{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T14:09:58Z","timestamp":1790518198416,"version":"4.1.0"},"reference-count":56,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2019,6,20]],"date-time":"2019-06-20T00:00:00Z","timestamp":1560988800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacoepidemiology and Drug"],"published-print":{"date-parts":[[2019,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Purpose<\/jats:title><jats:p>In June 2013, following recommendations from the World Health Organization (WHO) and Food and Drug Administration (FDA), the European Medicines Agency agreed updates to the codeine product information regarding use for pain in children younger than 12 years and children undergoing tonsillectomy or adenoidectomy (TA) for obstructive sleep apnoea. This study was conducted to (a) assess effectiveness of these measures on codeine prescribing in the \u201creal\u2010world\u201d setting and (b) test feasibility of a study using a common protocol by regulators with access to databases.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The study was performed using BIFAP (Spain), CPRD (UK), and IMS\u00ae Disease Analyzer (France and Germany) databases. Prescribers included general practitioners (GPs) (France and UK), GPs and paediatricians together (Spain), and GPs, paediatricians, and ear, nose, and throat (ENT) specialists separately (Germany). Between January 2010 and June 2015, prevalence of codeine prescribing was obtained every 6 months, and a time series analysis (joinpoint) was performed. Codeine prescribing within \u00b130 days of TA was also identified. Furthermore, doses, durations, and prior prescribing of other analgesics were investigated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Over the 5\u2010year period, codeine prescribing decreased in children younger than 12 years (by 84% in France and Spain, 44% in GP practices in Germany, and 33% in the United Kingdom). The temporal pattern was compatible with the regulatory intervention in France and the United Kingdom, whereas a decrease throughout the study period was seen in Germany and Spain. Decreased prescribing associated with TA was suggested in ENT practices in Germany.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Codeine prescribing for children decreased in line with introduced regulatory measures. Multidatabase studies assessing impact of measures by EU regulators are feasible.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pds.4836","type":"journal-article","created":{"date-parts":[[2019,6,20]],"date-time":"2019-06-20T10:30:02Z","timestamp":1561026602000},"page":"1086-1096","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["A European multicentre drug utilisation study of the impact of regulatory measures on prescribing of codeine for pain in children"],"prefix":"10.1002","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9544-9163","authenticated-orcid":false,"given":"Karin","family":"Hedenmalm","sequence":"first","affiliation":[{"name":"Business, Data and Analytics Department European Medicines Agency  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Blake","sequence":"additional","affiliation":[{"name":"Specialised Scientific Disciplines Department European Medicines Agency  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Donegan","sequence":"additional","affiliation":[{"name":"Vigilance and Risk Management of Medicines Medicines and Healthcare Products Regulatory Agency  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel\u2010Angel","family":"Macia","sequence":"additional","affiliation":[{"name":"Division of Pharmacoepidemiology and Pharmacovigilance Spanish Agency for Medicines and Medical Devices  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Gil","sequence":"additional","affiliation":[{"name":"Division of Pharmacoepidemiology and Pharmacovigilance Spanish Agency for Medicines and Medical Devices  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Williams","sequence":"additional","affiliation":[{"name":"Pharmacovigilance and Risk Management Planning Medicines and Healthcare Products Regulatory Agency  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dolores","family":"Montero","sequence":"additional","affiliation":[{"name":"Division of Pharmacoepidemiology and Pharmacovigilance Spanish Agency for Medicines and Medical Devices  Madrid Spain"},{"name":"Spanish Medicines &amp; Medical Devices Agency (Agencia Espa\u00f1ola de Medicamentos y Productos Sanitarios)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianmario","family":"Candore","sequence":"additional","affiliation":[{"name":"Business, Data and Analytics Department European Medicines Agency  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Morales","sequence":"additional","affiliation":[{"name":"Pharmacovigilance and Epidemiology Department European Medicines Agency  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9838-7754","authenticated-orcid":false,"given":"Xavier","family":"Kurz","sequence":"additional","affiliation":[{"name":"Pharmacovigilance and Epidemiology Department European Medicines Agency  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Arlett","sequence":"additional","affiliation":[{"name":"Pharmacovigilance and Epidemiology Department European Medicines Agency  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,6,20]]},"reference":[{"key":"e_1_2_9_2_1","volume-title":"Codeine therapy and CYP2D6 genotype","author":"Dean L","year":"2012"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.tpj.6500285"},{"key":"e_1_2_9_4_1","unstructured":"World Health Organization.Unedited report of the 18th Expert Committee on the Selection and Use of Essential Medicines. Geneva Switzerland;2011."},{"key":"e_1_2_9_5_1","unstructured":"World Health Organisation.WHO guidelines on the pharmacological treatment of persisting pain in children with medical illnesses Geneva Switzerland;2012Contract No.: ISBN 978 92 4 154812 0"},{"key":"e_1_2_9_6_1","unstructured":"FDA Drug Safety Communication.Codeine use in certain children after tonsillectomy and\/or adenoidectomy may lead to rare but life\u2010threatening adverse events or death:thasso.com;2014[Available from:http:\/\/thasso.com\/fda\u2010drug\u2010safety\u2010communication\u2010codeine\u2010use\u2010in\u2010certain\u2010children\u2010after\u2010tonsillectomy\u2010andor\u2010adenoidectomy\u2010may\u2010lead\u2010to\u2010rare\u2010but\u2010life\u2010threatening\u2010adverse\u2010events\u2010or\u2010death\/."},{"key":"e_1_2_9_7_1","unstructured":"US Food and Drug Administration.Drug safety communications. Safety review update of codeine use in children; new boxed warning and contraindication on use after tonsillectomy and\/or adenoidectomy. US Food and Drug Administration;2012[Available from:https:\/\/www.fda.gov\/downloads\/drugs\/drugsafety\/ucm339116.pdf."},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.3109\/15360288.2014.938888"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.5055\/jom.2013.0156"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMp1302454"},{"key":"e_1_2_9_11_1","unstructured":"FDA.FDA Drug Safety Communication: FDA restricts use of prescription codeine pain and cough medicines and tramadol pain medicines in children; recommends against use in breastfeeding women United States of America 2017[Available from:https:\/\/www.fda.gov\/Drugs\/DrugSafety\/ucm549679.htm."},{"key":"e_1_2_9_12_1","unstructured":"EMA\/697484\/2012.Review of codeine\u2010containing medicines started London United Kingdom: European Medicines Agency;2012[Available from:http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/Referrals_document\/Codeine_containing_medicinal_products\/Procedure_started\/WC500133297.pdf."},{"key":"e_1_2_9_13_1","unstructured":"EMEA\/H\/A\u201031\/1342.Assessment report for codeine\u2010containing medicinal products indicated in the management of pain in children. Committee PRA;201324 June 2013. Report No."},{"key":"e_1_2_9_14_1","unstructured":"EMA\/350259\/2013.PRAC recommends restricting the use of codeine when used for pain relief in children London United Kingdom;2013[Available from:http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/Referrals_document\/Codeine_containing_medicinal_products\/Recommendation_provided_by_Pharmacovigilance_Risk_Assessment_Committee\/WC500144445.pdf."},{"key":"e_1_2_9_15_1","unstructured":"BfArM.Codeine: genetic polymorphism\u2014paediatric deaths.2012[Available from:https:\/\/www.bfarm.de\/SharedDocs\/Risikoinformationen\/Pharmakovigilanz\/EN\/RI\/2012\/RI\u2010codeinhaltige\u2010am\u2010kinder.html."},{"key":"e_1_2_9_16_1","unstructured":"BfArM.Medicinal products containing codeine for treatment of pain in children: key messages from the PRAC for consideration.2013[Available from:https:\/\/www.bfarm.de\/SharedDocs\/Risikoinformationen\/Pharmakovigilanz\/EN\/RI\/2013\/RI\u2010codeinhaltige\u2010am\u2010kinder.html."},{"key":"e_1_2_9_17_1","unstructured":"ANSM.Le Comit\u00e9 pour l'Evaluation des Risques en mati\u00e8re de Pharmacovigilance (PRAC) lance une r\u00e9\u00e9valuation du rapport b\u00e9n\u00e9fice\/risque des m\u00e9dicaments contenant de la cod\u00e9ine et des m\u00e9dicaments contenant du diclof\u00e9nac \u2010 Retour d'information sur le PRAC.2012[Available from:http:\/\/ansm.sante.fr\/S\u2010informer\/Travaux\u2010de\u2010l\u2010Agence\u2010Europeenne\u2010des\u2010Medicaments\u2010EMA\u2010Comite\u2010pour\u2010l\u2010evaluation\u2010des\u2010risques\u2010en\u2010matiere\u2010de\u2010pharmacovigilance\u2010PRAC\/Le\u2010Comite\u2010pour\u2010l\u2010Evaluation\u2010des\u2010Risques\u2010en\u2010matiere\u2010de\u2010Pharmacovigilance\u2010PRAC\u2010lance\u2010une\u2010reevaluation\u2010du\u2010rapport\u2010benefice\u2010risque\u2010des\u2010medicaments\u2010contenant\u2010de\u2010la\u2010codeine\u2010et\u2010des\u2010medicaments\u2010contenant\u2010du\u2010diclofenac\u2010Retour\u2010d\u2010information\u2010sur\u2010le\u2010PRAC."},{"key":"e_1_2_9_18_1","unstructured":"ANSM.M\u00e9dicaments \u00e0 base de t\u00e9traz\u00e9pam d'almitrine de ran\u00e9late de strontium et de cod\u00e9ine (chez l'enfant) \u2010 Retour d'information sur le PRAC.2013[Available from:http:\/\/ansm.sante.fr\/S\u2010informer\/Travaux\u2010de\u2010l\u2010Agence\u2010Europeenne\u2010des\u2010Medicaments\u2010EMA\u2010Comite\u2010pour\u2010l\u2010evaluation\u2010des\u2010risques\u2010en\u2010matiere\u2010de\u2010pharmacovigilance\u2010PRAC\/Medicaments\u2010a\u2010base\u2010de\u2010tetrazepam\u2010d\u2010almitrine\u2010de\u2010ranelate\u2010de\u2010strontium\u2010et\u2010de\u2010codeine\u2010chez\u2010l\u2010enfant\u2010Retour\u2010d\u2010information\u2010sur\u2010le\u2010PRAC."},{"key":"e_1_2_9_19_1","unstructured":"ANSM.M\u00e9dicaments contenant du diclof\u00e9nac de l'hydroxy\u00e9thylamidon de la cod\u00e9ine (pour l'enfant) et solutions pour nutrition parent\u00e9rale pour pr\u00e9matur\u00e9s: Avis et recommandations du PRAC.2013[Available from:http:\/\/ansm.sante.fr\/var\/ansm_site\/storage\/original\/application\/7fdcee31af258aed8eccb755ad52e443.pdf."},{"key":"e_1_2_9_20_1","unstructured":"ANSM.M\u00e9dicaments \u00e0 base de t\u00e9traz\u00e9pam d'almitrine de ran\u00e9late de strontium et de cod\u00e9ine (chez l'enfant): avis et recommandations du PRAC \u2010 Communiqu\u00e9 de l'EMA.2013[Available from:http:\/\/ansm.sante.fr\/var\/ansm_site\/storage\/original\/application\/a8691b2745368aa4073132f117ba1efc.pdf."},{"key":"e_1_2_9_21_1","unstructured":"MHRA.Codeine\u2010containing pain relief in children. Safety review initiated following post\u2010surgical fatalities in ultra\u2010rapid metabolisers.2012[Available from:https:\/\/www.gov.uk\/drug\u2010safety\u2010update\/codeine\u2010containing\u2010pain\u2010relief\u2010in\u2010children."},{"key":"e_1_2_9_22_1","unstructured":"MHRA.Codeine for analgesia: restricted use in children because of reports of morphine toxicity2013Available from:https:\/\/www.gov.uk\/drug\u2010safety\u2010update\/codeine\u2010for\u2010analgesia\u2010restricted\u2010use\u2010in\u2010children\u2010because\u2010of\u2010reports\u2010of\u2010morphine\u2010toxicity."},{"key":"e_1_2_9_23_1","unstructured":"AEMPS.Code\u00edna: restricciones de uso como analg\u00e9sico en pediatr\u00eda.2013Available from:https:\/\/www.aemps.gob.es\/informa\/notasInformativas\/medicamentosUsoHumano\/seguridad\/2013\/NI\u2010MUH_FV_17\u20102013\u2010codeina.htm."},{"key":"e_1_2_9_24_1","unstructured":"Royal College of Anaesthetists.Guidance for the administration of codeine and alternative opioid analgesics in children United Kingdom.2013Available from:https:\/\/www.rcoa.ac.uk\/system\/files\/CodeineGuidance2013.pdf."},{"key":"e_1_2_9_25_1","unstructured":"Kvalitetsregistret f\u00f6r tonsilloperation.Nationella riktlinjer f\u00f6r farmakologisk behandling av sm\u00e4rta och illam\u00e5ende i samband med tonsillotomi och tonsillektomi p\u00e5 barn och ungdomar (< 18 \u00e5r) Sweden.2013Available from:https:\/\/registercentrum.blob.core.windows.net\/ton\/r\/Nationella\u2010riktlinjer\u2010f\u2010r\u2010sma\u2010rtlindring\u2010vid\u2010tonsilloperation\u2010ByUdVd6c.pdf."},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.anorl.2014.06.001"},{"key":"e_1_2_9_27_1","unstructured":"EU collaboration strengthens safety monitoring of medicines.European Commission publishes three\u2010year report on implementation of pharmacovigilance legislation [press release]. United Kingdom.2016."},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3713-c1"},{"key":"e_1_2_9_29_1","first-page":"1","volume-title":"Draft Reflection paper on a strategy for best evidence. Framework for EU regulatory network to conduct research","author":"EMA\/508487\/2014","year":"2015"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2017-1765"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/lary.26719"},{"issue":"12","key":"e_1_2_9_32_1","first-page":"881","article-title":"Provision of analgesics to children before and after the new recommendations on codeine","volume":"137","author":"Fredheim OMS","year":"2017","journal-title":"Tidsskrift for den Norske laegeforening: tidsskrift for praktisk medicin, ny raekke"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijporl.2017.07.040"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.5863\/1551-6776-23.4.293"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1097\/ACO.0000000000000455"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1111\/anae.12836"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/lary.24599"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1111\/anae.12716"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2013-4057"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1111\/coa.12216"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1186\/1824-7288-40-16"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1136\/archdischild-2013-304974"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1111\/pan.12190"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.3821\/145.6.cpj276"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.3821\/145.5.cpj222"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0212-6567(02)79129-4"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyv098"},{"key":"e_1_2_9_48_1","unstructured":"Information provided by IQVIA\/IMS Health.2016."},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.5414\/CPP47617"},{"key":"e_1_2_9_50_1","unstructured":"European Medicines Agency.Restrictions on use of codeine for pain relief in children\u2014CMDh endorses PRAC recommendation London United Kingdom 2013[Available from:http:\/\/www.ema.europa.eu\/ema\/index.jsp?curl=pages\/news_and_events\/news\/2013\/06\/news_detail_001829.jsp&mid=WC0b01ac058004d5c1."},{"key":"e_1_2_9_51_1","unstructured":"AnnexIV.Timetable for the implementation of the agreementAvailable from:http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/Referrals_document\/Codeine_containing_medicinal_products\/Position_provided_by_CMDh\/WC500147069.pdf."},{"key":"e_1_2_9_52_1","unstructured":"CracknellC.Codeine now restricted to prescription\u2010only. The Connexion.201713 July 2017;Sect. French News."},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0258(20000215)19:3<335::AID-SIM336>3.0.CO;2-Z"},{"key":"e_1_2_9_54_1","unstructured":"National Cancer Institute.Joinpoint Regression Program version 4.5.0.1 \u2010 June 2017.2017."},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1541-0420.2006.00528.x"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1532-2149.2012.00189.x"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.13469"}],"container-title":["Pharmacoepidemiology and Drug Safety"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fpds.4836","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pds.4836","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/pds.4836","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pds.4836","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,9]],"date-time":"2023-09-09T17:40:08Z","timestamp":1694281208000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/pds.4836"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,6,20]]},"references-count":56,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2019,8]]}},"alternative-id":["10.1002\/pds.4836"],"URL":"https:\/\/doi.org\/10.1002\/pds.4836","archive":["Portico"],"relation":{},"ISSN":["1053-8569","1099-1557"],"issn-type":[{"value":"1053-8569","type":"print"},{"value":"1099-1557","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,6,20]]},"assertion":[{"value":"2018-12-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-04-23","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-06-20","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}