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Co-ordination group for Human Use EMA/H/A-31/1347 EMA/CMDh/559693/2013 Agreement of the Co-ordination group for mutual recognition and decentralised procedures for human use, pursuant to article 107k (1) and (2) of directive 2001/83/EC, for Medicinal products Names: International non-proprietary name: Pharmaceutical forms: Strengths: Routes of administration: see Annex I terbutaline, salbutamol, hexoprenaline, ritodrine, fenoterol, isoxsuprine see Annex I see Annex I see Annex I Basis for Agreement Pursuant to Article 31 of Directive 2001/83/EC resulting from the evaluation of data relating to pharmacovigilance of an authorised medicinal product, Hungary initiated a procedure on 27 November 2012. The notification for the procedure is appended to this Agreement. The procedure started on 29 November 2012. The steps taken for the assessment of the referred matter are detailed in the PRAC assessment report appended to this Agreement. The recommendation was adopted by the PRAC on 5 September 2013 and is appended to this Agreement. The CMDh has considered the PRAC recommendation in accordance with Article 107k(1) of Directive 2001/83/EC. Agreement 1. Pursuant to Article 107k(1) and (2) of Directive 2001/83/EC, the CMDh, having considered the matter and the appended PRAC recommendation, is of the opinion by consensus that the marketing authorisations should be varied or revoked, as applicable. The variation to the terms of the marketing authorisations or the revocation, as applicable applies to the medicinal products referred to in Annex I. Agreement of the Co-ordination group for mutual recognition and decentralised procedures for human use, pursuant to article 107k (1) and (2) of directive 2001/83/EC, for EMA/CMDh/559693/2013 Page 1 2. The scientific conclusions and grounds for variation to the terms of the marketing authorisations or the revocation, as applicable are set out in the Annex II. 3. The relevant sections of the summary of product characteristics and package leaflet are set out in Annex III. 4. The conditions affecting the marketing authorisations are set out in Annex IV. 5. The timetable for the implementation of the CMDh agreement is set out in Annex V. To the extent that other medicinal products containing terbutaline, salbutamol, hexoprenaline, ritodrine, fenoterol, isoxsuprine not included in Annex I are currently authorised in the EU, or are subject to future authorisation procedures by the Member States, the CMDh recommends that the Member States concerned take due consideration of the scientific conclusions in Annex II. This agreement is forwarded to the Member States, to Iceland and Norway and to the marketing authorisation holders for the above mentioned medicinal product, together with its annexes and appendices. London, 23 October 2013 On behalf of the CMDh Dr Peter Bachmann, Chair Agreement of the Co-ordination group for mutual recognition and decentralised procedures for human use, pursuant to article 107k (1) and (2) of directive 2001/83/EC, for EMA/CMDh/559693/2013 Page 2 Annex I List of the names, pharmaceutical forms, strengths of the medicinal products, routes of administration, marketing authorisation holders in the Member States Agreement of the Co-ordination group for mutual recognition and decentralised procedures for human use, pursuant to article 107k (1) and (2) of directive 2001/83/EC, for EMA/CMDh/559693/2013 Page 3 Member State Marketing authorisation (in EEA) holder Belgium SCS Boehringer Ingelheim SA INN fenoterol Avenue Ariane 16 Invented name BEROTEC Strengths 0.5mg/10ml 0,5MG/10 ML Pharmaceutic Routes of al forms administration Solution for Intravenous use injection B-1200 Woluwe-SaintLambert Belgium Germany Boehringer Ingelheim Pharma fenoterol GmbH & Co. KG Partusisten 0.025mg/ml intrapartal Concentrate for Intravenous use solution for Binger Str. 173 injection 55216 Ingelheim Germany Germany Boehringer Ingelheim Pharma fenoterol Partusisten 0.5mg/10ml Concentrate for GmbH & Co. KG solution for Binger Str. 173 infusion Intravenous use 55216 Ingelheim Germany Germany Boehringer Ingelheim Pharma fenoterol Partusisten 5mg Tablet Oral use GmbH & Co. KG Binger Str. 173 55216 Ingelheim Germany Agreement of the Co-ordination group for mutual recognition and decentralised procedures for human use, pursuant to article 107k (1) and (2) of directive 2001/83/EC, for EMA/CMDh/559693/2013 Page 4 Member State Marketing authorisation (in EEA) holder Poland Teva Pharmaceuticals Polska INN fenoterol Invented name Fenoterol Teva Strengths 0.05mg/ml Sp. z o.o. Pharmaceutic Routes of al forms administration Solution for Intravenous use injection ul. Emilii Plater 53 00-113 Warszawa Poland Poland GlaxoSmithKline fenoterol Fenoterol GSK 5mg Tablet Oral use fenoterol Partusisten, 0.05mg/ml Concentrate for Intravenous use Pharmaceuticals S.A. ul. Grunwaldzka 189 60-322 Poznań Poland The Boehringer Ingelheim B.V. Netherlands Comeniusstraat 6 concentraat voor solution for 1817 MS Alkmaar oplossing voor infusion The Netherlands intraveneuze infusie 50 microgram/ml Member State Marketing authorisation (in EEA) holder Austria Takeda Austria GmbH INN hexoprenaline Invented name Strengths Pharmaceutical Routes of forms administration Intravenous use Gynipral 25 μg - 0.025mg/5m Concentrate for St.-Peter-Straße 25 Konzentrat zur l solution for A -4020 Linz Infusionsbereitun Austria g Agreement of the Co-ordination group for mutual recognition and decentralised procedures for human use, pursuant to article 107k (1) and (2) of directive 2001/83/EC, for EMA/CMDh/559693/2013 infusion Page 5 Member State Marketing authorisation (in EEA) holder Austria Takeda Austria GmbH INN hexoprenaline St.-Peter-Straße 25 Invented name Gynipral 10 μg / Strengths 0.01mg/2ml 2 ml - Ampullen Pharmaceutical Routes of forms administration Solution for Intravenous use injection/infusion A -4020 Linz Austria Bulgaria NYCOMED Austria GmbH hexoprenaline Gynipral 0.005mg/ml St.-Peter-Straße 25 Solution for Intravenous use injection A -4020 Linz Austria Bulgaria NYCOMED Austria GmbH hexoprenaline Gynipral 0.5mg Tablet Oral use hexoprenaline GYNIPRAL 0,5 0.5mg Tablet Oral use 0.005mg/ml Solution for Intravenous use St.-Peter-Straße 25 A -4020 Linz Austria Czech Republic Takeda Austria GmbH St.-Peter-Straße 25 MG A -4020 Linz Austria Czech Republic Takeda Austria GmbH hexoprenaline St.-Peter-Straße 25 GYNIPRAL 10 MCG/2 ML injection/infusion A -4020 Linz Austria Czech Republic Takeda Austria GmbH hexoprenaline GYNIPRAL 25 0.025mg/5m Concentrate for St.-Peter-Straße 25 MCG l solution for A -4020 Linz KONCENTRÁT Austria PRO PŘÍPRAVU Intravenous use infusion INFÚZE Agreement of the Co-ordination group for mutual recognition and decentralised procedures for human use, pursuant to article 107k (1) and (2) of directive 2001/83/EC, for EMA/CMDh/559693/2013 Page 6 Member State Marketing authorisation (in EEA) holder Estonia NYCOMED Austria GmbH INN Invented name Strengths Pharmaceutical Routes of forms administration hexoprenaline GYNIPRAL 0.5mg Tablet Oral use hexoprenaline Gynipral 0.5mg Tablet Oral use hexoprenaline Gynipral 0.025mg/5m Concentrate for Intravenous use l solution for St.-Peter-Straße 25 A -4020 Linz Austria Lithuania NYCOMED Austria GmbH St.-Peter-Straße 25 A -4020 Linz Austria Lithuania NYCOMED Austria GmbH St.-Peter-Straße 25 A -4020 Linz injection /infusion Austria Lithuania NYCOMED Austria GmbH hexoprenaline Gynipral 0.01mg/2ml St.-Peter-Straße 25 Solution for Intravenous use injection/infusion A -4020 Linz Austria Romania NYCOMED Austria GmbH hexoprenaline St.-Peter-Straße 25 GYNIPRAL 0,5 0.5mg Tablet Oral use 0.01mg/2ml Solution for Parenteral use mg, A -4020 Linz Austria Romania NYCOMED Austria GmbH St.-Peter-Straße 25 hexoprenaline GYNIPRAL 10 μg/2 ml injection A -4020 Linz Austria Agreement of the Co-ordination group for mutual recognition and decentralised procedures for human use, pursuant to article 107k (1) and (2) of directive 2001/83/EC, for EMA/CMDh/559693/2013 Page 7 Member Marketing authorisation State (in holder INN Invented name Strengths Pharmaceutical Routes of forms administration Solution for injection Intramuscular use, EEA) Italy Istituto Luso Farmaco d'Italia isoxsuprine VASOSUPRINA ILFI 10mg/2ml SpA intravenous use Via W. Tobagi 8 20068 Peschiera Borromeo (MI) Italy Italy Istituto Luso Farmaco d'Italia isoxsuprine SpA VASOSUPRINA 30mg RETARD Modified-release Oral use tablet Via W. Tobagi 8 20068 Peschiera Borromeo (MI) Italy Portugal Tecnifar - Indústria Técnica isoxsuprine Dilum Retard 30mg Farmacêutica, S.A. Prolonged-release Oral use tablet Rua Tierno Galvan Amoreiras Torre 3 - 12, 1099-036 Portugal Agreement of the Co-ordination group for mutual recognition and decentralised procedures for human use, pursuant to article 107k (1) and (2) of directive 2001/83/EC, for EMA/CMDh/559693/2013 Page 8 Member Marketing authorisation State (in holder INN Invented name Strengths Pharmaceutical Routes of forms administration EEA) Belgium EUMEDICA N.V. ritodrine PRE-PAR 10 MG 10mg Tablet Oral use ritodrine PRE-PAR 50MG/5ML 50mg/5ml Solution for Intravenous use Av. Winston Churchill 67 B-1180 Bruxelles Belgium Belgium EUMEDICA N.V. Av. Winston Churchill 67 injection B-1180 Bruxelles Belgium Greece Galenica SA ritodrine YUTOPAR 10mg Tablet Oral use ritodrine YUTOPAR 50mg/5ml Solution for Intravenous use; Injection Intramuscular use Solution for Intramuscular use 4, Eleftherias Street Kifisia 14564 Greece Greece Galenica SA 4, Eleftherias Street Kifisia 14564 Greece Italy Istituto Luso Farmaco d'Italia SpA ritodrine MIOLENE 10mg/2ml Injection Via W. Tobagi 8 20068 Peschiera Borromeo (MI) Italy Agreement of the Co-ordination group for mutual recognition and decentralised procedures for human use, pursuant to article 107k (1) and (2) of directive 2001/83/EC, for EMA/CMDh/559693/2013 Page 9 Member Marketing authorisation State (in holder INN Invented name Strengths Pharmaceutical Routes of forms administration EEA) Italy Istituto Luso Farmaco ritodrine MIOLENE 10mg Tablet Oral use ritodrine MIOLENE 50mg/5ml Solution for Intravenous use d'Italia SpA Via W. Tobagi 8 20068 Peschiera Borromeo (MI) Italy Italy Istituto Luso Farmaco d'Italia SpA infusion Via W. Tobagi 8 20068 Peschiera Borromeo (MI) Italy Luxembourg Eumedica S.A. ritodrine Pre-Par comprimés 10mg Tablet Intravenous use ritodrine Pre-Par solution 50mg/5ml Solution for Intravenous use Av. Winston Churchill 67 B-1180 Bruxelles Belgium Luxembourg Eumedica S.A. Av. Winston Churchill 67 injectable injection/infusion B-1180 Bruxelles Belgium Spain Laboratorio Reig Jofre SA. Gran Capita 10 ritodrine PRE-PAR AMPOLLAS 10mg/ml Solution for Intravenous use; injection Intramuscular use Sant Joan Despi Barcelona 08970 Spain Agreement of the Co-ordination group for mutual recognition and decentralised procedures for human use, pursuant to article 107k (1) and (2) of directive 2001/83/EC, for EMA/CMDh/559693/2013 Page 10 Member Marketing authorisation State (in holder INN Invented name Strengths Pharmaceutical Routes of forms administration Tablet Oral use EEA) Spain Laboratorio Reig Jofre SA. ritodrine Gran Capita 10 PRE-PAR 10 mg 10mg COMPRIMIDOS Sant Joan Despi Barcelona 08970 Spain Member Marketing authorisation State (in holder INN Invented name Strengths Pharmaceutical Routes of forms administration Solution for Intravenous use EEA) Belgium GlaxoSmithKline salbutamol Pharmaceuticals S.A./N.V. VENTOLIN POUR 5mg PERFUSION I.V. injection Site Apollo, 2-4-6 B-1300 Wavre Belgium Belgium GlaxoSmithKline salbutamol VENTOLIN I.M.-S.C. 0.5mg Pharmaceuticals S.A./N.V. Solution for Intramuscular use, injection Subcutaneous use Oral solution Oral use Site Apollo, 2-4-6 B-1300 Wavre Belgium Belgium GlaxoSmithKline salbutamol VENTOLIN 4MG 4mg Pharmaceuticals S.A./N.V. Site Apollo, 2-4-6 B-1300 Wavre Belgium Agreement of the Co-ordination group for mutual recognition and decentralised procedures for human use, pursuant to article 107k (1) and (2) of directive 2001/83/EC, for EMA/CMDh/559693/2013 Page 11 Member Marketing authorisation State (in holder INN Invented name Strengths Pharmaceutical Routes of forms administration EEA) Belgium GlaxoSmithKline salbutamol VENTOLIN 2 MG 2mg Oral solution Oral use salbutamol SALBUTAMOL 4mg Tablet Oral use 0.5mg/ml Solution for Intramuscular use, injection Subcutaneous use Concentrate for Intravenous use Pharmaceuticals S.A./N.V. Site Apollo, 2-4-6 B-1300 Wavre Belgium Cyprus Remedica Ltd Aharnon Street tablets 4 mg Industrial Estate 3508 Lemesos Cyprus Denmark GlaxoSmithKline Pharma salbutamol Ventoline A/S Nykær 68 DK-2605 Brøndby Denmark Denmark GlaxoSmithKline Pharma salbutamol Ventoline 1mg/ml A/S infusion Nykær 68 DK-2605 Brøndby Denmark France Laboratoire salbutamol SALBUMOL GlaxoSmithKline 0,5 mg/1 ml, 100, route de Versailles solution for 78163 Marly-le-Roi Cedex injection 0.5mg/ml Solution for Intravenous use, injection Intramuscular use, Subcutaneous use France Agreement of the Co-ordination group for mutual recognition and decentralised procedures for human use, pursuant to article 107k (1) and (2) of directive 2001/83/EC, for EMA/CMDh/559693/2013 Page 12 Member Marketing authorisation State (in holder INN Invented name Pharmaceutical Routes of forms administration 1mg Suppository Rectal use 2mg Tablet Oral use 5mg/5ml Solution for Intravenous use Strengths EEA) France Laboratoire salbutamol GlaxoSmithKline SALBUMOL 1 mg, suppository 100, route de Versailles 78163 Marly-le-Roi Cedex France France Laboratoire salbutamol GlaxoSmithKline SALBUMOL 2 mg tablet 100, route de Versailles 78163 Marly-le-Roi Cedex France France Laboratoire salbutamol SALBUMOL FORT GlaxoSmithKline 5 mg / 5 ml 100, route de Versailles solution for infusion infusion 78163 Marly-le-Roi Cedex France France MYLAN SAS salbutamol SALBUTAMOL 117, allée des Parcs MYLAN 5 mg/5 ml, 69800 Saint-Priest solution for infusion 5mg/5ml Solution for Intravenous use infusion France France Laboratoire Renaudin salbutamol SALBUTAMOL Z A. Errobi RENAUDIN 5 mg/5 Itxassou ml, 64250 Cambo les Bains Solution for infusion 5mg/5ml Solution for Intravenous use infusion France Agreement of the Co-ordination group for mutual recognition and decentralised procedures for human use, pursuant to article 107k (1) and (2) of directive 2001/83/EC, for EMA/CMDh/559693/2013 Page 13 Member Marketing authorisation State (in holder INN Invented name Strengths Pharmaceutical Routes of forms administration Solution for Subcutaneous, Injection intramuscular, EEA) Ireland GlaxoSmithKline (Ireland) salbutamol Ventolin 500 Limited micrograms/ml Stonemasons Way Solution for Rathfarnham Injection 0.5mg/ml intravenous Dublin 16 Ireland Ireland GlaxoSmithKline (Ireland) salbutamol Ventolin 1mg/ml 1mg/ml Concentrate for Limited Concentrate for solution for Stonemasons Way Solution for intravenous Rathfarnham Intravenous infusion Dublin 16 Infusion Intravenous use Ireland Lithuania Warszawskie Zakłady salbutamol Farmaceutyczne Polfa S.A. SALBUTAMOL WZF 2mg Tablet Oral use 4mg Tablet Oral use 2mg Tablet Oral use Polfa ul. Karolkowa 22/24 01-207 Warszawa Poland Lithuania Warszawskie Zakłady salbutamol Farmaceutyczne Polfa S.A. SALBUTAMOL WZF Polfa ul. Karolkowa 22/24 01-207 Warszawa Poland Luxembourg GlaxoSmithKline salbutamol Ventolin comprimés Pharmaceuticals S.A./N.V. Site Apollo, 2-4-6 B-1300 wavre Belgium Agreement of the Co-ordination group for mutual recognition and decentralised procedures for human use, pursuant to article 107k (1) and (2) of directive 2001/83/EC, for EMA/CMDh/559693/2013 Page 14 Member Marketing authorisation State (in holder INN Invented name Strengths Pharmaceutical Routes of forms administration EEA) Luxembourg GlaxoSmithKline salbutamol Ventolin comprimés 4mg Tablet Oral use salbutamol Ventolin solution 0.5mg/ml Solution for Intravenous use Pharmaceuticals S.A./N.V. Site Apollo, 2-4-6 B-1300 wavre Belgium Luxembourg GlaxoSmithKline Pharmaceuticals S.A./N.V. injectable injection Site Apollo, 2-4-6 B-1300 wavre Belgium Luxembourg GlaxoSmithKline salbutamol Ventolin solution à Pharmaceuticals S.A./N.V. diluer pour Site Apollo, 2-4-6 perfusion 5mg/5ml Solution for Intravenous use injection B-1300 wavre Belgium Poland Warszawskie Zakłady salbutamol Salbutamol WZF 0.5mg/ml Farmaceutyczne Polfa S.A. Solution for Intravenous use, Injection Intramuscular use, ul. Karolkowa 22/24 Subcutaneous use 01-207 Warszawa Poland Poland Warszawskie Zakłady salbutamol Salbutamol WZF 2mg Tablet Oral use Farmaceutyczne Polfa S.A. ul. Karolkowa 22/24 01-207 Warszawa Poland Agreement of the Co-ordination group for mutual recognition and decentralised procedures for human use, pursuant to article 107k (1) and (2) of directive 2001/83/EC, for EMA/CMDh/559693/2013 Page 15 Member Marketing authorisation State (in holder INN Invented name Strengths Pharmaceutical Routes of forms administration EEA) Poland Warszawskie Zakłady salbutamol Salbutamol WZF 4mg Tablet Oral use salbutamol ventilan 4mg Tablet Oral use salbutamol ventilan 5mg/5ml Solution for Intravenous use Farmaceutyczne Polfa S.A. ul. Karolkowa 22/24 01-207 Warszawa Poland Portugal Glaxo Wellcome Farmacêutica, Lda. Rua Dr. António Loureiro Borges, 3 - Arquiparque Miraflores 1495-131 Algés, Lisbon Portugal Portugal Glaxo Wellcome Farmacêutica, Lda. infusion Rua Dr. António Loureiro Borges, 3 - Arquiparque Miraflores 1495-131 Algés, Lisbon Portugal Portugal Glaxo Wellcome salbutamol ventilan 0.5mg/ml Farmacêutica, Lda. Rua Dr. António Loureiro Solution for Intravenous use, Injection Subcutaneous use Intramuscular use Borges, 3 - Arquiparque Miraflores 1495-131 Algés, Lisbon Portugal Agreement of the Co-ordination group for mutual recognition and decentralised procedures for human use, pursuant to article 107k (1) and (2) of directive 2001/83/EC, for EMA/CMDh/559693/2013 Page 16 Member Marketing authorisation State (in holder INN Invented name Strengths Pharmaceutical Routes of forms administration Solution for Parenteral use EEA) Romania GLAXO WELLCOME UK salbutamol VENTOLIN®, Limited soluţie injectabilă, Glaxo Wellcome House 0,5 mg/ml 0.5mg/ml injection Berkeley Avenue Greenford Middlesex UB6 0NN United Kingdom Slovak Warszawskie Zakłady Republic Farmaceutyczne Polfa S.A. salbutamol Salbutamol WZF 2mg Tablet Oral use 4mg Tablet Oral use 2mg Tablet Oral use 2mg Tablet Oral use Polfa 2 mg ul. Karolkowa 22/24 01-207 Warszawa Poland Slovak Warszawskie Zakłady Republic Farmaceutyczne Polfa S.A. salbutamol Salbutamol WZF Polfa 4 mg ul. Karolkowa 22/24 01-207 Warszawa Poland Slovenia GSK d.o.o. salbutamol Cvetkova ulica 29 Ventolin 2 mg tablete 1000 Ljubljana Slovenija United Actavis UK Limited Kingdom Whiddon Valley salbutamol Salbutamol Tablets BP 2mg Barnstaple North Devon EX32 8NS United Kingdom Agreement of the Co-ordination group for mutual recognition and decentralised procedures for human use, pursuant to article 107k (1) and (2) of directive 2001/83/EC, for EMA/CMDh/559693/2013 Page 17 Member Marketing authorisation State (in holder INN Invented name Pharmaceutical Routes of forms administration 4mg Tablet Oral use 2mg Tablet Oral use 4mg Tablet Oral use 1mg/ml Solution for Intravenous use, injection Subcutaneous use Strengths EEA) United Actavis UK Limited Kingdom Whiddon Valley salbutamol Salbutamol Tablets BP 4mg Barnstaple North Devon EX32 8NS United Kingdom salbutamol United Teva UK Limited Asmaven 2 / Kingdom Bampton Road Salbutamol Tablets Hampden Park BP 2mg Eastbourne East Sussex BN22 9AG United Kingdom salbutamol United Teva UK Limited Asmaven 4 / Kingdom Bampton Road Salbutamol Tablets Hampden Park BP 4mg Eastbourne East Sussex BN22 9AG United Kingdom salbutamol United Glaxo Wellcome UK Kingdom Limited Ventolin Solution for Intravenous Stockley Park West Infusion Uxbridge Middlesex UB11 1BT United Kingdom Agreement of the Co-ordination group for mutual recognition and decentralised procedures for human use, pursuant to article 107k (1) and (2) of directive 2001/83/EC, for EMA/CMDh/559693/2013 Page 18 Member Marketing State authorisation holder INN Invented name Strengths Pharmaceutical Routes of forms administration Solution for injection Subcutaneous use, (in EEA) Austria AstraZeneca Österreich terbutaline GmbH Bricanyl 0,5 mg - 0.5mg/ml Ampullen Intravenous use Schwarzenbergplatz 7 A-1037 Vienna Austria Cyprus Medochemie Ltd terbutaline 1-10 Constantinoupoleos ATALINE tablets 2.5mg Tablet Oral use 1.5mg/5ml Syrup Oral use 0.5mg/ml Solution for injection Intravenous use, 2.5 mg Street 3505 Lemesos Cyprus Cyprus Medochemie Ltd terbutaline 1-10 Constantinoupoleos ATALINE syrup 1.5 mg/5ml Street 3505 Lemesos Cyprus France AstraZeneca terbutaline BRICANYL 0.5 1, place Renault mg/1 ml 92844 Rueil Malmaison Solution for Cedex injection Subcutaneous use France Hungary AstraZeneca Kft. Bocskai út 134-146. terbutaline Bricanyl 0,5 mg/ml oldatos injekció 0.5mg/ml Solution for injection Intravenous use or infusion Budapest 1113 Hungary Agreement of the Co-ordination group for mutual recognition and decentralised procedures for human use, pursuant to article 107k (1) and (2) of directive 2001/83/EC, for EMA/CMDh/559693/2013 Page 19 Member Marketing State authorisation holder INN Invented name Strengths Pharmaceutical Routes of forms administration Solution for injection Subcutaneous, or infusion intramuscular, (in EEA) Ireland AstraZeneca UK Limited terbutaline 600 Capability Green micrograms/ml Luton, LU1 3LU solution for United Kingdom Norway Bricanyl 500 AstraZeneca AS 0.5mg/ml intravenous injection or infusion terbutaline Bricanyl 0.5mg/ml Solution for injection Parenteral use terbutaline Bricanyl 0.3mg/ml Oral solution Oral use terbutaline Bricanyl 5mg Film- coated tablet Oral use terbutaline Bricanyl Depot 7.5mg Prolonged- release Oral use Innspurten 15 0663 Oslo Norway Norway AstraZeneca AS Innspurten 15 0663 Oslo Norway Norway AstraZeneca AS Innspurten 15 0663 Oslo Norway Norway AstraZeneca AS Innspurten 15 tablet 0663 Oslo Norway Sweden Sweden AstraZeneca AB terbutaline Bricanyl® 0.5mg/ml Solution for injection SE - 151 85 Södertälje Concentrate for Sweden solution for injection AstraZeneca AB terbutaline Bricanyl® 0.3mg/ml Oral solution Intravenous use Oral use SE - 151 85 Södertälje Sweden Agreement of the Co-ordination group for mutual recognition and decentralised procedures for human use, pursuant to article 107k (1) and (2) of directive 2001/83/EC, for EMA/CMDh/559693/2013 Page 20 Member Marketing State authorisation holder INN Invented name Strengths Pharmaceutical Routes of forms administration Solution for injection Intravenous use, (in EEA) terbutaline United AstraZeneca UK Limited Bricanyl Injection 0.5mg/ml Kingdom 600 Capability Green Intramuscular use, Luton, LU1 3LU Subcutaneous use United Kingdom United AstraZeneca UK Limited Kingdom 600 Capability Green terbutaline Bricanyl Tablets 5mg Tablet Oral use 0.3mg/ml Oral solution Oral use 5mg Luton, LU1 3LU United Kingdom United AstraZeneca UK Limited Kingdom 600 Capability Green terbutaline Bricanyl Syrup Luton, LU1 3LU United Kingdom Agreement of the Co-ordination group for mutual recognition and decentralised procedures for human use, pursuant to article 107k (1) and (2) of directive 2001/83/EC, for EMA/CMDh/559693/2013 Page 21 Annex II Scientific conclusions and grounds for revocation or variation as applicable to the terms of the marketing authorisations and detailed explanation for the differences from the PRAC recommendation EMA/CMDh/559693/2013 Page 22 Scientific conclusions and grounds for revocation or variation as applicable to the terms of the marketing authorisations and detailed explanation for the differences from the PRAC recommendation The CMDh considered the below PRAC recommendation dated 5 September 2013 with regards to the terbutaline, salbutamol, hexoprenaline, ritodrine, fenoterol and isoxsuprine containing medicinal products: 1. Overall summary of the scientific evaluation of terbutaline, salbutamol, hexoprenaline, ritodrine, fenoterol and isoxsuprine containing medicinal products by PRAC (see Annex I) On 27 November 2012, further to evaluation of data resulting from pharmacovigilance activities, Hungary informed the European Medicines Agency, pursuant to Article 31 of Directive 2001/83/EC, of their consideration that the risk-benefit balance of short-acting beta-agonists (SABAs) containing medicinal products authorised in obstetric indications has become unfavourable, taking into account the cardiovascular events reported. Hungary considered it was in the interest of the Union to refer the matter to the PRAC and expressed concerns with regards to the posology and warnings reflected in the product information. The short-acting beta-agonists (SABAs) (also known as beta-mimetics), salbutamol, terbutaline, fenoterol, ritodrine, hexoprenaline and isoxsuprine are all nationally authorised and have been on the market within the EU since the 1960s. Authorised obstetric indications for SABAs differ across Member States. The authorised obstetric indications include partus prematurus, tocolysis (for some products use is restricted to particular weeks of gestation but for others no specific gestation period is specified), external cephalic version (ECV), and hyper-uterine contractility. Fenoterol also contains descriptions of emergency uses in the indications such as dystocias in the dilation and expulsion stages of labour (such as uterine hyperactivity or spasm occurring either spontaneously or as a result of mechanical obstruction or over stimulation by oxytocic agents); intrauterine asphyxia (as indicated by signs such as foetal heart rate decelerations or incipient to moderate foetal acidosis); obstetric emergencies (such as cord prolapse or imminent uterine rupture); uterine relaxation in acute indications such as caesarean section. Isoxsuprine and hexoprenaline tablets also have ‘threatened abortion’ within the indications and a posology for prophylaxis of labour. Both formulations of hexoprenaline are also indicated for immobilisation of the uterus pre, during and post cerclage surgery. During this review, data from clinical studies, post-marketing reporting and published literature, including relevant treatment guidelines, have been assessed. Oral, parenteral and suppositories formulations have been included in this assessment. There are no formulations for inhalation authorised in obstetric indications. Safety Previous safety reviews have highlighted the risk of myocardial ischaemia associated with the use of SABAs in obstetric indications and that these products should be used with caution in tocolysis, and other obstetric indications. This review by PRAC assessed all existing data in terms of safety of EMA/CMDh/559693/2013 Page 23 cardiovascular events when in use in these indications and the outcome of the review is summarised below. Salbutamol The review of all cardiovascular events for salbutamol showed this medicinal product can induce serious cardiovascular adverse events, which can result in the death of the mother and/or foetus. A total of 98 reports which included cardiovascular events were identified, the majority of which were cardiac arrhythmias, such as, tachycardia or palpitations. Two of the reports of tachycardia developed further and were fatal. There were a number of reports of pulmonary oedema contributing to the events and one case reported pulmonary oedema in association with cardiomegaly, after taking a course of tablets for five weeks, when tocolysis failed. Two cases of tocolysis maintained with suppositories only were also reported to develop pulmonary oedema. The PRAC noted eight infant fatalities, two of which were in association with pulmonary oedema and cardiovascular events. Many of these reports occurred in association with both salbutamol intravenous (i.v.) and oral salbutamol; it would appear that this adverse event is not specific to a particular formulation. Fenoterol A review of safety data for fenoteral showed that the cardiovascular events tachycardia and palpitations were frequently reported in clinical studies and are listed as very common side effects of the drug. In 10 clinical studies comprising 425 pregnant women, angina pectoris and arrhythmia were reported only in one case each. Myocardial infarction or serious arrhythmias were not reported in the clinical trial reports available to the MAH. Approximately 9% of the 425 women in these trials were exposed to the oral formulation and approximately 2% of the reported adverse events were associated with the oral formulation of the drug. Tachycardia, palpitations, and changes of blood pressure accounted for about 2/3 of the adverse events associated with the oral formulation. Terbutaline Safety data from MAH clinical trials and meta-analyses of well-designed clinical trials have been assessed. However these data only gave limited safety information. Hibbard (1996) performed a casecontrol study to investigate whether there is an association between long-term oral terbutaline use and peripartum cardiomyopathy. Four patients with no pre-existing cardiac pathology developed peripartum cardiomyopathy while on prolonged oral terbutaline for various treatment durations (9.5-53 days). Even after correction of potentially confounding variables, the relationship remained significant between long-term oral terbutaline therapy for preterm labour and subsequent peripartum cardiomyopathy. Published studies deliver conflicting results and interpretations on the safety of terbutaline (and beta agonists) in tocolysis. Occurrence of typical adverse effects characteristic of beta receptor stimulation are well documented, and range from mild and transient discomfort to serious cardiovascular side effects requiring prompt medical intervention, e.g. in case of arrhythmias or pulmonary oedema. There is hardly any evidence of maternal death in these studies and very limited data on adverse foetal outcomes (e.g. tachycardia, hyperinsulinaemia). Eight cases of neonatal/foetal death including abortions have been identified by the MAH. Information on fatal foetal or neonatal conditions was not sufficient to draw any conclusions on the association with intrauterine exposure to terbutaline. Furthermore, premature delivery is an established risk factor of neonatal morbidity and mortality. Regardless of this, 18 serious cardiovascular cases have been identified in EudraVigilance showing that, not only predisposed, but also otherwise healthy subjects have developed serious cardiovascular EMA/CMDh/559693/2013 Page 24 complications. This again highlights the importance of close medical surveillance during therapy, and questions the safety of outpatient tocolysis with terbutaline. Ritodrine The use of ritodrine is associated with risks of major cardiac and pulmonary dysfunction (rarely myocardial infarction), alteration in glycaemia and blood potassium concentration, gastro-intestinal disorders, tremors, headache and erythema. More rarely, cases of anxiety, dizziness, blood dyscrasias, rhabdomyolysis, severe cutaneous adverse reactions (SCARs), and anaphylactic shock have been described. The seriousness of AEs seems to be directly related to the dose of ritodrine administered to the patient, but also to the treatment duration as most of life-threatening AEs occurred after prolonged ritodrine administration (>72h to months). During the period 2002-2012, a total of 210 cases including at least one adverse event after ritodrine treatment were reported. These cases of adverse events under ritodrine therapy included both welldocumented case reports from the literature and cases recorded by the MAH from spontaneous reporting from healthcare personnel or Health Authorities. With the exception of reports on rhabdomyolysis and SCARs, the cases were mostly in accordance with the known safety profile of ritodrine. Hexoprenaline According to the published studies intravenous administration of hexoprenaline is very commonly accompanied with occurrence of adverse drug reactions. Maternal tachycardia is the most commonly reported adverse reaction following intravenous hexoprenaline administration. Maternal hypotension, palpitations, tremor, flush, sweating, headache and nausea also occurred commonly. More serious adverse drug reactions have been recorded individually – chest pain, dyspnoea, ileus, loss of consciousness, arrhythmia and also several case reports of pulmonary oedema (four in a publication by Van Iddekinge et al., 1991, one in the EV database, four in the PSUR) have been reported. In contrast to other SABAs, no maternal fatality and no case of myocardial infarction have been reported following hexoprenaline administration for tocolysis. For oral hexoprenaline there are very few safety data. One case report of uterine haemorrhage exists however it is confounded by concomitant uterine pathology. Isoxsuprine Post-marketing data were summarised for isoxsuprine from 2000 to 2013; no serious AEs were reported for the i.v. product, and three non-serious events were reported. For the oral tablet, three serious AEs were reported (loss of consciousness, trismus and a serious skin reaction), and six nonserious AEs for the tablet. Overall safety conclusions Based on all data available for all SABAs considered in this review (terbutaline, salbutamol, hexoprenaline, ritodrine, fenoterol, isoxsuprine), there is evidence that oral and suppository formulations are associated with serious and dose dependent adverse events. With injectable formulations there are safety issues during prolonged use of these active substances in the context of the obstetric indications, however there may be benefit in administering parental formulations in the obstetric indication of tocolysis in the short-term (maximum 48 hours). The risk to EMA/CMDh/559693/2013 Page 25 the mother and foetus could be minimised if active substances are administered by obstetricians/physicians experienced in the use of tocolytic agents. Oral formulations and suppositories are used for the maintenance in tocolysis after the injectable forms have been administered, and considering the cardiovascular safety profile, the PRAC considers that these medicinal products no longer demonstrate a favourable benefit-risk balance. For the parenteral formulations, the PRAC having considered all the available data and specifically for the management of uncomplicated premature labour recommends that these active substances should be given for short term management (up to 48 hours) between 22 and 37 weeks of gestation in patients with no medical or obstetric contraindication to tocolytic therapy. In addition specific guidance on the method of administration should be given for these injectable formulations. Treatment should be carried out in facilities adequately equipped to perform continuous monitoring of maternal and foetus health status. These should be administered as early as possible after the diagnosis of premature labour, and after evaluation of the patient to eliminate any contra-indications of use. This should include an adequate assessment of the patient's cardiovascular status with monitoring by electrocardiogram (ECG) throughout treatment in order to identify the early onset of cardiovascular events and further minimise the risk of a serious cardiovascular event. SABAs should not be used in women with a history of heart disease or in conditions of the mother or foetus in which prolongation of the pregnancy is hazardous. Careful control of the level of hydration is essential to avoid the risk of maternal pulmonary oedema. The use of SABAs in emergency conditions and to enable external cephalic version is supported as this reflects limited duration of use and minimal dosing, and from a safety perspective these indications should be maintained, where authorised. Efficacy Salbutamol, terbutaline, fenoterol, ritodrine, hexoprenaline and isoxsuprine are authorised in obstetric indications since the 1960s. Data available from clinical trials, post-marketing reports and literature were considered in this review. The PRAC identified serious limitations of the efficacy data for oral and suppository formulations, and noted the available new evidence and/or current medical knowledge on the use of these products for obstetric indications. Having considered the cardiovascular adverse reactions profile associated with the use of these medicinal products in obstetric indications, the PRAC concluded that oral forms and suppositories should no longer be used to supress contractions of the womb. Some of the products for oral use or suppositories referred in this procedure are authorised only in obstetric indications. Removal of these indications as per the PRAC recommendation will result to the revocation of these marketing authorisations. For these specific products a recall of the products is being recommended by the PRAC. The available data showed that injectable forms are effective at supressing labour contractions in the short term (up to 48 hours). For these indications which include short term management of uncomplicated tocolysis the PRAC recommended the parenteral products should only be administered for short term management (up to 48 hours) of the obstetric indications in patients between 22 and 37 weeks of gestation. The duration of treatment should not exceed 48 hours as data show that the main effect of tocolytic therapy is a delay in delivery of up to 48 hours. This delay may be used to administer glucocorticoids or to implement other measures known to improve perinatal health. The PRAC as well recommended that the use of the parental formulations for ECV and emergency is considered favourable where these indications are already authorised. EMA/CMDh/559693/2013 Page 26 With regards to the window of lowest gestational viability, the PRAC noted an epidemiological review of obstetric interventions in European countries (Kollée et al, 2009) andmore recently by US (Kyser et al., 2012) which suggests it is between 22 and 24 weeks. Therefore, in order to help optimise safe and effective use, the gestational age should be reflected in the indication The PRAC concluded that the benefits of injectable forms outweighed the cardiovascular risks in restricted conditions of use: these active substances should be given for short term management (up to 48 hours) between 22 and 37 weeks of gestation in patients with no medical or obstetric contraindication to tocolytic therapy. As part of the risk minimisation measures the PRAC proposed revised indications for the parenteral formulations taking all the data into account, and making clear the conditions for which these products are indicated. The use should be contraindicated in patients at a gestational age less than 22 weeks, in patients with pre-existing ischaemic heart disease or those patients with significant risk factors for ischaemic heart disease and in patients with threatened abortion during the first and second trimester of gestation. The committee also stressed that in the patients receiving these parenteral medicinal products the blood pressure and heart rate, electrolyte and fluid balance, glucose and lactate levels and potassium levels should be continuous monitored. Benefit-risk balance Having noted the above, the PRAC concluded that the benefit-risk balance is not favourable for the oral formulations and suppositories in view of the overall available safety data, in particular in relation to the risk of serious cardiovascular events, and limited efficacy. Therefore these medicinal products should no longer be indicated in the obstetrics therapeutic indication. The product information for these medicinal products should be updated accordingly; therefore these marketing authorisations should be varied. Products for which the oral and suppository formulations are only used in obstetric indications should have their licenses revoked and recalled from the market. With regards to parenteral SABAs (salbutamol, terbutaline, fenoterol, ritodrine, hexoprenaline and isoxsuprine) containing medicinal products in the obstetric indications, the PRAC concluded that the benefit-risk balance is favourable as the benefits continue to outweigh the risks. For these indications which include short term management of uncomplicated tocolysis the PRAC recommended the parenteral products should only be administered for short term management (up to 48 hours) in patients between 22 and 37 weeks of gestation. The PRAC as well recommended that the use of the parental formulations for ECV and emergency is considered favourable where these indications are already authorised. Patients should be closely monitored for signs of cardiovascular adverse reactions throughout treatment. Parenteral medicinal SABA products should be contraindicated in patients at less than 22 weeks of gestation, in patients with pre-existing ischaemic heart disease or those patients with significant risk factors for ischaemic heart disease and in patients with threatened abortion during the first and second trimester of gestation. In addition, blood pressure and heart rate, electrolyte and fluid balance, glucose and lactate levels and potassium levels should be continuously monitored. The Committee concluded that there was a need for further risk minimisation measures to inform healthcare professionals of the new restrictions on use and monitoring requirements introduced to ensure safe use of the parenteral formulations in the obstetric indications and to inform of the unfavourable benefit-risk balance of the oral and suppositories formulations in these indications. EMA/CMDh/559693/2013 Page 27 Grounds for PRAC recommendation Whereas, The PRAC considered the procedure under Article 31 of Directive 2001/83/EC resulting from pharmacovigilance data, for short-acting beta-agonists (SABAs) (salbutamol, terbutaline, fenoterol, ritodrine, hexoprenaline and isoxsuprine) containing medicinal products in the obstetric indications (see Annex I). The Committee reviewed all available data from clinical studies, pharmacoepidemiological studies, published literature and post-marketing experience on the safety of short-acting beta-agonists (SABAs) (salbutamol, terbutaline, fenoterol, ritodrine, hexoprenaline and isoxsuprine) containing medicinal products in the obstetric indications. The Committee is of the opinion that the benefits of the parenteral formulations of short-acting beta-agonists (SABAs) (salbutamol, terbutaline, fenoterol, ritodrine, hexoprenaline and isoxsuprine) containing medicinal products continue to outweigh the risks in the treatment of in the obstetric indications of short term management of uncomplicated tocolysis. The Committee in addition stressed that the parenteral products should only be administered for short term management (up to 48 hours) of the obstetric indications in patients between 22 and 37 weeks of gestation. Patients should be closely monitored for signs of cardiovascular adverse reactions throughout treatment. The Committee considered that in view of the currently available safety data in order to maintain a favourable benefit-risk balance, these parenteral SABAs (salbutamol, terbutaline, fenoterol, ritodrine, hexoprenaline and isoxsuprine) containing medicinal products should be contraindicated in patients at a gestational age less than 22 weeks, in patients with pre-existing ischaemic heart disease or those patients with significant risk factors for ischaemic heart disease and in patients with threatened abortion during the first and second trimester of gestation. The committee also stressed that in the patients receiving these parenteral medicinal products the blood pressure and heart rate, electrolyte and fluid balance, glucose and lactate levels and potassium levels should be monitored throughout treatment. For the oral and suppositories formulations in view of the overall available safety data, in particular in relation to the risk of serious cardiovascular events, and very limited efficacy data, the PRAC concluded in accordance with Article 116 of Directive 2001/83/EC that the benefit-risk balance is not favourable and therefore these medicinal products should no longer be indicated in the obstetrics therapeutic indication. The Committee concluded that there was need for further risk minimisation measures such as information to healthcare professionals to inform on the outcome of the review and the safe use of the parenteral formulations in the obstetric indications. Therefore, in accordance with Articles 31 and 32 of Directive 2001/83/EC, the PRAC recommends the variation to the terms of the marketing authorisations, or revocation, as applicable, for all medicinal products referred to in Annex I and for which the amendments to the product information are set out in Annex III of the recommendation. a. Oral and suppository formulations which are only authorised in the indications proposed to be removed (in accordance with changes to the product information as set out in Annex III) should EMA/CMDh/559693/2013 Page 28 have their marketing authorisations revoked and should be recalled within given deadlines. The conditions for the revocation of the marketing authorisations of these products, as applicable, are set out in Annex IV. b. All other marketing authorisations of SABAs (salbutamol, terbutaline, fenoterol, ritodrine, hexoprenaline and isoxsuprine) containing medicinal products indicated in tocolysis and other obstetric indications (see Annex I) should be varied (in accordance with changes to the product information as set out in Annex III). c. All marketing authorisation holders should implement risk minimisation measures. 2. Detailed explanation for the differences from the PRAC recommendation Having reviewed the PRAC recommendation, the CMDh agreed with the overall scientific conclusions and grounds for recommendation. However, the CMDh considered that a minor change was necessary to the wording proposed in the conditions to the Marketing Authorisations (Annex IV). The CMDh proposed to shorten the time for recall of the products with only obstetric indications and for which revocation is applicable to ensure that prompt action is taken on products with no marketing authorisation. CMDh Agreement The CMDh, having considered the PRAC recommendation dated 5 September 2013 pursuant to Article 107k(1) and (2) of Directive 2001/83/EC, reached an agreement on the variation or revocation as applicable of the marketing authorisations of terbutaline, salbutamol, hexoprenaline, ritodrine, fenoterol and isoxsuprine containing products for which the relevant sections of the summary of product characteristics and package leaflet are set out in Annex III and subject to the conditions set out in Annex IV. The timetable for the implementation of the agreement is set out in Annex V. EMA/CMDh/559693/2013 Page 29 Annex III Amendments to relevant sections of the summary of product characteristics and package leaflets Note: This Summary of Product Characteristics, labelling 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. EMA/CMDh/559693/2013 Page 30 A. Oral formulation medicinal products and suppositories [All oral formulations and suppositories (see Annex I) should delete the obstetric indications from their product information. In addition, any reference to the obstetric indications in all other sections of the Product information, for example in section 4.2 “Posology and methods of administration” of the Summary of Product characteristics, as well as any reference to the obstetric indications in the Package Leaflet should be removed] EMA/CMDh/559693/2013 Page 31 B. Parenteral medicinal products for obstetric indications [The existing product information shall be amended (insertion, replacement or deletion of the text as appropriate) to reflect the agreed wording as provided below] I. Summary of Product Characteristics Go to top of the page 4.1 Therapeutic indications [The currently approved obstetric indications should be deleted and replaced by the following:] For the short term management of uncomplicated premature labour To arrest labour between 22 and 37 weeks of gestation in patients with no medical or obstetric contraindication to tocolytic therapy. [The following obstetric indications to be retained only where currently authorised] External cephalic version [to be retained only where currently authorised] Emergency use in specified conditions [to be retained only where currently authorised] Go to top of the page 4.2 Posology and method of administration [The wording below should be inserted in this section] […] In the short term management of uncomplicated premature labour. Treatment with <invented name> should only be initiated by obstetricians/physicians experienced in the use of tocolytic agents. It should be carried out in facilities adequately equipped to perform continuous monitoring of maternal and foetus health status. Duration of treatment should not exceed 48 hours as data show that the main effect of tocolytic therapy is a delay in delivery of up to 48 hours; no statistically significant effect on perinatal mortality or morbidity has been observed in randomised, controlled trials. This short term delay may be used to implement other measures known to improve perinatal health. <invented name> should be administered as early as possible after the diagnosis of premature labour, and after evaluation of the patient to eliminate any contra-indications to the use of <INN SABA> (see section 4.3). This should include an adequate assessment of the patient's cardiovascular status with supervision of cardiorespiratory function and ECG monitoring throughout treatment (see section 4.4). [Details on dose and infusion rate will need to be adapted to specifics for individual drug substances i.e. retained as is per product any reference to continuing treatment with oral maintenance therapy should be removed.] Special cautions for infusion: The dose must be individually titrated with reference to suppression of contractions, increase in pulse rate and changes in blood pressure, which are limiting factors. These parameters should be carefully monitored during treatment. A maximum maternal heart rate of 120 beats per min should not be exceeded. Careful control of the level of hydration is essential to avoid the risk of maternal pulmonary oedema EMA/CMDh/559693/2013 Page 32 (see section 4.4). The volume of fluid in which the drug is administered should thus be kept to a minimum. A controlled infusion device should be used, preferably a syringe pump. […] 4.3 Contraindications [The wording below should be inserted in this section] […] <invented name> is contra-indicated in the following conditions: - Any condition at a gestational age < 22 weeks - threatened abortion during the 1st and 2nd trimester - any condition of the mother or foetus in which prolongation of the pregnancy is hazardous, e.g. severe toxaemia, intrauterine infection, vaginal bleeding resulting from placenta praevia, eclampsia or severe preeclampsia, placental abruption, or cord compression. - intrauterine foetal death, known lethal congenital or lethal chromosomal malformation. as a tocolytic agent in patients with pre-existing ischaemic heart disease or those patients with significant risk factors for ischaemic heart disease. <invented name> is also contraindicated in any pre-existing medical conditions with which a betamimetic would have an untoward effect e.g., pulmonary hypertension and cardiac disorders such as hypertrophic obstructive cardiomyopathy or any type of obstruction of the left ventricular outflow tract, e.g. aortic stenosis. […] 4.4 Special warnings and precautions for use [The wording below should be inserted in this section] […] Tocolysis Any decision to initiate therapy with <invented name> should be undertaken after careful consideration of the risks and benefits of treatment. Treatment should only be carried out in facilities adequately equipped to perform continuous monitoring of maternal and foetal health status. Tocolysis with beta-agonists is not recommended when membranes have ruptured or the cervix dilation is beyond 4cm. <invented name> should be used with caution in tocolysis and supervision of cardiorespiratory function and ECG monitoring, should be performed throughout treatment. The following monitoring measures must be constantly applied to the mother and, when feasible/appropriate, to the foetus: - blood pressure and heart rate - ECG - electrolyte and fluid balance – to monitor for pulmonary oedema - glucose and lactate levels – with particular regard to diabetic patients - potassium levels– beta-agonists are associated with a decrease in serum potassium which increases the risk of arrhythmias (see section 4.5) Treatment should be discontinued if signs of myocardial ischaemia (such as chest pain or ECG changes) develop. EMA/CMDh/559693/2013 Page 33 <invented name> should not be used as a tocolytic agent in patients with significant risk factors for, or a suspicion of any kind of pre-existing heart disease (e.g. tachyarrhythmias, heart failure, or valvular heart disease; see section 4.3). In premature labour in a patient with known or suspected cardiac disease, a physician experienced in cardiology should assess the suitability of treatment before intravenous infusion with <invented name>. Pulmonary oedema As maternal pulmonary oedema and myocardial ischaemia have been reported during or following treatment of premature labour with beta-agonists, careful attention should be given to fluid balance and cardio-respiratory function. Patients with predisposing factors including multiple pregnancies, fluid overload, maternal infection and pre-eclampsia may have an increased risk of developing pulmonary oedema. Administration with a syringe pump as opposed to i.v. infusion will limit risk of fluid overload. If signs of pulmonary oedema or myocardial ischaemia develop, discontinuation of treatment should be considered (see section 4.2 and 4.8). Blood pressure and heart rate Increases in maternal heart rate of the order of 20 to 50 beats per minute usually accompany infusion of beta-agonists. The maternal pulse rate should be monitored and the need to control such increases by dose reduction or drug withdrawal should be evaluated on a case by case basis. Generally maternal pulse rate should not be allowed to exceed a steady rate of 120 beats per minute. Maternal blood pressure may fall slightly during the infusion; the effect being greater on diastolic than on systolic pressure. Falls in diastolic pressure are usually within the range of 10 to 20mmHg. The effect of infusion on foetal heart rate is less marked, but increases of up to 20 beats per minute may occur. In order to minimise the risk of hypotension associated with tocolytic therapy, special care should be taken to avoid caval compression by keeping the patient in the left or right lateral positions throughout the infusion. Diabetes Administration of beta agonists is associated with a rise of blood glucose. Therefore blood glucose and lactate levels should be monitored in mothers with diabetes and diabetic treatment adjusted accordingly to meet the needs of the diabetic mother during tocolysis (see section 4.5). Hyperthyroidism <invented name> should only be administered cautiously to patients suffering from thyrotoxicosis after careful evaluation of the benefits and risks of treatment. […] 4.5 Interaction with other medicinal products and other forms of interaction [The wording below should be inserted in this section] […] Halogenated anaesthetics Owing to the additional antihypertensive effect, there is increased uterine inertia with risk of haemorrhage; in addition, serious ventricular rhythm disorders due to increased cardiac reactivity, have been reported on interaction with halogenated anaesthetics. Treatment should be discontinued, whenever possible, at least 6 hours before any scheduled anaesthesia with halogenated anaesthetics. Corticosteroids EMA/CMDh/559693/2013 Page 34 Systemic corticosteroids are frequently given during premature labour to enhance foetal lung development. There have been reports of pulmonary oedema in women concomitantly administered with beta-agonists and corticosteroids. Corticosteroids are known to increase blood glucose and can deplete serum potassium, therefore concomitant administration should be undertaken with caution with continuous patient monitoring owing to the increased risk of hyperglycaemia and hypokalaemia (see section 4.4). Anti-diabetics The administration of beta-agonists is associated with a rise of blood glucose, which can be interpreted as an attenuation of anti-diabetic therapy; therefore individual anti-diabetic therapy may need to be adjusted (see section 4.4). Potassium depleting agents Owing to the hypokalaemic effect of beta-agonists, concurrent administration of serum potassium depleting agents known to exacerbate the risk of hypokalaemia, such as diuretics, digoxin, methyl xanthines and corticosteroids, should be administered cautiously after careful evaluation of the benefits and risks with special regard to the increased risk of cardiac arrhythmias arising as a result of hypokalaemia (see section 4.4). […] Go to top of the page 4.8 Undesirable effects [The wording below should be inserted in this section] […] The most common undesirable effects of <invented name> are correlated with the betamimetic pharmacological activity and may be limited or avoided by a close monitoring of hemodynamic parameters, such as blood pressure and heart rate, and an appropriate adjustment of the dose. They normally recede upon therapy discontinuation. Cardiac disorders Very common: *Tachycardia. Common: *Palpitations, *decrease in diastolic pressure Rare: *Cardiac arrhythmias, e.g. atrial fibrillation, Myocardial ischaemia (see section 4.4) Metabolism and nutrition disorders Common - *Hypokalaemia Rare - *Hyperglycaemia Vascular disorders Common: Rare: *Hypotension (see section 4.4) *Peripheral vasodilatation. Respiratory, thoracic and mediastinal disorders Uncommon: *Pulmonary oedema. * These reactions have been reported in association with the use of short acting beta-agonists in obstetric indications and are considered class effects (see section 4.4) […] EMA/CMDh/559693/2013 Page 35 II. Package Leaflet Section 1. What <invented name> is and what it is used for. [This section should replace any existing one which reflects the obstetric indications and should read as follows:] <invented name> is <also> used in women who have unexpectedly gone into early labour (premature labour) between the 22nd and 37th week of gestation, to provide a short delay in the early delivery of the baby. You will receive <invented name> for a maximum of 48 hours. This will give your doctor or midwife time to take extra measures that will improve the health of your baby. Section 2. [The wording below should be inserted in the relevant sections] […] Before you have <invented name> Do not have <invented name> if: you are less than 22 weeks pregnant - If you suffer from or have a known risk of developing ischaemic heart disease (disease characterized by reduced blood supply to your heart muscle, causing symptoms such as chest pain (angina)) - If you have ever experienced miscarriage in the first two trimesters of your pregnancy. - If you are pregnant and you or your baby have certain conditions when prolongation of your pregnancy would be dangerous (such as severe high blood pressure, infection of the womb, bleeding, placenta is covering the birth canal or is detaching, or your baby has died inside the womb) - If you suffer from heart disease with palpitations (for example heart valve disorder) or longstanding lung disease (for example chronic bronchitis, emphysema) causing an increase of blood pressure to your lungs (pulmonary hypertension) Take special care with <invented name>: It is important to check with your doctor or nurse before having your injection if: you have had problems with your pregnancy, - if during pregnancy, your waters have broken. - you have too much fluid in the lungs causing breathlessness (pulmonary oedema) - you have high blood pressure - you are diabetic. If so, you may need some additional blood sugar tests when you are given <invented name>. you have an overactive thyroid gland - you have a history of heart disease characterised by breathlessness, palpitations or angina (see Do not use <invented name> if). EMA/CMDh/559693/2013 Page 36 Your doctor will monitor your heart and your unborn baby. Your doctor may also take blood tests to monitor for changes in your blood (see section 3). Taking other medicines Tell your doctor, nurse or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription. This includes herbal medicines. <invented name> can have an effect on the way some medicines work, and some medicines can effect how <invented name> works. In particular tell your doctor, nurse or pharmacist if you are taking: - medicines for an irregular or fast heartbeat (such as digoxin) - Other beta-blocker medicines (such as atenolol or propranolol), including eye drops (such as timolol) - Xanthine medicines (such as theophylline or aminophylline) - steroid medicines (such as prednisolone). - water tablets, also known as diuretics (such as frusemide) - medicines for diabetes to reduce your blood sugar (such as insulin, metformin, of glibenclamide). If you are scheduled for surgery with general anaesthetics your doctor will stop the administration of <invented name> 6 hours before surgery whenever possible to protect you from adverse effects (e.g. irregular heart beat or bleeding of your womb). Section 3. [The wording below should be inserted in the relevant sections] […] How to use <invented name> You will never be expected to give yourself this medicine. It will always be given to you by a person who is qualified to do so after careful consideration of the balance of benefits of <invented name> to your baby and the potential untoward effects the treatment may have on you. To temporarily delay premature labour You will be given <invented name> by a doctor where facilities are available to continually monitor your health and that of your baby throughout administration. The following measures will be taken where necessary: Blood pressure and heart rate. Your doctor will consider the lowering of your dose or discontinuing <invented name> if your heart rate exceeds 120 beats per minute. Electrocardiography (ECG, electric activity of your heart) Tell your doctor immediately if you experience chest pain during treatment. If there are changes in ECG recording and you have chest pain your doctor will stop the administration of <invented name>. EMA/CMDh/559693/2013 Page 37 Balance of water and salts in your body. Tell your doctor immediately if you experience coughing or shortness of breath during treatment. If any signs indicate that there is a build-up of fluid in your lungs (also known as pulmonary oedema) (e.g. coughing or shortness of breath), your doctor may stop the administration of <invented name>. Blood sugar level and the occurrence of low body pH with a build-up of lactate in your blood (also known as lactic acidosis) Blood potassium levels (low potassium levels may be associated with a risk of irregular heart beat) Section 4. [The wording below should be inserted in the relevant sections] […] Possible side effects Important side effects to look out for when treated for premature labour: Rare (affects less than 1 in 1,000 people) Chest pain (due to heart problems such as angina). If this happens to you, tell your doctor or nurse straight away. The following side effects have also been observed with all beta-agonists like <invented name> when used to delay premature labour. Very common (affects more than 1 in 10 people) - Fast heart beats Common (affects less than 1 in 10 people) - Pounding heart beat (palpitations), - Low blood pressure which may cause light-headedness or dizziness - Low levels of potassium in your blood which may cause muscle weakness, thirst, or “pins and needles” Uncommon (affects less than 1 in 100 people) - Fluid accumulation in the lungs (pulmonary oedema) which may cause difficulty breathing Rare (affects less than 1 in 1,000 people) - Unusual or irregular heartbeats - High levels of sugar (glucose) and/or lactic acid in your blood - Flushing (reddening) of the face EMA/CMDh/559693/2013 Page 38 Annex IV Conditions to the marketing authorisation EMA/CMDh/559693/2013 Page 39 Conditions to the marketing authorisation National Competent Authorities (NCAs) of Member States or Reference Member States (RMS) where applicable, shall ensure that the following conditions are fulfilled by the MAH(s): Conditions Date DHPC Communication circulation according to the CMDh agreed communication plan and conditions. Within 30 days after CMDh agreement The products with only obstetric indications and for which revocation is applicable (instead of variation to the terms of the marketing authorisation) should be recalled from the market by the Marketing Authorisation Holders by 25th November 2013 at the latest. By 25th November 2013 EMA/CMDh/559693/2013 at the latest Page 40 Annex V Timetable for the implementation of the agreement Agreement of the Co-ordination group for mutual recognition and decentralised procedures for human use, pursuant to article 107k (1) and (2) of directive 2001/83/EC, for EMA/CMDh/559693/2013 Page 41 Timetable for the implementation of the agreement Adoption of CMDh agreement: Transmission to National Competent Authorities of the translations of the annexes to the agreement: Implementation of the agreement by the Member States (submission of the variation by the 23 October 2013 19 November 2013 19 December 2013 Marketing Authorisation Holder(s) as applicable): Agreement of the Co-ordination group for mutual recognition and decentralised procedures for human use, pursuant to article 107k (1) and (2) of directive 2001/83/EC, for EMA/CMDh/559693/2013 Page 42 Appendix 1 Grounds for the procedure (notification) Appendix 2 PRAC Recommendation Appendix 3 Direct Healthcare Professional Communication and Communication Plan as agreed by CMDh on 23 October 2013
