Annex I List of the names, pharmaceutical form(s ......Germany betapharm Arzneimittel GmbH Kobelweg 95 D-86156 Augsburg Germany MCP-beta Tropfen 4.21mg/ml Oral solution Oral use Germany

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

1

Member State (in EEA)

Marketing authorisation holder

Product name Strength Pharmaceutical form

Route of administration

Austria Hexal Pharma GmbH Stella-Klein-Löw-Weg 17 1020 Wien Austria

Metogastron 10 mg - Ampullen 10mg/2ml Solution for injection Intramuscular use Intravenous use

Austria Hexal Pharma GmbH Stella-Klein-Löw-Weg 17 1020 Wien Austria

Metogastron 4 mg/ml - Tropfen 4mg/ml Oral drops, solution Oral use

Austria Abbott Products GmbH Perfektastraße 84A 1230 Wien Austria

Paspertin - Filmtabletten 10mg Film-coated tablet Oral use


Paspertin 10 mg - Ampullen 10mg/2ml Solution for injection Intramuscular use Intravenous use


Paspertin 50 mg - Konzentrat zur Infusionsbereitung

50mg/10ml Concentrate for solution for infusion

Intravenous use


Paspertin 4 mg/ml - Tropfen 4mg/ml Oral drops, solution Oral use

2





Belgium Sanofi-Aventis Belgium N.V. Culliganlaan 1 C 1831 Diegem Belgium

Primperan 10mg Tablet Oral use


Primperan 1mg/ml Oral solution Oral use


Primperan 10mg/2ml Solution for injection Intramuscular use Intravenous use


Primperan 20 mg 20mg Suppository Rectal use

Belgium Takeda Belgium Gentsesteenweg 615 1080 Brussel Belgium

Dibertil 5mg Capsule, soft Oral use

Belgium Takeda Belgium Gentsesteenweg 615 1080 Brussel Belgium


3





Bulgaria Sopharma PLC 16 Iliensko Shosse Str. Sofia 1220 Bulgaria

Antiemetin 5mg/ml Solution for injection Intramuscular use Intravenous use

Bulgaria Sopharma PLC 16 Iliensko Shosse Str. Sofia 1220 Bulgaria

Antiemetin 5mg/ml Syrup Oral use

Bulgaria AWD.pharma GmbH&Co.KG Wasastrasse 50 Radebeul 01445 Germany

Cerucal 10mg Tablet Oral use

Bulgaria Lek Pharmaceuticals d.d. Verovskova 57 Ljubljana 1526 Slovenia

Degan 10mg/2ml Solution for injection Intramuscular use Intravenous use

Bulgaria Lek Pharmaceuticals d.d. Verovskova 57 Ljubljana 1526 Slovenia

Degan 10mg Tablet Oral use

Bulgaria CSC Pharmaceuticals Ltd. 10 Assen Yordanov str. Sofia 1592 Bulgaria

Pramidin 10 10 mg/spray Nasal spray, solution Nasal use

4





Bulgaria CSC Pharmaceuticals Ltd. 10 Assen Yordanov str. Sofia 1592 Bulgaria

Pramidin 20 20 mg/spray Nasal spray, solution Nasal use

Bulgaria Alkaloid Ltd 2 Ricardo Vakarini str. Sofia 1404 Bulgaria

Reglan 10mg Tablet Oral use

Cyprus Sanofi Aventis Cyprus ltd Charalambou Mouskou 14 2015 Strovolos Nicosia Cyprus

Primperan for adults suppository 20mg

20mg Suppository Rectal use


Primperan solution for injection 10mg/2ml

10mg/2ml Solution for injection Intramuscular use Intravenous use


Primperan tablets 10mg 10mg Tablet Oral use

Cyprus Medochemie ltd 1-10 Constantinoupoleos street P.O.BOX 51409 3505 Lemesos Cyprus

Elitan tablets 10mg 10mg Tablet Oral use

5





Cyprus Medochemie ltd 1-10 Constantinoupoleos street P.O.BOX 51409 3505 Lemesos Cyprus

Elitan injection 10mg/2ml 10mg/2ml Injection Intramuscular use Intravenous use

Cyprus Remedica ltd Aharnon street P.O.Box 51706 3508 Lemesos Cyprus

Cloperan tablets 10mg 10mg Tablet Oral use

Cyprus Accord Healthcare Ltd Sage House 319 Pinner Road North Harrow Middlesex HA1 4HF United Kingdom

Metoclopramide Accord 10 mg tablet

10mg Tablet Oral use

Czech Republic Lek Pharmaceuticals d.d. Verovškova 57 1526 Ljubljana Slovenia

Degan 10 mg tablety 10mg Tablet Oral use

Czech Republic Lek Pharmaceuticals d.d. Verovškova 57 1526 Ljubljana Slovenia

Degan 10 mg roztok pro injekci 5mg/ml Solution for injection Intramuscular use Intravenous use

Czech Republic Hexal AG Industriestrasse 25 83607 Holzkirchen Germany

Mcp hexal 10 10mg Tablet Oral use

6





Czech Republic Teva Pharmaceuticals CR, s.r.o. Radlická 3185/1c 150 00 Prague Czech Republic


Czech Republic Teva Pharmaceuticals CR, s.r.o. Radlická 3185/1c 150 00 Prague Czech Republic

Cerucal 5mg/ml Solution for injection Intramuscular use Intravenous use

Denmark Sanofi-aventis Denmark A/S Slotsmarken 13 DK-2970 Hørsholm Denmark


Denmark Sanofi-aventis Denmark A/S Slotsmarken 13 DK-2970 Hørsholm Denmark

Primperan 20mg Suppository Rectal use

Denmark Orion Corporation Orionintie 1A FI-02200 Espoo Finland

Emperal 10mg Tablet Oral use

Denmark Temmler Pharma GmbH & Co KG, Temmlerstrasse 2 DE-35039 Marburg Germany

Gasto-Timelets 30mg Prolonged-release capsule, hard

Oral use

7





Estonia Teva Pharma B.V. Computerweg 10 3542 DR Utrecht The Netherlands

CERUCAL 10mg Tablet Oral use

Finland sanofi-aventis Oy Huopalahdentie 24 00350 Helsinki Finland





Primperan 5mg/ml Solution for injection Intramuscular use Intravenous use

France Sanofi Aventis France 1-13, boulevard Romain Rolland 75014 Paris France

PRIMPERAN 10 mg, comprimé sécable



PRIMPERAN 10 mg, suppositoire sécable


8






PRIMPERAN 20 mg, suppositoire



PRIMPERAN ENFANTS 2,6 mg/ml, solution buvable

2,6mg/ml Oral solution Oral use


PRIMPERAN NOURRISSONS ET ENFANTS 2,6 mg/ml, solution buvable

2,6mg/ml Oral drops, solution Oral use


PRIMPERAN 0,1% ADULTES, solution buvable édulcorée au cyclamate de sodium et à la saccharine sodique

0.10% Oral drops, solution Oral use


PRIMPERAN 0,1%, solution buvable édulcorée à la saccharine sodique

0.10% Oral solution Oral use


PRIMPERAN 10 mg/2 ml, solution injectable en ampoule


9






PRIMPERAN 100 mg, solution injectable


France Laboratoire Renaudin Z A. Errobi Itxassou 64250 Cambo les Bains France

CHLORHYDRATE DE METOCLOPRAMIDE RENAUDIN 10 mg/2 ml, solution injectable en ampoule


France Laboratoire Renaudin Z A. Errobi Itxassou 64250 Cambo les Bains France

CHLORHYDRATE DE METOCLOPRAMIDE RENAUDIN 20 mg/ml, solution injectable

20mg/ml Solution for injection Intramuscular use Intravenous use

France Panpharma ZI du Clairay Luitré 35133 Fougères France

DICHLORHYDRATE DE METOCLOPRAMIDE PANPHARMA 100 mg/5 ml, solution injectable (IM, IV) en ampoule

100mg/100 ml Solution for injection Intramuscular use Intravenous use

France Laboratoires Richard rue du Progrès ZI des Reys de Saulce 26270 Saulce sur Rhone France

CHLORHYDRATE DE METOCLOPRAMIDE RICHARD 1 mg/ml, solution buvable

1mg/ml Oral solution Oral use

France Mylan SAS 117, allée des Parcs 69800 Saint-Priest France

METOCLOPRAMIDE MYLAN 10 mg, comprimé sécable


10





France Sandoz 49, avenue Georges Pompidou 92300 Levallois-Perret France

METOCLOPRAMIDE SANDOZ 10 mg, comprimé sécable


France Meda Pharma France 25, boulevard de l'Amiral Bruix 75016 Paris France

ANAUSIN METOCLOPRAMIDE 15 mg, comprimé à libération prolongée

15mg Prolonged-release tablet Oral use

France Techni-Pharma 7, rue de l'Industrie BP 717 98014 Monaco Cedex Monaco

PROKINYL L.P. 15 mg, gélule à libération prolongée

15mg Prolonged-release capsule, hard

Oral use

Germany 1 A Pharma GmbH Keltenring 1 + 3 D-82041 Oberhaching Germany

MCP Tropfen-1 A-Pharma 4.21mg/1g Oral solution Oral use

Germany Abbott Arzneimittel GmbH Freundallee 9A 30173 Hannover Germany

Paspertin 10mg/2ml Ampullen 10mg/2ml Solution for injection Intramuscular use Intravenous use


Paspertin 50mg/10ml Ampullen 50mg/10ml Concentrate for solution for infusion

Intravenous use

11






Paspertin Filmtabletten 10mg Film-coated tablet Oral use


Paspertin Tropfen 4mg/ml Oral solution Oral use

Germany AbZ-Pharma GmbH Graf-Arco-Str. 3 89079 Ulm Germany

MCP AbZ 5 mg/ml Tropfen 5.91mg/ml Oral solution Oral use

Germany ALIUD PHARMA GmbH Gottlieb-Daimler-Str. 19 D-89150 Laichingen Germany

MCP AL 10 10.53mg Tablet Oral use


MCP AL retard 30mg Prolonged-release capsule, hard

Oral use


MCP AL Tropfen 4.21mg/1ml Oral solution Oral use

12





Germany AWD.pharma GmbH & Co.KG Wasastr. 50 D-01445 Radebeul Germany

Cerucal inject 10.54mg/2ml Solution for injection Intramuscular use Intravenous use

Germany AWD.pharma GmbH & Co.KG Wasastr. 50 D-01445 Radebeul Germany

Metoclopramid AWD 10 mg Tabletten

10.53mg Tablet Oral use

Germany axcount Generika AG Max-Planck-Str. 36b D-61381 Friedrichsdorf Germany

MCP axcount Tropfen 4.21mg/ml Oral solution Oral use

Germany betapharm Arzneimittel GmbH Kobelweg 95 D-86156 Augsburg Germany

MCP-beta Tropfen 4.21mg/ml Oral solution Oral use

Germany CT Arzneimittel GmbH Graf-Arco-Str. 3 79079 Ulm Germany

MCP-CT 10mg/2ml Ampullen 10mg/2ml Solution for injection Intramuscular use Intravenous use


MCP-CT 30mg Retardkapseln 30mg Prolonged-release capsule, hard

Oral use

13






MCP-CT 4mg/1ml Tropfen 5.2mg/ml Oral solution Oral use

Germany DOCPHARM Arzneimittelvertrieb GmbH & Co Greschbachstr. 7 D-76229 Karlsruhe Germany

Metoclopramid Injektionslösung 10ml PB

52.65mg/10ml Solution for injection Intravenous use

Germany Dolorgiet GmbH & Co.KG Otto-von-Guericke-Str. 1 D-53757 Sankt Augustin Germany

Gastronerton 465mg/100ml Oral solution Oral use

Germany Dolorgiet GmbH & Co.KG Otto-von-Guericke-Str. 1 D-53757 Sankt Augustin Germany

Gastronerton 8.92mg Tablet Oral use

Germany hameln pharmaceuticals GmbH Langes Feld 13 D-31789 Hameln Germany

Metoclo-hameln 5mg/ml, Injektionslösung

10.53mg/2ml Solution for injection Intramuscular use Intravenous use

Germany Heumann Pharma GmbH & Co. Generica KG Südwestpark 50 D-90449 Nürnberg

Gastrosil 10mg Amp. 10mg/2ml Solution for injection Intramuscular use Intravenous use

14





Germany Heumann Pharma GmbH & Co. Generica KG Südwestpark 50 D-90449 Nürnberg Germany

Gastrosil 20 mg Supp. 20mg Suppository Rectal use


Gastrosil 50mg Amp. 52.7mg/10ml Solution for injection Intravenous use


Gastrosil akut Tropfen 5.97mg/ml Oral solution Oral use


Gastrosil retard 31.6mg Prolonged-release capsule, hard

Oral use


Gastrosil retard mite 15.8mg Prolonged-release capsule, hard

Oral use


Gastrosil Tabletten 10.54mg Tablet Oral use

15






Gastrsosil Tropfen 5.97mg/ml Oral solution Oral use


MCP Heumann 10mg Tabletten 10.53mg Tablet Oral use

Germany HEXAL AG Industriestr. 25 D-83607 Holzkirchen Germany

MCP Hexal 10 10.53mg Tablet Oral use


MCP Hexal injekt 10.53mg/2ml Solution for injection Intramuscular use Intravenous use


MCP Hexal Tropfen 4.21mg/ml Oral solution Oral use

Germany Mylan dura GmbH Wittichstr. 6 D-64295 Darmstadt Germany

MCP dura 4 mg/ml Tropfen zum Einnehmen

4.21mg/ml Oral solution Oral use

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

MCP-ratiopharm 10 mg Tabletten

11.82mg Tablet Oral use


MCP-ratiopharm 10mg Zäpfchen


16






MCP-Ratiopharm 30 mg Retardkapseln

30mg Prolonged-release capsule

Oral use


MCP-ratiopharm 4 mg/ml Tropfen



MCP-ratiopharm SF 10mg/2ml Injektionslösung



MCP-ratiopharm SF 50 mg/10 ml Konzentrat zur Herstellung einer Infusionslösung

50mg/10ml Concentrate for solution for infusion

Intravenous use

Germany Sandoz Pharmaceuticals GmbH Raiffeisenstr. 11 D-83607 Holzkirchen

MCP Sandoz 10mg Tabletten 10.53mg Tablet Oral use

Germany Sandoz Pharmaceuticals GmbH Raiffeisenstr. 11 D-83607 Holzkirchen Germany

MCP Sandoz 4mg/ml Tropfen zum Einnehmen, Lösung


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

MCP STADA 10 mg Tabletten 10.53mg Tablet Oral use

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

MCP STADA 4mg/1ml Tropfen zum Einnehmen, Lösung


17





Germany Temmler Pharma GmbH & Co.KG Temmlerstr. 2 D-35039 Marburg Germany

Cerucal 10.54mg Tablet Oral use

Germany Temmler Pharma GmbH & Co.KG Temmlerstr. 2 D-35039 Marburg Germany

Cerucal retard 30mg Prolonged-release capsule, hard

Oral use

Greece Sanofi Aventis AEBE 348 Syngrou avenue Building A 176 74 Kalithea – Athens Greece

PRIMPERAN 10mg Suppository Rectal use


PRIMPERAN 20mg Suppository Rectal use


PRIMPERAN 10mg/2ml Solution for injection Intramuscular use Intravenous use


PRIMPERAN 5mg/5ml Syrup Oral use


PRIMPERAN 10mg Tablet Oral use

18





Hungary AWD Pharma GmbH&Co. KG Wasastrasse 50 Radebeul 1445 Germany

CERUCAL 5 mg/ml oldatos injekció

5mg/ml Solution for injection Parenteral use

Hungary AWD Pharma GmbH&Co. KG Wasastrasse 50 Radebeul 1445 Germany

CERUCAL tabletta 10mg Tablet Oral use

Iceland Nycomed Pharma AS P.O Box 205 NO-1375, Asker Norway

Afipran 10mg Tablet Oral use


Afipran 20mg Suppository Rectal use


Afipran 5mg/ml Solution for injection Intramuscular use Intravenous use

Ireland Mercury Pharmacuticals (Ireland) Ltd 4045 Kingswood Road Citywest Business Park Co. Dublin Ireland

Metoclopramide 10mg/2ml Solution for injection Intramuscular use Intravenous use

Ireland Amdipharm Limited Regency House Miles Gray Road Basildon Essex, SS14 3AF United Kingdom

Maxolon 5mg/ml Solution for injection Intramuscular use Intravenous use

19





Ireland Amdipharm Limited Regency House Miles Gray Road Basildon Essex, SS14 3AF United Kingdom

Maxolon 10mg Tablet Oral use

Italy Sanofi-Aventis spa Viale Luigi BODIO, 37/B 20158 Milano Italy

PLASIL 10mg/2ml Solution for injection Intramuscular use Intravenous use


PLASIL 1mg/ml Syrup Oral use


PLASIL 4mg/ml Oral drops, solution Oral use


PLASIL 10mg Tablet Oral use

Italy Teofarma srl Via Fratelli Cervi, 8 27010 Valle Salimbene Pavia Italy

RANDUM 10mg Tablet Oral use

Italy F.I.R.M.A. spa Via Scandicci, 37 50143 Firenze Italy

CLOPAN 10mg Solution for injection Intramuscular use Intravenous use

Italy Sirton Medicare spa Piazza XX Settembre, 2 22079 Villa Guardia - COMO Italy

PRAMIDIN 10 mg/spray Nasal spray, solution Nasal use

20





Italy Sirton Medicare spa Piazza XX Settembre, 2 22079 Villa Guardia - COMO Italy

PRAMIDIN 20 mg/spray Nasal spray, solution Nasal use


DIGESTIVO S.PELLEGRINO 5mg Effervescent tablet Oral use


DIGESTIVO S.PELLEGRINO 5mg Effervescent granules Oral use

Italy Hospira Italia srl Via Orazio, 20/22 80122 NAPOLI Italy

METOCLOPRAMIDE CLORIDRATO HOSPIRA

10mg Solution for injection Intramuscular use Intravenous use

Italy Farmakopea spa Via Cavriana, 14 20134 MILANO Italy

ISAPRANDIL 5mg Effervescent tablet Oral use

Italy Farmakopea spa Via Cavriana, 14 20134 MILANO Italy

ISAPRANDIL 5mg Effervescent granules Oral use

Latvia Pharmaceutical Works POLPHARMA SA 19 Pelplińska Street 83-200 Starogard Gdański Poland

Metoclopramid Polpharma 10 mg tablets


Latvia Pharmaceutical Works POLPHARMA SA 19 Pelplińska Street 83-200 Starogard Gdański Poland

Metoclopramid Polpharma 10 mg/2 ml solution for injection


21





Latvia Teva Pharma B.V. Computerweg 10 3542 DR Utrecht The Netherlands

Cerucal 10 mg tablets 10mg Tablet Oral use

Lithuania Teva Pharma B.V. Computerweg 10 3542 DR Utrecht The Netherlands


Lithuania Medochemie Ltd. p.o box 51409 CY-3505, Limassol Cyprus

ELITAN 5mg/ml Solution for injection Intramuscular use Intravenous use

Lithuania Pharmaceutical Works POLPHARMA SA 19 Pelplińska Street 83-200 Starogard Gdański Poland

Metoclopramid Polpharma 10mg Tablet Oral use

Lithuania Pharmaceutical Works POLPHARMA SA 19 Pelplińska Street 83-200 Starogard Gdański Poland

Metoclopramid Polpharma 10mg/2ml Solution for injection Intramuscular use Intravenous use

Luxembourg Nycomed Belgium s.a. 615, chaussee de Gand B-1080 Bruxelles Belgium


Luxembourg Nycomed Belgium s.a. 615, chaussee de Gand B-1080 Bruxelles Belgium


22





Luxembourg Dolorgiet Gmbh&Co Otto-von-Guericke-Str. 1 D-53757 Sankt Augustin Germany

Gastronerton 4,65mg/ml Oral drops Oral use

Luxembourg Dolorgiet Gmbh&Co Otto-von-Guericke-Str. 1 D-53757 Sankt Augustin Germany

Gastronerton 8,92mg Tablet Oral use

Luxembourg Ratiopharm GMBH Arzneimittel Graf-Arco-Str. 3 D-89079 Ulm Germany

MCP Ratiopharm 5,2mg Oral drops Oral use


MCP Ratiopharm 10mg Suppository Rectal use


MCP Ratiopharm 10mg Tablet Oral use


mcP Ratiopharm SF 10mg/2ml Solution for injection Intramuscular use Intravenous use


MCP Ratiopharm-30 30mg Modified-release capsule, soft

Oral use

23





Luxembourg Eurogenerics s.a. Heizel Esplanade B22 1020 Laeken Belgium

Metoclopramide EG-10 10mg Capsule, soft Oral use

Luxembourg Sanofi-Aventis Belgium Culliganlaan 1 C 1831 Diegem Belgium

Primperan adultes 20mg Suppository Rectal use

Luxembourg Hexal AG Industriestr. 25 D-83607 Holzkirchen Germany

MCP Hexal-10 10mg Tablet Oral use


MCP Hexal Injekt 10mg/2ml Solution for injection Intramuscular use Intravenous use


MCP Hexal Tropfen 4mg/ml Oral drops Oral use







24





Malta Accord Healthcare Ltd Sage House 319 Pinner Road North Harrow Middlesex HA1 4HF United Kingdom

Metoclopramide 10 mg tablets 10mg Tablet Oral use

Malta Antigen International Limited Chandler House Castle Street, Roscrea County Tipperary Ireland

Metoclopramide Injection BP 10mg/2ml Solution for Injection


Malta Hameln Pharmaceuticals Ltd. Nexus, Gloucester Business Park Gloucester GL3 4AG United Kingdom

Metoclopramide 5 mg/ml Injection


Malta Medochemie Limited 1-10 Constantinoupleos Str 3011 Limassol Cyprus

Elitan 10mg tablet 10mg Tablet Oral use

Malta Medochemie Ltd. 1-10, Constantinoupleos Street 3011 Limassol Cyprus

Elitan Injection, 10mg/2ml, Solution for Injection

10mg Solution for injection Intramuscular use Intravenous use

25





Malta Remedica Ltd. Limassol Industrial Estate Aharnon Street P.O. Box 51706 3508 Limassol Cyprus

Cloperan 10 10mg Tablet Oral use

Netherlands Sanofi-Aventis Netherlands B.V. Kampenringweg 45 D-E 2803 PE GOUDA The Netherlands

Primperan injectie 10/2 ml, oplossing voor injection 10 mg/2 ml

10mg/2ml Solution for injection Intravenous use


Primperan drank, drank 1 mg/ml



Primperan 10, zetpillen 10 mg 10mg Suppository Rectal use


Primperan 20, zetpillen 20 mg 20mg Suppository Rectal use

Netherlands Pharmachemie B.V. Swensweg 5 2031 GA HAARLEM The Netherlands

Metoclopramide HCl 10 PCH, tabletten 10 mg


26





Netherlands Centrafarm B.V. Nieuwe Donk 3 4879 AC Etten Leur The Netherlands

Metoclopramide HCl CF 10 mg, tabletten


Netherlands Accord Healthcare B.V. De Waterman 15 A 4891 TL Rijsbergen The Netherlands

Metoclopramidemonohydrochloride Accord 10 mg Tabletten


Norway Nycomed Pharma AS Postboks 205 1372 Asker Norway

Afipran 5mg/ml Solution for injection Intramuscular use Intravenous use


Afipran 20mg Suppository Rectal use


Afipran 100 mg/ml Concentrate for solution for infusion

Intravenous use


Afipran 1mg/ml Oral solution Oral use


Afipran 10mg Tablet Oral use

27





Poland Zakłady Farmaceutyczne Polpharma SA ul. Pelplińska 19 83-200 Starogard Gdański Poland

Metoclopramidum 0,5% Polpharma


Poland Zakłady Farmaceutyczne Polpharma SA ul. Pelplińska 19 83-200 Starogard Gdański Poland

Metoclopramidum Polpharma 10mg Tablet Oral use

Portugal Sanofi - Produtos Farmacêuticos, Lda. Empreendimento Lagoas Park Edifício 7 - 3º Piso 2740-244 Porto Salvo Portugal


Portugal Labesfal - Laboratórios Almiro, S.A. Zona Industrial do Lagedo 3465-157 Santiago de Besteiros Portugal

Metoclopramida Labesfal 10mg/2ml Solution for injection Intramuscular use Intravenous use

Portugal Labesfal - Laboratórios Almiro, S.A. Zona Industrial do Lagedo 3465-157 Santiago de Besteiros Portugal

Metoclopramida Labesfal 10mg Tablet Oral use



28







Portugal Laboratório Medinfar - Produtos Farmacêuticos, S.A. l Ribeiro de Pavia, 1 - 1º - Venda Nova 2700-547 Amadora Portugal

Metoclopramida Medinfar 10mg/2ml Solution for injection Intramuscular use Intravenous use

Portugal Laboratório Medinfar - Produtos Farmacêuticos, S.A. Rua Manuel Ribeiro de Pavia 1 - 1 - Venda Nova 2700-547 Amadora Portugal

Metoclopramida Medinfar 10mg Tablet Oral use


Metoclopramida Medinfar 2,6mg/ml Oral drops, solution Oral use

29






Metoclopramida Medinfar 1mg/ml Oral solution Oral use

Romania S.C. LAROPHARM S.R.L. Şos. Alexandriei, nr 145 A B07-Bragadiru, jud Ilfov România

METOCLOPRAMID LAROPHARM 10mg Tablet Oral use

Romania S.C. SLAVIA PHARM S.R.L. B-dul Theodor Pallady nr. 44C Sector 3, Bucureşti 032266 România

METOCLOPRAMID 10mg Tablet Oral use

Romania S.C. MEDUMAN S.A. Str. Aleea Eroilor nr. 28, Vişeu de Sus, Judeţul Maramureş 435700 România

N - METOCLOPRAMID 10mg Tablet Oral use

Romania S.C. ARENA GROUP S.A Str. Stefan Mihaileanu, nr.31 sector 2; Bucuresti 024022 România

METOCLOPRAMID ARENA 10 mg


30





Romania S.C. TERAPIA S.A. Str. Fabricii nr. 124 Cluj - Napoca 400632 România

METOCLOPRAMID 10 mg 10mg Tablet Oral use

Romania S.C. BIOFARM S.A. Str. Logofăt Tăutu, nr. 99 sector 3, Bucureşti 031212 Romania

METOCLOPRAMID BIOFARM 1mg/5ml

1mg/5ml Syrup Oral use

Romania S.C. BIOFARM S.A. Str. Logofăt Tăutu, nr. 99 sector 3, Bucureşti 031212 Romania

METOCLOPRAMID 7mg/ml Oral drops, solution Oral use

Romania S.C. TERAPIA S.A. Str. Fabricii nr. 124 Cluj - Napoca 400632 România

METOCLOPRAMID 10 mg 10mg/2ml Solution for injection Intramuscular use Intravenous use

Romania Accord Healthcar Ltd Sage House 319 Pinner Road North Harrow Middlesex HA1 4HF United Kingdom

Metoclopramid Accord 10 mg comprimate


Slovak Republic TEVA Pharmaceuticals Slovakia s.r.o. Teslova 26 82102 Bratislava Slovakia


Slovak Republic AWD. pharma GmbH & Co.KG Wasastr. 50 01445 Radebeul Germany

Cerucal 10mg/2ml Solution for injection Intramuscular use Intravenous use

31





Slovak Republic Sandoz Pharmaceuticals d.d. Verovškova 57 1000 Ljubljana Slovenia

DEGAN 10 mg 10mg Tablet Oral use

Slovak Republic Sandoz Pharmaceuticals d.d. Verovškova 57 1000 Ljubljana Slovenia

DEGAN 10 mg/2 ml 10mg/2ml Solution for injection Intramuscular use Intravenous use

Slovenia Alkaloid-INT d.o.o. Ljubljana Slandrova ulica 4 1231 Ljubljana- Crnuce Slovenia

Reglan 1 mg/1 ml peroralna raztopina


Slovenia Alkaloid-INT d.o.o. Ljubljana Slandrova ulica 4 1231 Ljubljana- Crnuce Slovenia

Reglan 10 mg tablete 10mg Tablet Oral use

Spain Sanofi Aventis, S.A. Josep Plá, 2 08019 Barcelona Spain

PRIMPERAN 10 mg/2 ml SOLUCION INYECTABLE



PRIMPERAN 1mg/1ml SOLUCION ORAL



PRIMPERAN 10 mg COMPRIMIDOS


32






PRIMPERAN 260mg/100 ml GOTAS

2,6mg/ml Oral drops, solution Oral use


PRIMPERAN 100 mg/5 ml SOLUCION INYECTABLE


Spain Kern Pharma, S.L. Venus, 72. Poligono Industrial Colon II. 08228 Tarrasa Spain

METOCLOPRAMIDA KERN PHARMA 1 mg/ml SOLUCION ORAL


Spain Pensa Pharma, S.A.U Jorge Comín (médico pediatra) 3 - 46015 Valencia Spain

METOCLOPRAMIDA PENSA 1 mg/ml SOLUCION ORAL


Spain Accord Healthcare, S.L.U. Moll de Barcelona s/n World Trade Centre Edifici Est 6ª planta 08039 Barcelona Spain

METOCLOPRAMIDA ACCORD 10 mg COMPRIMIDOS


Sweden sanofi-aventis AB Box 14142 167 14 Bromma Sweden




33







United Kingdom Actavis UK Limited Whiddon Valley Barnstaple North evon EX32 8NS United Kingdom

Metoclopramide Tablets BP 10mg


United Kingdom Amdipharm plc Regency House Miles Gray Road, Basildon Essex SS14 3AF United Kingdom

Maxolon SR 15mg Modified-release capsules, hard

Oral use


Maxolon Tablets 10mg 10mg Tablet Oral use


Maxolon Injection 5mg/ml 0.5% w/v Solution for injection Intramuscular use Intravenous use


Maxolon High Dose 100mg/20ml

0.5% w/v Solution for injection Intravenous use

United Kingdom Chelonia Healthcare Limited Boumpoulinas 11, 3rd Floor Nicosia, CY-1060 Cyprus

Metoclopramide 10mg Tablets 10mg Tablet Oral use

34





United Kingdom Crescent Pharma Limited Units 3 & 4 Quidhampton Business Units Polhampton Lane, Overton Hampshire RG25 3ED United Kingdom


United Kingdom Ennogen Limited 78 York Street London W1H 1DP United Kingdom


United Kingdom Ennogen Limited 78 York Street London W1H 1DP United Kingdom

Metoclopramide 5mg/ml Injection

0.5% w/v Solution for injection Intramuscular use Intravenous use

United Kingdom Generics (United Kingdom) Limited Station Close, Potters Bar Hertfordshire EN6 1TL United Kingdom

Metoclopramide Tablets 10mg 10mg Tablet Oral use

United Kingdom Hameln Pharmaceuticals Limited Nexus, Gloucester Business Park Gloucester GL3 4AG United Kingdom

Metoclopramide Injection BP 5mg/ml

0.526% w/v Solution for injection Intramuscular use Intravenous use

United Kingdom Metwest Pharmaceuticals Limited 15 Runnelfield Harrow on the Hill Middlesex HA1 3NY United Kingdom


United Kingdom Pharmvit Limited 177 Bilton Road, Perivale Middlesex UB6 7HQ United Kingdom

Metoclopramide Tablets BP 10mg


35





United Kingdom Rosemont Pharmaceuticals Limited Rosemont House Yorkdale Industrial Park Braithwaite Street Leeds, W Yorkshire LS11 9XE United Kingdom

Metoclopramide Hydrochloride 5mg/5ml Oral Solution

5mg/5ml Oral solution Oral use

United Kingdom Rosemont Pharmaceuticals Limited Rosemont House Yorkdale Industrial Park Braithwaite Street Leeds, W Yorkshire LS11 9XE United Kingdom

Maxolon Paediatric Liquid 5mg/5ml Oral solution Oral use

United Kingdom Teva United Kingdom Limted Brampton Road Hampden Park, Eastbourne East Sussex BN22 9AG United Kingdom

Primperan; Metoclopramide Tablets BP 10mg


United Kingdom Accord Healthcare Ltd Sage House 319 Pinner Road North Harrow Middlesex HA1 4HF United Kingdom

Metoclopramide Hydrochloride 10 mg tablets


United Kingdom Mercury Pharma International Limited 4045 Kingswood Raod City West Business Park County Dublin Ireland

Metoclopramide 5mg/ml solution for injection


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Annex II

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

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Scientific conclusions Overall summary of the scientific evaluation of metoclopramide-only containing medicinal products (see Annex I)

Background information

Metoclopramide is a substituted benzamide used for its prokinetic and antiemetic properties. It possesses parasympathomimetic activity as well as being a dopamine-receptor (D2) antagonist with a direct effect on the chemoreceptor trigger zone. It also has serotonin-receptor (5-HT3) antagonist properties.

Metoclopramide has been authorised in the European Union since the 1960’s and marketing authorisations currently exist in all Member States as well as in Norway and Iceland. It is available in a variety of pharmaceutical forms (e.g. tablet, prolonged-release tablet, oral solution, suppository, solution for injection). Combination products are also approved, but this procedure focused on the assessment of the monocomponent products.

The authorised indications for the concerned products are different but can broadly be grouped in the following way:

• Chemotherapy or radiotherapy induced nausea and vomiting (CINV or RINV)

• Post-operative nausea and vomiting (PONV)

• Nausea and vomiting associated with migraine

• Nausea and vomiting of other origins

• Gastrointestinal motility disorders including gastroparesis

• Gastroesophageal reflux disease (GORD) and dyspepsia

• Adjuvant to surgical and radiological procedures

Each individual product is authorised for one or more of these indications, and in some cases the indication is specific to adults and/or children. There is no clear correlation between formulations and indications.

Metoclopramide crosses the blood-brain barrier and is associated to extrapyramidal disorders and other serious neurological adverse events, which are of particular concern in children.

In addition to the neurological risk, there is also a risk of occurrence of cardiovascular adverse events including rare but potentially serious reactions such as bradycardia, atrioventricular block, cardiac arrest, mainly reported with the formulations for intravenous use.

A paediatric worksharing procedure under Article 45 of Regulation (EC) No 1901/20061 to assess information from paediatric studies with metoclopramide has been concluded in 2010 with a recommendation that Member States should introduce the following changes to the product information:

• Contraindication in neonates;

1 Rapporteur’s public paediatric assessment report for paediatric studies submitted in accordance with Article 45 of Regulation (EC) No. 1901/2006, as amended, on Primperan (and others) / Metoclopramide (DE/W/007/pdWS/001), (2010). Retrieved from http://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/Paediatric_Regulation/Assessment_Reports/Article_45_work-sharing/Metoclopramid_Art.45_PdAR_Update.pdf

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http://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/Paediatric_Regulation/Assessment_Reports/Article_45_work-sharing/Metoclopramid_Art.45_PdAR_Update.pdf

http://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/Paediatric_Regulation/Assessment_Reports/Article_45_work-sharing/Metoclopramid_Art.45_PdAR_Update.pdf

• Only the intravenous formulations remain approved for use in paediatric patients >1 year of age, and only for the indication ‘treatment of postoperative nausea and vomiting’;

• Inclusion of specific warnings and precautions, mainly regarding the extrapyramidal adverse events.

After finalisation of the procedure under Article 45 of Regulation (EC) No 1901/2006, the Marketing Authorisation Committee of the French Competent Authority performed a national assessment of the benefit-risk balance of metoclopramide in children and decided, in October 2011, to extend the contraindication to all children under 18 years old for all formulations. This was based on insufficient evidence of efficacy in children in the concerned indications and on the safety issue of neurological symptoms.

Based on the risk of neurological and cardiovascular adverse events, as well as on the limited evidence of efficacy for all indications approved, the French Competent Authority triggered a referral under Article 31 of Directive 2001/83/EC and asked the CHMP to review the benefit-risk balance of metoclopramide-containing products in all populations, particularly in children and the elderly. The French Competent Authority considered it particularly important that the therapeutic indications and safety information be made consistent across Member States.

Efficacy data

Very limited high quality data exists in support of the efficacy of metoclopramide in the majority of the indications authorised in the European Union. Much of the available data is derived from trials designed to investigate newer agents such as the 5-HT3 receptor antagonists, and therefore do not always allow for a definite conclusion of the effect of metoclopramide due to the absence of a comparison to placebo. The doses, routes of administration and treatment durations of metoclopramide used in these studies are not always consistent, and only one specific dose-finding study was identified (in PONV).

Chemotherapy induced nausea and vomiting

The lack of placebo-controlled trial data prevents assessment of the absolute efficacy of metoclopramide in these indications. As such, based on the data assessed, the relative efficacy must be assessed in comparison to the 5-HT3 receptor antagonists.

Acute CINV

Based on data from both the Jantunen meta-analysis and the randomised clinical studies assessed, metoclopramide administered intravenously or orally is consistently inferior to 5-HT3 receptor antagonists for prevention of acute CINV for highly or moderately emetogenic chemotherapy.

Based on data submitted, when administered for highly emetic chemotherapy, metoclopramide appears to be effective by intravenous route at doses ranging from 6 to 10 mg/kg/day. When administered for moderately emetic chemotherapy, doses ranging from 30 to 60mg appear to be effective.

Of note, the review by Jantunen et al. describes the low metoclopramide doses used (20-80mg) as ‘inadequate’ and concludes that this may not be an appropriate comparator for 5-HT3 receptor antagonists.

Delayed CINV

The data presented in relation to the prevention of delayed CINV is predominantly in patients receiving moderately emetogenic chemotherapy, using oral metoclopramide at doses of 10-20 mg three or four times a day. This body of data is more consistent and indicates similar efficacy for these doses of metoclopramide given orally to the efficacy of 5-HT3 receptor antagonists.

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Radiotherapy induced nausea and vomiting

Data on the use of metoclopramide in the prevention of RINV is limited. However, there are no known unique differences in the mechanism of RINV when compared to CINV, and therefore it could be appropriate to extrapolate data from CINV to RINV.

While in some cases a high dose regimen (2-10mg/kg/day) is approved for prevention of acute RINV, studies have been conducted using 10 mg three times a day and the efficacy of this posology is not questioned.

Post-operative nausea and vomiting

The data presented in support of the effect of metoclopramide in post-operative nausea and vomiting indicates that it has similar efficacy to other active substances authorised in this indication. The almost totality of the data relates to the intravenous administration of metoclopramide, and in the majority of the studies assessed, a 10 mg dose was used.

Nausea and vomiting associated with migraine

The data presented is indicative of the efficacy of metoclopramide in acute migraine induced nausea and vomiting based on its anti-emetic properties. In addition, due to its prokinetic properties, metoclopramide may also play a role when given orally in combination with analgesics. Data on the dosing seems to indicate that individual doses of metoclopramide higher than 10mg do not result in increased efficacy.

Nausea and vomiting of other origins

The data presented is limited and was generated in different settings during which nausea and vomiting may occur. While it is difficult to conclude on absolute efficacy of metoclopramide in these individual settings, when taken together, the data are indicative of an effect on nausea and vomiting of different aetiologies.

Gastrointestinal motility disorders

The review by Lee et al. provides a complete overview of the evidence of efficacy in diabetic gastroparesis. While metoclopramide was found to improve gastric emptying and relieve symptoms in diabetic and idiopathic gastroparesis in short term treatment when compared to placebo, no consistent benefit was observed in the long term. Gastroparesis is often a chronic disorder, for which long term treatment is necessary, therefore existing data cannot be considered supportive of the use in this indication.

Gastroesophageal reflux disease and dyspepsia

Based on the data presented, there is little evidence of efficacy of metoclopramide in treatment of gastroesophageal reflux disease or dyspepsia and existing data is not consistent in terms of effect.

Furthermore, existing studies included a very small number of patients and focused on a small duration of treatment. It is also noted that there are other well-established agents available for this indication, including proton pump inhibitors and H2 receptor antagonists, for which a positive benefit-risk balance has been clearly demonstrated for acute and chronic use. Both gastroesophageal reflux disease and dyspepsia may be chronic diseases, and therefore existing data cannot be considered sufficient to support the use in these indications.

Adjuvant to surgical and radiological procedures

Very limited data exists in support of the efficacy of metoclopramide in this indication, and the existing data is not consistent. The studies assessed seem to indicate that metoclopramide reduces gastric

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transit time, but this did not affect the time taken to complete the examination. On the basis of such limited and inconsistent data, it is not possible to conclude positively on the efficacy of metoclopramide in this indication.

Paediatric population

The majority of the efficacy data submitted during the current procedure had already been assessed during the previous paediatric worksharing procedure under Article 45 of Regulation (EC) No 1901/2006, and the new data did not add relevant new elements to the previous assessment.

There is sufficient evidence of efficacy of metoclopramide in the treatment of post-operative nausea and vomiting in the paediatric population. For this indication, only the intravenous formulation is of relevance, in line with the outcome of the procedure under Article 45 of Regulation (EC) No 1901/2006.

With regards to the delayed CINV, the Committee agreed with the previous assessment that the data is limited and shows that metoclopramide is inferior to 5-HT3 receptor antagonists. However, it also took into consideration the recommendations of the British National Formulary for children (BNFc), which has been validated against emerging evidence, best practice guidelines and advice from a network of clinical experts. According to the BNFc, in patients at low risk of emesis, pre-treatment with metoclopramide continued for up to 24 hours after chemotherapy is often effective. For this indication, prophylaxis is usually initiated with a 5-HT3 receptor antagonist before chemotherapy and is followed by metoclopramide (usually oral) prescribed for a further 24-48 hours. This therapeutic alternative may be of particular relevance due to the association between prolonged use of 5-HT3 receptor antagonists and adverse effects of constipation and headache, which may be severe and poorly tolerated. Given the limited therapeutic alternatives for the paediatric population in this setting, it may be acceptable that delayed CINV is retained as a second line option despite the lack of robust efficacy data. For this particular indication in the paediatric population, both the parenteral and the oral pharmaceutical forms may be appropriate.

Renal and hepatic impairment

Established renal failure is defined as ClCr < 15 ml/min, therefore this cut-off should be included in any dosing recommendations. In this population, and based on the studies submitted, the clearance of metoclopramide has shown to be significantly impaired. As such, a dose reduction of 75% would be necessary. However, for patients with moderate to severe impairment (ClCr 15-60 ml/min), a 50% reduction remains appropriate.

The available evidence from small single dose studies suggests that metoclopramide clearance is substantially reduced in patients with hepatic cirrhosis. There appears to be no pharmacokinetic data on multiple-dosing, nor is there comparative data for different levels of hepatic impairment. In the absence of such data, no specific recommendation can be issued for lower levels of hepatic impairment. For severe hepatic impairment, the existing recommendation for 50% dose reduction is appropriate.

Safety data

Metoclopramide has long been associated with a risk of serious neurological adverse reactions such as acute extrapyramidal symptoms and irreversible tardive dyskinesia. From the data assessed, it appears that the risk of acute dystonias is increased when using high doses, and is higher in children than in adults. The elderly appear to be at particular risk of developing tardive dyskinesia following long-term treatment, which in some cases may be irreversible. The slow administration of intravenous doses as a slow bolus over at least 3 minutes lowers the risk of all dystonic reactions.

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In children there is also a significant number of reported cases of overdose. It is noted that the majority of cases involves the use of high concentration oral liquid formulations, which are currently approved under a number of different formulations (oral drops, oral solution, syrup) with very different concentrations and a range of administration devices. This raises an issue of dose accuracy and reproducibility, particularly with high concentration formulations, and may explain at least partially the reason behind the reports of accidental overdose in the paediatric population. It is possible that there is unintended misuse of the high concentration oral liquid formulations, leading to the inadvertent administration of doses higher than intended. If however risk minimisation measures are put in place to allow accurate dosing and address the risk of overdose, oral liquid formulations remain an important and suitable alternative for the paediatric population.

Although serious cardiovascular reactions have been reported with metoclopramide (mainly associated to the intravenous administration), no new significant signals have been identified. The Committee considered the proposal by one MAH to explicitly restrict intravenous administration to locations where resuscitation equipment is available, but noted that most places where intravenous drugs are administrated will already have such equipment.

The published epidemiological studies conducted in different countries on the safety of metoclopramide use during pregnancy consistently showed the absence of association between exposure during pregnancy and risk of major congenital malformations. Metoclopramide can therefore be used during pregnancy, if clinically justified. However, a few cases of extrapyramidal reactions in newborns exposed to metoclopramide before delivery have been identified. Therefore the risk to newborns cannot be excluded and metoclopramide should be avoided at the end of pregnancy.

Metoclopramide is excreted in breast milk, and although the available data does no raise concerns, effects in the breast fed infant cannot be excluded. Therefore it would be appropriate not to use metoclopramide during breastfeeding.

The available evidence in relation to CYP2D6 polymorphisms, when taken together with the data on interactions with CYP2D6 inhibitors, is suggestive that whilst CYP2D6 metabolism is not the main metabolic pathway for metoclopramide, the inhibition of this pathway due to polymorphisms or pharmacokinetic interactions with other drugs may potentially be clinically significant. Although the clinical significance is uncertain, patients should be monitored for adverse reactions.

Risk Minimisation Measures

The CHMP, having considered the data submitted, is of the opinion that in addition to product information amendments which include the use of the minimum effective dose and the limitation of treatment duration, the following risk minimisation activities are necessary for the safe and effective use of the medicinal product:

• Limiting the maximum concentration/dosing in certain formulations to ensure that patients are not unintentionally exposed to doses higher than the single recommended dose for the product.

• Oral liquid formulations intended to be used in children must be supplied with an appropriate measuring device (e.g. graduated oral syringe) to ensure accurate measuring of the dose and avoid accidental overdosing.

Overall conclusion

Limited data exists on the efficacy of metoclopramide in the different therapeutic indications authorised in the European Union; however, when taken together, it is indicative of the efficacy of the product in the management of nausea and vomiting of different origins. For the majority of the indications, there is clinical data evaluating the efficacy of the posology of 10 mg three times a day. While in some

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cases higher doses may be currently authorised, with the exception of acute CINV the existing data does not clearly indicate that higher doses result in increased efficacy. In addition, data is indicative that the burden of adverse reactions is increased with dose. Therefore, in order to minimise the risk of serious neurological adverse reactions such as acute extrapyramidal symptoms and irreversible tardive dyskinesia, the dose should be restricted to the minimum effective dose, which for adults is considered to be 10 mg three times daily.

Adults

For therapeutic indications such as delayed CINV, prevention of RINV, prevention of PONV and symptomatic treatment of nausea and vomiting including migraine induced nausea and vomiting, data is indicative of efficacy at low doses (10mg, three times daily) which minimise the risk of serious neurological adverse reactions. Therefore, for these indications the Committee considered the benefit-risk balance to be positive.

For the indication acute CINV, while there is some data indicative of efficacy, it requires the intravenous use of high doses of metoclopramide which carry higher risks not only of neurological but also cardiovascular adverse reactions (including cardiac arrest). For this reason, the Committee considered that the benefit-risk balance of metoclopramide in this indication is negative and recommended that it is deleted.

Considering the newly recommended posology, parenteral formulations with concentration higher than 5mg/ml currently approved in the European Union (mainly for the management of acute CINV) will not be suitable for administration of the 10mg dose, are therefore considered to have a negative benefit-risk balance and should be revoked.

For the indications gastrointestinal motility disorders including gastroparesis and gastroesophageal reflux disease and dyspepsia, the Committee noted that these are essentially chronic conditions for which long term use is often required. There is no data submitted to support the efficacy of metoclopramide in the required treatment duration, but there is evidence that the above mentioned risks are increased with prolonged treatment. Therefore the Committee considered that the benefit-risk balance of metoclopramide in these indications is negative.

For the indication adjuvant to surgical and radiological procedures, very limited efficacy data exists, and the existing data is not consistent. The studies assessed seem to indicate that metoclopramide reduces gastric transit time, but this did not translate into a clinically meaningful outcome (time taken to complete the examination). In the absence of an established benefit, and taking into account the safety profile of metoclopramide, the Committee considered that the benefit-risk balance of metoclopramide in this indication is negative.

Children

Very limited information exists to support the efficacy of metoclopramide in the paediatric population, in the majority of the indications. The exception is the treatment of established post-operative nausea and vomiting, which had already been recommended to be maintained in a previous worksharing procedure under Article 45 of Regulation (EC) No 1901/2006. While endorsing the conclusions of the previous assessment, the CHMP also took note of the fact that, in particular for the treatment of delayed CINV which can be quite a debilitating condition, there are limited alternative treatments available for the paediatric population. Metoclopramide has long been included in the British National Formulary for children (BNFc), which has been validated against emerging evidence, best practice guidelines and advice from a network of clinical experts. Therefore the Committee considered that, based on long term experience of use and the clinical need for treatment options in the paediatric population, the benefit-risk balance of metoclopramide for the prevention of delayed CINV in the

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paediatric population can be considered positive. For this indication and population, it is considered particularly important that oral formulations are available.

However the safety data seems to indicate that methaemoglobinaemia occurs almost exclusively in children, and that children are also at higher risk of serious neurological adverse reactions. Therefore use of metoclopramide should be reserved for situations where alternative treatments have not been effective or cannot be administered. Thus, for both treatment of established post-operative nausea and vomiting and prevention of delayed CINV in children, the use of metoclopramide should be reserved as a second line option.

Oral liquid formulations

The majority of cases of accidental overdose occurred in children and involve the use of high concentration oral liquid formulations. This may be due to an issue of dose accuracy and reproducibility, unclear information on dosing and possibly difficulties measuring and administering the correct dose, particularly with high concentration formulations and poorly validated devices. Therefore the Committee considered that it is an important risk minimisation measure to restrict the maximum concentration of oral liquid formulations to 1 mg/ml, to ensure that clear instructions are given in the product information on posology for paediatric patients and that these oral liquid formulations are supplied with an appropriate measuring device such as a graduated oral syringe.

Suppositories

It was noted by the Committee that a formulation of suppositories dosed at 20mg is currently approved in some Member States. As previously described, there is no evidence that doses above 10mg result in higher efficacy. However, the risk of serious neurological adverse reactions is increased. Considering the recommendation for posology to be defined as 10mg three times a day and the fact that this pharmaceutical form does not allow for adjustment of dose, the Committee considered that the benefit-risk balance of the suppositories dosed at 20mg is negative.

The CHMP endorsed a communication i.e. Dear Healthcare Professional Communication (DHPC), to rapidly communicate the outcome of the present review.

Following the adoption of the CHMP opinion in July 2013, a request for re-examination was received from one MAH concerned by the procedure.

Re-examination procedure

The MAH disagreed with the CHMP recommendation for revocation of oral liquid formulations with concentration higher than 1 mg/ml. The MAH considered that oral liquid formulations with concentration higher than 1 mg/ml continue to be useful for adult patients, in terms of dosing (less number of drops are necessary to achieve the intended dose with a higher concentration solution) and in terms of easiness of administration vis-à-vis tablets. Also, the onset of action may be faster with the solution in comparison to that of tablets, as tablets have first to be dissolved in the gastrointestinal tract. While considering that the concentration 4 mg/ml is appropriate for adults, the MAH recognised that it is too high for children and therefore proposed the measures to avoid the risk of overdose in children, including contraindication in this patient population.

No data was submitted by the MAH in support of the above claims.

In its July 2013 opinion, the CHMP recommended that for all indications in adults the single dose is 10 mg, up to three times daily. This posology applies to all oral formulations and is not dependent on body weight.

In respect of dose adjustment for renal and hepatic impairment, while it is correct that oral liquid formulations offer advantage over solid pharmaceutical forms, higher concentrations (such as 4

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mg/ml) do not have additional advantage over the proposed 1 mg/ml. Both the 50% and the 75% dose reductions recommended, respectively, in hepatic and renal impairment are easily achievable with the 1 mg/ml liquid formulations.

In its July 2013 opinion, the CHMP also recommended that oral liquid formulations be supplied with an appropriate measuring device such as a graduated oral syringe. If an appropriate measuring device is used as recommended, there will be no need to count drops. Using a device such as a graduated oral syringe may even be more convenient than counting drops and it ensures accurate and reproducible dosing in any situation, including when doses are reduced due to renal or hepatic impairment.

In its grounds for re-examination, the MAH also argued that in case of nausea drops are easier to swallow than tablets. There is no clinical data available to allow for a discussion on this point. The CHMP considered that formulations with concentration 1mg/ml are suitable for those patients that may prefer an oral liquid formulation to a solid pharmaceutical form.

Limited data exists on the onset of action of oral liquid formulations in comparison with tablets. An oral bioequivalence study of metoclopramide tablets compared to liquid showed that Cmax and Tmax are not significantly different for the two oral formulations. Therefore, the Committee considered that the available evidence does not support the assumption that oral liquid formulations have a faster onset of action than tablets.

The MAH considered in its grounds that for oral liquid solutions a concentration of 4 mg/ml is too high for children and that there is a risk of overdose in this population. In order to minimise the risk of overdose in children, the MAH proposed to add the statement ‘for adults’ in the label of oral liquid formulations with concentration > 1 mg/ml, and a contraindication in the paediatric population. The Committee noted this proposal from the MAH, but it also took note of the fact that, even if not specifically approved for paediatric use, high concentration oral liquid formulations are associated with risks in this population. Post marketing data is suggestive of unintended misuse of these formulations (oral drops, oral solution, syrup), approved under a range of concentrations and with a range of administration devices potentially leading to the inadvertent administration of doses higher than intended. In this scenario where the unintended misuse is already taking place, to include a contraindication in the product information alongside a statement in the labelling is unlikely to be sufficient to change administration habits.

In conclusion, the Committee considered that oral liquid formulations with concentration 1 mg/ml are suitable for all situations mentioned, and that the availability of higher concentrations carries a risk of overdose in the paediatric population that is unlikely to be resolved by the proposed changes to the product information.

Benefit–risk balance

The Committee, as a consequence, concluded that the benefit-risk balance of metoclopramide-containing medicinal products remains positive, taking into account the changes to the product information and risk minimisation measures recommended.

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Grounds for the revocation / variation to the terms of the marketing authorisation

Whereas

• The Committee considered the procedure under Article 31 of Directive 2001/83/EC for metoclopramide-containing medicinal products.

• The Committee considered the totality of the data submitted in support of the efficacy and safety of metoclopramide.

• The Committee considered that metoclopramide is associated with a risk of serious adverse events, including neurological adverse events such as extrapyramidal symptoms and irreversible tardive dyskinesia. The risks are increased when using high doses or during long-term treatment, and in particular for extrapyramidal symptoms the risk is higher in children than in adults.

• The Committee considered that the risk of serious neurological adverse events can be minimised by using lower doses of metoclopramide and limiting treatment duration. The Committee also considered that the risk of unintentional overdose and associated adverse events in children can be lowered by limiting the maximum concentration of oral liquid formulations.

• The Committee noted that the available data do not support clinically significant efficacy for the indications which require long term use (‘gastrointestinal motility disorders including gastroparesis’, ‘gastroesophageal reflux disease and dyspepsia’) and for the indication ‘adjuvant to surgical and radiological procedures’.

• The Committee also noted that the data supporting the therapeutic indication ‘prevention of acute chemotherapy induced nausea and vomiting’ is indicative of efficacy but requires the use of high doses.

• In view of the available data the Committee concluded, subject to the amendments to the product information and implementation of the risk minimisation measures, that the benefit-risk balance of metoclopramide-containing products:

o Is favourable in adults for ‘prevention of delayed chemotherapy induced nausea and vomiting’ (oral and rectal routes)

o Is favourable in adults for ‘prevention of radiotherapy induced nausea and vomiting’ (parenteral, oral and rectal routes)

o Is favourable in adults for ‘prevention of post-operative nausea and vomiting’ (parenteral route only)

o Is favourable in adults for ‘symptomatic treatment of nausea and vomiting, including acute migraine induced nausea and vomiting’ (parenteral route) and ‘symptomatic treatment of nausea and vomiting, including acute migraine induced nausea and vomiting. Metoclopramide can be used in combination with oral analgesics to improve the absorption of analgesics in acute migraine’ (oral route)

o Is favourable in children between 1 and 18 years of age for ‘prevention of delayed chemotherapy induced nausea and vomiting, as second line option’ (parenteral and oral routes)

o Is favourable in children between 1 and 18 years of age for ‘treatment of established post-operative nausea and vomiting, as second line option’ (parenteral route only)

• In view of the available data the Committee also concluded that the benefit-risk balance of metoclopramide-containing products:

o Is not favourable in children under 1 year of age for any indication.

o Is not favourable for ‘prevention of acute chemotherapy induced nausea and vomiting’

o Is not favourable for ‘gastrointestinal motility disorders, including gastroparesis’

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o Is not favourable for ‘gastroesophageal reflux disease and dyspepsia’

o Is not favourable for oral liquid formulations with concentration higher than 1mg/ml

o Is not favourable for parenteral formulations with concentration higher than 5mg/ml

o Is not favourable for rectal formulations dosed at 20mg

Therefore, in accordance with Article 116 of Directive 2001/83/EC, the CHMP recommends:

• The revocation of the marketing authorisations for:

− oral liquid formulations with concentration higher than 1mg/ml

− parenteral formulations with concentration higher than 5mg/ml

− rectal formulations dosed at 20mg

• The variation to the terms of the marketing authorisation for the remaining metoclopramide-containing medicinal products referred to in Annex I, for which the relevant sections of the summary of product characteristics and package leaflet are set out in annex III of the CHMP opinion. Oral liquid formulations shall be supplied with an appropriate measuring device such as a graduated oral syringe.

The Committee, as a consequence, concluded that the benefit-risk balance of metoclopramide-containing medicinal products remains positive, taking into account the changes to the product information and risk minimisation measures recommended.

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Annex III

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

Note:

The relevant sections of the Summary of Product Characteristics and package leaflet are the outcome of the referral procedure.

The product information shall 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.

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Metoclopramide-containing products The following wording should be included in the SmPC of the marketing authorisations to be varied, as relevant:

Summary of Product Characteristics 4.1 Therapeutic indications

Parenteral route/IM-IV

Adult population

{Tradename} is indicated in adults for:

- Prevention of post operative nausea and vomiting (PONV) - Symptomatic treatment of nausea and vomiting, including acute migraine induced nausea and vomiting - Prevention of radiotherapy induced nausea and vomiting (RINV). Paediatric population {Tradename} is indicated in children (aged 1-18 years) for:

- Prevention of delayed chemotherapy induced nausea and vomiting (CINV) as a second line option - Treatment of established post operative nausea and vomiting (PONV) as a second line option Oral route

Adult population


- Prevention of delayed chemotherapy induced nausea and vomiting (CINV) - Prevention of radiotherapy induced nausea and vomiting (RINV). - Symptomatic treatment of nausea and vomiting, including acute migraine induced nausea and vomiting. Metoclopramide can be used in combination with oral analgesics to improve the absorption of analgesics in acute migraine. Paediatric population {Tradename} is indicated in children (aged 1-18 years) for:

- Prevention of delayed chemotherapy induced nausea and vomiting (CINV) as a second line option Rectal route

Adult population


- Prevention of delayed chemotherapy induced nausea and vomiting (CINV) - Prevention of radiotherapy induced nausea and vomiting (RINV) 4.2 Posology and method of administration

Parenteral route

The solution can be administered intravenously or intramuscularly. Intravenous doses should be administered as a slow bolus (at least over 3 minutes).

All indications (adult patients)

For prevention of PONV a single dose of 10mg is recommended. For the symptomatic treatment of nausea and vomiting, including acute migraine induced nausea and vomiting and for the prevention of radiotherapy induced nausea and vomiting (RINV): the recommended single dose is 10 mg, repeated up to three times daily

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The maximum recommended daily dose is 30 mg or 0.5mg/kg body weight. The injectable treatment duration should be as short as possible and transfer to oral or rectal treatment should be made as soon as possible.

All indications (paediatric patients aged 1-18 years)

The recommended dose is 0.1 to 0.15 mg/kg body weight, repeated up to three times daily by intravenous route. The maximum dose in 24 hours is 0.5 mg/kg body weight.

Dosing table

Age Body Weight Dose Frequency

1-3 years 10-14 kg 1 mg Up to 3 times daily


5-9 years 20-29 kg 2.5 mg Up to 3 times daily


15-18 years Over 60kg 10 mg Up to 3 times daily

The maximum treatment duration is 48 hours for treatment of established post operative nausea and vomiting (PONV).

The maximum treatment duration is 5 days for prevention of delayed chemotherapy induced nausea and vomiting (CINV).

Oral route


For immediate release preparations The recommended single dose is 10 mg, repeated up to three times daily. For prolonged release preparations 15mg strength The recommended single dose is 15 mg, repeated up to twice daily. 30mg strength The recommended dose is 30mg once daily. For all preparations The maximum recommended daily dose is 30 mg or 0.5mg/kg body weight. The maximum recommended treatment duration is 5 days. Prevention of delayed chemotherapy induced nausea and vomiting (CINV) (paediatric patients aged 1-18 years)

The recommended dose is 0.1 to 0.15 mg/kg body weight, repeated up to three times daily by oral route. The maximum dose in 24 hours is 0.5 mg/kg body weight.

Dosing table






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[Appropriate measuring device must be provided with the product, and instructions for use must be included in the SmPC]

The maximum treatment duration is 5 days for prevention of delayed chemotherapy induced nausea and vomiting (CINV).

For tablets/capsules/granules Appropriate additional information regarding posologies adaptation should be implemented in the SmPC depending on the strength of the formulations

For formulations which cannot be used to administer a 5mg dose Tablets/capsules/granules are not suitable for use in children weighing less than 61 kg. Other pharmaceutical forms/strengths may be more appropriate for administration to this population. For formulations which can be used to administer a 5mg dose Tablets/capsules/granules are not suitable for use in children weighing less than 30 kg. Other pharmaceutical forms/strengths may be more appropriate for administration to this population Rectal route


The recommended single dose is 10 mg, repeated up to three times daily. The maximum recommended daily dose is 30 mg or 0.5mg/kg body weight. The maximum recommended treatment duration is 5 days. All routes of administration at the exception prolonged release preparations

Method of administration:

A minimal interval of 6 hours between two administrations is to be respected, even in case of vomiting or rejection of the dose (see section 4.4).

15mg strength prolonged release preparations



30 mg strength prolonged release preparations



All routes of administration

Special population

Elderly In elderly patients a dose reduction should be considered, based on renal and hepatic function and overall frailty. Renal impairment: In patients with end stage renal disease (Creatinine clearance ≤ 15 ml/min), the daily dose should be reduced by 75%. In patients with moderate to severe renal impairment (Creatinine clearance 15-60 ml/min), the dose should be reduced by 50% (see section 5.2). Hepatic impairment: In patients with severe hepatic impairment, the dose should be reduced by 50% (see section 5.2).

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Appropriate additional information regarding posologies adaptation should be implemented in the SmPC depending on the formulations for these specific populations:

<Other pharmaceutical forms/strengths may be more appropriate for administration to this/these population(s)> <This formulation is not suitable for administration to this/these population(s)> Paediatric population Metoclopramide is contraindicated in children aged less than 1 year (see section 4.3).

4.3 Contraindications

For all formulations

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

- Gastrointestinal haemorrhage, mechanical obstruction or gastro-intestinal perforation for which the stimulation of gastrointestinal motility constitutes a risk

- Confirmed or suspected pheochromocytoma, due to the risk of severe hypertension episodes

- History of neuroleptic or metoclopramide-induced tardive dyskinesia

- Epilepsy (increased crises frequency and intensity)

- Parkinson’s disease

- Combination with levodopa or dopaminergic agonists (see section 4.5)

- Known history of methaemoglobinaemia with metoclopramide or of NADH cytochrome-b5 deficiency.

- Use in children less than 1 year of age due to an increased risk of extrapyramidal disorders (see section 4.4)

For rectal formulations - Recent history of proctitis or rectal bleeding

- Use in children below 18 years of age

4.4 Special warnings and precautions for use

For all routes of administration at the exception of prolonged release preparations

Neurological Disorders

Extrapyramidal disorders may occur, particularly in children and young adults, and/or when high doses are used. These reactions occur usually at the beginning of the treatment and can occur after a single administration. Metoclopramide should be discontinued immediately in the event of extrapyramidal symptoms. These effects are generally completely reversible after treatment discontinuation, but may require a symptomatic treatment (benzodiazepines in children and/or anticholinergic anti-Parkinsonian medicinal products in adults).

The time interval of at least 6 hours specified in the section 4.2 should be respected between each metoclopramide administration, even in case of vomiting and rejection of the dose, in order to avoid overdose.

Prolonged treatment with metoclopramide may cause tardive dyskinesia, potentially irreversible, especially in the elderly. Treatment should not exceed 3 months because of the risk of tardive dyskinesia (see section 4.8). Treatment must be discontinued if clinical signs of tardive dyskinesia appear.

Neuroleptic malignant syndrome has been reported with metoclopramide in combination with neuroleptics as well as with metoclopramide monotherapy (see section 4.8). Metoclopramide should be discontinued immediately in the event of symptoms of neuroleptic malignant syndrome and appropriate treatment should be initiated.

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Special care should be exercised in patients with underlying neurological conditions and in patients being treated with other centrally-acting drugs (see section 4.3)

Symptoms of Parkinson’s disease may also be exacerbated by metoclopramide.

For the 15 mg strengh prolonged release preparations








For the 30 mg strengh prolonged release preparations








For all routes of administration

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Methaemoglobinemia

Methemoglobinemia which could be related to NADH cytochrome b5 reductase deficiency has been reported. In such cases, metoclopramide should be immediately and permanently discontinued and appropriate measures initiated (such as treatment with methylene blue).

Cardiac Disorders There have been reports of serious cardiovascular undesirable effects including cases of circulatory collapse, severe bradycardia, cardiac arrest and QT prolongation following administration of metoclopramide by injection, particularly via the intravenous route (see section 4.8). Special care should be taken when administering metoclopramide, particularly via the intravenous route to the elderly population, to patients with cardiac conduction disturbances (including QT prolongation), patients with uncorrected electrolyte imbalance, bradycardia and those taking other drugs known to prolong QT interval. Intravenous doses should be administered as a slow bolus (at least over 3 minutes) in order to reduce the risk of adverse effects (e.g. hypotension, akathisia).

Renal and Hepatic Impairment

In patients with renal impairment or with severe hepatic impairment, a dose reduction is recommended (see section 4.2).

Additional statements related to excipients

[To be completed nationally, if necessary]

4.5 Interaction with other medicinal products and other forms of interaction


Contraindicated combination Levodopa or dopaminergic agonists and metoclopramide have a mutual antagonism (see section 4.3).

Combination to be avoided Alcohol potentiates the sedative effect of metoclopramide.

Combination to be taken into account Due to the prokinetic effect of metoclopramide, the absorption of certain drugs may be modified.

Anticholinergics and morphine derivatives Anticholinergics and morphine derivatives may have both a mutual antagonism with metoclopramide on the digestive tract motility.

Central nervous system depressants (morphine derivatives, anxiolytics, sedative H1 antihistamines, sedative antidepressants, barbiturates, clonidine and related) Sedative effects of Central Nervous System depressants and metoclopramide are potentiated.

Neuroleptics Metoclopramide may have an additive effect with other neuroleptics on the occurrence of extrapyramidal disorders.

Serotonergic drugs The use of metoclopramide with serotonergic drugs such as SSRIs may increase the risk of serotonin syndrome. Digoxin Metoclopramide may decrease digoxin bioavailability. Careful monitoring of digoxin plasma concentration is required.

Cyclosporine Metoclopramide increases cyclosporine bioavailability (Cmax by 46% and exposure by 22%). Careful monitoring of cyclosporine plasma concentration is required. The clinical consequence is uncertain.

Mivacurium and suxamethonium Metoclopramide injection may prolong the duration of neuromuscular block (through inhibition of plasma cholinesterase).

Strong CYP2D6 inhibitors

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Metoclopramide exposure levels are increased when co-administered with strong CYP2D6 inhibitors such as fluoxetine and paroxetine. Although the clinical significance is uncertain, patients should be monitored for adverse reactions.

4.6 Fertility, pregnancy and lactation


Pregnancy A large amount of data on pregnant women (more than 1000 exposed outcomes) indicates no malformative toxicity nor foetotoxicity. Metoclopramide can be used during pregnancy if clinically needed. Due to pharmacological properties (as other neuroleptics), in case of metoclopramide administration at the end of pregnancy, extrapyramidal syndrome in newborn cannot be excluded. Metoclopramide should be avoided at the end of pregnancy. If metoclopramide is used, neonatal monitoring should be undertaken. Breastfeeding Metoclopramide is excreted in breast milk at low level. Adverse reactions in the breast-fed baby cannot be excluded. Therefore metoclopramide is not recommended during breastfeeding. Discontinuation of metoclopramide in breastfeeding women should be considered. 4.7 Effects on ability to drive and use machines


Metoclopramide may cause drowsiness, dizziness, dyskinesia and dystonias which could affect the vision and also interfere with the ability to drive and operate machinery.

4.8 Undesirable effects

All routes of administration Adverse reactions listed by System Organ Class. Frequencies are defined using the following convention: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), not known (cannot be estimated from the available data).

Systeme Organ Class Frequency Adverse reactions

Blood and lymphatic system disorders Not known Methaemoglobinaemia, which could be

related to NADH cytochrome b5 reductase deficiency, particularly in neonates (see section 4.4) Sulfhaemoglobinaemia, mainly with concomitant administration of high doses of sulphur-releasing medicinal products

Cardiac disorders Uncommon Bradycardia, particularly with intravenous

formulation Not known Cardiac arrest, occurring shortly after

injectable use, and which can be subsequent to bradycardia (see section 4.4); Atrioventricular block, Sinus arrest particularly with intravenous formulation; Electrocardiogram QT prolonged; Torsade de Pointes;

Endocrine disorders* Uncommon Amenorrhoea, Hyperprolactinaemia, Rare Galactorrhoea Not known Gynaecomastia Gastrointestinal disorders Common Diarrhoea General disorders and administration site conditions Common Asthenia

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Immune system disorders Uncommon Hypersensitivity Not known Anaphylactic reaction (including anaphylactic

shock particularly with intravenous formulation

Nervous system disorders Very

common Somnolence

Common Extrapyramidal disorders (particularly in children and young adults and/or when the recommended dose is exceeded, even following administration of a single dose of the drug) (see section 4.4), Parkinsonism, Akathisia

Uncommon Dystonia, Dyskinesia, Depressed level of consciousness

Rare Convulsion especially in epileptic patients

Not known Tardive dyskinesia which may be persistent, during or after prolonged treatment, particularly in elderly patients (see section 4.4), Neuroleptic malignant syndrome (see section 4.4)

Psychiatric disorders Common Depression Uncommon Hallucination Rare Confusional state Vascular disorder

Common: Hypotension, particularly with intravenous formulation

Not known Shock, syncope after injectable use Acute hypertension in patients with phaeochromocytoma (see section 4.3)

* Endocrine disorders during prolonged treatment in relation with hyperprolactinaemia (amenorrhoea, galactorrhoea, gynaecomastia).

The following reactions, sometimes associated, occur more frequently when high doses are used: - Extrapyramidal symptoms: acute dystonia and dyskinesia, parkinsonian syndrome, akathisia, even

following administration of a single dose of the medicinal product, particularly in children and young adults (see section 4.4).

- Drowsiness, decreased level of consciousness, confusion, hallucination.

4.9 Overdose


Symptoms

Extrapyramidal disorders, drowsiness, decreased level of consciousness, confusion, hallucination, and cardio-respiratory arrest may occur.

Management

In case of extrapyramidal symptoms related or not to overdose, the treatment is only symptomatic (benzodiazepines in children and/or anticholinergic anti-parkinsonian medicinal products in adults).

A symptomatic treatment and a continuous monitoring of the cardiovascular and respiratory functions should be carried out according to clinical status.

5.2 Pharmacokinetic properties

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Renal impairment

The clearance of metoclopramide is reduced by up to 70% in patients with severe renal impairment, while the plasma elimination half-life is increased (approximately 10 hours for a creatinine clearance of 10-50 mL/minute and 15 hours for a creatinine clearance <10 mL/minute).

Hepatic impairment

In patients with cirrhosis of the liver, accumulation of metoclopramide has been observed, associated with a 50% reduction in plasma clearance.

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Package Leaflet

1. What Tradename is and what it is used for Tradename is an antiemetic. It contains a medicine called “metoclopramide”. It works on a part of your brain that prevents you from feeling sick (nausea) or being sick (vomiting). Parenteral route/IM-IV

Adult population

{Tradename} is used in adults:

- to prevent nausea and vomiting that may occur after surgery - to treat nausea and vomiting including nausea and vomiting which may occur with a migraine - to prevent nausea and vomiting caused by radiotherapy Paediatric population {Tradename} is used in children (aged 1-18 years) only if other treatment does not work or cannot be used:

- to prevent delayed nausea and vomiting that may occur after chemotherapy - to treat nausea and vomiting that has occurred after surgery Oral route

Adult population

{Tradename} is used in adults:

- to prevent delayed nausea and vomiting that may occur after chemotherapy - to prevent nausea and vomiting caused by radiotherapy - to treat nausea and vomiting including nausea and vomiting which may occur with a migraine.

Metoclopramide can be taken with oral painkillers in case of migraine to help painkillers work more effectively.

Paediatric population {Tradename} is indicated in children (aged 1-18 years) if other treatment does not work or cannot be used to prevent delayed nausea and vomiting that may occur after chemotherapy

Rectal route

Adult population

{Tradename} is indicated in adults:

- to prevent delayed nausea and vomiting that may occur after chemotherapy - to prevent nausea and vomiting caused by radiotherapy 2 What you need to know before you are given {Tradename}

Do not take {Tradename} if: For all formulations

- you are allergic to metoclopramide or any of the other ingredients of this medicine (listed in section 6).

- you have bleeding, obstruction or a tear in your stomach or gut. - you have or may have a rare tumour of the adrenal gland, which sits near the kidney

(pheochromocytoma). - you have ever had involuntary muscle spasms (tardive dyskinesia), when you have been treated

with a medicine. - you have epilepsy - you have Parkinson’s disease

58

- you are taking levodopa (a medicine for Parkinson’s disease) or dopaminergic agonists (see below “Other medicines and Tradename”)

- you have ever had an abnormal blood pigment levels (methaemoglobinemia) or NADH cytochrome-b5 deficiency

Do not give {Tradename} to a child less than 1 year of age (see below “Children and adolescents”). For rectal formulation - you have recently experienced inflammation and/or bleeding from your back passage (anus/rectum) - you are below 18 years of age. Do not take {Tradename} if any of the above apply to you. If you are not sure, talk to your doctor, pharmacist or nurse before you take Tradename. Warnings and precautions For all routes of administration

Talk to your doctor, pharmacist or nurse before taking {Tradename} if: - you have a history of abnormal heart beats (QT interval prolongation) or any other heart problems - you have problems with the levels of salts in your blood, such as potassium, sodium and

magnesium. - you are using other medicines known to affect the way your heart beats - you have any neurological (brain) problems - you have liver or kidney problems. The dose may be reduced (see section 3). Your doctor may perform blood tests to check your blood pigment levels. In cases of abnormal levels (methaemoglobinemia), the treatment should be immediately and permanently stopped. For immediate release oral formulations You must wait at least 6 hours between each metoclopramide dose, even in case of vomiting and rejection of the dose, in order to avoid overdose. For 15mg prolonged release oral formulations You must wait at least 12 hours between each metoclopramide dose, even in case of vomiting and rejection of the dose, in order to avoid overdose. For 30mg prolonged release oral formulations You must wait at least 24 hours between each metoclopramide dose, even in case of vomiting and rejection of the dose, in order to avoid overdose. Do not exceed 3-month treatment because of the risk of involuntary muscle spasms. Children and adolescents For all formulations

Uncontrollable movements (extrapyramidal disorders) may occur in children and young adults. This medicine must not be used in children below 1 year of age because of the increased risk of the uncontrollable movements (see above “Do not take {Tradename} if”).

Other medicines and {Tradename} For all routes of administration

Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines. This is because some medicines can affect the way {Tradename} works or {Tradename} can affect how other medicines work. These medicines include the following: - levodopa or other medicines used to treat Parkinson’s disease (see above “Do not take

{Tradename} if”) - anticholinergics (medicines used to relieve stomach cramps or spasms) - morphine derivatives (medicines used to treat severe pain) - sedative medicines - any medicines used to treat mental health problems - digoxin (medicine used to treat heart failure) - cyclosporine (medicine used to treat certain problems with the immune system) - mivacurium and suxamethonium (medicines used to relax muscles)

59

- fluoxetine and paroxetine (medicine used to treat depression) {Tradename} with alcohol For all routes of administration

Alcohol should not be consumed during treatment with metoclopramide because it increases the sedative effect of {Tradename}. Pregnancy, breast-feeding For all routes of administration

If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before being given this medicine. If necessary, {Tradename} may be taken during pregnancy. Your doctor will decide whether or not you should be given this medicine. {Tradename} is not recommended if you are breast-feeding because metoclopramide passes into breast milk and may affect your baby. Driving and using machines For all routes of administration

You may feel drowsy, dizzy or have uncontrollable twitching, jerking or writhing movements and unusual muscle tone causing distortion of the body after taking {Tradename}. This may affect your vision and also interfere with your ability to drive and use machines. Additional statements related to excipients

[To be completed nationally, if necessary]

3. How to take {Tradename}

Parenteral route

The medicine will normally be given to you by a doctor or a nurse. It will be given as a slow injection into a vein (over at least 3 minutes) or by injection into a muscle. In adults patients For the treatment of nausea and vomiting including nausea and vomiting which may occur with a migraine and for the prevention of nausea and vomiting caused by radiotherapy: the recommended single dose is 10 mg, repeated up to 3 times daily. The maximum recommended dose per day is 30 mg or 0.5 mg/kg body weight. For the prevention of nausea and vomiting that may occur after surgery prevention: a single dose of 10mg is recommended. All indications (paediatric patients aged 1-18 years) The recommended dose is 0.1 to 0.15 mg/kg body weight, repeated up to 3 times daily, given by slow injection into a vein.

The maximum dose in 24 hours is 0.5 mg/kg body weight.

Dosing table






60


The treatment should not exceed 48 hours for treatment of nausea and vomiting that has occurred after surgery.

The treatment should not exceed 5 days for prevention of delayed nausea and vomiting that may occur after chemotherapy.

Oral route


For immediate release preparations The recommended single dose is 10 mg, repeated up to three times daily. For prolonged release preparations 15mg strength The recommended single dose is 15 mg, repeated up to twice daily. 30mg strength The recommended dose is 30mg once daily. The maximum recommended dose per day is 30 mg or 0.5 mg/kg body weight. The maximum recommended treatment duration is 5 days. To prevent delayed nausea and vomiting that may occur after chemotherapy (children aged 1-18 years)

The recommended dose is 0.1 to 0.15 mg/kg body weight, repeated up to 3 times daily, taken by mouth (oral route).

The maximum dose in 24 hours is 0.5 mg/kg body weight.

Dosing table







Device / instruction for use

You should not take this medicine for more than 5 days to prevent delayed nausea and vomiting that may occur after chemotherapy. For tablets/capsules/granules Appropriate additional information regarding posologies adaptation should be implemented in the SmPC depending on the strength of the formulations

For formulations which cannot be used to administer a 5mg dose {Tradename} is not suitable for use in children weighing less than 61 kg. Other pharmaceutical forms/strengths may be more appropriate for administration. For formulations which can be used to administer a 5mg dose {Tradename} is not suitable for use in children weighing less than 30 kg. Other pharmaceutical forms/strengths may be more appropriate for administration.

61

Rectal route


The recommended single dose is 10 mg, repeated up to 3 times daily. The maximum recommended dose per day is 30 mg or 0.5mg/kg body weight. The maximum recommended treatment duration is 5 days. All routes of administration

Method of administration

For immediate release oral formulations You must wait at least 6 hours between each metoclopramide dose, even in case of vomiting and rejection of the dose, in order to avoid overdose. For 15mg prolonged release oral formulations You must wait at least 12 hours between each metoclopramide dose, even in case of vomiting and rejection of the dose, in order to avoid overdose. For 30mg prolonged release oral formulations You must wait at least 24 hours between each metoclopramide dose, even in case of vomiting and rejection of the dose, in order to avoid overdose.


Older people The dose may need to be reduced depending on kidney problems, liver problems and overall health. Appropriate additional information regarding posologies adaptation should be implemented in the PIL depending on the formulations:

<Other pharmaceutical forms/strengths may be more appropriate for administration> <This formulation is not suitable for administration> Adults with kidney problems Talk to your doctor if you have kidney problems. The dose should be reduced if you have moderate or severe kidney problems. Appropriate additional information regarding posologies adaptation should be implemented in the PIL depending on the formulations:

<Other pharmaceutical forms/strengths may be more appropriate for administration> <This formulation is not suitable for administration> Adults with liver problems Talk to your doctor if you have liver problems. The dose should be reduced if you have severe liver problems.

Appropriate additional information regarding posologies adaptation should be implemented in the PIL depending on the formulations:

<Other pharmaceutical forms/strengths may be more appropriate for administration> <This formulation is not suitable for administration> Children and adolescents Metoclopramide must not be used in children aged less than 1 year (see section 2).

For all routes of administration

If you take more {Tradename} than you should

62

Contact your doctor or pharmacist straight away. You may experience uncontrollable movements (extrapyramidal disorders), feel drowsy, have some troubles of consciousness, be confused, have hallucination and heart problems. You doctor may prescribe you a treatment for these signs if necessary. For all routes of administration

If you forget to take {Tradename} Do not take a double dose to make up for a forgotten dose. If you have any further questions on the use of this medicine, ask your doctor, nurse or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. For all formulations

Stop the treatment and talk straight away to your doctor, pharmacist or nurse if you experience one of the following signs while having this medicine: - uncontrollable movements (often involving head or neck). These may occur in children or young

adults and particularly when high doses are used. These signs usually occur at the beginning of treatment and may even occur after one single administration. These movements will stop when when treated appropriately.

- high fever, high blood pressure, convulsions, sweating, production of saliva. These may be signs of a condition called neuroleptic malignant syndrome.

- Itching or skin rashes, swelling of the face, lips or throat, difficulty in breathing. These may be signs of an allergic reaction, which may be severe.

Very common (may affect more than 1 in 10 people) • feeling drowsy.

Common (may affect up to 1 in 10 people) • depression • uncontrollable movements such as tics, shaking, twisting movements or muscle contracture

(stiffness, rigidity) • symptoms similar to Parkinson disease (rigidity, tremor) • feel restless • blood pressure decrease (particularly with intravenous route) • diarrhoea • feeling weak. Uncommon (may affect up to 1 in 100 people) • raised levels of a hormone called prolactin in the blood which may cause: milk production in men,

and women who are not breast-feeding • irregular periods • hallucination • decreased level of consciousness • slow heartbeat (particularly with intravenous route) • allergy Rare (may affect up to 1 in 1,000 people) • confusional state • convulsion (especially in patients with epilepsy). Not known (frequency cannot be estimated from the available data) • abnormal blood pigment levels: which may change the colour of your skin • abnormal development of breasts (gynaecomastia) • involuntary muscle spasms after prolonged use, particularly in elderly patients • high fever, high blood pressure, convulsions, sweating, production of saliva. These may be signs

of a condition called neuroleptic malignant syndrome • changes in heart beat, which may be shown on an ECG test

63

• cardiac arrest (particularly with injection route) • shock (severe decrease of heart pressure) (particularly with injection route) • fainting (particularly with intravenous route) • allergic reaction which may be severe (particularly with intravenous route) • very high blood pressure. If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any side effects not listed in this leaflet.

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Documents

Annex I List of the names, pharmaceutical form(s ......Germany betapharm Arzneimittel GmbH Kobelweg 95 D-86156 Augsburg Germany MCP-beta Tropfen 4.21mg/ml Oral solution Oral use Germany