11 February 2013 EMA/65632/2013/ Drug utilisation of codeine in children: EMA analyses of The Health Improvement Network and of the IMS Health German databases 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8613 E -mail [email protected] Website www.ema.europa.eu An agency of the European Union 1. PASS information Title Drug utilisation of codeine in children: EMA analyses of The Health Improvement Network and of the IMS Health German databases Protocol version identifier 1.0 Date of last version of the protocol 18 January 2013 EU PAS Register No: Study not registered Active substance Codeine ATC code: R05DA04, N02AA59, N02AA79 Medicinal product(s): Product reference: Procedure number: Study initiator EMA Research question and objectives On 3 October 2012, the European Medicines Agency started a review of codeine-containing medicines under Article 31 of Directive 2001/83/EC. Recent concerns have arisen over an increased risk of morphine toxicity when codeine is given to children after surgery. In particular, cases have been reported of fatal or life-threatening respiratory depression in children who are ultra-rapid metabolisers and were given codeine after surgical removal of the tonsils. On 31 October 2012 the scope of the review was extended from post-surgery pain relief in children to pain relief in children. This study seeks to determine the extent to which codeine is prescribed or dispensed to children and the incidence of death occurring within this population. Analyses are done in the THIN database (UK general practice) and IMS database (German general and specialists practice). Authors Gianmario Candore & Kristian Svendsen 2. Marketing authorisation holder Marketing authorisation holder(s) Multiple 2 Table of contents 1. PASS information ................................................................................... 2 2. Marketing authorisation holder ............................................................... 2 3. Responsible parties ................................................................................. 5 4. Rationale and background ....................................................................... 5 5. Research question and objectives ........................................................... 5 6. Research methods ................................................................................... 6 6.1. Study design - THIN ............................................................................................. 6 6.1.1. Setting ............................................................................................................. 6 6.1.2. Variables .......................................................................................................... 6 6.1.3. Data sources ..................................................................................................... 7 6.1.4. Study size ........................................................................................................ 7 6.1.5. Data management ............................................................................................. 7 6.1.6. Data analysis .................................................................................................... 7 6.1.7. Limitations of the research methods .................................................................... 7 6.2. Study design - IMS ............................................................................................... 7 6.2.1. Setting ............................................................................................................. 7 6.2.1. Variables .......................................................................................................... 8 6.2.2. Data sources ..................................................................................................... 8 6.2.5. Study size ........................................................................................................ 8 6.2.3. Data management ............................................................................................. 8 6.2.4. Data analysis .................................................................................................... 8 6.2.5. Limitations of the research methods .................................................................... 8 6.3. Study design – Comparison of prevalence in UK, Germany, Denmark and Sweden ....... 8 6.3.1. Setting ............................................................................................................. 8 6.3.2. Variables .......................................................................................................... 8 6.3.3. Data sources ..................................................................................................... 8 6.3.4. Study size ........................................................................................................ 9 6.3.5. Data management ............................................................................................. 9 6.3.6. Data analysis .................................................................................................... 9 6.3.7. Limitations of the research methods .................................................................... 9 7. Plans for disseminating and communicating study results ...................... 9 8. Results .................................................................................................. 10 8.1. THIN ................................................................................................................. 10 8.2 IMS ................................................................................................................... 14 8.3 Comparison of prevalence in UK, Germany, Denmark and Sweden ............................ 15 8.4 Discussion and summary ...................................................................................... 16 3 9. References ............................................................................................ 18 ANNEX 1. Codes used in THIN analysis ...................................................... 19 ANNEX 2. Codes used in IMS analysis ........................................................ 28 4 List of Abbreviations AMR: Acceptable Mortality Reporting ATC: Anatomical Therapeutic Chemical, World Health Organisation classification system for drugs. CYP2D6: Cytochrome P450 2D6, liver enzyme EMA: European Medicines Agency EU: European Union GP: General Practitioner, Family Doctor PRAC: Pharmacovigilance Risk Assessment Committee THIN: The Health Improvement Network 3. Responsible parties Project lead: Gianmario Candore & Kristian Svendsen Clinical lead: Kevin Blake Statistical and sign-off: Jim Slattery 4. Rationale and background On 3 October 2012, the European Medicines Agency (EMA) started a review of codeine-containing medicines at the request of the United Kingdom regulatory authority under Article 31 of Directive 2001/83/EC. Codeine is a widely used analgesic, authorised for use in adults and children and also indicated as a cough suppressant. In the European Union (EU), codeine-containing medicines have been approved via national procedures, and are available either on prescription or over the counter in different Member States. Codeine is marketed as a single-ingredient medicine or in combination with other substances such as acetyl salicylic acid or paracetamol. Codeine is converted into morphine in the body by the CYP2D6 enzyme. It is well known that some patients who are ‘CYP2D6 ultra-rapid metabolisers’ convert codeine to morphine at a faster than normal rate, resulting in higher than normal levels of morphine in their blood. High levels of morphine can lead to toxic effects such as breathing difficulties. Prevalence of the mutations causing ultra-rapid metabolising varies widely between countries and has been estimated in Europe from 1% in the Nordic countries and 4% in Germany up to 10% of the Portuguese, Italian, Greek and Spanish population (Ingelman-Sundberg, 2005). Recent concerns have arisen over an increased risk of morphine toxicity when codeine is given to children after surgery. In particular, a very small number of cases have been reported of fatal or life-threatening respiratory depression in children who are ultra-rapid metabolisers and were given codeine after surgical removal of the tonsils or adenoids. After discussions, on 31 October 2012 the scope of the review was extended from post-surgery pain relief in children to pain relief in children. 5. Research question and objectives The PRAC review will evaluate the impact of new and existing information from available sources on the benefit risk balance of codeine-containing medicines when used for pain relief in children. 5 The present analyses concern the utilisation of codeine in children and the incidence of death occurring within this population. Codeine has a wide variety of formulations, combinations and indications. Since both pain and cough, codeine’s two primary indications, are symptoms belonging to many different possible indications this limited the possibility to conduct a proper analysis of reasons for use. We decided to focus on a single indication: tonsillectomy/adenoidectomy since it is frequently performed in young children, may require post-operative pain relief and was mentioned by the FDA in their enquiry into the use of codeine in children (FDA, 2012). Analyses will be performed in the THIN database (UK general