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Adverse Drug Reactions in Children the Contribution of Off-Label

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Adverse Drug Reactions in Children The Contribution of Off-label & Unlicensed Prescribing Thesis submitted in accordance with the requirements of the University of Liverpool for the degree of Doctor in Philosophy by Jennifer Ruth Bellis October 2013 Abstract Adverse drug reactions (ADRs) in children are common but their predictors are not fully characterised. It is known that both increasing age and number of concomitant medicines increase ADR risk in children, and there is also some evidence that off-label and unlicensed medicine use may contribute. The purpose of the thesis was to characterise ADRs in children, focusing on known risk factors, which have not been adequately evaluated in the literature. The contribution of off-label and unlicensed prescribing to ADR risk in children was assessed in two large prospective studies. In the first study, which evaluated ADR-related hospital admissions, off-label or unlicensed medicines were more likely to be implicated in an ADR than authorised medicines (relative risk 1.67, 95% CI 1.38, 2.02, p < 0.001). In a multivariate analysis, patients admitted under the care of oncology were more likely to have experienced an ADR (odds ratio (OR) 25.70, 95% CI 14.56, 45.38, p < 0.001). The following risk factors were also associated with increased ADR risk: increasing age (OR 1.04, 95% CI 1.00, 1.08, p = 0.045), number of authorised medicines (OR 1.25, 95% CI 1.16, 1.35, p < 0.001) and number of off-label or unlicensed medicines (OR 1.23, 95% CI 1.10, 1.36, p < 0.001). In a sub-group analysis which excluded oncology patients, age and number of authorised medicines predicted ADR risk (OR 1.05, 95% CI 1.01, 1.09, p = 0.023 and OR 1.33, 95% CI 1.23, 1.44, p < 0.001 respectively) but the number of off-label and unlicensed medicines did not (OR 1.04, 95% CI 0.89, 1.12, p = 0.627). The second prospective study examined ADRs occurring in paediatric inpatients. Again, off-label or unlicensed medicines were more likely to be implicated in an ADR than authorised medicines (OR 2.25, 95% CI 1.95, 2.59, p < 0.001). Medicines licensed in children but given to a child below the minimum age or weight recommended had the greatest risk of being implicated in an ADR. Multivariate analysis showed that increasing age (HR 1.04, 95% CI 1.02, 1.05, p < 0.001) and receipt of a general anaesthetic (HR 5.30, 95% CI 4.42, 6.35, p < 0.001) were positive predictors of ADR risk. Both the number of authorised (HR 1.22, 95% CI 1.17, 1.26, p < 0.001) and the number of off-label or unlicensed (HR 1.27, 95% CI 1.20, 1.34, p < 0.001) medicines were predictors of ADR risk. ADR detection in the above studies was based on intensive surveillance. One possible method of detecting ADRs may be through the ICD-10 clinical coding system but this has not been investigated for paediatrics. Only 31.5% of the 241 ADRs evaluated from the prospective admissions study were coded correctly using at least one ICD-10 code. The clinical coding system could contribute to pharmacovigilance if deficiencies in how ADRs are recorded in the case notes and the clinical coding system can be addressed. An important ADR detected in the admissions study was the occurrence of haemorrhage post-tonsillectomy which has been attributed to the use of dexamethasone. In order to analyse this further, a systematic review and meta-analysis of dexamethasone and non- steroidal anti-inflammatory drug (NSAID) use in paediatric tonsillectomy was undertaken. Although there were a large number of randomised controlled trials and observational studies in this area, analysis of all of these led to the conclusion that there was insufficient evidence to rule out an increased risk of haemorrhage with dexamethasone use whether in combination with NSAID or not (Peto odds ratio for dexamethasone versus another intervention 1.41, 95% CI 0.89, 2.25, p = 0.15). Further, well powered, well designed studies are needed in this area. I An important ADR detected in the in-patient study was post-operative nausea and vomiting. More detailed analysis was therefore undertaken to identify the risk factors for post-operative vomiting (POV), with a view to developing a risk score. The following were all identified as predictors of POV risk: age (OR 1.06, 95% CI 1.03, 1.10, p<0.001), duration of anaesthesia (OR 1.00, 95% CI 1.00, 1.01, p <0.001) and the use of intra-operative analgesics (OR 2.22, 95% CI 1.58, 3.12, p < 0.001). However, it was not possible to develop a robust model to predict the risk of POV because of the heterogeneity of the patient groups, the types of surgery, and the different clinical practices between different anaesthetists in terms of anti-emetic (choice, timing and doses). The use of off-label and unlicensed medicines in children is common but necessary and these medicines are frequently associated with ADRs. The rational prescribing of medicines is an important measure in the reduction of ADR risk and a solid evidence-base is a pre- requisite. The aim should be that the minimum number of medicines is used safely and effectively, at the lowest dose possible, for the minimum duration necessary. I Acknowledgements I would like to express my sincere gratitude to my supervisors, Professor Munir Pirmohamed, Professor Tony Nunn and Dr Jamie Kirkham for sharing their wealth of knowledge, expertise and enthusiasm and for guiding this work from start to finish. I would also like to thank the NIHR for providing funding for the ADRIC Programme and the ADRIC senior investigators for allowing me the opportunity to work within that programme and to undertake a research degree. Thank you to the individuals who contributed to the work within this thesis and who also provided me with encouragement and support. Dr Ruairi Gallagher, Kim Bird and Barbara McAvoy were the admissions study team and helped to develop the inpatient study methodologies. Dr Signe Thiesen, Helena Mannix, Louise Bracken, Jennifer Duncan, Elizabeth Conroy and Dr Duncan Applebe were the inpatient study team. Gavin Roper from Alder Hey pharmacy department assisted with the identification of medicines during both observational studies. Contributors to the systematic review chapter were Dr Yoon Loke, Dr Su Golder and Miss Su De. Dr Rishi Diwan advised on the risk score development. I would also like to thank Barbara Richards and Rebekah Hughes who were the indispensable ADRIC programme administrators. Finally, thank you to family and friends who have supported me in this undertaking. This thesis is dedicated to my father. II Table of contents Abstract ……………………. ............................................................................................................. I Acknowledgements .................................................................................................................. II Table of contents .................................................................................................................... III List of tables …………….. .......................................................................................................... VII Table of figures ……… ............................................................................................................... X Abbreviations used in this thesis ............................................................................................ XI Publications and presentations arising from work in this thesis .......................................... XIII 1 Introduction ..................................................................................................................... 1 1.1 Background .............................................................................................................. 1 1.2 Adverse drug reactions in children .......................................................................... 2 1.2.1 Definition of adverse drug reaction .................................................................. 2 1.2.2 Detection of adverse drug reactions ................................................................ 3 1.2.3 Incidence of adverse drug reactions in children............................................... 6 1.2.4 Risk factors for adverse drug reactions in children .......................................... 9 1.2.5 Adverse drug reaction mechanisms ............................................................... 11 1.2.6 Evaluation of adverse drug reactions ............................................................. 16 1.3 Off-label and unlicensed medicine use .................................................................. 26 1.3.1 The regulation of medicines ........................................................................... 26 1.3.2 Definitions of off-label and unlicensed medicine use .................................... 27 1.3.3 Reasons for, and prevalence of, off-label and unlicensed medicine use in children ........................................................................................................... 30 1.4 Off-label and unlicensed medicine use and adverse drug reactions in children – an overview of the existing literature ......................................................................... 31 1.4.1 Search strategy and study selection ............................................................... 31 1.4.2 Prospective studies ......................................................................................... 32 1.4.3 Retrospective studies ..................................................................................... 38 1.4.4 Studies of spontaneous
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    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 2 September 2010 (02.09.2010) WO 2010/099522 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 45/06 (2006.01) A61K 31/4164 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/4045 (2006.01) A61K 31/00 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (21) International Application Number: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/US2010/025725 HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (22) International Filing Date: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, 1 March 2010 (01 .03.2010) ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (25) Filing Language: English SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, (26) Publication Language: English TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 61/156,129 27 February 2009 (27.02.2009) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (71) Applicant (for all designated States except US): ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, HELSINN THERAPEUTICS (U.S.), INC.
  • 54450: Myalex

    54450: Myalex

    Ann Rheum Dis: first published as 10.1136/ard.28.6.590 on 1 November 1969. Downloaded from Ann. rheum. Dis. (1969), 28, 590 EVALUATION IN MAN OF FENCLOZIC ACID (I.C.I. 54,450: Myalex*), A NEW ANTI-INFLAMMATORY AGENT I. SERUM CONCENTRATION STUDIES IN HEALTHY INDIVIDUALS AND IN PATIENTS WITH RHEUMATOID ARTHRITIS BY T. M. CHALMERS, J. E. F. POHL, AND D. S. PLATT From the Departments of Rheumatology and Medicine, Manchester Royal Infirmary, and the Research Department, LC.I. Pharmaceuticals Division, Alderley Park, Macclesfield, Cheshire Fenclozic acid (I.C.I. 54,450; 2-(p-chlorophenyl) the activity of fenclozic acid was compared with that thiazol-4-ylacetic acid; Myalex*) (Hepworth, New- of aspirin. bould, Platt, and Stacey, 1969) is one representative The object of this first paper is to present the of a series of thiazolyl acetic acids which was active serum concentration data obtained in preliminary in the adjuvant-induced arthritis test in rats (New- studies in healthy individuals and in patients. A bould, 1963) and which merited more detailed subsequent paper deals with the results of the double- models blind cross-over trial in patients with rheumatoid evaluation on this and other laboratory by copyright. (Newbould, 1969). arthritis. Serum concentration studies in laboratory animals (Platt, 1969) showed that, at therapeutically active Methods doses, fenclozic acid was distributed within the Serum level studies were made in ten normal subjects "albumin space" (c. 10-15 per cent. body weight) (nine male, one female) from the staffs of the Depart- in rats, mice, guinea-pigs, dogs, and monkeys.