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Transcript
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
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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