PROMOTING SAFETY OF MEDICINES FOR CHILDREN

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  • PROMOTING SAFETY OF MEDICINESFOR CHILDREN

    ISBN 978-92-4-156343-7

    PROMOTING SAFETY OF MEDICINES FOR CHILDREN

    Pharmacovigilance and medicine safety issues in children arerelevant to everyone who has an interest in and cares about thehealth of children. The purpose of this guideline is I) to present acase for the importance of the improving safety monitoring ofmedicines for children, II) to describe possible ways of achieving itand III) to provide an outline for national pharmacovigilanceprogrammes to make them more sensitive and open to adversereactions to medicines in children.

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  • WHO LIBRARY CATALOGUING-IN-PUBLICATION DATA:

    Promoting safety of medicines for children

    1.Pharmaceutical preparations - administration and dosage.2.Child. 3.Infant. 4.Safety. 5.Drug monitoring. 6.Adverse drug reactionreporting systems. 7.Guidelines. I.World Health Organization.

    ISBN 978-92-4-156343-7 (NLM classification: WS 366)

    WORLD HEALTH ORGANIZATION 2007

    All rights reserved. Publications of the World Health Organizationcan be obtained from WHO Press, World Health Organization,20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264;fax: +41 22 791 4857; e-mail: bookorders@who.int). Requests forpermission to reproduce or translate WHO publications whetherfor sale or for noncommercial distribution should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-mail:permissions@who.int).

    The designations employed and the presentation of the material inthis publication do not imply the expression of any opinionwhatsoever on the part of the World Health Organizationconcerning the legal status of any country, territory, city or area orof its authorities, or concerning the delimitation of its frontiers orboundaries. Dotted lines on maps represent approximate borderlines for which there may not yet be full agreement.

    The mention of specific companies or of certain manufacturersproducts does not imply that they are endorsed or recommendedby the World Health Organization in preference to others of asimilar nature that are not mentioned. Errors and omissionsexcepted, the names of proprietary products are distinguished byinitial capital letters.

    All reasonable precautions have been taken by the World HealthOrganization to verify the information contained in thispublication. However, the published material is being distributedwithout warranty of any kind, either expressed or implied. Theresponsibility for the interpretation and use of the material lies withthe reader. In no event shall the World Health Organization beliable for damages arising from its use.

    Printed in France

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    PROMOTING SAFETY OF MEDICINESFOR CHILDREN

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    Acknowledgements

    This publication was developed following a recommendation of the WHOAdvisory Committee for the Safety of Medicinal Products. The draft manuscripthas been widely circulated and discussed at several consultations withinternational experts in regulatory affairs and in paediatrics. WHO isparticularly grateful to Nilima A. Kshirsagar, India, Hansjrgen Seyberth,Germany, and the Karolinska, Sweden for their initial input to this manuscript.Sincere thanks are also due to the following persons for their valued expertisein evaluating this publication.

    Niamh Arthur, Ireland, Jrgen Beckmann, Germany, Ulf Bergman, Sweden, David Coulter, New Zealand, Gerald Dal Pan, USA, I. Ralph Edwards, Sweden, Murilo Freitas Dias, Brazil, Kenneth Hartigan-Go, Philippines, Li Dakui, China, Sten Olsson, Sweden, June Raine, UK, Anders Rane, Sweden, Gunilla Sjln-Forsberg, Sweden, Rachida Soulaymani-Bencheikh, Morocco.

    Technical editing: Mary R. Couper, WHO and Susan KaplanArt direction: Guillaume Desbiolles, Calleo PortageAssistance in production of document: Caroline Scudamore, WHO

    WHO expresses its sincere appreciation to the Government of Sweden forproviding financial support to finance the drafting of the manuscript.

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    Promoting safety of medicines for children

    1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . p. 72 Current situation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . p. 92.1 Problems with medicine treatment

    in children and adolescents around the world. . . . . . . . . . . . . . p. 92.2 Consequences of present status of the use

    of medicines in children (environmental aspects). . . . . . . . . p. 102.3 General risk factors that predispose

    children to develop an adverse reaction to a medicine (medical aspects) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . p. 11

    2.4 Differences between paediatric populations and adults . . . . . . . p. 122.5 The need for additional, independent studies

    on the development of paediatric medicines . . . . . . . . . . . . . p. 162.6 Current legal and regulatory framework . . . . . . . . . . . . . . . . . . . p. 172.7 Consequences of the lack of studies

    of medicines development in children and authorization of paediatric medicines . . . . . . . . . . . . . . . . . p. 19

    3 The essential role of safety monitoring in the life-cycle of a medicine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . p. 21

    3.1 Pre-marketing assessment of medicine safety . . . . . . . . . . . . p. 213.2 Post-marketing monitoring of medicine

    safety for medicines already on the market including those used off-label . . . . . . . . . . . . . . . . . . . . . . . . . . . . . p. 22

    3.3 Benefit-to-risk considerations in children. . . . . . . . . . . . . . . . . . . p. 234 Medication errors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . p. 254.1 Increased risk of medication errors in children . . . . . . . . . . . . p. 254.2 Incidence of medication errors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . p. 265 Primary responsibility of stakeholders . . . . . . . . . . . . . . . . . . . . . . . p. 296 Guidance: measures to be taken. . . . . . . . . . . . . . . . . . . . . . . . . . . . . p. 336.1 Improvement of awareness among stakeholders . . . . . . . . . p. 346.2 Methods, approaches and infrastructure

    for an effective system for medicine safety monitoring at the national level . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . p. 35

    6.3 Implementation of methods and structural changes for effective monitoring of medicine safety at the national level . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . p. 36

    6.4 Impact measurement and audit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . p. 377 Measures to be taken by WHO. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . p. 39

    References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . p. 41

    Annex I Pharmacovigilance methods. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . p. 43References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . p. 50

    Annex 2 Recent information on adverse reactions to marketed medicines in children. . . . . . . . . . . . . . . . . . . . . . . . . . . p. 51

    References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . p. 57

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    1. INTRODUCTION

    Monitoring the safety of medicine use in children is of paramount importancesince, during the clinical development of medicines, only limited data on thisaspect are generated through clinical trials. Use of medicines outside thespecifications described in the licence (e.g. in terms of formulation, indications,contraindications or age) constitutes off-label and off-licence use and these area major area of concern.

    These guidelines are intended to improve awareness of medicine safety issuesamong everyone who has an interest in the safety of medicines in children andto provide guidance on effective systems for monitoring medicine safety in thepaediatric populations. The document will be of interest to all health-careprofessionals, medicine regulatory authorities, pharmacovigilance centres,academia, the pharmaceutical industry and policy-makers.

    Systems for monitoring medicine safety are described in Annex 1 - Pharmacovigilancemethods and some examples of recent information on adverse reactionsto marketed medicines are discussed in Annex 2.

    Pharmacovigilance is the science and activities relating to the detection,assessment, understanding and prevention of adverse effects or any otherpossible medicine-related problems (1). For the purposes of this document,an adverse reaction to a medicine (ADR) includes not only reactions occurringduring normal use of medicines, but also reactions due to errors in medicineadministration, non-adherence, overdose, off-label use, drug abuse andadverse effects due to the use of traditional and complementary medicines.It does not address the paediatric use of vaccines. Separat