Nedjelja 10431 Croatia

Epinephrine EpiPen 0,3 mg otopina za injekciju

0,3 mg Solution for injection Intramuscular use

Croatia Medical Intertrade d.o.o. Dr. Franje Tuđmana 3 Sveta Nedjelja 10431 Croatia

Epinephrine EpiPen Jr 0,15 mg otopina za injekciju

0,15 mg Solution for injection Intramuscular use

Cyprus Lincoln Medical Ltd Unit 8 Wilton Business Centre Wilton, Salisbury SP2 0AH United Kingdom

Epinephrine Anapen 300 mcg/0.3ml

Solution for injection Intramuscular use

5

Member State (in EEA)

Marketing authorisation holder

INN Invented name Strength Pharmaceutical form

Route of administration

Cyprus Lincoln Medical Ltd Unit 8 Wilton Business Centre Wilton, Salisbury SP2 0AH United Kingdom

Epinephrine Anapen Junior 150 mcg/0.3ml

Solution for injection Intramuscular use

Czech Republic

MEDA Pharma s.r.o. Kodaňská 1441/46 110 00 Prague 10 Czech Republic

Epinephrine Epipen 300 mikrogramů 0,3 mg per dose (0,3 mg/0,3 ml)

Solution for injection in pre-filled pen

Intramuscular use

Czech Republic

MEDA Pharma s.r.o. Kodaňská 1441/46 110 00 Prague 10 Czech Republic

Epinephrine Epipen JR. 150 mikrogramů

0,15 mg per dose (0,15 mg/0,3 ml)

Solution for injection in pre-filled pen

Intramuscular use

Czech Republic

Lincoln Medical Ltd Unit 8 Wilton Business Centre Wilton, Salisbury SP2 0AH United Kingdom

Epinephrine Anapen injekční roztok 300 mikrogramů/0,3 ml (předplněná injekční stříkačka)

0,3 mg per dose (0,3 mg/0,3 ml)

Solution for injection Intramuscular use

Czech Republic

Lincoln Medical Ltd Unit 8 Wilton Business Centre Wilton, Salisbury SP2 0AH United Kingdom

Epinephrine Anapen Junior injekční roztok 150 mikrogramů/0,3 ml (předplněná injekční stříkačka)

0,15 mg per dose (0,15 mg/0,3 ml)

Solution for injection Intramuscular use

Denmark Lincoln Medical Limited Unit 8 Wilton Business Centre Wilton Salisbury SP2 0AH United Kingdom

Adrenaline Anapen 300 mcg/0,3 ml

Solution for injection Intramuscular use

6

Member State (in EEA)

Marketing authorisation holder

INN Invented name Strength Pharmaceutical form

Route of administration

Denmark Lincoln Medical Ltd Unit 8 Wilton Business Centre Wilton, Salisbury SP2 0AH United Kingdom

Adrenaline Anapen Junior 150 mcg/0,3 ml

Solution for injection Intramuscular use

Denmark Meda AS Solvang 8 DK-3450 Allerød Denmark

Adrenaline EpiPen 0,3 mg/dose Solution for injection Intramuscular use

Denmark Meda AS Solvang 8 DK-3450 Allerød Denmark

Adrenaline EpiPen Jr. 0,15 mg/dose

Solution for injection Intramuscular use

Denmark ALK-Abello A/S Bøge Alle 6-8 DK-2970 Hørsholm Denmark

Adrenaline Jext 150 mcg Solution for injection, prefilled pen

Intramuscular use

Denmark ALK-Abello A/S Bøge Alle 6-8 DK-2970 Hørsholm Denmark

Adrenaline Jext 300 mcg Solution for injection, prefilled pen

Intramuscular use

Estonia Lincoln Medical Ltd Unit 8 Wilton Business Centre Wilton, Salisbury SP2 0AH United Kingdom

Epinephrine ANAPEN 150 mcg/0,3ml

Solution for injection in pre-filled syringe

Intramuscular use

7

Member State (in EEA)

Marketing authorisation holder

INN Invented name Strength Pharmaceutical form

Route of administration

Estonia Lincoln Medical Ltd Unit 8 Wilton Business Centre Wilton, Salisbury SP2 0AH United Kingdom

Epinephrine ANAPEN 300 mcg/ 0,3ml

Solution for injection in pre-filled syringe

Intramuscular use

Estonia SIA Meda Pharma Vienibas gatve 109, Riga LV-1058 Latvia

Epinephrine EPIPEN 150 mcg/ 0,3ml

Solution for injection in pre-filled pen

Intramuscular use

Estonia SIA Meda Pharma Vienibas gatve 109, Riga LV-1058 Latvia

Epinephrine EPIPEN 300 mcg/0,3ml

Solution for injection in pre-filled pen

Intramuscular use

Finland Lincoln Medical Ltd Unit 8 Wilton Business Centre Wilton, Salisbury SP2 0AH United Kingdom

Adrenaline ANAPEN 0.3 mg / 0.3 ml

Solution for injection in pre-filled syringe

Intramuscular use

Finland Lincoln Medical Ltd Unit 8 Wilton Business Centre Wilton, Salisbury SP2 0AH United Kingdom

Adrenaline ANAPEN JUNIOR 0.15 mg / 0.3 ml

Solution for injection in pre-filled syringe

Intramuscular use

Finland Meda Oy Vaisalantie 4 02130 Espoo Finland

Adrenaline EPIPEN 300 mikrog Solution for injection in pre-filled pen

Intramuscular use

8

Member State (in EEA)

Marketing authorisation holder

INN Invented name Strength Pharmaceutical form

Route of administration

Finland Meda Oy Vaisalantie 4 02130 Espoo Finland

Adrenaline EPIPEN JR. 150 mikrog Solution for injection in pre-filled pen

Intramuscular use

Finland ALK-Abello A/S Bøge Alle 6-8 B.O.BOX 408 2970 Horsholm Denmark

Adrenaline tartrate JEXT 150 mikrog Solution for injection in pre-filled pen

Intramuscular use

Finland ALK-Abello A/S Bøge Alle 6-8 B.O.BOX 408 2970 Horsholm Denmark

Adrenaline tartrate JEXT 300 mikrog Solution for injection in pre-filled pen

Intramuscular use

France BIOPROJET PHARMA 9 Rue Rameau 75002 Paris France

Adrenaline ANAPEN 150 microgrammes/0,3 ml, solution for injection in pre-filled syringe

150 µg/0,3 ml

Solution for injection in pre-filled syringe

Intramuscular use

France BIOPROJET PHARMA 9 Rue Rameau 75002 Paris France

Adrenaline ANAPEN 300 microgrammes/0,3 ml, solution for injection in pre-filled syringe

300 µg/0,3 ml

Solution for injection in pre-filled syringe

Intramuscular use

France Meda Pharma 25 boulevard de l’Amiral Bruix 75016 Paris France

Adrenaline EPIPEN 0,15 mg/0,3 ml, solution for injection in pre-filled pen

0,15 mg/0,3 ml

Solution for injection in pre-filled pen

Intramuscular use

9

Member State (in EEA)

Marketing authorisation holder

INN Invented name Strength Pharmaceutical form

Route of administration

France Meda Pharma 25 boulevard de l’Amiral Bruix 75016 Paris France

Adrenaline EPIPEN 0,30 mg/0,3 ml, solution for injection in pre-filled pen

0,30 mg/0,3 ml

Solution for injection in pre-filled pen

Intramuscular use

France ALK-Abelló A/S Boge Allé 6-8. 2970 Horsholm Denmark

Adrenaline JEXT 150 microgrammes, solution for injection in pre-filled pen

150 µg Solution for injection in pre-filled pen

Intramuscular use

France ALK-Abelló A/S Boge Allé 6-8. 2970 Horsholm Denmark

Adrenaline JEXT 300 microgrammes, solution for injection in pre-filled pen

300 µg Solution for injection in pre-filled pen

Intramuscular use

Germany ALK-ABELLO A/S Boge Alle 6-8 2970 Horsholm Denmark

Epinephrine JEXT 300 Mikrogramm Injektionslösung in einem Fertigpen

0,3 mg /0,3 ml

Solution for injection Intramuscular use

Germany ALK-ABELLO A/S Boge Alle 6-8 2970 Horsholm Denmark

Epinephrine JEXT 150 Mikrogramm Injektionslösung in einem Fertigpen

0,15 mg /0,15 ml

Solution for injection Intramuscular use

Germany Lincoln Medical Ltd. Unit 8 Wilton Buisiness Centre Wilton, Salisbury SP2 0AH United Kingdom

Epinephrine Anapen 300 Mikrogramm Injektionslösung

300 µg/ 0,3 ml

Solution for injection Intramuscular use

10

Member State (in EEA)

Marketing authorisation holder

INN Invented name Strength Pharmaceutical form

Route of administration

Germany Lincoln Medical Ltd. Unit 8 Wilton Buisiness Centre Wilton, Salisbury SP2 0AH United Kingdom

Epinephrine Anapen Junior 150 Mikrogramm Injektionslösung

150 µg/ 0,3 ml

Solution for injection Intramuscular use

Germany MEDA Pharma GmbH & Co. KG Benzstr. 1 61352 Bad Homburg Germany

Epinephrine Fastjekt 2 mg/ 2 ml Solution for injection Intramuscular use

Germany MEDA Pharma GmbH & Co. KG Benzstr. 1 61352 Bad Homburg Germany

Epinephrine FASTJEKT Junior 0,5 mg/ 1 ml Solution for injection Intramuscular use

Germany PharmaSwiss Ceska republika s.r.o. Jankovcova 1569/2c 170 00 Prague Czech Republic

Epinephrine Emerade 150 Mikrogramm Injektionslösung in einem Fertigpen

0,5 mg/ 0,5 ml

Solution for injection Intramuscular use

Germany PharmaSwiss Ceska republika s.r.o. Jankovcova 1569/2c 170 00 Prague Czech Republic

Epinephrine Emerade 300 Mikrogramm Injektionslösung in einem Fertigpen

0,5 mg/ 0,5 ml

Solution for injection Intramuscular use

11

Member State (in EEA)

Marketing authorisation holder

INN Invented name Strength Pharmaceutical form

Route of administration

Germany PharmaSwiss Ceska republika s.r.o. Jankovcova 1569/2c 170 00 Prague Czech Republic

Epinephrine Emerade 500 Mikrogramm Injektionslösung in einem Fertigpen

0,5 mg/ 0,5 ml

Solution for injection Intramuscular use

Greece Lincoln Medical Ltd Unit 8 Wilton Business Centre Wilton, Salisbury SP2 0AH United Kingdom

Epinephrine ANAPEN 300 mcg/ 0,3ml

Solution for injection Intramuscular use

Greece Lincoln Medical Ltd Unit 8 Wilton Business Centre Wilton, Salisbury SP2 0AH United Kingdom

Epinephrine ANAPEN 150 mcg/0,3ml

Solution for injection Intramuscular use

Greece DOCTUM FARMAKEYTIKI K. GIOKARIS & SIA A.E., 1st Km Leof. Paianias-Markopoulou, 19002 Paiania, Greece

Epinephrine FASTPEN 0,15 mg/3ml Solution for injection Intramuscular use

Greece DOCTUM FARMAKEYTIKI K. GIOKARIS & SIA A.E., 1st Km Leof. Paianias-Markopoulou, 19002 Paiania, Greece

Epinephrine FASTPEN 0,30 mg/0,3ml

Solution for injection Intramuscular use

12

Member State (in EEA)

Marketing authorisation holder

INN Invented name Strength Pharmaceutical form

Route of administration

Hungary Lincoln Medical Ltd Unit 8, Wilton Business Centre Wilton,Salisbury SP2 0AH United Kingdom

Adrenaline ANAPEN 300 mikrogramm/0,3 ml oldatos injekció előretöltött fecskendőben

300 microgramm/0,3 ml

Solution for injection in pre-filled syringe

Intramuscular use

Hungary Lincoln Medical Ltd Unit 8, Wilton Business Centre Wilton ,Salisbury SP2 0AH United Kingdom

Adrenaline ANAPEN JUNIOR 150 mikrogramm/0,3 ml oldatos injekció előretöltött fecskendőben

150 microgramm/0,3 ml

Solution for injection in pre-filled syringe

Intramuscular use

Hungary Meda Pharma Hungary Kft. Váci út 91. Budapest H-1139 Hungary

Adrenaline EPIPEN 300 mikrogramm oldatos injekció előre töltött tollban

300 microgramm/0,3 ml

Solution for injection in pre-filled pen

Intramuscular use

Hungary Meda Pharma Hungary Kft. Váci út 91. Budapest H-1139 Hungary

Adrenaline EPIPEN JUNIOR 150 mikrogramm oldatos injekció előre töltött tollban

150 microgramm/0,3 ml

Solution for injection in pre-filled pen

Intramuscular use

Iceland Lincoln Medical Ltd Unit 8 Wilton Business Centre Wilton, Salisbury SP2 0AH United Kingdom

Adrenalinum (Epinephrinum)

Anapen 300 microg/0,3 ml

Solution for injection Intramuscular use

Iceland Lincoln Medical Ltd Unit 8 Wilton Business Centre Wilton, Salisbury SP2 0AH United Kingdom

Adrenalinum (Epinephrinum)

Anapen Junior 150 microg/0,3 ml

Solution for injection Intramuscular use

13

Member State (in EEA)

Marketing authorisation holder

INN Invented name Strength Pharmaceutical form

Route of administration

Iceland Meda AB Pipers väg 2A, Box 906 SE-170 09, Solna Sweden

Adrenalinum (Epinephrinum)

EpiPen 300 microg Solution for injection Intramuscular use

Iceland Meda AB Pipers väg 2A, Box 906 SE-170 09, Solna Sweden

Adrenalinum (Epinephrinum)

EpiPen Junior 150 microg Solution for injection Intramuscular use

Iceland ALK-Abelló A/S Böge Alle 6-8, 2970 Horsholm Denmark

Adrenalinum bítartrat (Epinephrinum bítartrat)

Jext 150 microg Solution for injection Intramuscular use

Iceland ALK-Abelló A/S, Böge Alle 6-8, 2970 Horsholm Denmark

Adrenalinum bítartrat (Epinephrinum bítartrat)

Jext 300 microg Solution for injection Intramuscular use

Ireland Lincoln Medical Ltd Unit 8 Wilton Business Centre, Wilton, Salisbury SP2 0AH United Kingdom

Adrenaline (epinephrine) BP

Anapen 300 micrograms in 0.3ml solution for injection in a pre-filled syringe

300 micrograms in 0.3ml solution

Solution for injection in a pre-filled syringe

Intramuscular use

Ireland Lincoln Medical Ltd Unit 8 Wilton Business Centre, Wilton, Salisbury SP2 0AH United Kingdom

Adrenaline (epinephrine) BP

Adrenaline (epinephrine) BP

150 micrograms in 0.3ml solution

Solution for injection in a pre- filled syringe

Intramuscular use

14

Member State (in EEA)

Marketing authorisation holder

INN Invented name Strength Pharmaceutical form

Route of administration

Ireland Meda Health Sales Ireland Limited Unit 34/35, Block A Dunboyne Business Park Dunboyne, Co. Meath Ireland

Adrenaline Ph. Eur. Epipen 300 micrograms solution for injection in pre-filled pen

300 micrograms in 0.3ml solution

Solution for injection in a pre-filled pen

Intramuscular use

Ireland Meda Health Sales Ireland Limited Unit 34/35, Block A Dunboyne Business Park Dunboyne, Co. Meath Ireland

Adrenaline Ph. Eur. Epipen Junior 150 micrograms solution for injection in pre-filled pen

150 micrograms

Solution for injection in a pre-filled pen

Intramuscular use

Ireland ALK-Abello A/S Boge Alle 6-8 DK-2970 Horsholm Denmark

Adrenaline (as adrenaline tartrate)

Jext 300 micrograms solution for injection in pre-filled pen

300 micrograms

Solution for injection in pre-filled pen

Intramuscular use

Ireland ALK-Abello A/S Boge Alle 6-8 DK-2970 Horsholm Denmark

Adrenaline (as adrenaline tartrate)

Jext 150 micrograms solution for injection in pre-filled pen

150 micrograms

Solution for injection in pre-filled pen

Intramuscular use

Italy MEDA PHARMA S.P.A. Viale Brenta 18 20139 Milano Italy

Adrenaline FASTJEKT 330 mcg Solution for injection in a prefilled injector

Intramuscular use

Italy MEDA PHARMA S.P.A. Viale Brenta 18 20139 Milano Italy

Adrenaline FASTJEKT 165 mcg Solution for injection in a prefilled injector

Intramuscular use

15

Member State (in EEA)

Marketing authorisation holder

INN Invented name Strength Pharmaceutical form

Route of administration

Italy ALK-ABELLÓ A/S Boge Alle 6-8 DK-2970 Horsholm Denmark

Adrenaline tartrate JEXT 300 mcg Solution for injection in a prefilled pen

Intramuscular use

Italy ALK-ABELLÓ A/S Boge Alle 6-8 DK-2970 Horsholm Denmark

Adrenaline tartrate JEXT 150 mcg Solution for injection in a prefilled pen

Intramuscular use

Italy Lincoln Medical Ltd Unit 8 Wilton Business Centre Wilton, Salisbury SP2 0AH United Kingdom

Adrenaline CHENPEN 300 mcg Solution for injection in a prefilled syringe

Parenteral use

Italy Lincoln Medical Ltd Unit 8 Wilton Business Centre Wilton, Salisbury SP2 0AH United Kingdom

Adrenaline CHENPEN 150 mcg Solution for injection in a prefilled syringe

Parenteral use

Latvia Lincoln Medical Ltd Unit 8 Wilton Business Centre Wilton, Salisbury SP2 0AH United Kingdom

Epinephrine Anapen 150 micrograms/0,3 ml solution for injection in pre-filled syringe

150 micrograms/0,3 ml

Solution for injection in pre-filled syringe

Intramuscular use

16

Member State (in EEA)

Marketing authorisation holder

INN Invented name Strength Pharmaceutical form

Route of administration

Latvia Lincoln Medical Ltd Unit 8 Wilton Business Centre Wilton, Salisbury SP2 0AH United Kingdom

Epinephrine Anapen 300 micrograms/0,3 ml solution for injection in pre-filled syringe

300 micrograms/0,3 ml

Solution for injection in pre-filled syringe

Intramuscular use

Latvia Meda Pharma SIA Vienibas gatve 109 Riga, LV-1058 Latvia

Epinephrine Epipen 150 micrograms solution for injection in pre-filled pen

150 micrograms

Solution for injection in pre-filled pen

Intramuscular use

Latvia Meda Pharma SIA Vienibas gatve 109 Riga, LV-1058 Latvia

Epinephrine Epipen 300 micrograms solution for injection in pre-filled pen

300 micrograms

Solution for injection in pre-filled pen

Intramuscular use

Lithuania Lincoln Medical Ltd Unit 8, Wilton Business Centre Wilton Salisbury SP2 0AH United Kingdom

Epinephrine Anapen 300 microgram/ 0,3 ml

Solution for injection in pre-filled syringe

Intramuscular use

Lithuania Lincoln Medical Ltd Unit 8, Wilton Business Centre Wilton Salisbury SP2 0AH United Kingdom

Epinephrine Anapen 150 microgram/ 0,3 ml

Solution for injection in pre-filled syringe

Intramuscular use

Lithuania SIA Meda Pharma Vienibas gatve 109 Riga LV-1058 Latvia

Epinephrine Epipen 300 microgram/ 0,3 ml

Solution for injection in pre-filled pen

Intramuscular use

17

Member State (in EEA)

Marketing authorisation holder

INN Invented name Strength Pharmaceutical form

Route of administration

Lithuania SIA Meda Pharma Vienibas gatve 109 Riga LV-1058 Latvia

Epinephrine Epipen 150 microgram/ 0,3 ml

Solution for injection in pre-filled pen

Intramuscular use

Luxembourg Lincoln Medical Ltd. Unit 8, Wilton Business Centre, Wilton Salisbury SP2 OAH United kingdom

Adrenalin Anapen 150 µg Solution for injection in pre-filled pen

Intramuscular use

Luxembourg Lincoln Medical Ltd. Unit 8, Wilton Business Centre, Wilton Salisbury SP2 OAH United kingdom

Adrenalin Anapen 300 µg Solution for injection in pre-filled pen

Intramuscular use

Luxembourg Meda Pharma GmbH&Co.KG Benzstrasse 1 61352 Bad Homburg Germany

Adrenalin (hydrochloride)

Fastjekt 300 µg Solution for injection in pre-filled pen

Intramuscular use

Luxembourg Meda Pharma GmbH&Co.KG Benzstrasse 1 61352 Bad Homburg Germany

Adrenalin (hydrochloride)

Fastjekt junior 150 µg Solution for injection in pre-filled pen

Intramuscular use

Luxembourg Alk Abello A/S Boge Alle 6-8 2970 Horsholm Denmark

Adrenalin (tartrate) Jext 150 µg Solution for injection in pre-filled pen

Intramuscular use

18

Member State (in EEA)

Marketing authorisation holder

INN Invented name Strength Pharmaceutical form

Route of administration

Luxembourg Alk Abello A/S Boge Alle 6-8 2970 Horsholm Denmark

Adrenalin (tartrate) Jext 300 µg Solution for injection in pre-filled pen

Intramuscular use

Malta Lincoln Medical Limited Unit 8 Wilton Business Centre Wilton Salisbury SP2 0AH United Kingdom

Adrenalin Anapen 300 micrograms in 0.3ml solution for injection in a pre-filled syringe

300 micrograms/0.3ml

Solution for injection Intramuscular use

Malta Lincoln Medical Limited Unit 8 Wilton Business Centre Wilton Salisbury SP2 0AH United Kingdom

Adrenalin Anapen Junior 150 micrograms in 0.3ml solution for injection in a pre-filled syringe

150 micrograms/0.3ml

Solution for injection Intramuscular use

Norway Lincoln Medical limited Unit 8 Wilton Business Centre Wilton Salisbury SP2 0AH Great Britain

Adrenaline Anapen 300 microg/0,3 ml

Solution for injection in pre-filled syringe

Intramuscular use

Norway Lincoln Medical limited Unit 8 Wilton Business Centre Wilton Salisbury SP2 0AH Great Britain

Adrenaline Anapen Junior 150 microg/0,3 ml

Solution for injection in pre-filled syringe

Intramuscular use

Norway Meda AS Askerveien 61 Postboks 194 1371 Asker Norway

Adrenaline EpiPen 300 microg Solution for injection in pre-filled syringe

Intramuscular use

19

Member State (in EEA)

Marketing authorisation holder

INN Invented name Strength Pharmaceutical form

Route of administration

Norway Meda AS Askerveien 61 Postboks 194 1371 Asker Norway

Adrenaline EpiPen Jr 150 microg Solution for injection in pre-filled syringe

Intramuscular use

Norway ALK-Abelló AS Bøge Alle 6-8 DK-2970 Hørsholm Denmark

Adrenaline tartrate Jext 150 microg Solution for injection in pre-filled syringe

Intramuscular use

Norway ALK-Abelló AS Bøge Alle 6-8 DK-2970 Hørsholm Denmark

Adrenaline tartrate Jext 300 microg Solution for injection in pre-filled syringe

Intramuscular use

Poland Warszawskie Zakłady Farmaceutyczne POLFA S.A. ul. Karolkowa 22/24 01-207 Warszawa

Adrenaline Adrenalina WZF 300 mcg/0,3 ml

Solution for infusion in prefilled syringe/pen

Intramuscular use

Poland Lincoln Medical Limited Unit 8, Wilton Business Centre, Wilton, Salisbury SP2 0AH United Kingdom

Adrenaline Anapen 300 mcg Solution for infusion Intramuscular use

Poland Lincoln Medical Limited Unit 8, Wilton Business Centre, Wilton, Salisbury SP2 0AH United Kingdom

Adrenaline Anapen Junior 150 mcg Solution for infusion Intramuscular use

20

Member State (in EEA)

Marketing authorisation holder

INN Invented name Strength Pharmaceutical form

Route of administration

Poland Meda Pharma GmbH & Co. KG Benzstrasse 1 61352 Bad Homburg Germany

Adrenaline EpiPen Jr. 150 mcg / dose

Solution for infusion Intramuscular use

Poland Meda Pharma GmbH & Co. KG Benzstrasse 1 61352 Bad Homburg Germany

Adrenaline EpiPen Senior 300 mcg / dose

Solution for infusion Intramuscular use

Portugal Lincoln Medical Ltd. Unit 8, Wilton Business Centre, Wilton SP2 0AH Salisbury United Kingdom

Adrenaline Anapen 0,15 mg/0,3 ml 0.15 mg/0.3 ml

Solution for injection Intramuscular use

Portugal Lincoln Medical Ltd. Unit 8, Wilton Business Centre, Wilton SP2 0AH Salisbury United Kingdom

Adrenaline Anapen 0,3 mg/0,3 ml 0.3 mg/0.3 ml

Solution for injection Intramuscular use

Portugal Meda Pharma - Produtos Farmacêuticos, S.A. Rua do Centro Cultural, 13 1749-066 Lisboa Portugal

Adrenaline Epipen 0.15 mg/0.3 ml

Solution for injection in pre-filled syringe

Intramuscular use

Portugal Meda Pharma - Produtos Farmacêuticos, S.A. Rua do Centro Cultural, 13 1749-066 Lisboa Portugal

Adrenaline Epipen 0.3 mg/0.3 ml

Solution for injection in pre-filled syringe

Intramuscular use

21

Member State (in EEA)

Marketing authorisation holder

INN Invented name Strength Pharmaceutical form

Route of administration

Romania MEDA Pharma GmbH & Co. KG Benzstr. 1, 61352 Bad Homburg v.d. Höhe Germany

Adrenalină (epinefrină)

EpiPen 150 micrograme 150 micrograms/dose

Solution for injection in a pre-filled pen

Intramuscular use

Romania MEDA Pharma GmbH & Co. KG Benzstr. 1, 61352 Bad Homburg v.d. Höhe Germany

Adrenalină (epinefrină)

EpiPen 300 micrograme 300 micrograms/dose

Solution for injection in a pre-filled pen

Intramuscular use

Slovak Republic

Meda Pharma spol. s r. o. Trnavská cesta 50 821 02 Bratislava Slovak Republic

Epinephrine EpiPen 300 µg/dose Solution for injection in pre-filled pen

Intramuscular use

Slovak Republic

Meda Pharma spol. s r. o. Trnavská cesta 50 821 02 Bratislava Slovak Republic

Epinephrine EpiPen Jr. 150 µg/dose Solution for injection in pre-filled pen

Intramuscular use

Slovak Republic

ALK-Abelló A/S Boge Allé 6-8 DK-2970 Horsholm Denmark

Epinephrine Jext 150 mikrogramov 150 µg/dose Solution for injection in pre-filled pen

Intramuscular use

Slovak Republic

ALK-Abelló A/S Boge Allé 6-8 DK-2970 Horsholm Denmark

Epinephrine Jext 300 mikrogramov 300 µg/dose Solution for injection in pre-filled pen

Intramuscular use

22

Member State (in EEA)

Marketing authorisation holder

INN Invented name Strength Pharmaceutical form

Route of administration

Slovenia Lincoln Medical Ltd Unit 8 Wilton Business Centre Wilton, Salisbury SP2 0AH United kingdom

Adrenaline Anapen 300 mikrogramov/0,3 ml raztopina za injiciranje v napolnjeni injekcijski brizgi

300 mcg/0,3 ml

Solution for injection in pre-filled syringe

Intramuscular use

Slovenia Lincoln Medical Ltd Unit 8 Wilton Business Centre Wilton, Salisbury SP2 0AH United kingdom

Adrenaline Anapen za otroke 150 mikrogramov/0,3 ml raztopina za injiciranje v napolnjeni injekcijski brizgi

150 mcg/0,3 ml

Solution for injection in pre-filled syringe

Intramuscular use

Slovenia Meda Pharma GmbH & Co. KG, Benzstrasse 1 61352 Bad Homburg Germany

Adrenaline Epipen 300 mikrogramov/0,3 ml raztopina za injiciranje v napolnjenem injekcijskem peresniku

300 mcg/0,3 ml

Solution for injection in pre-filled pen

Intramuscular use

Slovenia Meda Pharma GmbH & Co. KG, Benzstrasse 1 61352 Bad Homburg Germany

Adrenaline Epipen za otroke 150 mikrogramov/0,3 ml raztopina za injiciranje v napolnjenem injekcijskem peresniku

150 mcg/0,3 ml

Solution for injection in pre-filled pen

Intramuscular use

Spain MEDA PHARMA, SAU Avda. de Castilla, 2 Edificio Berlín 2ª planta Parque Empresarial San Fernando 28830 San Fernando de Henares (Madrid) Spain

Adrenaline Altellus 150 microgramos niños, solución inyectable en pluma precargada

0.15 mg/0.3 ml

Solution for injection in pre-filled pen

Intramuscular use

23

Member State (in EEA)

Marketing authorisation holder

INN Invented name Strength Pharmaceutical form

Route of administration

Spain MEDA PHARMA, SAU Avda. de Castilla, 2 Edificio Berlín 2ª planta Parque Empresarial San Fernando 28830 San Fernando de Henares (Madrid) Spain

Adrenaline Altellus 300 microgramos adultos solución inyectable en pluma precargada

0.30 mg/0.3 ml

Solution for injection in pre-filled pen

Intramuscular use

Spain Lincoln Medical Ltd Unit 8 Wilton Business Centre Wilton, Salisbury SP2 0AH United Kingdom

Adrenaline Anapen 0,15 mg/0,3 ml solución inyectable en jeringa precargada

0.15 mg/0.3 ml

Solution for injection in pre-filled syringe

Intramuscular use

Spain Lincoln Medical Ltd Unit 8 Wilton Business Centre Wilton, Salisbury SP2 0AH United Kingdom

Adrenaline Anapen 0,30 mg/0,3 ml solución inyectable en jeringa precargada

0.30 mg/0.3 ml

Solution for injection in pre-filled syringe

Intramuscular use

Spain ALK ABELLÓ, S/A Bloque Alle, 6-8 DK-2970 Horsholm Denmark

Adrenaline tartrate Jext 150 microgramos solución inyectable en pluma precargada

0.15 mg/0.3 ml

Solution for injection in pre-filled pen

Intramuscular use

Spain ALK ABELLÓ, S/A Bloque Alle, 6-8 DK-2970 Horsholm Denmark

Adrenaline tartrate Jext 300 microgramos solución inyectable en pluma precargada

0.30 mg/0.3 ml

Solution for injection in pre-filled pen

Intramuscular use

24

Member State (in EEA)

Marketing authorisation holder

INN Invented name Strength Pharmaceutical form

Route of administration

Sweden Meda AB Box 906 170 09 Solna Sweden

Adrenaline EpiPen 300 mikrogram

Solution for injection in pre-filled pen

Parenteral use

Sweden Meda AB Box 906 170 09 Solna Sweden

Adrenaline EpiPen jr 150 mikrogram

Solution for injection in pre-filled pen

Parenteral use

Sweden Lincoln Medical Ltd Unit 8 Wilton Business Centre Wilton Salisbury SP20AH United Kingdom

Adrenaline Anapen 0,3 mg/dose Solution for injection in pre-filled syringe

Parenteral use

Sweden Lincoln Medical Ltd Unit 8 Wilton Business Centre Wilton Salisbury SP20AH United Kingdom

Adrenaline Anapen Junior 0,15 mg/dose

Solution for injection in pre-filled syringe

Parenteral use

Sweden ALK-Abelló A/S Boge Allé 6-8 DK-2970 Horsholm Denmark

Adrenaline tartrate Jext 300 mikrogram

Solution for injection in pre-filled pen

Parenteral use

Sweden ALK-Abelló A/S Boge Allé 6-8 DK-2970 Horsholm Denmark

Adrenaline tartrate Jext 150 mikrogram

Solution for injection in pre-filled pen

Parenteral use

25

Member State (in EEA)

Marketing authorisation holder

INN Invented name Strength Pharmaceutical form

Route of administration

Sweden PharmaSwiss Ceska republika s.r.o. Jankovcova 1569/2c 170 00 Prague Czech Republic

Adrenaline tartrate Emerade 500 mikrogram

Solution for injection in pre-filled pen

Parenteral use

Sweden PharmaSwiss Ceska republika s.r.o. Jankovcova 1569/2c 170 00 Prague Czech Republic

Adrenaline tartrate Emerade 300 mikrogram

Solution for injection in pre-filled pen

Parenteral use

Sweden PharmaSwiss Ceska republika s.r.o. Jankovcova 1569/2c 170 00 Prague Czech Republic

Adrenaline tartrate Emerade 150 mikrogram

Solution for injection in pre-filled pen

Parenteral use

Sweden Meda AB Box 906 170 09 Solna Sweden

Adrenaline Nepipe 300 mikrogram

Solution for injection in pre-filled pen

Parenteral use

Sweden Meda AB Box 906 170 09 Solna Sweden

Adrenaline Nepipe Junior 150 mikrogram

Solution for injection in pre-filled pen

Parenteral use

26

Member State (in EEA)

Marketing authorisation holder

INN Invented name Strength Pharmaceutical form

Route of administration

The Netherlands

Lincoln Medical Ltd. Unit 8 Wilton Business Centre Wilton, Salisbury SP2 0AH United Kingdom

Adrenaline Anapen, oplossing voor injectie

0,3 microgram/ dosis

Solution for injection Intramuscular use

The Netherlands

Lincoln Medical Ltd. Unit 8 Wilton Business Centre Wilton, Salisbury SP2 0AH United Kingdom

Adrenaline Anapen junior, oplossing voor injectie

0,15 microgram/ dosis

Solution for injection Intramuscular use

The Netherlands

Meda Pharma B.V. Krijgsman 20 1186 DM Amstelveen The Netherlands

Adrenaline EpiPen Junior 150 microgram/dosis

0,15 microgram/ dosis

Solution for injection in a pre-filled syringe

Intramuscular use

The Netherlands

Meda Pharma B.V. Krijgsman 20 1186 DM Amstelveen The Netherlands

Adrenaline EpiPen 300 microgram/dosis

0,3 microgram/ dosis

Solution for injection in a pre-filled syringe

Intramuscular use

The Netherlands

ALK-Abelló A/S Boge Allé 6-8 DK-2970 Horshlom Denmark

Adrenaline Jext 150 microgram, oplossing voor injectie

0,15 microgram/ dosis

Solution for injection Intramuscular use

The Netherlands

ALK-Abelló A/S Boge Allé 6-8 DK-2970 Horshlom Denmark

Adrenaline Jext 300 microgram, oplossing voor injectie

0,3 microgram/ dosis

Solution for injection Intramuscular use

27

Member State (in EEA)

Marketing authorisation holder

INN Invented name Strength Pharmaceutical form

Route of administration

United Kingdom

Alk Abello A-S Boge Alle 6-8 Hersholm 2970 Denmark

Adrenaline tartrate Jext 150 micrograms solution for injection in pre-filled pen

150 micrograms

Solution for injection Intramuscular use

United Kingdom

Alk Abello A-S Boge Alle 6-8. Hersholm 2970 Denmark

Adrenaline tartrate Jext 300 micrograms solution for injection in pre-filled pen

300 micrograms

Solution for injection Intramuscular use

United Kingdom

Aurum Pharmaceuticals Limited, Bampton Road Harold Hill Romford Essex RM3 8UG United Kingdom

Adrenaline acid tartrate

Adrenaline (epinephrine) 1 in 1000 solution for injection BP auto-injector

1 in 1000 Solution for injection Intramuscular/subcutaneous use

United Kingdom

Meda Pharmaceuticals Limited, Skyway House Parsonage Road, Takeley Bishops Stortford CM22 6PU United Kingdom

Adrenaline Epipen auto-injector 0.3mg

0.3 mg Solution for injection Intramuscular use

United Kingdom

Meda Pharmaceuticals Limited Skyway House, Parsonage Road, Takeley Bishops Stortford CM22 6PU United Kingdom

Adrenaline Epipen auto-injector 0.15mg

0.15 mg Solution for injection Intramuscular use

United Kingdom

PharmaSwiss Ceska republika s.r.o. Jankovcova 1569/2c 170 00 Prague Czech Republic

Adrenaline tartrate Emerade 150 micrograms solution for injection in pre-filled pen

150 micrograms

Solution for injection Intramuscular use

28

Member State (in EEA)

Marketing authorisation holder

INN Invented name Strength Pharmaceutical form

Route of administration

United Kingdom

PharmaSwiss Ceska republika s.r.o. Jankovcova 1569/2c 170 00 Prague Czech Republic

Adrenaline tartrate Emerade 300 micrograms solution for injection in pre-filled pen

300 micrograms

Solution for injection Intramuscular use

United Kingdom

PharmaSwiss Ceska republika s.r.o. Jankovcova 1569/2c 170 00 Prague Czech Republic

Adrenaline tartrate Emerade 500 micrograms solution for injection in pre-filled pen

500 micrograms

Solution for injection Intramuscular use

29

Annex II

Scientific conclusions and grounds for variation to the terms of the marketing authorisations

30

Scientific conclusions

Overall summary of the scientific evaluation

Auto-injectors were invented in the 1960s following military research in the United States of America (USA). They were originally used for the administration in the field of atropine, the antidote to nerve agents in biological weapons. The first adrenaline auto-injectors (AAI) were developed and introduced into the medical market approximately 25 years ago in the USA. Adrenaline auto-injectors are indicated in the emergency treatment of severe allergic reactions (anaphylaxis) to e.g. insect stings or bites, foods, drugs and other allergens as well as idiopathic or exercise-induced anaphylaxis.

The United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA) undertook a review of all authorised adrenaline auto-injectors to evaluate the most effective site for injection, the clarity of instructions for use as well as the most appropriate auto-injector needle length for ensuring intramuscular (IM) delivery of the adrenaline injection. A key finding of the review was that there is no robust evidence that the administration devices deliver adrenaline intramuscularly in all patients. Variability in skin-to-muscle depth (STMD), gender, needle length and the device mechanism itself are important factors which determine whether the route of delivery is IM or SC. The matter was then referred to the Committee for Medicinal Products for Human Use (CHMP) for a review under Article 31 of Directive 2001/83/EC.

The use of adrenaline to treat anaphylaxis is established as the recommended first-line treatment. The efficacy of adrenaline in the treatment of anaphylaxis is well-supported by anecdotal and retrospective evidence. The safety of adrenaline is also well-established, and it has demonstrated a particularly strong safety profile with intramuscular (IM) administration. The preferred route of administration in an emergency situation has been established as IM, although intravenous administration may be indicated in severe cases. Published clinical data indicate that the rate of absorption is prolonged if the adrenaline is delivered subcutaneously (SC).

The CHMP has considered the totality of the available non-clinical and clinical evidence on the delivery of adrenaline from adrenaline auto-injectors and on whether the product information contains clear and detailed instructions for appropriate use. The CHMP considered also the results of consultations with healthcare professionals, experts and the Pharmacovigilance Risk Assessment Committee (PRAC).

It is widely accepted that IM delivery is superior to SC delivery in achieving the rate of rise and levels of plasma adrenaline that are most effective to treat anaphylaxis. However, there is insufficient evidence to ensure, even under optimal circumstances, IM delivery of adrenaline to all patients with the currently available auto-injectors authorised in the EU and, even if the medicine is delivered IM, that exposure from a single injection will be sufficient. If IM delivery is insufficient with one injection, administration of a second injection is recommended.

Most of the evidence for penetration of adrenaline into the tissue relies on non-clinical data using a gelatin model or a porcine model. While these non-clinical models have demonstrated that the adrenaline is projected beyond the tip of the needle to a greater or lesser extent the CHMP was of the view that it remains questionable how representative of the human tissue these models are.

Results from PK studies (Simons, 19981, 20012) support the guidelines recommendation (e.g. UK Resuscitation Guideline) that an intramuscular injection is the preferred route of administration in the treatment of anaphylaxis as a rapid response is important in ensuring a non-fatal outcome.

1 F. Estelle R. Simons, MD, FRCPC, Janet R Roberts, MD, FRCPC, Xiaochen Gu, PhD, and Keith J. Simons, PhD. Epinephrine absorption in children with a history of anaphylaxis. Journal of allergy and clinical immunology. January 1998 2 F. Estelle R. Simons, MD, FRCPC, Xiaochen Gu, PhD, and Keith J. Simons, PhD. Epinephrine absorption in adults: Intramuscular versus subcutaneous injection. Journal of allergy and clinical immunology 108(5); 2001, 871-873

31

The main clinical data available focus on demonstrating the skin-to-muscle depth (STMD) in adults and children and the CHMP noted that there is inconsistency across the studies with some finding no correlation between STMD and Body Mass Index (BMI) or weight (Song (2005)3, Stecher (2009)4) and others finding a correlation (Bhalla (2013)5, Bewick (2013)6).

However, there is agreement that in general STMD is greater than the length of the needles of currently available adrenaline auto-injectors in many patients, both adult and child.

The STMD is only one factor affecting whether or not the adrenaline reaches the muscle layer. The CHMP agreed that there are many factors that may affect whether the adrenaline is delivered to the muscle or the subcutaneous tissue when an adrenaline auto-injector is used.

The needle length is another factor and the UK Resuscitation Council Guidelines do suggest a 25mm needle is optimal for intramuscular injection; however the CHMP noted that these guidelines are written for use in the hospital setting where healthcare professionals will generally inject the adrenaline using a manual needle and syringe, not an auto-injector.

Other factors such as the mechanism of action (spring loaded or not) and method of administration (swing and jab or place and press) of the device, the angle of placement on the skin and the force used to activate the device also play a part. The CHMP noted the inconsistency amongst studies as to the part played by compression of the tissue. Some investigators are of the opinion that even when the needle length is shorter than the STMD, IM injection is still possible as the physical compression of subcutaneous tissue by the force of the device can help to overcome the deficit in needle length. On the other hand, other investigators express an opinion that compression may preferentially involve muscle rather than subcutaneous tissue and therefore the needle deficit is not overcome by compression. The barrier of the fascia lata – the fibrous tissue surrounding the muscle – also needs to be considered. Until these uncertainties can be resolved, there is a need for more definitive evidence in humans of the speed and extent of delivery of adrenaline into the circulation following use of different adrenaline auto-injectors, from which it may be possible to infer site of delivery.

The CHMP acknowledged that patient/carer compliance with the use of the auto-injectors is also very important as evidenced by the study by Brown J et al (2015)7. The fact that 15% of mothers were unable to ‘fire’ the auto-injector successfully supports that patients’ training tools need to be improved and that training needs to be repeated at regular intervals. The CHMP agreed that proper training of both patients/carers and healthcare professionals and comprehensive educational materials are of paramount importance.

The CHMP noted the lack of clinical evidence from randomised, controlled trials, due to the logistical and ethical problems involved with conducting such trials in emergency situations, particularly with a placebo control. However, the CHMP was of the view that PK and PD studies in healthy volunteers representing the broad range of phenotypes, or imaging studies in healthy volunteers to understand the influence of different factors on distribution, exposure and activity of adrenaline when administered via an adrenaline auto-injector device could be considered.

3 Song T, Nelson M, Chang J, et al. Adequacy of the epinephrine auto-injector needle length in delivering epinephrine to the intramuscular tissues. Ann Allergy Asthma Immunol 2005;94:539-542 4 Dawn Stecher, Blake Bulloch, Justin Sales, Carrie Schaefer and Laine Keahey. Epinephrine Auto-injectors: Is Needle Length Adequate for Delivery of Epinephrine Intramuscularly? Paediatrics. 2009, 124(1):p65-70 5 Bhalla, M.C., B.D. Gable, J.A. Frey, M.R. Reichenbach, and S.T. Wilber, Predictors of epinephrine autoinjector needle length inadequacy. Am J Emerg Med, 2013. 6 Daniel C. Bewick, MD, Neville B. Wright, MD, Richard S. Pumphrey, MD, Peter D. Arkwright, MD, DPhil. Anatomic and anthropometric determinants of intramuscular versus subcutaneous administration in children with epinephrine autoinjectors. J Allergy Clin Immunol Pract Month 2013. Clinical Communication 7 Brown J, Tuthill D, Alfaham M et al. (2013) A randomised maternal evaluation of epinephrine autoinjection devices. Paediatr. Allergy Immunol. 00:1-5.

32

The CHMP sought the advice of experts on the feasibility of conducting imaging or PK studies or any other trials or tests that could be performed as well as the advice of the PRAC on potential databases or other data sources that might hold information on actual device usage.

The experts consulted unanimously agreed that a PK study in humans would be useful in order to gain information on the optimum parameters of administration; the group also noted the possibility to collect PD data in this same study. The PRAC considered that there were no identified data sources that would permit a formal epidemiological approach for assessing actual usage or device failure of adrenaline auto-injectors in the EU.

The CHMP noted that generally there is a large degree of consistency between the product information for the different auto-injectors in particular as regards main messages such as to seek emergency medical assistance immediately after a single administration, the use with caution in certain patient populations and that adrenaline should be administered intramuscularly in order to maximise the possibility of a positive outcome in the treatment of anaphylaxis. However, the CHMP considered that few points merit further clarification.

The CHMP therefore recommended amendments to the product information, in order to reflect the uncertainties in whether a single administration would suffice for any given episode and advise that patients are prescribed two pens which they should carry at all times, to include a recommendation for immediate associates of patients to be trained to use the AAI and to include information on the needle length. The CHMP also recommended further risk minimisation measures, including educational materials, to be submitted and agreed via risk management plans. The educational materials include but are not limited to a training device, instructional audio-visual material and a checklist for prescribers aiming to facilitate the discussion between the prescriber and the patient and to provide sufficient information on the optimal way of use, administration and storage of the product.

Furthermore, the CHMP imposed a PK/PD study in order to understand the influence of different factors on distribution, exposure and activity of adrenaline when administered via an adrenaline auto-injector device and encouraged the possibility for a study to assess the effectiveness of the proposed risk minimisation measures and the conduct of an observational study to assess usage and incidence of lack of efficacy and device failure.

The CHMP concluded that the benefit-risk balance for adrenaline auto-injectors remains favourable subject to the agreed changes to the product information and the above-mentioned additional risk minimisation measures.

Grounds for the CHMP opinion

Whereas

• The CHMP considered the procedure under Article 31 of Directive 2001/83/EC for adrenaline auto-injectors.

• The CHMP considered the totality of the available non-clinical and clinical data to inform whether adrenaline administered via an auto-injector is delivered intramuscularly or subcutaneously, including submissions by marketing authorisation holders, consultations with healthcare professionals, experts and the Pharmacovigilance Risk Assessment Committee (PRAC).

• The CHMP considered that the efficacy of adrenaline in the treatment of anaphylaxis is well-supported by anecdotal and retrospective evidence and that the safety of adrenaline is also

33

well-established, and it has demonstrated a strong safety profile particularly with IM administration.

• The CHMP considered that the preferred route of administration of adrenaline in an emergency situation has been established as IM, although intravenous administration may be indicated in severe cases.

• The CHMP considered that there are multiple factors that may affect whether adrenaline is delivered to the muscle or the subcutaneous tissue when an adrenaline auto-injector is used such as the needle length, the mechanism of action of the device, the angle of placement on the skin, the force used to activate the device and the patient/carer compliance. Training and education of both patients/carers and healthcare professionals was considered of paramount importance.

• The CHMP noted that the product information for the different auto-injectors would benefit from an update to include warnings and precautions on uncertainties in whether a single administration would suffice for any given episode and advise that patients are prescribed two pens which they should carry at all times, training of immediate associates of patients and inclusion of information on the needle length.

• The CHMP concluded that there was a need for further risk minimisation measures such as educational materials to be submitted and agreed via risk management plans. The CHMP also concluded on the need for a PK/PD study to be conducted in order to understand the influence of different factors on distribution, exposure and activity of adrenaline when administered via an adrenaline auto-injector device.

The CHMP concluded that the benefit-risk balance for adrenaline auto-injectors remains favourable subject to the conditions to the marketing authorisations and taking into account the amendments to the product information and other risk minimisation measures recommended.

Therefore, in accordance with Articles 31 and 32 of Directive 2001/83/EC, the CHMP recommends the variation to the terms of the marketing authorisation for all medicinal products referred to in Annex I and for which the amendments of the relevant sections of the summary of product characteristics and package leaflet are set out in Annex III.

The conditions affecting the marketing authorisations are set out in Annex IV.

34

Annex III

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

Note:

This Summary of Product Characteristics and package leaflet is the outcome of the referral procedure.

The product information may be subsequently updated by the Member State competent authorities, in liaison with the Reference Member State, as appropriate, in accordance with the procedures laid down in Chapter 4 of Title III of Directive 2001/83/EC.

35

For all adrenaline auto-injectors referred to in Annex I

A. Summary of Products Characteristics

Section 4.2 - Posology and method of administration

[The section should be amended to reflect the following wording]

[…]

In the absence of clinical improvement or if deterioration occurs, a second injection with an additional [Invented name] may be administered 5–15 minutes after the first injection. It is recommended that patients are prescribed two [Invented name] pens which they should carry at all times.

[…]

Section 4.4 - Special warnings and precautions for use

[The section should be amended to reflect the following wording]

[…]

All patients who are prescribed [Invented name] should be thoroughly instructed to understand the indications for the use and the correct method of administration (see section 6.6). It is strongly advised also to educate the patient’s immediate associates (e.g. parents, caregivers, teachers) for the correct usage of the [Invented name] in case support is needed in the emergency situation.

[…]

Section 6.5 - Nature and contents of container

[The section should be amended to reflect the exposed needle length of the device(s)]

[To be completed nationally]

36

For all adrenaline auto-injectors referred to in Annex I

B. Package Leaflet

Section 3 – How to use [Invented name]

[The section should be amended to reflect the following wording]

[…]

Sometimes a single dose of adrenaline may not be sufficient to completely reverse the effects of a serious allergic reaction. For this reason, your doctor is likely to prescribe more than one [Invented name] for you. If your symptoms have not improved or have deteriorated within 5-15 minutes after the first injection, either you or the person with you should give a second injection. For this reason you should carry more than one [Invented name] with you at all times.

[…] It is recommended that your family members, carers or teachers are also instructed in the correct use of [Invented name].

[…]

Section 6 – Contents of the pack and other information

[…]

What [Invented name] looks like and contents of the pack

[The section should be amended to reflect the exposed needle length of the device(s)]

[To be completed nationally]

37

For EpiPen/Nepipe and associated names

B. Package Leaflet

Section 3 – How to use [Invented name]

[…]

[The MAH(s) should submit improved diagram in the instructions for use by increasing the size and ensuring that it clearly shows that the injection should be in the antero-lateral aspect of the thigh]

[…]

38

Annex IV

Conditions to the marketing authorisation

39

Conditions to the marketing authorisation

National Competent Authorities of Member States or Reference Member State(s), if applicable, shall ensure that the following conditions are fulfilled by the MAHs:

Conditions Date Each Marketing Authorisation Holder of adrenaline auto-injectors shall perform a PK/PD study to understand the influence of different factors on distribution, exposure and activity of adrenaline when administered via their adrenaline auto-injector device.

The protocol shall be submitted to the National Competent Authorities:

The final study report shall be submitted to the National Competent Authorities:

Within 6 months of the Commission Decision for this procedure

Within 20 months of the Commission Decision for this procedure

The Marketing Authorisation Holders of adrenaline auto-injectors shall submit to the National Competent Authorities a Risk Management Plan containing key elements as described in the CHMP assessment report (including educational materials). The educational materials should ensure that healthcare professionals and patients/carers are able to successfully administer the product based on the instructions in the product information.

Within 6 months of the Commission Decision for this procedure