annex i list of the names, pharmaceutical forms, strengths...

Annex I

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

1

Member State EU/EEA

Marketing authorisation

holder

INN Strength Product name Pharmaceutical form

Route of administration

Belgium Medgenix Benelux Vliegveld 21 8560 Wevelgem Belgium

pholcodine 15 mg/15ml Sulfogaiacol 300 mg/15ml

1.00 mg/ml (pholcodine)

Broncho-Pectoralis Pholcodine

Syrup Oral use


pholcodine eucalyptolum camphora syntheticum gaiacolum phenolum

10.00 mg 120 mg 156 mg 50 mg 10 mg

Eucalyptine Pholcodine (Adult)

Suppository Rectal use


pholcodine eucalyptolum camphora syntheticum gaiacolum phenolum

5.00 mg 80 mg 100 mg 30 mg 6 mg

Eucalyptine Pholcodine (Child)


Belgium Novum Pharma Latem Business Park Xavier De Cocklaan 66 box 3 9830 Sint-Martens-Latem Belgium

pholcodine 5 mg/5ml Doxylaminii succinas 5 mg/5ml Kalii guaiacolsulfonas 47,5 mg/5ml Natrii benzoas 50 mg/5ml

1.00 mg/ml (pholcodine)

Pholco-mereprine Syrup Oral use

Belgium Sanofi-Aventis Belgium NV Culliganlaan 1C 1831 Diegem Belgium

pholcodine 0,12 g 1.20 mg/ml Cotrane Folcodine Syrup Oral use

France AEROCID 248 bis, rue Gabriel Péri B.P. 126 94232 Cachan Cedex FRANCE

myrte (huile essentielle de) (deterpenee) ; alpha-terpinéol ; pholcodine

0,05g/100g; 0,0025g/100g; 0,05g/100g

Myrtine Enfants, sirop Syrup Oral use

2

Member State EU/EEA


holder



France AMIDO 37, avenue Gabriel Péri BP 232 92503 Rueil-Malmaison Cedex FRANCE

coquelicot (petale de) (extrait sec de) ; pholcodine ; sodium (benzoate de)

0,2/100g, 0,075g/100g 1g/100g

Pulmadol Enfants, sirop

Syrup Oral use

France BAYER SANTE FAMILIALE 33, rue de l'Industrie 74240 Gaillard FRANCE

pholcodine 0,075g/100g Broncorinol toux seche enfants, sirop

Syrup Oral use

France BAYER SANTE FAMILIALE 33, rue de l'Industrie 74240 Gaillard FRANCE

pholcodine 0,100g/100g Broncorinol adultes toux seche pholcodine, sirop

Syrup Oral use

France BOUCHARA RECORDATI 68, rue Marjolin 92300 Levallois-Perret FRANCE

biclotymol ; chlorphénamine (maléate de) ; pholcodine

0,2g/100ml; 0,012g/100ml; 0,120g/100ml

Hexapneumine adultes, sirop

Syrup Oral use


biclotymol ; chlorphénamine (maléate de) ; pholcodine

0,15/100ml; 0,01g/100ml 0,1g/100ml

Hexapneumine enfants, sirop

Syrup Oral use


biclotymol ; cinéole ; pholcodine

0,0800g; 0,0700g; 0,0050g

Hexapneumine enfants, suppositoire



biclotymol ; cinéole ; pholcodine

0,160g; 0,140g; 0,015g

Hexapneumine adultes, suppositoire


3

Member State EU/EEA


holder



France BRIDOUX 6, rue Salengro 62160 Bully les Mines FRANCE

pholcodine ; sodium (benzoate de)

0,0846g/100g;2g/100g

Pulmosodyl adulte, sirop

Syrup Oral use

France COOPER Place Lucien-Auvert 77020 Melun Cedex FRANCE

pholcodine ; érysimum (extrait sec d')

1mg/ml; 1,5mg/ml

Clarix toux seche pholcodine erysimum adultes, sirop

Syrup Oral use

France COOPER Place Lucien-Auvert 77020 Melun Cedex FRANCE


0,1g/100ml; 0,150g/100ml

Clarix toux seche pholcodine erysimum adultes sans sucre, sirop édulcoré au maltitol liquide et au cyclamate de sodium

Syrup Oral use

France FERLUX 24, avenue d'Aubière BP 151 63804 Cournon d'Auvergne Cedex FRANCE

pholcodine 133mg/100ml Dimetane sans sucre 133 mg/100 ml, sirop

Syrup Oral use

France GENEVRIER 280, rue de Goa Les Trois Moulins - Parc de Sophia Antipolis 06600 Antibes FRANCE

pholcodine 0,0850g/100ml Codotussyl toux seche enfants, sirop

Syrup Oral use


pholcodine 133mg/100ml Codotussyl toux seche adultes, sirop

Syrup Oral use

4

Member State EU/EEA


holder




cinéole ; pholcodine

0,05g 0,005g

Codotussyl Enfants, suppositoire



cinéole ; pholcodine

0,1g; 0,02g

Codotussyl adultes, suppositoire


France HEPATOUM 1 bis, rue de Plaisance 94130 Nogent Sur Marne FRANCE

chlorphénamine (maléate de) ; pholcodine

0,01300g/100ml; 0,08g/100ml

Broncalene adultes, sirop

Syrup Oral use



0,01g/100ml; 0,0500g/100ml

Broncalene enfants, sirop

Syrup Oral use



0,0133g/100ml 0,08g/100ml

Broncalene adultes sans sucre, sirop édulcoré à la saccharine sodique

Syrup Oral use

France MEDIFLOR 37, rue St Romain 69008 Lyon FRANCE

guaïfénésine ; pholcodine

0,200g/100ml; 0,100g/100ml

Ephedromel, sirop Syrup Oral use

France MEDIFLOR 37, rue St Romain 69008 Lyon FRANCE

pholcodine ; sulfogaïacol

0,050g/100g; 3g/100g

Pectoral Richelet sans sucre, solution buvable édulcorée à la saccharine sodique

Oral solution Oral use

5

Member State EU/EEA


holder



France PIERRE FABRE MEDICAMENT 45, place Abel Gance 92100 Boulogne Billancourt FRANCE

erysimum (sommite fleurie d') (extrait fluide de) ; pholcodine

2,4g/100g; 0,082g/100g

Polery enfants, sirop Syrup Oral use

France SANOFI AVENTIS FRANCE 1-13, boulevard Romain Rolland 75014 Paris FRANCE

pholcodine 0,060g/100ml Rhinathiol enfants toux seche 0,06 % pholcodine, sirop

Syrup Oral use


pholcodine 0,060g/100ml Respilene enfants 3 mg/5 ml, sirop

Syrup Oral use


pholcodine 0,12g/100ml Pholcodine delalande adultes 0,12 %, sirop

Syrup Oral use


pholcodine 0,12g/100ml Pharmakod 0,12 % adultes toux seche, sirop

Syrup Oral use


pholcodine 0,12g/100ml Rhinathiol adultes toux seche 0,12 % pholcodine, sirop

Syrup Oral use

6

Member State EU/EEA


holder




pholcodine 0,12g/100ml Pholcodine winthrop adultes 0,12 %, sirop

Syrup Oral use


pholcodine ; sodium (ténoate de)

0,133g/100ml; 1g

Trophires adultes, sirop

Syrup Oral use


pholcodine 0,12g/100ml Respilene adultes 0,12 pour cent, sirop

Syrup Oral use


pholcodine ; sodium (ténoate de)

0,06g/100ml 1g/100ml

Trophires enfants, sirop

Syrup Oral use

France UCB PHARMA 420 Avenue Estienne d'Orves Défense Ouest 92700 Colombes FRANCE

MYRTE (huile essentielle de) (deterpenee) ; pholcodine

20mg; 18mg

Atouxx adultes, capsule

Capsule Oral use

France URGO 42, rue de Longvic BP 157 21304 Chenôve Cedex FRANCE

pholcodine 0,200g/100ml Humex adultes toux seche pholcodine, sirop

Syrup Oral use

7

Member State EU/EEA


holder



France URGO 42, rue de Longvic BP 157 21304 Chenôve Cedex FRANCE

pholcodine 0,125g/100ml Humex enfants toux seche pholcodine, sirop

Syrup Oral use

France ZAMBON FRANCE 13, rue René Jacques 92138 Issy-les-Moulineaux Cedex FRANCE

pholcodine 1,31 mg/ml Flucalyptol toux seche pholcodine 1,31 mg/ml, sirop

Syrup Oral use


pholcodine 1,31 mg/ml Biocalyptol, sirop Syrup Oral use


pholcodine 131mg/100ml Flucalyptol toux seche pholcodine 1,31 mg/ml sans sucre, sirop edulcoré à la saccharine sodique et au maltitol liquide

Syrup Oral use


gaïacol ; pholcodine

19,750mg/100ml; 131 mg/100ml

Biocalyptol a la pholcodine, sirop

Syrup Oral use


pholcodine 131mg/100ml Biocalyptol 6,55 mg/5 ml sans sucre, sirop édulcoré à la saccharine sodique et au maltitol liquide

Syrup Oral use

8

Member State EU/EEA


holder





0,1/100ml; 0,150/100ml

Pholcodyl, sirop Syrup Oral use

Ireland GlaxoSmithKline Consumer Healthcare (Ireland) Limited, Stonemasons Way, Rathfarnham, Dublin 16, Ireland

Paracetamol, Pseudoephedrine hydrochloride, Pholcodine

500mg, 30mg, 5mg

Day Nurse Capsules Capsule, hard Oral use

Ireland GlaxoSmithKline Consumer Healthcare (Ireland) Limited, Stonemasons Way, Rathfarnham, Dublin 16, Ireland


500mg, 30mg, 5mg

Solpadeine Cold & Flu Capsules

Capsule, hard Oral use

Ireland Pinewood Laboratories Ltd, Ballymacarbry, Clonmel, Co. Tipperary, Ireland

Pholcodine 5mg Pholcodex 5mg/5ml oral solution


Ireland The Boots Company Plc, 1 Thane Road West, Nottingham, NG2 3AA, United Kingdom


500 mg 30 mg, 5 mg

Nirolex day cold & flu capsules


Ireland The Boots Company Plc, 1 Thane Road West, Nottingham, NG2 3AA, United Kingdom


1000mg/30ml, 60mg/30ml 10mg/30ml,

Nirolex day cold & flu oral solution


9

Member State EU/EEA


holder



Lithuania ORIVAS UAB, J.Jasinskio 16B LT-01112 Vilnius, Lithuania

Pholcodine, Chlorphenamine, Biclotymol

120mg 12mg 200mg/100ml

Hexapneumine Adults Syrup Oral use

Lithuania ORIVAS UAB, J.Jasinskio 16B LT-01112 Vilnius, Lithuania

Pholcodine, Chlorphenamine, Biclotymolm

100mg 10mg 150mg/100ml

Hexapneumine Children

Syrup Oral use

Luxembourg COOPERATION PHARM.FRANCAISE PLACE LUCIEN AUVERT 77020 MELUN CEDEX France

Erysimum extr.sec Pholcodine

0.150g 0.100g

Clarix Syrup Oral use

Luxembourg COOPERATION PHARM.FRANCAISE PLACE LUCIEN AUVERT 77020 MELUN CEDEX France

Erysimum extr.sec Pholcodine

0.150g 0.100g

Clarix sans sucre Syrup Oral use

Luxembourg Eurogenerics S.A. ESPLANADE HEYSEL, B.22 1020 BRUXELLES Belgium

Pholcodine phenylephrine hcl

100mg/100ml 67mg/100ml

Pectorhinyl Syrup Oral use

Luxembourg Eurogenerics S.A. ESPLANADE HEYSEL, B.22 1020 BRUXELLES Belgium

Pholcodine phenylephrine hcl

50mg/100ml 50mg/100ml

pectorhinyl junior Syrup Oral use

Luxembourg MEDGENIX BENELUX S.A 21, VLIEGVELD 8560 WEVELGEM Belgium

camphre eucalyptol gaiacol phenol pholcodine

156mg 120mg 50mg 10mg 10mg

Eucalyptine-Pholcodine Adultes


10

Member State EU/EEA


holder



Luxembourg MEDGENIX BENELUX S.A 21, VLIEGVELD 8560 WEVELGEM Belgium

camphre eucalyptol gaiacol phenol pholcodine

100mg 80mg 30mg 6mg 5mg

Eucalyptine-Pholcodine Enfants


Luxembourg NOVUM PHARMA 66-3, XAVIER DE COCKLAAN 9830 SINT-MARTENS-LATEM Belgium

doxylamine pholcodine benzoate sodique sulfogaiacol

5mg 5mg 50mg 47.5mg

Pholco Mereprine Syrup Oral use

Luxembourg SANOFI-AVENTIS BELGIUM 1C, CULLIGANLAAN 1831 DIEGEM Belgium

pholcodine thiophene carboxylate eucalyptus huile essentielle parahydroxybenzoate de methyle parahydroxybenzoate de propyle

0.060g 1g 0.250ml 0.080g 0.030g/100ml

Trophires Enfants Syrup Oral use


pholcodine thiophene carboxylate eucalyptus huile essentielle parahydroxybenzoate de methyle parahydroxybenzoate de propyle

0.133g 1g 0.250ml 0.080g 0.030g

Trophires Adultes Syrup Oral use


Pholcodine 1.2mg/ml Cotrane Pholcodine Syrup Oral use

11

Member State EU/EEA


holder



Malta Beecham Group PLC 980, Great West Road Brentford, Middlesex TW 8 9 GS United Kingdom

Paracetamol, Pseudoephedrine Hydrochloride, Pholcodine

500mg 30mg 5mg

Day Nurse Hard capsules Oral use

Malta Beecham Group PLC 980, Great West Road Brentford, Middlesex TW 8 9 GS United Kingdom

Paracetamol Pseudoephedrine Hydrochloride Pholcodine

Active Ingredient per 30 ml Paracetamol 1g Pseudoephedrine Hydrochloride 60 mg Pholcodine 10 mg

Day Nurse Oral solution Oral use

Malta Thornton & Ross Limited Linthwaite Huddersfield West Yorkshire HD7 5QH United Kingdom

Pholcodine, Ephedrine Hydrochloride, Chlorphenamine Maleate

Pholcodine BP 5.0mg Ephedrine Hydrochloride BP 8.0mg Chlorphenamine Maleate BP 2.0mg

Cofsed Liquid Oral suspension Oral use

Slovenia Alkaloid d.o.o., Slandrova ulica 4, Ljubljana 1231, Slovenia

pholcodine 0,8 mg/ml Folkodin Alkaloid 0,8 mg/ml peroralna raztopina za otroke



pholcodine 1 mg/ml Folkodin Alkaloid 1 mg/ml peroralna raztopina


12

Member State EU/EEA


holder




pholcodine 10 mg Folkodin Alkaloid 10 mg trde kapsule


Spain ROTTAPHARM, S.L.Avda. Diagonal, 67-69 Barcelona 08019 Spain

pholcodine ; cineol ; cherry laurel water ; menthol ; terpineol ; benzocaine

4 mg 3 mg 5mg 4 mg 2 mg 1 mg

Caltoson Balsamico Tablets Oral use

United Kingdom

Alliance Pharmaceuticals Limited, Avonbridge House, Bath Road, Chippenham, Wiltshire, SN15 2BB, United Kingdom

pholcodine 5 mg Pavacol-D Oral liquid Oral use

United Kingdom

Ayrton Saunders Limited, North Way, Walworth Industrial Estate, Andover, Hampshire, SP10 5AZ, United Kingdom

pholcodine 5 mg Pholcodine Linctus BP Oral solution Oral use

United Kingdom

Ayrton Saunders Limited, North Way, Walworth Industrial Estate, Andover, Hampshire, SP10 5AZ, United Kingdom

pholcodine 5 mg Cupal Linctus Oral liquid Oral use

13

Member State EU/EEA


holder



United Kingdom

Beecham Group PLC, 980 Great West Road, Brentford, Middlesex, TW8 9GS, United Kingdom

Psedoephedrine Hydrochloride ; Pholcodine ; Paracetamol

60mg; 10 mg, 1000 mg

Day Nurse Oral solution Oral use

United Kingdom


Psedoephedrine Hydrochloride ; Pholcodine ; Paracetamol

30 mg, 5 mg, 500 mg

Day Nurse Capsules Oral use

United Kingdom


Promethazine Hydrochloride, Paracetamol, Dextromethorphan hydrobromide Pholcodine; Pseudoephedrine

10mg 500mg 7.5mg 5mg 30mg

Day and Night Nurse capsules (nb this is a combination of Day Nurse and Night Nurse capsules in one pack)

Capsules Oral use

United Kingdom


Pholcodine; Diphenhydramine hydrochloride

3.75mg/5ml; 12.5mg/5ml

Cough Nurse Night Time Syrup

Oral liquid Oral use

United Kingdom

Bell Sons & Company Druggist limited. Gifford House, Slaidburn Crescent, Southport, Mersyside, PR9 9AL, United Kingdom

pholcodine 0.1%w/w Bell Pholcodine Linctus Oral liquid Oral use

14

Member State EU/EEA


holder



United Kingdom

Bell Sons & Company Druggist limited. Gifford House, Slaidburn Crescent, Southport, Mersyside, PR9 9AL, United Kingdom

pholcodine 0.2% w/w Bell Strong Pholcodine Linctus


United Kingdom

Ernest Jackson and company Limited, 29 High Street, Crediton, Devon, EX17 3AP, United Kingdom

pholcodine 0.12%w/w Potter's Pholcodine cough pastilles

Lozenge Oral use

United Kingdom

LCM Limited, Linthwaite, Huddersfield, West Yorkshire, HD7 5QH, United Kingdom


United Kingdom

Line Range Limited, c/o Orbis consumer products Limited, Cunard Road, Park Royal, London NW10 6PN, United Kingdom

Pseudoephedrine Hydrochloride ; Pholcodine ; Diphenhydramine Hydrochloride ; Paracetamol ; Ethanol

6.67 mg, 1.67 mg, 1.67 mg, 100 mg, 96% 1ml

Night time Cold relief Oral solution Oral use

15

Member State EU/EEA


holder



United Kingdom

Line Range Limited, c/o Orbis consumer products Limited, Cunard Road, Park Royal, London NW10 6PN, United Kingdom

Pseudoephedrine Hydrochloride ; Pholcodine ; Paracetamol

6.67 mg/5ml, 1.67 mg/5ml, 100 mg/5ml

Day time cold relief Oral liquid Oral use

United Kingdom

LPC Medical (UK) Limited, 2 Covent Garden Close, Luton, Bedfordshire, LU4 8QB, United Kingdom

pholcodine 10 mg Hill's Balsam Dry cough liquid


United Kingdom

Mcneil Products Limited, Regulatory Affairs, Dorking Road, Walton Oaks, KT20 7NS, United Kingdom

pholcodine 2 mg Benylin Children's dry cough

Syrup Oral use

United Kingdom

Novartis Consumer Health UK Limited, Wimblehurst Road, Horsham, West Sussex, RH12 5AB, United Kingdom

Promethazine Hydrochloride ; Pholcodine

1.5mg, 1.5 mg

Tixylix night cough oral solution


United Kingdom


Psedoephedrine Hydrochloride ; Chlorpheniramine maleate ; Pholcodine

20 mg, 2 mg, 5 mg

Tixylix cough and Cold Syrup Oral use

16

Member State EU/EEA


holder



United Kingdom


Pholcodine 4mg Tixylix Dry cough Oral solution Oral use

United Kingdom

Pinewood Laboratories Limited, Ballymacarbry, Clonmel, Co Tipperary, Ireland

pholcodine 5 mg Pholcodine Cough Linctus

Syrup Oral use

United Kingdom

Pinewood Laboratories Limited, Ballymacarbry, Clonmel, Co Tipperary, Ireland

pholcodine 10 mg Strong Pholcodine Linctus BP


United Kingdom

Sterling Pharmaceuticals Limited, 288 Upper Balsall Heath Road, Birmingham, B12 9DR, United Kingdom

pholcodine 5 mg Pholcodine Linctus BP. Oral solution Oral use

United Kingdom

Sterling Pharmaceuticals Limited, 288 Upper Balsall Heath Road, Birmingham, B12 9DR, United Kingdom

pholcodine 10 mg Strong Pholcodine Linctus BP.


17

Member State EU/EEA


holder



United Kingdom

The Boots company PLC, 1 Thane Road West, Nottingham, NG2 3AA United Kingdom

diphenhydramine Chloride ; Pholcodine

12.5 mg 3.75 mg

Boots cough relief for Adults Liquid


United Kingdom


diphenhydramine Chloride ; Pholcodine

12.5 mg, 1.5 mg

Boots cough relief for Children Syrup


United Kingdom


Pholcodine 2 mg Boots Dry Cough Syrup 6 years+

Syrup Oral use

United Kingdom


Paracetamol, Pseudoephedrine Hydrochloride, Pholcodine

3.333 %w/v, 0.2% w/v, 0.033 % w/v

Boots Night cough relief oral solution


United Kingdom


Paracetamol ; Pseudoephedrine Hydrochloride ; Pholcodine

3.333 %w/v, 0.2% w/v 0.033 % w/v

Boots Day cold and Flu relief oral solution


United Kingdom


Paracetamol ; Pseudoephedrine Hydrochloride ; Diphenhydramine Hydrochloride ; Pholcodine

3.333 %w/v, 0.2% w/v, 0.083% w/v, 0.033 % w/v

Boots Pharmacy cold and Flu night liquid


18

Member State EU/EEA


holder



United Kingdom


Pholcodine ; Paracetamol ; Psedoephedrine Hydrochloride

5 mg 500mg 30mg

Boots Pharmacy cold and Flu Day capsules

Capsules Oral use

United Kingdom


Pholcodine ; Paracetamol ; Diphenhydramine Psedoephedrine Hydrochloride

5 mg, 500mg, 12.5mg 30mg

Boots Pharmacy Cold and Flu Night Capsules

Capsules Oral use

United Kingdom


pholcodine 0.1% w/w Boots Pholcodine Linctus BP


United Kingdom


Pholcodine; Paracetamol; diphenhydramine hydrochloride; Pseudoephedrine hydrochloride

5mg 500mg 12.5mg 30mg

Boots Pharmacy Cold and Flu 24 Hour Capsules (Nb this is a pack containing a combination of Day and Night capsules)

Capsules Oral use

United Kingdom

Thornton & Ross Limited, Linthwaite, Huddersfield, West Yorkshire, HD7 5QH United Kingdom

Pholcodine ; Ephedrine Hydrochloride ; Chlorpheniramine maleate

5mg, 8mg, 2mg

Cofsed Linctus Oral liquid Oral use

United Kingdom


Pholcodine ; Ephedrine Hydrochloride ; Chlorpheniramine maleate

2mg, 4mg, 1mg

Cofsed Paediatric Linctus


19

Member State EU/EEA


holder



United Kingdom


pholcodine 5mg Care Pholcodine 5mg/5ml Oral solution


United Kingdom


pholcodine 2mg Galenphol Paediatric Linctus oral liquid 2.0 mg/5ml


United Kingdom


pholcodine 10mg Galenphol Strong Linctus


United Kingdom


pholcodine 5 mg Covonia Dry cough sugar free formula


United Kingdom

Wise Pharmaceuticals Limited, 7 Oxford Street, Manchester, M1 4PB, United Kingdom


20

21

Member State EU/EEA


holder



United Kingdom

Wise Pharmaceuticals Limited, 7 Oxford Street, Manchester, M1 4PB, United Kingdom

pholcodine 10 mg Strong Pholcodine Linctus


Annex II

Scientific conclusions and grounds for the maintenance of the marketing authorisations presented by the EMA

22

Scientific conclusions Overall summary of the scientific evaluation of pholcodine-containing products (see Annex I) Background information Pholcodine is an opiate with central antitussive action used for treatment of cough and cold symptoms in children and adults. The first clinical studies on efficacy of pholcodine as an antitussive agent are dated 1950. Pholcodine has been marketed for decades in the European Union, where currently marketing authorisations exist in Belgium, France, Ireland, Lithuania, Luxembourg, Malta, Slovenia, Spain and United Kingdom, either subject to medical prescription or as non-prescription medicines. On 28 January 2011, France triggered a referral under Article 31 of Directive 2001/83/EC, as amended. The CHMP was requested to give its opinion on whether the marketing authorisations for medicinal products containing pholcodine-containing medicinal products should be maintained, varied, suspended or withdrawn. The concerns of the French Medicines Agency arose from the potential risk that pholcodine may lead to IgE-sensitisation to neuromuscular blocking agents (NMBAs). Literature has been published suggesting a link between pholcodine consumption and cross sensitisation to NMBAs, resulting in anaphylactic reactions during surgery. The published data refers mainly to Norway and Sweden, where pholcodine is no longer marketed. In France, data from spontaneous reporting suggests a 25% increase in the number of anaphylactic shocks to NMBAs in the period 2008/2009 when compared to the 2003/2004 period. This coincides with a 9% increase in the consumption of pholcodine-containing products in France between the two periods. As a consequence, the French Medicines Agency changed the prescription status of pholcodine–containing medicines to prescription only and triggered this referral. Scientific discussion There has been extensive use of pholcodine-containing products over the course of several decades, which has allowed the collection of relevant safety data. The majority of the adverse events reported in clinical trials, literature and post-marketing experience are gastrointestinal disorders and psychiatric disorders, which are adverse events known and commonly reported with opiates. The existent data seems to indicate that pholcodine is at least as safe as codeine, with the advantage that it does not share the same potential for addiction. In recent years, observations in Norway led one team of researchers to raise the possibility that high consumption of cough mixtures in these countries was related to increased prevalence of IgE antibodies to pholcodine, morphine and suxamethonium, and ultimately higher incidence of IgE-mediated anaphylactic reactions to NMBAs1,2. Based on immunological analyses determining the prevalence of antibodies to these active substances in different populations, and reporting rates for NMBA-related anaphylaxis during anaesthesia, researchers concluded that withdrawal of pholcodine from the market in Norway significantly lowered within 1-2 years levels of IgE and IgE antibodies to pholcodine and, within 3 years, the frequency of NMBA suspected anaphylaxis. Data from Sweden where pholcodine has not been marketed since the 80’s is indicative, like in Norway, that the level of IgE-sensitisation to pholcodine has been decreasing over time in parallel to a decrease in the number of NMBA-related anaphylaxis cases3. The evidence in support of this derives from ecological studies conducted by a single research team relying on spontaneously reported adverse reactions to NMBAs. While the data from Sweden and Norway appear to be consistent, other factors can explain the observations. In recent years the Norwegian network for anaphylaxis under general anaesthesia, which collects these reports, has been subject to less intense promotion, and therefore it is possible that the observed decrease in reporting does not actually reflect lower occurrence. It is also noted that in Norway, although there is a lower number of anaphylaxis reports since

1 Johansson SGO et al. National pholcodine consumption and the prevalence of IgE-sensitisation; a multicenter study. Allergy 2010 Apr; 65 (4): 498-502. 2 Florvaag E, Johansson SGO, Irgens Å, de Pater GH. IgE-sensitisation to the cough suppressant pholcodine and the effects of its withdrawal from the Norwegian market. Allergy 2011; 66: 955–960. 3 Johansson SGO and al. Pholcodine caused anaphylaxis in Sweden 30 years ago. Allergy 2009; 64: 820-821.

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pholcodine was withdrawn, the severity of the reactions reported has not changed. Class II and III reactions still represent the majority of the reported cases, same as when pholcodine was still marketed. The absence of any report of IgE-mediated anaphylactic reaction to NMBAs in Sweden since 1990 raises further questions on the reliability of the data, as regardless of pholcodine use NMBAs would still be expected to cause anaphylactic reactions and the Swedish data does not appear to reflect this expected background rate. In countries with small populations such as Norway (4.8 million) and Sweden (9.3 million), confounding factors such as a change in anaesthetic procedures, type of products used in anaesthesia and overall use of NMBAs could play a role in explaining the findings. Even assuming that there is some biological plausibility for the pholcodine-sensitisation and that the spontaneously reported cases reflect the actual prevalence of anaphylactic reactions during surgery, a broad range of other agents may also be responsible. If indeed other substances containing quaternary ammonium ions have the ability to induce cross-sensitisation to NMBAs, and if such substances can be found in numerous household products, the specificity of IgE to pholcodine has to be questioned. This could explain the reason why data from countries such as the USA or the Netherlands does not fit with the pholcodine hypothesis: in these countries pholcodine is not marketed, and still prevalence of IgE to pholcodine and morphine was found to be high. Ultimately, even if the prevalence of sensitisation is high, the clinical relevance of these findings is questionable. A further issue for consideration is that anaphylactic reactions to pholcodine itself appear to be rare. Very few cases have been described with a substance that has been extensively used for decades and that is even available in some countries without medical prescription. An ad-hoc expert group composed mainly of immunologists and anaesthesiologists was consulted to provide advice to CHMP on this issue. The group had split views about the strength of the evidence of an association between pholcodine exposure and allergic reactions to NMBAs, although it was agreed that this is an issue that warrants further investigation. The majority of the experts considered that although sensitisation to pholcodine and development of allergic reactions to NMBAs is a possibility, the existing evidence is weak mainly due to inconsistencies and methodological bias. To support this opinion, some experts referred to the data from the USA showing that there is sensitisation even in the absence of pholcodine consumption, which strengthens the view that other substances are able to trigger this kind of cross-sensitisation. Other experts questioned the specificity of the tests used by the Norwegian research team to detect IgE sensitisation to pholcodine, referred to the lack of a rigorous inclusion criterion for anaphylaxis (ie permitting cases undergoing spontaneous recovery, or a 'mild' presentation) in the investigations, and reference was also made to the use of spontaneously reported adverse events to determine incidence of NMBA-related anaphylaxis. Divergent opinions were expressed on the strength of the epidemiological evidence, based on the Swedish and the Norwegian experiences and the quasi experiment resulting from the discontinuation of the drug in the two countries at different timings and the biological plausibility of the hypothesis. The experts also considered that the decision to use a NMBA is based on clinical need and cannot be avoided, regardless of history of pholcodine use. Therefore investigating pholcodine exposure prior to anaesthesia is currently not done and it would likely be a complicated process, as the majority of patients either will not know or will not remember that they have taken it. In a real-life situation where specialists are unable to take this factor into account in clinical practice, investigation of the pholcodine exposure in individual patients prior to anaesthesia is not considered to be of benefit as it will not change anaesthetic practice. There is a large body of literature demonstrating the existence of centrally-acting cough suppressant properties of opiates, and pholcodine in particular has been used in this indication since the 1950’s. Being an old product, the methodology used in most efficacy studies with pholcodine would be considered poor by modern standards. Most studies were not adequately controlled, either with active or placebo medications, and some were performed using combination products, which makes it difficult to isolate and measure the efficacy of the single component pholcodine. No study has been performed on the long term effects of pholcodine. Nevertheless, the existing data is consistent and supportive of the efficacy of pholcodine in the treatment of acute non-productive cough.

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The most recent study conducted by Zambon and published in 2006, comparing pholcodine and dextrometorphan in a randomised and blinded design, showed they had similar efficacy in reducing day and night-time cough frequencies in adult patients suffering with acute non-productive cough. This study has limitations such as a lack of a placebo control arm and the non-validated and subjective nature of the outcomes (cough frequency and intensity), but an effect was observed very early in the treatment. The results support the efficacy of pholcodine in the treatment of acute non-productive cough. Conclusion and recommendations Taking into account all of the above, the CHMP concluded that the evidence of a link between pholcodine and NMBA-related anaphylaxis is circumstantial, not entirely consistent and does not support the conclusion that there is a significant risk of cross-sensitisation to NMBAs and subsequent development of anaphylaxis during surgery. Further data needs to be generated to clarify the possibility of an association between pholcodine use and NMBA-related anaphylaxis. The Committee therefore concluded that, based on currently available information, the benefits of pholcodine in the treatment of non-productive cough outweigh the risks, and that the benefit-risk balance of pholcodine-containing products in the treatment of non-productive cough is positive under normal conditions of use. The Committee therefore recommended the maintenance of the marketing authorisation for pholcodine-containing products. Nevertheless the Committee considered that the possibility of an association between pholcodine use and NMBA-related anaphylaxis needs to be further investigated. For this purpose, Marketing Authorisation Holders shall conduct a case-control study as described in annex III of this opinion. The draft protocol of the study should be submitted to CHMP within 3 months of the Commission Decision. Considering that as a part of this procedure: - The CHMP already assessed the evidence available to date from across the Member States on this topic, and during the assessment has been able to identify its shortcomings - The preliminary proposals for the study protocol submitted by different MAHs have already been reviewed by the CHMP during this referral procedure The Committee considers it important to coordinate the review of the protocol of the case-control study to ensure the studies are suited to generate the data required to assess the possible association between pholcodine use and NMBA-related anaphylactic reactions.

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Grounds for the maintenance of the marketing authorisations The Committee reviewed the available data on the safety and efficacy of pholcodine, particularly the data in support of a link between pholcodine use and development of NMBA-related anaphylaxis. The Committee considered that evidence of an association between pholcodine use and development of NMBA-related anaphylaxis is circumstantial, not entirely consistent and therefore does not support the conclusion that there is a significant risk of cross-sensitisation to NMBAs and subsequent development of anaphylaxis during surgery. The Committee also considered that data from clinical trials and extensive post marketing use has demonstrated the efficacy of pholcodine in the treatment of non productive cough. The Committee therefore concluded that, based on currently available information, the benefit-risk balance of pholcodine-containing products in the treatment of non-productive cough is positive under normal conditions of use. The Committee recommended the maintenance of the marketing authorisations for the medicinal products referred to in Annex I. The conditions affecting the marketing authorisations are set out in Annex III.

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Annex III

Conditions of the marketing authorisation

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National Competent Authorities, coordinated by the Reference Member State where applicable, shall ensure that the following conditions are fulfilled by the Marketing Authorisation Holders: A case-control study shall be performed to further investigate the possibility of an association between pholcodine use and NMBA-related anaphylactic reactions. A draft protocol should be submitted to CHMP for assessment and approval within 3 months of the Commission Decision. The final study report should be submitted to the National Competent Authorities by December 2016.

annex i list of the names, pharmaceutical forms, strengths...

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