WHO The Selection and Use of Essential Medicines

Publication date: 2007

WHO Technical Report Series 946 THE SELECTION AND USE OF ESSENTIAL MEDICINES Report of the WHO Expert Committee, 2007 (including the 15th Model List of Essential Medicines) This report presents the recommendations of the WHO Expert Committee responsible for updating the WHO Model List of Essential Medicines. The fi rst part contains a summary of the Committee’s considerations and justifi cations for additions and changes to the Model List, including its recommendations. Annexes to the main report include the revised version of the WHO Model List of Essential Medicines (the 15th) and a list of all items on the Model List sorted according to their 5-level Anatomical Therapeutic Chemical (ATC) classifi cation codes. Other annexes cover the proposed procedure for updating and disseminating the WHO Model List of Essential Medicines, and the revised procedure for updating the content of the Interagency Emergency Health Kit. TH E SELECTIO N AN D USE O F ESSEN TIAL M EDICIN ES W HO Technical Report Series — 946 ISBN 9789241209465 TRS946 cover.indd 1TRS946 cover.indd 1 28.11.2007 11:57:3228.11.2007 11:57:32 The World Health Organization was established in 1948 as a specialized agency of the United Nations serving as the directing and coordinating authority for international health matters and public health. One of WHO’s constitutional functions is to provide objective and reliable information and advice in the fi eld of human health, a responsibility that it fulfi ls in part through its extensive programme of publications. The Organization seeks through its publications to support national health strategies and address the most pressing public health concerns of populations around the world. 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WHO Technical Report Series, No. 932, 2006 (146 pages) WHO model formulary 2006 (available in CD-ROM format only) SELECTED WHO PUBLICATIONS OF RELATED INTEREST Further information on these and other WHO publications can be obtained from WHO Press, World Health Organization, 1211 Geneva 27, Switzerland (tel. +41 22 791 3264; fax: +41 22 791 4857; e-mail: bookorders@who.int; order on line: http://www.who.int/bookorders) TRS946 cover.indd 2TRS946 cover.indd 2 19.11.2007 15:26:3619.11.2007 15:26:36 This report contains the collective views of an international group of experts, and does not necessarily represent the decisions or the stated policy of the World Health Organization WHO Technical Report Series 946 THE SELECTION AND USE OF ESSENTIAL MEDICINES Report of the WHO Expert Committee, 2007 (including the 15th Model List of Essential Medicines) Geneva 2007 WHO Library Cataloguing-in-Publication DataPublications of the World Health Organization enjoy copyright protection in accordance with the TRS946.indd iTRS946.indd i 19.11.2007 15:29:3119.11.2007 15:29:31 WHO Library Cataloguing-in-Publication Data WHO Expert Committee on the Selection and Use of Essential Medicines (15th: 2007: Geneva, Switzerland) The selection and use of essential medicines: report of the WHO Expert Committee, 2007: (including the 15th model list of essential medicines). (WHO technical report series; no. 946) 1. Essential drugs - standards. 2. Formularies - standards. 3. Drug information services - organization and administration. 4. Drug utilization. 5. Pharmaceutical preparations - classifi cation. 6. Guidelines. I. Title. II. Title: 15th model list of essential medicines. III. Series. ISBN 978 92 4 120946 5 (LC/NLM classifi cation: QV 55) ISSN 0512-3054 © World Health Organization 2007 All rights reserved. Publications of the World Health Organization can 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 for permission to reproduce or translate WHO publications — whether for 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 in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specifi c companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. This publication contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the World Health Organization. Typeset in Switzerland Printed in Switzerland TRS946.indd iiTRS946.indd ii 19.11.2007 15:29:3419.11.2007 15:29:34 iii Contents 1. Introduction 1 2. Open session 2 3. Update on current activities 4 3.1 Procedure to update and disseminate the Model List 4 3.2 Proposal for subcommittee on essential medicines for children 6 3.3 Proposal on listing fi xed-dose combination products for infectious diseases 8 3.4 Report from the Advisory Committee on Safety of Medicinal Products 10 3.5 Update of dosage forms and strengths for products on the Model List 10 3.6 Rare diseases proposal 12 3.7 Procedure for updating the content of the Interagency Emergency Health Kit 13 3.8 Late agenda item on medicines for acute care 14 3.9 Report on WHO Model Formulary 14 3.10 Report on Drug Bulletin manual 15 3.11 Review of proposal regarding critically important antibiotics 15 3.12 Advice on draft resolution on rational use of medicines 16 4. Changes made in revising the Model List by section: medicines for all populations 18 4.1 Section 2: addition of prolonged-release morphine 18 4.2 Section 6.1: deletion of levamisole as anthelminthic 19 4.3 Section 6.2.1: Beta lactam: addition of cefazolin/cefalexin 20 4.4 Section 6.2.4: Antituberculosis medicines 22 4.5 Section 6.4.2: Antiretrovirals 24 4.6 New section under 6.4.3: Addition of new section and medicine ribavirin 35 4.7 Late item: antiviral medicines for pandemic infl uenza 35 4.8 Section 6.5.2: Antileishmaniasis: addition of paromomycin 36 4.9 Section 6.5.3: Antimalarial medicines 37 4.10 Review of Section 6.5.5: Antitrypanosomal medicines 40 4.11 Section 7: Antimigraine medicines 42 4.12 Section 8.2: Cytotoxic drugs 44 4.13 Review of section 8.4: Medicines used in palliative care 45 4.14 Section 12.6: Lipid-lowering drugs: addition of simvastatin 46 4.15 Section 18.3: Contraceptives 48 4.16 Section 19.2: Sera and immunoglobulins 52 4.17 Review of section 19.3: Vaccines 54 4.18 Section 21.1: Ophthalmological preparations – Anti-infective agents 56 4.19 Section 24: Psychotherapeutic medicines – 24.2.1: Medicines used in depressive disorders 58 TRS946.indd iiiTRS946.indd iii 19.11.2007 15:29:3419.11.2007 15:29:34 iv 5. Paediatric medicines 59 5.1 Section 5: Anticonvulsants/antiepileptics 59 5.2 Section 6.2.4: Antituberculosis medicines 62 5.3 Section 6.5.3: Antimalarial medicines 63 5.5 Section 25: Medicines acting on the respiratory tract 64 5.6 Section 27: Vitamins and minerals 65 6. Summary of recommendations – additions, changes and deletions to the Model List 66 References 70 Annex 1 Declaration of interests of Committee Members 79 Annex 2 The 15th WHO Model List of Essential Medicines 81 Annex 3 The Anatomical Therapeutic Chemical (ATC) classifi cation system 117 Annex 4 Alphabetical list of essential medicines (with ATC classifi cation code numbers) 138 Annex 5 Proposed procedure to update and disseminate the WHO Model List of Essential Medicines 146 Annex 6 Revised procedure for updating the content of the Interagency Emergency Health Kit 152 TRS946.indd ivTRS946.indd iv 19.11.2007 15:29:3419.11.2007 15:29:34 v WHO Expert Committee on the Selection and Use of Essential Medicines Geneva, 19–23 March 2007 Members Dr Lisa Bero, (Rapporteur), University of California, San Francisco, CA, USA Dr Noël Cranswick, Director, Clinical Pharmacology, Royal Children’s Hospital, Parkville, Victoria, Australia Dr Rohini Fernandopulle, Senior Lecturer, Department of Pharmacology, Faculty of Medicine, University of Colombo, Sri Lanka Dr Anwar-ul Hassan Gilani, National Professor of Pharmacology, Department of Biological and Biomedical Sciences, Faculty of Health Sciences, The Aga Khan University, Karachi, Pakistan Dr Usha Gupta, Delhi Society for Promotion of Rational Use of Drugs, Delhi Government Dispensary, New Delhi, India Dr Abdelkader Helali, Director, Centre National de Pharmacovigilance et Matériovigilance, Ministère de la Santé et de la Population, Alger, Algeria Dr Alar Irs, Deputy Director-General, State Agency of Medicines, University of Tartu, Tartu, Estonia Dr Youping Li, Chinese Cochrane Centre, West China Hospital, Sichuan University, Chengdu, People’s Republic of China Dr Liliana de Lima, Executive Director, International Association for Hospice and Palliative Care, Houston, TX, USA Mr Dinesh Mehta, Executive Editor, British National Formulary, Royal Pharmaceutical Society of Great Britain, London, England Dr Marcus M. Reidenberg, (Chair), Chief, Division of Clinical Pharmacology, Weill Medical College of Cornell University, New York, NY, USA Dr Sri Suryawati, Director, Centre for Clinical Pharmacology and Medicine Policy Studies, Gadjah Mada University, Yogyakarta, Indonesia Dr Susan Walters, Lyons, ACT, Australia Dr Lenita Wannmacher, Department of Clinical Pharmacology, School of Medicine, University of Passo Fundo, Rio Grande do Sul, Brazil Temporary advisers Professor Hany Abdel-Aleem, Department of Obstetrics and Gynecology, Assiut University Hospital, Assiut, Egypt Dr Albert Figueras, Fundació Institut Català de Farmacología, Servei de Farmacología Clínica, Hospital Vall d’Hebron, Barcelona, Spain Mr Andy Gray, Department of Therapeutics and Medicines Management, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, South Africa TRS946.indd vTRS946.indd v 19.11.2007 15:29:3519.11.2007 15:29:35 vi Dr Estrella Paje-Villar, Professor of Paediatrics and Pharmacology, Faculty of Medicine, University of Sto. Tomas, Sampaloc, Manila, Philippines Dr Thamizhanban Pillay, Pharmaceutical Economic Evaluation, National Department of Health, Pretoria, South Africa Representatives of other organizations United Nations Children’s Fund (UNICEF) Dr Hanne Bak Pedersen, UNICEF Supply Division, Copenhagen, Denmark United Nations Population Fund (UNFPA) Dr Lindsay Edouard, Senior Adviser, Reproductive Health Branch, United Nations Population Fund, New York, USA Secretariat Dr Suzanne Hill, Scientist, Policy, Access and Rational Use (PAR)/Medicines Policy and Standards (PSM) and Secretary of the WHO Expert Committee on the Selection and Use of Essential Medicines, WHO, Geneva, Switzerland Dr Hans V. Hogerzeil, Director, Medicines Policy and Standards (PSM), WHO, Geneva, Switzerland Dr Clive Ondari, Coordinator, Policy, Access and Rational Use (PAR)/Medicines Policy and Standards (PSM), WHO, Geneva, Switzerland Dr Jane Roberston, Policy, Access and Rational Use (PAR)/Medicines Policy and Standards (PSM), WHO, Geneva, Switzerland Dr Budiono Santoso, Health Technology and Pharmaceuticals, Health Sector Development, DHS/PHA, WHO Regional Offi ce for the Western Pacifi c (WPRO), Manila, Philippines Dr Lilia Ziganshina, Policy, Access and Rational Use (PAR)/Medicines Policy and Standards (PSM), WHO, Geneva, Switzerland Dr Howard Zucker, Assistant Director-General, Health Technology and Pharmaceuticals (HTP Cluster), WHO, Geneva, Switzerland TRS946.indd viTRS946.indd vi 19.11.2007 15:29:3519.11.2007 15:29:35 1 1. Introduction The WHO Expert Committee on the Selection and Use of Essential Medicines met in Geneva from 19 to 23 March 2007. The meeting was opened on behalf of the Director-General by Dr Howard Zucker, Assistant Director-General for Health Technology and Pharmaceuticals. He stated that WHO’s medicines programme is very important to Member States and that the recommendations made by its Expert Committees were critical. He briefl y explained some aspects of the Committee procedures. He stated that the Committee is not a representative one, that all members participated in their personal capacity and are not allowed to take instructions from any government or any other authority. (See Annex 1 for Committee members’ declarations of interest.) Prior to the open session, Dr Hans V. Hogerzeil, Director of the Department of Medicines Policy and Standards, addressed the Committee. He noted that this would be the fourth meeting of the Expert Committee operating under the new procedures approved in 2002 and that the early posting of most documents on the web site, together with the rounds of review and comments prior to the meeting ensured the transparency of the process. Dr Hogerzeil also noted that this year is the 30th anniversary of the Essential Medicines List, and that it was timely to examine the future role of the list particularly in the context of supporting primary health care, identifi ed by the Director-General as a priority for WHO. The WHO Secretariat requested and received agreement from the Committee to hold an open session as part of its meeting (see section 2). The purpose of the open session was to allow all stakeholders to participate in the discussions and to comment on issues relating to the WHO Model List of Essential Medicines. Furthermore, for members of the Expert Committee it provides an opportunity to receive, at fi rst-hand, additional information and opinion on matters under consideration. Discussions and opinions put forward during the open session are refl ected in the report of the meeting. The Committee decided to maintain the reporting format adopted at previous meetings. A summary of the Committee’s deliberations on each of the items under discussion is presented in the main body of the report. The updated version of the Model List (the 15th Model List), including a general introduction and explanatory notes, is presented in Annex 2. This Annex is also posted on the WHO web site and available in printed form in all six offi cial languages of the Organization. A list of items on the Model List ordered by their corresponding Anatomical Therapeutical Chemical (ATC) classifi cation code number(s) is attached as Annex 3. The full texts of the applications for changes, additions or deletions with all the evidence and references, as well as the external reviews and comments TRS946.indd 1TRS946.indd 1 19.11.2007 15:29:3519.11.2007 15:29:35 received, are not included in this report but remain available on the WHO web site, and are accessible through the Essential Medicines Library (http://mednet3.who.int/EMLib/). Information on medicines deleted from the Model List in the past is retained in a separate section of the library. 2. Open session The open session of the meeting was opened by Dr Howard Zucker, on behalf of the Director-General. He stated that all information submitted to the Committee in support of the evidence-based decisions would be placed in the public domain through the WHO web site. He reminded participants that all comments made during the open session would be noted and taken into consideration by the Committee when formulating fi nal recommendations in subsequent private sessions. Dr Zucker noted that 2007 was the 30th year of the Essential Medicines List. It was appropriate that in the 30th year, the 120th session of the WHO Executive Board had adopted two important draft resolutions in relation to medicines that would be discussed by the Committee. One resolution recommended an approach to rational use of medicines and the second recommended a programme of activities to improve medicines for children. Dr Zucker requested the Committee to give careful consideration to the proposal for a formal subcommittee to establish a list of essential medicines for children. As part of the open session, participants were briefed about various activities relating to the Model List (see Section 3). A number of issues were raised and debated during the open session. HIV The participants were informed about the current public health approach being used by the WHO HIV/AIDS Department. Professor Gilks described this as “managed public sector care”, with the aim of scaling up the programme on the basis of the principles of universal access and limited choices rather than based on the needs of individual patients. He outlined guidelines developed by the Department in 2006, the strategic and programmatic importance of fi xed-dose combinations to increase adherence to medication regimens, to decrease pill burden and, over time, to contribute to reduced drug resistance. The methods being used by the HIV/AIDS Department to identify the preferred treatment options were outlined. Safety A representative from the Quality Assurance and Safety: Medicines (QSM) team presented a summary of the fourth meeting of the WHO Advisory 2 TRS946.indd 2TRS946.indd 2 19.11.2007 15:29:3619.11.2007 15:29:36 3 Committee on the Safety of Medicinal Products (ACSoMP) held in February 2007. Key discussion points for the meeting were a strategy document for safety of medicines, a document on promoting the safety of medicines used to treat children and preparation of an advocacy document for pharmacovigilance. The QSM team had prepared documents addressing safety issues relevant to a number of applications under consideration by the Expert Committee. International Union of Basic and Clinical Pharmacology A presentation was made to the Committee on behalf of the Paediatric Subcommittee of the Clinical Pharmacology Division of the International Union of Basic and Clinical Pharmacology (IUPHAR), describing children as a neglected population. Children are “neglected” in the sense that they do not have access to treatment with medicinal products that meet the same standards of quality, safety and effi cacy as the treatments available to adults, although international agreements on human rights give children the right to the same level of health and health care enjoyed by others. The presentation highlighted the challenges of developing medicines for children, and the need to recognize fi ve phases of development, each of which differed with regard to metabolism and drug handling. Progress had been made within the regulatory authorities in the USA and the European Union (EU), refl ecting a commitment to the development of medicines for children. IUPHAR has formed a number of Paediatric Expert Groups at the European Agency for the Evaluation of Medical Products (EMEA) in the last three years to assess the needs of children in major clinical areas. Médecins Sans Frontières The Committee was informed about the Médecins Sans Frontières Campaign for Access to Essential Medicines. Médecins Sans Frontières supported the initiative to create an Essential Medicines List for children, encouraged WHO to accelerate the publication of this list, and urged WHO to ensure that the research and development of products for children takes place. Médecins Sans Frontières acknowledged the importance of fi xed-dose combinations in the treatment of AIDS and commented on specifi c applications to be considered by the Expert Committee (fi xed-dose combinations for HIV/AIDS and antitrypanosomal medicines). Médecins Sans Frontières recognized the role of listing medicines on the Model List in creating an incentive for producers and providers to improve the quality of a product. Médecins Sans Frontières urged the Committee not to consider the cost of a product in its deliberations. International Society of Paediatric Oncology A written statement was provided to the Committee by the President of the International Society of Paediatric Oncology (SIOP). The President TRS946.indd 3TRS946.indd 3 19.11.2007 15:29:3619.11.2007 15:29:36 4 expressed the Society’s commitment to an Essential Medicines List for Children and requested that the Society be able to participate in the deliberations with WHO. The Society recognized that about 80% of children worldwide who develop cancer currently do not receive optimal care and often do not even receive any supportive or palliative care. The Society has identifi ed a number of important steps required to make progress in the area of improved oncology and palliative care medicines for children. It wishes to encourage countries to adopt the principle of dedicated specialist units to concentrate expertise, reduce wastage and improve survival and quality of life of children with life-threatening conditions. Polyvalent human immunoglobulins Representatives from Chandigarh Hospital, India, and the Primary Immunodefi ciency Association, England, addressed the Committee on the application for the reinstatement of polyvalent human immunoglobulins (IGs). They outlined the role of IGs as replacement therapy for primary immunodefi ciency disorders, a number of which occurred in children, and as immunomodulatory agents. The representative from Chandigarh Hospital addressed what he described as misunderstandings about the treatment of these diseases, pointing out that without IGs morbidity and mortality from these conditions were substantial. The representative of the Primary Immunodefi ciency Association spoke as a patient and reiterated the statements of his co-speaker and suggested that his own experience illustrated the effi cacy and safety of IGs and the value of treatment with them. Additional comments Discussion was invited on the matters raised in the open session. The IUPHAR representative provided further comments on paediatric medicines. Comments on the application for immunoglobulins were made on behalf of the International Patient Organisation for Primary Immunodefi ciencies (IPOPI). A representative of the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) stressed the importance of the Committee considering the availability of quality products in its deliberations. Support from Health Action International (HAI) for the establishment of a steering group to engage stakeholders as part of the Rational Use of Medicines proposal was expressed. 3. Update on current activities 3.1 Procedure to update and disseminate the Model List The current “Procedure to update and disseminate the WHO Model List of Essential Medicines” was approved by the Executive Board in 2001 and TRS946.indd 4TRS946.indd 4 30.11.2007 14:29:3230.11.2007 14:29:32 5 has been used by the Expert Committee on Selection and Use of Essential Medicines since that time. The Committee has now had considerable experience in the use of these procedures, and some changes have been made as experience in evidence-based selection of medicines has developed. The Secretariat therefore proposed an update to the “Procedure” to refl ect that experience. The amendments are generally minor and refl ect the methods of reviewing applications and seeking public comment through the web site, as well as the need to ensure that adequate information is provided about each medicine in an application. The Committee supported the proposed updates and recommended that the Secretariat take appropriate steps to fi nalize them. 3.1.2 Procedure for between-meeting decisions The WHO Expert Committee on Selection and Use of Essential Medicines has met nearly every two years since it was fi rst established in 1977. In accordance with the WHO Regulations for Expert Advisory Panels and Expert Committees, the report of each committee has been fi nalized at the end of its meeting. No between-meeting decisions have been taken so far, although occasionally changes have been made to the report of the meeting and its recommendations after the conclusion of the meeting, based on written approval by all Expert Committee members. A number of other WHO programmes are reliant to a greater or lesser extent on the Model List of Essential Medicines. In particular, the programmes on HIV/AIDS, malaria and tuberculosis (TB) link their procured medicines closely to those included on the Model List, and the Prequalifi cation Programme also considers whether a medicine is on the Model List when specifying the “Expressions of Interest” for its programme. In these areas, and in the area of emerging diseases, there is an increasing need to update the Model List more often than every two years. The Regulations do not specify the methods for making decisions between formal meetings of the Committee. To accommodate the possibility of between-meeting decisions being required, it is therefore proposed to have the Committee adjourn at the end of its formal meeting and formally remain in existence until the next Committee is appointed. The Committee supported the need for making decisions about amending the Model List more often than every two years. The “between meetings” proposal of the Secretariat was one option but the Committee recommended that other options, such as more frequent meetings or virtual meetings, should also be considered. The Committee discussed whether regulatory approval of a medicine would be a prerequisite for its inclusion in the Model List. Although the decision TRS946.indd 5TRS946.indd 5 19.11.2007 15:29:3619.11.2007 15:29:36 6 to include a medicine in the Model List is generally post-regulatory, this may not always be possible. 3.2 Proposal for subcommittee on essential medicines for children In August 2006, a joint WHO–UNICEF expert consultation on essential medicines for children was held to review some of the problems associated with access to essential medicines for children. The report of the meeting is available at: http://www.who.int/medicines/publications/ UNICEFconsultation.pdf The meeting produced a list of recommended actions to be undertaken by WHO and UNICEF to improve access to essential medicines for children. One of the key recommendations was to update the WHO Model List of Essential Medicines to include essential medicines for children, based on their clinical needs and the burden of disease. In January 2007, the 120th Session of the Executive Board of the World Health Assembly (WHA) adopted a draft resolution (EB120.13) requesting the Director-General and Member States to take action to make available better medicines for children. This resolution outlines a comprehensive programme for the work needed. The WHO Secretariat has commissioned a number of preliminary papers as part of the evidence needed to support the recommendation for updating the Model List to meet the needs of children. In so doing, it has become clear that developing an up-to-date list of essential medicines for children is likely to require additional meetings of appropriate experts, as there is more work than can be completed as part of the usual agenda of the regular meetings of the Expert Committee. The are several reasons for this. The technical scope of the work needed requires additional consultation and time, for example, for developing the criteria for defi ning essential medicines for children, including defi ning age groups within “childhood”, as different age groups have different patterns of disease and different needs. A position statement on the types of dosage form to be defi ned as “essential” needs to be developed. All existing dosage forms currently on the list for children would need to be reviewed and ratifi ed as essential, and additional products would need to be reviewed, according to priorities to be established. Furthermore, the technical expertise necessary to review applications for essential medicines for children requires skills additional to those needed for a review of adult medicines. It needs to take account not only of paediatric clinical medicines, but also of factors such as the different pharmacokinetics of medicines in children of different ages. In terms of advocacy and promoting access to essential medicines for children there are distinct advantages to initially having a separate process for TRS946.indd 6TRS946.indd 6 19.11.2007 15:29:3619.11.2007 15:29:36 7 determining essential medicines for children, although in the medium-term (3–5 years) it is unlikely to be necessary to maintain a separate system. According to WHO regulations governing Expert Committees, the mechanism that can be used for this purpose is the establishment of a subcommittee of the Expert Committee with specifi c terms of reference. Formal subcommittees of Expert Committees need to be recommended by the relevant Expert Committee and approved by the Executive Board or World Health Assembly (Regulations for Expert Advisory Panels and Committees, 4.10 and 4.11). The rules governing the operation of subcommittees are the same as those governing the operation of the parent Expert Committee. Through UNITAID, the International Drug Purchase Facility being established with funding from Brazil, France, Chile, Norway and the United Kingdom, resources are now available to allow the fi rst meeting of such a subcommittee to take place in July 2007. UNITAID is being established as an innovative funding mechanism to accelerate access to high-quality drugs and diagnostics for HIV/AIDS, malaria and TB in countries with a high burden of disease. The Secretariat proposed that the fi rst meeting in July 2007 would be followed by a second meeting in mid-2008, to complete development of an Essential Medicines List for Children. It is unlikely that the subcommittee would need to continue to exist after the second meeting. It could therefore report to the 2009 regular meeting of the Expert Committee, and make proposals on how the specialized functions necessary to maintain the Essential Medicines List for Children could be carried forward. The subcommittee could be dissolved if the work were complete. The Expert Committee considered the proposal to establish a subcommittee on the Selection and Use of Essential Medicines for Children, with the following terms of reference: — develop a WHO Model List of Essential Medicines for Children, based on their clinical needs and the burden of disease; — develop suitability criteria for dosage forms of medicines for children with particular reference to the developing world; — review the feasibility of manufacturing appropriate formulations for those priority medicines for which none currently exist, specifi cally considering requirements for use in resource-limited settings and availability of data on effi cacy and safety in the appropriate age groups; — identify the gaps in clinical research regarding safety and effi cacy of essential medicines for children to improve suboptimal prescribing and dosing, and also to facilitate regulatory approval of paediatric formulations; and — report to the Expert Committee on the Selection and Use of Essential Medicines in 2009. TRS946.indd 7TRS946.indd 7 19.11.2007 15:29:3719.11.2007 15:29:37 8 The Committee noted the comments from the representatives of SIOP and IUPHAR supporting the proposal. It also noted the resolution from the 120th session of the Executive Board, EB120.13, requesting the Director-General and Member States to take action to make available better medicines for children. It therefore decided to recommend to the Director-General and the Executive Board that a subcommittee be established as proposed in the Secretariat documents. 3.3 Proposal on listing fi xed-dose combination products for infectious diseases The “Procedure to update and disseminate the WHO Model List of Essential Medicines, Criteria for Selection” was modifi ed in 2005 to include the following statement regarding fi xed-dose combination products (FDCs): “Most essential medicines should be formulated as single compounds. Fixed-dose combination products are selected only when the combination has a proven advantage over single compounds administered separately in therapeutic effect, safety, adherence or in delaying the development of drug resistance in malaria, tuberculosis and HIV/AIDS.” Given that the agenda for this meeting required consideration of several applications for new FDCs for the three main infectious diseases, the Secretariat sought clarifi cation of the principles on which drug selection should be based, before any individual application is considered. From a regulatory viewpoint, for FDCs it would also be necessary to demonstrate bioequivalence of the single combined dose unit with the components administered at the same doses separately but concomitantly. These requirements for effi cacy of the combination beyond that of the individual drugs and for bioequivalence are relevant to all clinical areas, including infectious diseases. The Committee noted the report of the 2005 Expert Committee (1) which described a number of different scenarios for possible registration of FDC products. It seemed likely that most products to be considered by the Committee would be described according to “Scenario 2” in the specifi cations i.e. “the new FDC contains the same actives in the same doses as an established regime of single entity products, and the dosage regimen is the same or the established regimen may involve combinations of single entities and FDCs, for example a single entity fi nished pharmaceutical product (FPP) combined with an FDC–FPP that contains two actives. In all cases, the established regime has a well characterized safety and effi cacy profi le, and all the FPPs used in obtaining clinical evidence have been shown to be of good quality.” TRS946.indd 8TRS946.indd 8 19.11.2007 15:29:3719.11.2007 15:29:37 9 Accepting this, the Committee noted that for products fi tting this description, this would imply that clinical trials of the FDC would not usually be required; bioequivalence between the FDC and the components could be used to infer clinical effi cacy and safety of the combination. The Committee considered the evidence available to support the proposal that FDCs improve adherence, noting the results from two recent systematic reviews (2, 3) that address the question of whether FDCs have a positive effect on adherence to medication regimens and also the WHO report from a meeting in 2003.1 These reviews reveal that there have been very few clinical trials that have assessed the relationship between FDCs and adherence to treatment, and those studies that exist have signifi cant methodological fl aws. There is therefore limited direct evidence that strongly supports the benefi ts of use of FDCs. However, the WHO report of 2003 noted that “FDCs/CBCs are very important tools for scaling up treatment for HIV and AIDS, TB and malaria and remain the fi rst choice when they are available. Fixed-dose combinations and co-blistered combinations (CBCs) must be considered as one element in an effort to ensure adherence that also includes supportive counselling, appropriate information and other measures.” One advantage of FDCs compared to loose combinations is that if one component of a loose combination is missing, resistance is more likely to develop. A disadvantage is that the optimal combinations of components may change rapidly. The Committee recognized the rapid development of the science of therapeutics in the area of infectious disease and that new FDCs may be conceptually appropriate. The Committee recognized that some FDCs could encourage rational prescribing (e.g. because they would avoid use of antagonist compounds together). The Committee also considered whether or not a decision to list an FDC requires the existence of a prequalifi ed product or whether the Committee wishes to identify FDCs that are clinically desirable, to list them and use this mechanism to encourage reputable manufacturers to produce quality products to recognized specifi cations. On balance the Committee decided that it will consider listing some existing FDCs that would be useful to countries that use the list for procurement. However, the Committee also wants to encourage the development of new FDCs and trials comparing these. 1 Fixed-dose combinations for HIV/AIDS, tuberculosis, and malaria. Report of a Meeting held 16–18 December 2003, Geneva, at: http://www.who.int/medicinedocs TRS946.indd 9TRS946.indd 9 19.11.2007 15:29:3719.11.2007 15:29:37 10 The Committee decided that co-packaged products for use in combination but not formulated as an FDC, can be assumed to be covered by listing individual components. Overall, the Committee, having reviewed its current criteria for listing FDCs as essential medicines, decided to retain them unchanged. 3.4 Report from the Advisory Committee on Safety of Medicinal Products The fourth meeting of the Advisory Committee on Safety of Medicinal Products (ACSoMP) took place on 26–27 February 2007. Reports on the safety of medicines proposed for addition to the Model List were provided by members of the Advisory Committee for review by the Expert Committee. The Committee recognized the usefulness of the reports provided. The Committee noted that it would also be helpful to have: — summaries of safety data (in contrast to the raw data) that also distinguish between data from areas with rigorous adverse event reporting systems and those from areas with no such reporting systems; — interpretation of and opinion on the safety data; and — safety data in advance of the meeting, for experts to review with the application. The Expert Committee also noted that it would be useful if the ACSoMP could develop a mechanism for collecting and interpreting safety data on currently listed medicines and reporting these data to the Committee on a regular basis. Such a reporting system could be used to promote safe use of medicines by providing early warnings of problems and could contribute to developing a process for the rapid deletion of products for safety reasons. The Safety Committee could also point out gaps in the available safety data. 3.5 Update of dosage forms and strengths for products on the Model List In 2006, the University of Liverpool, England, carried out a complete review of the web site of the WHO Medicines Library. The Committee noted the detailed report of the review. During the review, a number of products on the 14th WHO Model List of Essential Medicines were identifi ed for which the dosage form and strength given in the List were not available in a sample of markets. For some products alternative dosage forms and strengths exist in at least one of the markets. Subsequent review of the missing products in additional markets fi nally led to identifi cation of six medicines that do not appear to be registered products and in addition an important error in the strength of TRS946.indd 10TRS946.indd 10 19.11.2007 15:29:3719.11.2007 15:29:37 11 a medicine. The Secretariat carried out a limited review of the evidence for each and proposed actions for the Committee to consider: — aluminium acetate: proposed for fast-track deletion on the grounds that there was no evidence of benefi t; — iopanoic acid: proposed for fast-track deletion on the grounds of only being used as diagnostic agent in an obsolete investigation; — neomycin/bacitracin: proposed for possible deletion on the grounds of limited evidence of benefi t and alternatives being available; — nifurtimox: proposal that this medicine should be retained on the grounds of evidence of benefi t in the treatment of Chagas disease and that further information be sought about dosage form and strength; — propyliodone: proposed for fast-track deletion, on the grounds of being used for an investigation that is now obsolete; — triclabendazole: proposal that this medicine should be retained on the grounds of evidence of benefi t in fascioliasis and paragonimiasis and that further information be sought about dosage form and strength; — epinephrine: proposed change in dosing strength from 1 mg to 100 microgram/ml. The Committee agreed to delete iopanoic acid and propyliodone and to change the dose for epinephrine. The Committee noted that these proposed actions had been posted on the meeting web site for 2 months and were also circulated through e-drug, the electronic discussion group, and no comments or objections to the proposed deletions had been received. The Committee proposed to retain aluminium acetate and neomycin/bacitracin as different strengths of products had been identifi ed. However, it was noted that Section 13 of the Model List – Dermatological Medicines – was in need of general review. The Committee agreed upon the following principles for specifying dosage form and strength, and recommended that the list be revised accordingly. In general: • When a product has been in use for some years and there is a traditional means of expressing dose, change would lead to confusion. In such cases no change should be made. • WHO should follow the guidelines in the International Pharmacopoeia as to expression of dose. • Even if changes to expression of dose are desirable, it is not appropriate for the Essential Medicines Committee to make such changes unilaterally. Subject to the above, in general: • The dose of acids and bases should be expressed in terms of the free acid or free base, even if the product is presented as a salt. The salt TRS946.indd 11TRS946.indd 11 19.11.2007 15:29:3819.11.2007 15:29:38 12 form should be indicated in brackets in the form “(present as the [hydrochloride])”. • When a drug is formulated as a solvate, dose should be expressed in terms of the anhydrous substance. • The dose of esters should be expressed in terms of the ester. Different esters may have different potencies. • If: — a new product has been formulated to contain a “rounded” dose; and — pivotal clinical trials have been conducted with the specifi ed product and — one or more major regulatory authorities have approved the product in these terms, or the product is widely available; then the dose should continue to be expressed in this manner even if it does not meet the above criteria. It was also noted that clarifi cation of dose expression will highlight anomalies on the Model List but the clinical importance of differences may not be so clear. 3.6 Rare diseases proposal In 2005, the Committee considered the issue of rare diseases as a result of concerns expressed about the possible deletion from the Model List of factor VIII and factor IX and medicines for other rare diseases also known as “orphan diseases’’. At that time the Committee suggested that there was a need for WHO to establish a policy advisory group on rare diseases to study this issue. The discussion paper has now been published by Stolk et al. (4) in the Bulletin of the World Health Organization with an accompanying editorial (5). The Committee further considered the option of establishing an advisory group to consider medicines for rare diseases and to agree on selection criteria for medicines for orphan diseases. The alternative proposal is to develop mechanisms to formally incorporate cost-effectiveness analysis as a basis for decision-making for all products. The technical requirements for cost-effectiveness evaluation of pharmaceuticals at the global level are substantial, and require methodological development. The Committee might need to defi ne “acceptable” cost-effectiveness thresholds, as has emerged from decision- making systems using cost-effectiveness evaluations in Australia and the UK (6). The Committee acknowledged the methodological diffi culties related to assessing applications for medicines for rare diseases. The Committee decided to maintain the current approach for selecting essential medicines including medicines for rare diseases. This is, effectively, maintaining the approach of considering comparative effectiveness, safety, TRS946.indd 12TRS946.indd 12 19.11.2007 15:29:3819.11.2007 15:29:38 13 cost and need, taking overall public health into consideration. WHO is encouraged to develop relevant cost-effectiveness methodologies for the selection of essential medicines for rare diseases. 3.7 Procedure for updating the content of the Interagency Emergency Health Kit The agencies of the United Nations system and international and nongovernmental organizations are increasingly called upon to respond to large-scale emergencies, many of which pose a serious threat to health. Much of the assistance provided in such situations is in the form of medicines and medical devices (renewable and equipment). During the 1980s, WHO took up the question of how emergency responses could be facilitated through effective emergency preparedness measures. The aim was to encourage the standardization of medicines and medical supplies needed in emergencies to permit a swift and effective response to the need for medicines and medical devices by providing standard, pre- packed kits that could be kept in readiness to meet priority health needs in emergencies. The “WHO Emergency Health Kit” was the fi rst such kit when it was launched in 1990. The second kit, “The New Emergency Health Kit 98” was the outcome of the revision and further harmonization by WHO in collaboration with a large number of international and nongovernmental agencies. The third kit, the “Interagency Emergency Health Kit 2006” (IEHK 2006), accommodates emergency care of people with AIDS, the increasing antimicrobial resistance to commonly available antimalarials and antibiotics, injection safety policy, and the experience of agencies using the emergency health kit in the fi eld. The content of the emergency health kit is based on the health needs of 10 000 people for a period of three months, the acute phase of an emergency. The kit is composed of 10 basic units and one supplementary unit. Over the years, the number of partners included has risen from two in the early 1980s to more than 10 partners and suppliers in 2006. The kit was last updated by consensus and there were some diffi culties and delays in doing so. As a result, the Secretariat has proposed a process to formalize future revisions, including oversight by the Expert Committee after appropriate consultation. The Committee reviewed the proposal to update the procedures for revising the Emergency Health Kit and, with the following modifi cations, endorsed the proposal from the Secretariat. The Model List will serve as a basis for including medicines in the IEHK. Therefore, if a medicine already appears on the Model List, a full application will not be required. Supplementary TRS946.indd 13TRS946.indd 13 19.11.2007 15:29:3819.11.2007 15:29:38 14 information on quantities and sources of the medicines may be required. The Committee noted that the IEHK does not currently address the needs of children. The procedures are described in Annex 6. 3.8 Late agenda item on medicines for acute care The Committee commented on a late agenda item, which proposed identifying medicines used for acute or emergency care. The Secretariat was requested to systematically gather data to create a list of the types of medicines currently used in emergency care and to compare this list with the Model List. 3.9 Report on WHO Model Formulary The WHO Model Formulary (WMF) was fi rst published in 2002, after the WHO Expert Committee on Selection and Use of Essential Medicines recommended its development in 1995. The original purpose of the Formulary was: “to provide general information and information on prototype drugs in the Model List of Essential Drugs according to the specifi cations as shown in the sample drug information sheet overleaf. This information could then be adapted by countries according to their own needs and would be a key element in rational drug use.” The WMF was updated in 2004, and published as a book, a CD and in an online version. In addition, a manual designed to assist countries to adapt the WMF to national needs was published. Both the 2002 and 2004 editions of the WMF were prepared by the Royal Pharmaceutical Society (RPS) of Great Britain on contract to WHO, and the manual benefi ted from considerable input from the Society as well. The preparation for the 2006 edition did not start until October 2005. There were numerous subsequent delays in the process and the 2006 edition was not published on the web site until January 2007. The Committee noted the review of the need for the formulary carried out by the Medicines Policy and Standards department of WHO. From the relatively limited feedback, it would seem that the WMF is used in a variety of ways for many different purposes, including as a reference in clinical practice or as a policy tool. Importantly, the print version was reported to be used by more respondents than the electronic version. The WMF is also used by UNICEF as the source of drug information related to the products it supplies, is included (in printed form) as a reference book in emergency health kits, and has been adapted by several countries and organizations. The WMF can serve as a source document for a national formulary. This could be achieved by providing an electronic document that can be edited and adapted. TRS946.indd 14TRS946.indd 14 19.11.2007 15:29:3819.11.2007 15:29:38 15 The Committee considered the report from the Secretariat, the response from the RPS and comments by expert reviewers. Overall, it is apparent that there is a need for the Model Formulary, as it is an important source of drug information in settings with limited resources. The printed version is essential. However, the Committee agreed that the current production process was not satisfactory and therefore supported the proposal by the Secretariat to consider other ways of generating and maintaining the text. Possible options discussed were: — full technical review of monographs only for newly added medicines; — less frequent production of the formulary; — development of mechanisms for dealing with different electronic formats; — local producton of print copies, or invitation of competitive bids for production. The Committee recommended a pilot project to produce national formularies derived from an electronic version of the WMF and suffi cient funding to accomplish this goal. The Committee also noted the report on the technical update of the Essential Medicines Library. 3.10 Report on Drug Bulletin manual In 2005, WHO and the International Society of Drug Bulletins (ISDB) published a manual entitled “Starting or strengthening a drug information bulletin”. The authors came from both developed and developing countries. The manual provides detailed information on drug bulletins, planning, the editorial process, reviewing a new drug, design and production of the bulletin, dissemination, evaluating quality and usefulness of the product, and partnership and collaboration. The fi rst 100 copies of the manual were produced with the fi nancial support of the European Union. ISDB objected to this arrangement and the manual is now only available electronically on the WHO and ISDB web sites. The Committee noted the report on the manual, regretted the lack of adequate publication and dissemination and endorsed the proposal that the manual be included on the CD-ROM with the WHO Model Formulary. 3.11 Review of proposal regarding critically important antibiotics In 2005, the Committee considered a report from a working group consultation that took place in February 2005 in Canberra, Australia, with the remit of developing the concept of critically important antibiotics. This involved defi ning criteria for classifying antibiotics according to their level of importance for use in humans and then classifying all antibiotics according TRS946.indd 15TRS946.indd 15 19.11.2007 15:29:3919.11.2007 15:29:39 16 to these criteria. It is envisaged that recommendations will be made that antibiotics deemed critically important should not be used in non-humans. The results of the consultation are reported in the document Critically important antibacterial agents for human medicine for risk management strategies of non-human use. The Committee noted the value of this report and recognized its importance for human health. The Committee endorsed the concept of identifying antibiotics that should be reserved for use only in humans and supports WHO taking the initiative to identify these antibiotics. It was noted that the labels of “critically” and “highly” important could be confusing and the full defi nitions of these categories could be used instead. In response to the specifi c questions put to the Committee, the following comments were made: • How does the concept of critically important antibiotics fi t in with that of essential antibiotics? If the two concepts are different, how can we ensure there is a clear understanding of the two concepts by Member States and other interested parties? This will necessarily require consideration of the criteria for defi ning essential antibiotics and critically important antibiotics. The Committee noted that the report states that this list of antibiotics is different to the antibiotics on the Model List. • What process should be used for taking forward the issue of critically important antibiotics that are also essential antibiotics? Should a committee of experts sit regularly to advise WHO on how to preserve the effectiveness of these drugs taking into consideration human use as well as animal use? What should be its structure, procedures and membership? The Committee recommends that WHO establish an advisory group that will meet regularly to produce and update the list of antibiotics that are permissible or not for non-human use. This should be an interagency structure involving the Food and Agriculture Organization of the United Nations (FAO) and the World Organisation for Animal Health (OIE). • How should antibiotics that are deemed essential (i.e. included in the Model List of Essential Medicines), but not critically important be dealt with? Should specifi c recommendations be made with regard to their use in animals? The Committee urges the newly constituted Advisory Group to consider these questions. 3.12 Advice on draft resolution on rational use of medicines In 2005, the 58th World Health Assembly discussed Rational use of medicines by prescribers and patients (7) in the context of the threat posed to global TRS946.indd 16TRS946.indd 16 19.11.2007 15:29:3919.11.2007 15:29:39 17 health security by antimicrobial resistance and adopted resolution WHA58.27 on Improving the containment of antimicrobial resistance. At that time many Member States underlined the need for more to be done to rectify the serious global problem of irrational use of medicines. Thus, the Executive Board discussed Rational use of medicines: progress in implementing the WHO Medicines Strategy (8) at its 118th session in May 2006 and again at its 120th session in January 2007. EB resolution 120.R12 was adopted for further consideration at the World Health Assembly in May 2007. The Committee considered the resolution and the Secretariat’s report, together with the other referenced documents and the proposed plan of implementation, and considered the following questions: • Does the present EB resolution to be submitted to the WHA in May 2007 suffi ciently address the needs outlined in the Secretariat's report? If not, what is missing and what needs to be added? The Committee felt that the resolution provided a good starting point for implementing the proposed global programme to promote rational drug use. • Should a steering committee be established to oversee implementation of a global programme to promote rational use of medicines as envisioned in the present Secretariat's report and draft resolution? If so: — Should it be a subcommittee of the Expert Committee on Selection and Use of Essential Medicines? — What should be its membership? — How often should it meet? The Committee endorsed the formation of an Advisory Group which could draw members from WHO panels or Expert Committees, including, for example, the Essential Medicines Committee. The Committee recommended that the Advisory Group include technical advisers and that the Secretariat choose the specifi c structure for the group. Members of the Essential Medicines Committee expressed interest in being part of the Advisory Group. • What major steps in addition to those suggested above should be undertaken to implement the resolution and establish a global programme to promote rational use of medicines that includes the setting up of national programmes as recommended by the second International Conference on Improving Use of Medicines (ICIUM) 2004? A fi rst step would be to form a multidisciplinary Advisory Group with appropriate membership, including representation from the WHO regions. The Committee acknowledged the importance of WHO taking a leadership role in promoting rational drug use worldwide. The Model List of Essential Medicines is a mechanism for promoting rational drug use and the Committee supports additional efforts to promote rational use. TRS946.indd 17TRS946.indd 17 19.11.2007 15:29:3919.11.2007 15:29:39 18 The Committee recognized the lack of coordination within rational use programmes at the country level and the diffi culty in gaining access to local data on medicine use. The proposed resolution could assist Member States in taking advantage of programmes that WHO has already set up. WHO could expand its network of relevant people in each country who are active in promoting rational use of medicines. The Committee raised concerns about the diffuse nature of the specifi c programme proposed, and thus supported the idea of an Advisory Group to guide implementation of the programme. The Committee noted that the issue of irrational use of medicines is global and that a global approach coordinated by WHO is essential. The Committee, therefore, strongly endorses Resolution EB120.R12 “Rational Use of Medicines” and is eager to see WHO implement more vigorous leadership and evidence-based advocacy of rational use of medicines. 4. Changes made in revising the Model List by section: medicines for all populations 4.1 Section 2: addition of prolonged-release morphine An application for inclusion of morphine (as sulfate) 10, 30 and 60 mg modifi ed-release tablets was submitted by the Cochrane Pain, Palliative and Supportive Care Group, with support from the International Association for Hospice and Palliative Care. Expert reviews of the application were prepared by: Dr Liliana De Lima1 and Dr Alar Irs.2 Comments in support of the application were received from Dr Lembit Rägo, Coordinator, QSM/WHO. Additional supporting statements were received from Médecins Sans Frontières. The Committee noted that the application provided a thorough review of the evidence regarding the effectiveness and safety of the prolonged-release morphine formulation for management of chronic pain, based on systematic review (9) of its use in patients with chronic cancer pain. The public health need for inclusion of a new formulation of morphine on the Model List was fully substantiated. The current problems of inadequate access to morphine for use in palliative care in many countries were also described. As noted by the expert reviewers, the clinical evidence showed that the modifi ed- release formulation and immediate-release formulations are equivalent for pain management in chronically ill (cancer) patients. Quantitative estimates of the analgesic effect were not calculated by the authors of the review 1 Dr Liliana de Lima, International Association for Hospice and Palliative Care, Houston, TX, USA, is a Member of the Expert Committee. 2 Dr Alar Irs, State Agency of Medicines, University of Tartu, Tartu, Estonia, is a Member of the Expert Committee. TRS946.indd 18TRS946.indd 18 19.11.2007 15:29:3919.11.2007 15:29:39 19 owing to the insuffi ciency of comparable data for a meta-analysis to be undertaken. The Committee noted that modifi ed- and immediate-release morphine preparations share a common adverse effects profi le (nausea, vomiting, constipation, drowsiness and confusion). The Committee also noted that prolonged-release dosage forms may not be interchangeable because the nature of release modifi cation (rate and mechanism) may differ, and owing to the effect of patient variables (e.g. altered gastrointestinal motility or food intake) may not be the same for all products. Generic prolonged-release preparations of morphine are available worldwide and its inclusion on the Model List may stimulate production of generics. Overall the evidence provided in the application supports the public health need, effectiveness and safety of prolonged-release morphine formulation. The Committee therefore recommended that morphine sulfate 10-, 30- and 60-mg prolonged-release tablets be added to the Model List. These dosages are not applicable for paediatric patients and will be reviewed at the meeting of the Subcommittee on Children’s Medicines. 4.2 Section 6.1: deletion of levamisole as anthelminthic Expert reviews of the application for the deletion of levamisole as an anthelminthic were prepared by: Dr Eva M.A. Ombaka1 and Dr Usha Gupta.2 Additional supporting statements were received from The Center for Drug Reevaluation, SFDA, People’s Republic of China. After review, the Committee recommended that levamisole be retained on the Model List. In 2005, the Advisory Committee on Safety of Medicinal Products reviewed adverse events associated with levamisole. This review was prompted by a report from China which suggested that levamisole was associated with an encephalitis-like syndrome, levamisole-induced demyelinating encephalopathy. The Chinese literature contains 543 published reports of cases of this event. The 2005 meeting of the Advisory Committee proposed that the product should be deleted from the Model List given that it had been withdrawn from the Chinese national formulary, and then reviewed this recommendation together with the adverse event data from China at its most recent meeting in 2007. The main ground for the request for deletion was the toxicity of the medicine. The Committee noted the argument made that there are safer and more effective alternative anthelminthics, but no comparison of effectiveness was 1 Dr Eva M.A. Ombaka is Coordinator of the Ecumenical Pharmaceutical Network. 2 Dr Usha Gupta, Delhi Society for Promotion of Rational Use of Drugs, Delhi Government Dispensary, New Delhi, India, is a Member of the Expert Committee. TRS946.indd 19TRS946.indd 19 19.11.2007 15:29:4019.11.2007 15:29:40 20 provided. In addition to the Chinese literature, a search of other scientifi c publications identifi ed a further possible 4–6 cases of encephalopathy, but only in the context of cancer chemotherapy. Doses used to treat cancer patients are higher than doses for use as an anthelminthic and the duration of treatment is longer. No cases of encephalopathy were found in the Uppsala Monitoring Centre database. Noteworthy in the Chinese data is the apparent concentration of cases in one region where levamisole was being sold by “folk doctors”; 75.5% of cases were apparently reported as having occurred in patients who had obtained the drug from this source. This may call into question the quality and content of the product used. The Department of Control of Neglected Tropical Diseases opposed the deletion of levamisole for this indication. It noted that levamisole is effective, and may also be of value when used in combination with mebendazole in delaying the development of benzimidazole resistance, as noted in the recent treatment guidelines (10) which continue to recommend levamisole, for treatment of soil-transmitted helminthiasis but not in preventive programmes. In addition, there are few anthelminthics currently on the list or in development. The Committee noted that the evidence in the application is from one country. Although the reaction is recognized in the context of cancer chemotherapy, it does not seem to have been reported in the context of use as an anthelminthic from other settings. The assessment was made more diffi cult by the absence of a review of comparative effectiveness. The Committee therefore decided to retain levamisole on the Model List as an anthelminthic but will review it again in 2009. To inform this review, the Committee recommended that the ASCoMP gather additional information on the safety of levamisole at the doses and duration for which it is used as an anthelminthic. The Committee also anticipates a review of comparative effectiveness. 4.3 Section 6.2.1: Beta lactam: addition of cefazolin/cefalexin Expert reviews of the application were prepared by: Dr A. Helali1 and Dr Youping Li.2 In 2005, the Expert Committee considered the priority review on cefalosporins by the ISDB and requested that a formal application for the fi rst-generation cefalosporins (cefazolin and cefalexin) be submitted for the 2007 meeting. 1 Dr Abdelkader Helali, Centre National de Pharmacovigilance et Matériovigilance, Ministère de la Santé et de la Population, Alger, Algeria, is a Member of the Expert Committee. 2 Dr Youping Li, Chinese Cochrane Centre, West China Hospital, Sichuan University, Chengdu, People’s Republic of China, is a Member of the Expert Committee. TRS946.indd 20TRS946.indd 20 19.11.2007 15:29:4019.11.2007 15:29:40 21 The application was therefore commissioned by the Department of Medicines Policy and Standards. The proposal is to list cefazolin (injectable, 1 g/vial) for surgery prophylaxis and cefalexin (capsules, 250 mg/capsule and 500 mg/ capsule, and syrup (powder to be reconstituted with water – 125 mg/5 ml and 250 mg/5 ml) for treatment of skin infections which are a major public health problem especially in children and in developing countries. Both cefazolin and cefalexin are available as generic preparations. Cefazolin The application presented a summary of the evidence for the effectiveness of cefazolin for surgical prophylaxis. As noted by the expert reviewers, there is high-quality clinical evidence, based on a systematic review (11), that shows that cefazolin for surgical prophylaxis in women undergoing caesarean section is as effective as ampicillin (relative risk (RR) 1.24, 95% confi dence interval (CI): 0.84 –1.83) or second- or third-generation cefalosporins (RR 1.17, 95% CI: 0.97– 1.40) in preventing endometritis. Cefazolin has also been shown to be effective in preventing wound infection in patients undergoing peripheral arterial reconstruction (12). On balance, as the evidence provided in the application supported the public health need, effectiveness and safety of cefazolin, the Committee recommended that cefazolin (injectable, 1 gm/vial) be added to the core list, with a note “for use as surgical prophylaxis”. Cefalexin Cefalexin has been shown to be effective in treating skin and soft tissue infections in multiple trials in which it was compared with erythromycin, azithromycin, other third-generation cefalosporins and dicloxacillin (13), although the evidence is comparatively limited. The evidence from these trials has not been the subject of a Cochrane systematic review. The application refers to one of the studies which demonstrated equal effi cacy and safety of cefalexin compared to moxifl oxacin in 401 adults with uncomplicated skin infections (14), although this may not be relevant as moxifl oxacin is not on the Model List. A Cochrane review of interventions for impetigo (Koning, 2003) (13) was based on 57 trials involving 3533 participants, which compared 20 different oral medicines, including cefalexin, and 18 different topical treatments. The trials were in children and adults. Settings and countries were not specifi ed. The results did not show signifi cant differences in cure rates between oral antibiotics or topical and oral antibiotics. Cefalexin is generally well tolerated. In making its decision, the Committee noted that: • Cefalexin has been shown to be effective in treating skin and soft tissue infections in multiple trials and it is commonly used to treat staphylococcal infections. TRS946.indd 21TRS946.indd 21 19.11.2007 15:29:4019.11.2007 15:29:40 22 • Addition of a narrow-spectrum antimicrobial to the list could promote rational prescribing. • It can be an inexpensive alternative for patients who are allergic to penicillins. • Cefalexin in liquid form may be more acceptable to children than penicillin preparations. However, the Committee also recognized that cefalexin, in particular, is widely used for inappropriate treatment of viral infections of the upper respiratory tract in children in many countries. On balance, the Committee decided in view of the lower quality of the evidence for the comparative effectiveness of cefalexin, and the overall concerns about inappropriate use of antibiotics, not to add cefalexin to the Model List at this time. 4.4 Section 6.2.4: Antituberculosis medicines 4.4.1 Addition of rifampicin + isoniazid + ethambutol Fixed-dose combinations (FDCs) of anti-tuberculosis medicines (isoniazid + ethambutol tablet, rifampicin + isoniazid tablet, several strengths; rifampicin + isoniazid + pyrazinamide tablet, several strengths, including paediatric; and rifampicin + isoniazid + pyrazinamide + ethambutol tablet) are included on the Model List to improve adherence and are recommended by the WHO guidelines (15). An application for inclusion of a 3-FDC rifampicin 150/isoniazid 75/ethambutol 275 mg (RHE) was received from the STOP-TB Partnership. Expert reviews of the application were prepared by: Dr Alar Irs1 and Dr Youping Li.2 The Committee noted that there were no published trials that had used either the proposed FDC or the components in loose combination. One small bioequivalence study was presented. The major justifi cation for the product was as an additional fi xed-dose formulation for treatment of TB diagnostic category II as recommended in the WHO treatment guidelines (15). The clinical role of the product is in the continuation phase of treatment for category II patients, after the fi rst two months, when pyrazinamide is no longer effective. The doses of the components proposed in this combination are consistent with current dosing guidelines based on weight of patients (using four weight bands) and also with the quantities in the four-component 1 Dr Alar Irs, State Agency of Medicines, University of Tartu, Tartu, Estonia, is a Member of the Expert Committee. 2 Dr Youping Li, Chinese Cochrane Centre, West China Hospital, Sichuan University, Chengdu, People’s Republic of China, is a Member of the Expert Committee. TRS946.indd 22TRS946.indd 22 19.11.2007 15:29:4019.11.2007 15:29:40 23 FDC already on the Model List. Evidence for the safety of the three- component FDC is based on the use of the four products in combination. The Committee noted that the product is available through one supplier, but that there are no stringent regulatory authority approvals. Adding the product to the Model List might therefore be a stimulus to making available additional quality products. The product is listed on the Prequalifi cation Programme expression of interest (EOI) and as of the last public report, no triple FDCs were listed as prequalifi ed. The Committee considered its agreed criteria for FDCs (see Section 3). This combination is recommended in the relevant WHO treatment guidelines for category II TB patients, but there are only uncertain estimates of the size of this subpopulation. Although the Committee was concerned by the absence of clinical trial data, on the basis of pharmacological and microbiological evidence, it decided to include rifampicin 150 mg/isoniazid 75 mg/ ethambutol 275 mg on the core list. 4.4.2 Section 6.2.4: Review of quinolones for multidrug-resistant TB Expert reviews of the application were prepared by: Dr Rohini Fernandopulle1 and Dr Marcus M. Reidenberg.2 Comments in support of the application were received from Dr Mario Raviglione, Director, Stop TB (STB). Ciprofl oxacin 250 mg and 500 mg, levofl oxacin 250 mg and 500 mg, ofl oxacin 250 mg and 400 mg tablets are included in the 14th Model List as complementary medicines for second-line treatment for multidrug-resistant TB, to be used in specialized centres adhering to WHO standards for TB control. Levofl oxacin is the S-isomer (the active isomer) of the racemic mixture ofl oxacin. These medicines were marked for review at the meeting of the 15th Expert Committee. A review was commissioned by Stop TB to revise the listing for fl uoroquinolones. The review concluded that the single fl uoroquinolone to be nominated on the list should be levofl oxacin, but without a square box. The review argued that as levofl oxacin is the S-isomer of ofl oxacin, there is no need to list both medicines and therefore a square box is not needed. Ciprofl oxacin was not considered an appropriate alternative for routine use. The Committee noted that there was a very limited evidence base upon which to assess the relative clinical effectiveness of ciprofl oxacin, ofl oxacin and levofl oxacin. While there are some data to support lower minimum 1 Dr Rohini Fernandopulle, Department of Pharmacology, Faculty of Medicine, University of Colombo, Sri Lanka, is a Member of the Expert Committee. 2 Dr Marcus M. Reidenberg, Division of Clinical Pharmacology, Weill Medical College of Cornell University, New York, NY, USA, is a Member of the Expert Committee. TRS946.indd 23TRS946.indd 23 19.11.2007 15:29:4119.11.2007 15:29:41 24 inhibitory concentrations (MICs) and higher peak concentration (Cmax)/ MIC with levofl oxacin, it is diffi cult to translate this evidence into clinical practice recommendations. There is some evidence from observational studies (retrospective analyses of a series of treated patients) to suggest that levofl oxacin is superior to ofl oxacin (16). However, it is diffi cult to assess the infl uence of trends over time in prescribing, doses used and other clinical factors in the treatment decisions on these observations. The recommendation not to use ciprofl oxacin as an equivalent fi rst-line drug substitute is based on the observations from a small number of trials where ciprofl oxacin substituted into fi rst-line regimens in drug-sensitive TB resulted in an increased risk of relapse and prolonged time to cure (17). No data were presented on the cost-effectiveness of the fl uoroquinolones nor were comparative price data included in the review. However, International Drug Price Indicator estimates suggest that levofl oxacin could be a substantially more expensive treatment option. Given the absence of any randomized controlled trials comparing the relative effectiveness of the three fl uoroquinolones and of any evidence of substantially different adverse event profi les for these drugs, the Committee agreed that there were no compelling grounds on which to select one agent over the others for the treatment of multidrug-resistant TB. Comparative studies are needed. Current studies are examining the roles of moxifl oxacin and gatifl oxacin in TB, so further trial data on these three fl uoroquinolones are unlikely to become available. Given some evidence of the higher price of levofl oxacin than ofl oxacin and ciprofl oxacin and recognizing the concerns of STB about the costs of medicines if only levofl oxacin is listed, the Committee decided to include ofl oxacin on the complementary list. Rather than adding a square box, the Committee decided to add a footnote noting that the alternative is levofl oxacin based on availability, cost and programme considerations. 4.5 Section 6.4.2: Antiretrovirals 4.5.1 Section 6.4.2.1: Nucleoside reverse transcriptase inhibitors: addition of emtricitabine Expert reviews of the application were prepared by: Mr Andy Gray1 and Dr Abdelkader Helali. Dr Albert Figueras2 withdrew from the discussion of this and all other proposals on HIV medicines. 1 Mr Andy Gray, Department of Therapeutics and Medicines Management, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, South Africa, participated as Temporary Adviser in the Expert Committee. 2 Dr Albert Figueras, Fundació Institut Català de Famacología, Servei de Farmacología Clínica, Hospital Vall d’Hebron, Barcelona, Spain, participated as Temporary Adviser to the Expert Committee. TRS946.indd 24TRS946.indd 24 19.11.2007 15:29:4119.11.2007 15:29:41 25 In 2005, the Expert Committee considered an application from the manufacturer for inclusion of emtricitabine as an additional nucleoside reverse transcriptase inhibitor (NRTI). At that time, the application was based mainly on unpublished studies and the Committee deferred its decision on the product until the data were publicly available. The application has since been resubmitted. Emtricitabine is listed in the current WHO guidelines for the treatment of adults and children (18, 19) as one option for fi rst-line combination treatment as part of the NRTI backbone, and as an alternative to lamivudine (3TC). According to the guidelines, “FTC [emtricitabine] is an equivalent alternative to 3TC as it is structurally related to 3TC, shares the same effi cacy against HIV and hepatitis B virus and has the same resistance profi le.” The application provided an updated summary of the evidence, including seven trials in adults and two in children. The majority of the trials are those submitted for regulatory purposes, but most have now been published as peer reviewed papers. The trials were limited to developed countries and experience of the use of emtricitabine in developing countries remains limited. In summary, the trials show that: • Emtricitabine can be used in both treatment-naive and experienced patients. • The once daily treatment regimen is at least as effective as dosing with other medicines, as measured by effect on standard viral load and CD4 outcomes. • Emtricitabine has been used in combination with different medicines, as outlined in the WHO treatment guidelines, and therefore can be used in a variety of different combination treatments. • The effect on viral load is durable. • The product can be used in children from 3 months of age. • The safety profi le of the product, particularly with regard to hyper- pigmentation, is acceptable. There are no data on use of emtricitabine in pregnancy. A summary of accumulated safety data to date was also provided. The majority of reported use is in developed countries. Adverse reactions to emtricitabine are similar to those reported for other medicines in the class. The Committee considered the question of interchangeability with lamivudine, based on clinical trials directly comparing the two medicines. From the evidence provided, there did not appear to be any clinically signifi cant difference in effectiveness. No evidence of cost-effectiveness was provided. The Committee noted that there is a proposal from the current manufacturer for differential pricing for emtricitabine and tenofovir FDC, but not for emtricitabine alone. TRS946.indd 25TRS946.indd 25 19.11.2007 15:29:4119.11.2007 15:29:41 26 The Committee concluded that there is suffi cient evidence that emtricitabine is effective for treating HIV when used in combination regimens although little of this information comes from resource-poor settings. The safety profi le is similar to that of other medicines in the class. Although in practical terms it seems to be used as an alternative to lamivudine, there is insuffi cient evidence that it is in fact completely interchangeable and therefore listing it by reference to lamivudine with a square box could not be justifi ed. The major advantage of adding emtricitabine to the Model List would appear to be in promoting availability and access to an additional treatment option, as well as offering an alternative to other NRTIs. The Committee therefore added emtricitabine capsule and liquid formulation to the core Model List with a note that it is clinically interchangeable with lamivudine. 4.5.2 Section 6.4.2.1: NRTI: addition of tenofovir disoproxil fumarate Expert reviews of the application were prepared by: Mr Andy Gray and Dr Abdelkader Helali. A comment from Médecins Sans Frontières on the application was noted. In 2002, the following NRTIs were added to the core Model List: abacavir, didanosine, lamivudine, stavudine and zidovudine. In 2005, the Expert Committee considered an application from the manufacturer for tenofovir (TDF) as an additional NRTI. At that time the application was based mainly on unpublished studies and the Committee deferred a decision on the product until the data were publicly available. The application has since been resubmitted. Tenofovir is listed in current WHO treatment guidelines for adults and children (18, 19) as one option for fi rst-line combination treatment as part of the NRTI backbone, and as an alternative to abacavir (ABC). The application provides an updated summary of the evidence, but as noted by the Committee, did not adequately cover all published literature. Some of the supporting evidence is still in the form of conference proceedings and abstracts. The trials presented are restricted to phase III clinical trials comparing TDF to stavudine, or TDF plus TFC to zidovudine/lamivudine FDC or trials with TDF as an add-on treatment in patients with virological failure. The main evidence in the application consists of data from four key regulatory trials. There are ongoing trials in the African region and also in children, but there is as yet no approval for use of TDF in populations younger than 18 years of age. The application provided an updated review of safety information, dated October 2005. The concerns noted by the Committee in 2005 were the potential for renal toxicity, interactions, lactic acidosis, bone problems and liver problems. Although the supplement to the application provides lists of references that are related to these problems, there was no synthesis or overview of the information provided. The expert review prepared for the TRS946.indd 26TRS946.indd 26 19.11.2007 15:29:4119.11.2007 15:29:41 27 Committee summarized the information in the references, and notes that several other relevant publications have not been considered. Overall, renal problems with tenofovir appear to be real but rare and the uncertainty is therefore the level of monitoring that would be required. Changes in bone density do not appear to be clinically relevant and may be reversible. The data on interactions is based on the product information document and may or may not be suffi cient for global use. Lactic acidosis and lipodystrophy may be less of a problem with tenofovir than other currently available antiretrovirals (ARVs), especially stavudine. In summary, tenofovir has been found to be effective in terms of effect on standard end-points such as viral load measures, for the treatment of HIV- infected adults, when used in combination with other ARVs. The safety profi le is now better characterized than when it was considered in 2005, and considerable data are in the public domain. It is not yet approved for use in children. There are ongoing trials of its use in resource-poor settings. The Committee recommended adding tenofovir to the core Model List and noted that the monitoring requirements for this medicine are no different to those for other ARVs. 4.5.3 Section 6.4.2: Antiretrovirals Section 6.4.2.2: Non-nucleoside reverse transcriptase inhibitors: addition of new strength of efavirenz Supporting statements for the addition of a new strength of efavirenz were received from Médecins Sans Frontières. Efavirenz was added to the core Model List in 2002 as capsule, 50 mg, 100 mg and 200 mg and oral solution 150 mg/5 ml, when the Expert Committee added the section for non-nucleoside reverse transcriptase inhibitors to the Model List with a recommendation to use these medicines in addition to dual nucleoside core combinations as a third agent. An application for inclusion of a new dosage form of efavirenz, a 600-mg tablet, has now been submitted by Merck Sharp & Dohme Interpharma, La Celle Saint Cloud, France. The major advantage of the proposed new dosage form is that it can be given once daily, with a resultant reduction of pill burden and a presumed increase in adherence. The application presented results from three studies (20, 21, 22) to support this claim: two controlled trials and one small prospective cohort study. These studies showed that when used as part of different combination treatment regimens, efavirenz once daily was at least no worse than comparators (indinavir, nelfi navir) in terms of its effects on viral load. The benefi ts of once daily dosing on adherence were poorly substantiated as it was only measured in the cohort study. TRS946.indd 27TRS946.indd 27 19.11.2007 15:29:4219.11.2007 15:29:42 28 In addition, a Cochrane review (23), not included in the application, provides further evidence of the relative effectiveness and safety of efavirenz in combination treatment regimens, in comparison with nevirapine. Efavirenz is contraindicated in pregnancy and it is not approved for use in children under the age of 3 years. The Committee noted that when using the 600- mg form, safety considerations became important in patients whose body weight was less than 40 kg. Generic preparations of efavirenz are not presently available; the current cost is regulated by the manufacturer according to the prevalence of HIV in adults. Overall, the evidence provided in the application supports the need for the new dosage form. The Committee therefore recommended that efavirenz 600-mg tablet be added to the Model List for the fi rst-line therapy of patients with HIV as part of combination treatment regimens as recommended in the WHO treatment guidelines for HIV. Section 6.4.2.3: Protease inhibitors The Committee noted advice from the WHO Department of HIV/AIDS that the evidence for, and experience of use of protease inhibitors is rapidly evolving and new medicines in this class are becoming available. In addition, the dosage form and strength of lopinovir and ritonavir will need to refl ect developments in formulation to make heat-stable products. It is anticipated that an application for a heat-stable tablet formulation containing 200/50 mg lopinavir + ritonavir will be submitted for the next meeting. Selection of protease inhibitor(s) from the Model List will need to be determined by each country after consideration of international and national treatment guidelines and experience. Ritonavir is recommended for use in combinations as a pharmacological booster, and not as an antiretroviral in its own right. Therefore, the Committee recommended that the WHO Department of HIV/ AIDS conduct an urgent review of protease inhibitors in section 6.4.2.3. Ideally, this review should be conducted according to any new procedures that are developed for updating the list between meetings as the situation regarding protease inhibitors has highlighted the need for capacity for urgent updates of the Model List. 4.5.4 Fixed-dose combinations of antiretrovirals The HIV/AIDS Department of WHO provided an introduction to and overview of the programmatic aspects of use of FDC antiretrovirals. Based on the 2006 WHO treatment guidelines, a list of preferred combinations was presented, which the Committee then considered in its review of all of the proposals for FDCs for HIV. TRS946.indd 28TRS946.indd 28 19.11.2007 15:29:4219.11.2007 15:29:42 29 4.5.4.1 Addition of lamivudine/zidovudine In 2002, NRTIs were added to the core Model List: abacavir, didanosine, lamivudine, stavudine and zidovudine. At that time, an application for the combination product containing zidovudine 300 mg and lamivudine 150 mg was also presented, but the decision was to list only single components and to have a note in the Model List about FDC products. Zidovudine and lamivudine are both listed in the WHO treatment guidelines for adults and children (18, 24) as one option for the NRTI backbone for fi rst-line combination treatment, with either nevirapine or efavirenz as the NNRTI. Given as the combination, the dose is one FDC tablet twice daily with either nevirapine or efavirenz. Expert reviews of the application were prepared by: Dr Marcus M. Reidenberg. Additional statements were received from the Access to Essential Medicines Campaign, Médecins Sans Frontières. The evidence for comparative effectiveness and safety in this application is an update of the review presented in 2002. It is stated in the application that “in compiling the application, it was recognized that there are large numbers of commercial products containing this particular combination, some of which have been subject to rigorous regulatory assessment while others have not.” The application therefore proposes that adequately conducted trials of an FDC or trials involving the components concomitantly administered should be regarded as supportive evidence, i.e. studies that are indicative but not conclusive. The application also points out that if an individual product has been subject to stringent regulatory authority approval, bioequivalence between the FDC and the components can be accepted. Advantages of this two-drug FDC are: — ease of storage, procurement and distribution; and — harmonization of prevention of mother-to-child transmission. This application cites two systematic reviews (25, 26) as the main source of evidence to support the use of the FDC containing zidovudine and lamivudine. It is not clear which of the trials actually used FDCs. Some of the trials are the early comparisons of double versus monotherapy that became the basis of the general recommendation to use combinations of three or more antiretrovirals, which is now accepted as standard. The application notes that AZT/3TC should not be used alone in treatment, but must be used in combination. With respect to the impact of the FDC on adherence, the application describes two studies, one cohort study (Legoretta et al., 2005) (27) and one randomized controlled trial (RCT) (Enron et al.) (28) that compared adherence in patients who used FDCs containing AZT/3TC with adherence in those who used the individual components. The results of both studies TRS946.indd 29TRS946.indd 29 19.11.2007 15:29:4219.11.2007 15:29:42 30 suggest better adherence in patients using the FDCs, including when used as part of triple combination treatment regimens. The evidence for comparative safety combines the information on adverse events for the individual components with that on drop-out rates in the clinical trials. There do not appear to be any safety concerns that specifi cally relate to the use of the FDC. This combination has been used in a variety of settings as part of the roll-out of ARVs and a number of high-quality products are available. The Committee noted that the unit price and average cost of treatment with AZT/3TC varies enormously. Overall, this combination, one of several proposed in the WHO treatment guidelines, is a preferred combination for fi rst-line treatment, as one of the NRTI backbones. The combination can be used in most subpopulations of HIV patients, including pregnant women and children. Several products of adequate quality exist, containing appropriate doses of the components, and there have been clinical studies using the components of the FDC at the same doses, including two studies that show that its use leads to enhanced adherence, with no worse side-effects. There is also substantial experience of use of this product in resource-poor settings. The Committee therefore recommended that the FDC should be added to the Model List. 4.5.4.2 Addition of lamivudine/zidovudine/nevirapine In 2002, NRTIs were added to the core Model List: abacavir, didanosine, lamivudine, stavudine and zidovudine. As noted above, the role of FDCs in scale-up of treatment has become critical and the Department of HIV/ AIDS, WHO, has proposed that an FDC product containing zidovudine, lamivudine and nevirapine be included on the Model List. All three components are listed in the WHO treatment guidelines for adults and children (18, 24) as one option for fi rst-line combination treatment. Given as the combination, the dose is one FDC tablet twice daily. Expert reviews of the application were prepared by: Dr Marcus M. Reidenberg. Additional statements were received from the Access to Essential Medicines Campaign, Médecins Sans Frontières. The evidence for comparative effectiveness and safety in this application is based on a trial of the components given individually. Products of assured quality, including three approved by the WHO Prequalifi cation Programme exist. One observational study (29) evaluated FDC products in general, but it is not possible to separate results for AZT/3TC/NEV. The fi ve RCTs (30–34) using the components are comprehensively summarized in the application. The results of these trials show that: TRS946.indd 30TRS946.indd 30 19.11.2007 15:29:4219.11.2007 15:29:42 31 — AZT/3TC/NEV is effective in treating HIV and equivalent to 3TC/ stavudine/nevirapine. — AZT/3TC/NEV my be superior to AZT/3TC/nelfi navir in terms of effect on viral load, and possibly health-related quality of life, but seems equivalent in terms of effect on immune recovery. — AZT/3TC/NEV appears to be equivalent to AZT/3TC/abacavir in terms of effect on viral suppression. Although AZT/3TC/NEV has been used in a number of countries, there is little information on total exposure. Safety data from the randomized trials are consistent with the known adverse effect profi le of the three medicines. Lipodystrophy, rash and anaemia are well-characterized as adverse reactions. The Committee noted that this combination seems to be better tolerated that the stavudine-containing triple FDC and can be used in all relevant populations. No additional information on adherence with this FDC was found. Overall, this combination is one of several proposed in the WHO treatment guidelines, and is a preferred combination for fi rst-line treatment as it can be used in most subpopulations of HIV patients, including pregnant women and children. Several products of adequate quality exist, containing appropriate doses of the components and there are clinical studies using the components of the FDC at the same doses and one study using this FDC. There is substantial experience of use of this product in resource-poor settings. The Committee therefore recommended that the FDC containing zidovudine, lamivudine and nevirapine should be added to the Model List. 4.5.4.3 Addition of lamivudine/stavudine/nevirapine In 2002, NRTIs were added to the core Model List: abacavir, didanosine, lamivudine, stavudine and zidovudine. As part of the general proposal on FDCs, the Department of HIV/AIDS, WHO, has proposed that two FDC products containing stavudine, lamivudine and nevirapine be included on the Model List. All three are listed in the WHO treatment guidelines for adults and children (18, 24) as one option for fi rst-line combination treatment. Given as the combination, the dose is one FDC tablet twice daily. The strengths proposed are: — stavudine 30 mg, lamivudine 150 mg, nevirapine 200 mg for patients under 60 kg; — stavudine 40 mg, lamivudine 150 mg, nevirapine 200 mg (d4T/3TC/ NEV) for patients over 60 kg. Both products are available from multiple suppliers, including at least two prequalifi ed products. Expert reviews of the application were prepared by: Dr Marcus M. Reidenberg. Additional supporting statements were received from the Access to Essential Medicines Campaign, Médecins Sans Frontières. TRS946.indd 31TRS946.indd 31 19.11.2007 15:29:4219.11.2007 15:29:42 32 The evidence for comparative effectiveness and safety in this application is based on trials of the components given individually. In addition, there have been several large observational studies (29, 35) using the FDC product that confi rm its effectiveness and safety in a variety of settings, including in resource-poor countries. As noted in the application: “Changes to viral load measures and CD4 counts are similar to what have been seen in randomized trials and cohort studies performed in developed countries, but clinical event rates and in particular mortality have been higher in the resource-poor settings. This suggests that patients are commencing treatment at a more advanced stage in their illness and co-morbidities, in particular opportunistic and intercurrent infections, are more frequent at baseline. Also, diagnostic and treatment facilities are lacking. The data reviewed here, and the comments of the researchers, indicate that these factors are the most important determinants of the poorer clinical outcomes, rather than poor adherence, viral resistance or inferior quality of the drugs themselves.” Comparative safety is comprehensively described. As noted, d4T is the NRTI most commonly associated with lactic acidosis, lipoatrophy and peripheral neuropathy and therefore countries should be planning to move away from treatment regimens that include it. However, treatment options that include d4T are currently the most readily available so appropriate monitoring for short- and long-term toxicities is required. As noted by the Committee, this combination is one of several proposed in the WHO treatment guidelines, is a preferred combination for fi rst-line treatment, and can be used in most subpopulations of HIV patients, including pregnant women and in children. Several products of adequate quality exist, containing appropriate doses of the components and there have been clinical studies using the components of the FDC at the same doses as well as several observational studies using this FDC. There is substantial experience of use of this product in resource-poor settings, but there is signifi cant toxicity associated with this combination that may eventually lead to a decline in its use. It is widely available. The Committee also noted the advice from the HIV/AIDS Department that the FDC containing 40 mg stavudine would no longer be recommended, due to excess toxicity of the higher dose. The Committee therefore recommended that the FDC containing stavudine 30 mg, lamivudine and nevirapine should be added to the Model List, but not the product containing stavudine 40 mg. 4.5.4.4 Addition of emtricitabine and tenofovir disoproxil fumarate fi xed-dose combination In 2005, the Expert Committee considered an application from the manu- facturer for tenofovir (TDF) and emtricitabine as an FDC. At that meeting, the Committee noted “the fi xed-dose combination had only recently been TRS946.indd 32TRS946.indd 32 19.11.2007 15:29:4319.11.2007 15:29:43 33 approved by the US Food and Drug Administration, but that it is increasingly being used in national programmes. However, it would be illogical to consider the combination so long as the individual medicines had not been added to the Model List. The Committee concluded that listing of the combination at this stage would be premature, and decided to defer its decision because of the lack of information, for example, in comparison with lamivudine.” Tenofovir and emtricitabine are listed in current WHO treatment guidelines for adults (18) as one option for fi rst-line combination treatment as part of the NRTI backbone, and as an alternative to abacavir (ABC). Expert reviews of the application were prepared by: Mr Andy Gray and Dr Lenita Wannmacher.1 The evidence for comparative effectiveness and safety in this application consists of trials that were the basis of the USA’s regulatory approval of the FDC and two studies of bioequivalence and pharmacokinetics. It is not clear that any of the large trials used the proposed FDC. Safety data based on the use of the components individually and in combination, not as an FDC, is as presented in the applications for the single components. There is no evidence of use of this combination in resource-poor settings. The Committee noted that differential pricing of the FDC is proposed through an access programme: 30 days supply for US$ 26.25. No formal cost- effectiveness evaluation was provided. The Committee noted that this combination is one of several proposed in the WHO treatment guidelines, and is one combination for fi rst-line treatment. The combination can be used in adult HIV patients but not children; there is limited information about its use in pregnant women. It is specifi cally recommended for use in patients co-infected with hepatitis B virus (HBV). One product of adequate quality exists, containing appropriate doses of the components, and there have been clinical studies using the components of the FDC at the same doses, but no clinical studies of the use of the FDC; there are also bioequivalence and pharmacokinetic studies. There is limited experience of use of this product in resource-poor settings. The Committee therefore decided to add the combination of tenofovir and emtricitabine to the core list, noting particularly its utility in patients with HBV co-infection and with an accompanying note that 3TC is an acceptable alternative to FTC, based on knowledge of the pharmacology, the resistance patterns and clinical trials of ARVs. 1 Dr Lenita Wannmacher, Department of Clinical Pharmacology, School of Medicine, University of Passo Fundo, Teixeira Soares, Rio Grande do Sul, Brazil, is a Member of the Expert Committee. TRS946.indd 33TRS946.indd 33 19.11.2007 15:29:4319.11.2007 15:29:43 34 4.5.4.5 Addition of efavirenz, emtricitabine and tenofovir disoproxil fumarate FDC tablet A new application for a new FDC medicine, tablets containing 600 mg efavirenz, 200 mg emtricitabine and 300 mg tenofovir, to be listed in section 6.4.2 Antiretrovirals, as a combination of NRTIs and NNRTIs has been submitted by Merck Sharp & Dohme, France. The Committee received the letter from Merck as a late paper. Efavirenz, tenofovir and emtricitabine are listed in current WHO treat- ment guidelines for adults (18) as one option for fi rst-line combination treatment. As stated in the application, the triple combination has so far been registered in the USA only, although other regulatory approvals are being sought. Expert reviews of the application were prepared by: Dr Lenita Wannmacher. Additional supporting statements were received from the Access to Essential Medicines Campaign, Médecins Sans Frontières. The evidence for comparative effectiveness and safety in this application consisted of two studies: Study 934, published by Gallant et al. 2006 (36) and an observational study, ANRS 1207 in 40 subjects (presented as a poster only). Neither study used the proposed FDC. Gallant et al. compared treatment with the three components given separately with a FDC of AZT/ 3TC plus efavirenz, and the observational study appears to have used the individual components. Evidence of safety was based on the use of the components individually and in combination, not as an FDC, and is as presented in the other applications. Postmarketing safety reports from the use of the FDC were also provided but they reported adverse events only amd were unquantifi ed. Causality in relation to use of the FDC was not assessed. There was no evidence of use of this combination in resource- poor settings. The Committee noted that differential pricing of the FDC is proposed through an access programme, although the details were not provided in the application. The Committee noted that this combination is one of several proposed in the WHO treatment guidelines, and is one combination for fi rst-line treatment. The combination can be used in adult HIV patients but not children; efavirenz should not be used in pregnant women. It is specifi cally recommended for use in patients co-infected with HBV. One product of adequate quality exists, containing appropriate doses of the components and there has been one clinical study using the components of the FDC at the same doses and a small observational study using this FDC. The Committee therefore decided this FDC should be added to the core list, noting particularly its utility in patients with HBV co-infection. TRS946.indd 34TRS946.indd 34 19.11.2007 15:29:4319.11.2007 15:29:43 35 4.6 New section under 6.4.3: Addition of new section and medicine ribavirin An application has been received from the Department of Epidemic and Pandemic Alert and Response (CDS/EPR) at WHO for the inclusion of ribavirin on the Model List for the treatment of viral haemorrhagic fevers (VHF) particularly Lassa fever (LF), Argentine haemorrhagic fever (AHF), Crimean-Congo haemorrhagic fever (CCHF) and haemorrhagic fever with renal syndrome (HFRS). The listing is as an individual medicine. Expert reviews of the application were prepared by: Dr Lisa Bero.1 Additional statements were received from Médecins Sans Frontières. The Committee noted that the application provides a comprehensive review of the available clinical data on the use of ribavirin for the nominated haemorrhagic fevers. Most of the evidence is derived from case series and there have been few randomized or placebo controlled studies to assess the effi cacy of ribavirin. The data generally suggest that ribavirin shortens the course of illness and reduces mortality rates from LF, CCHF and HFRS. While it has been suggested that further studies are required to establish the effectiveness of ribavirin, haemorrhagic fevers are associated with high morbidity and mortality, and there are few treatment options. The application notes a wide range of prices for ribavirin. Given the potential benefi ts of treatment and the manageable side-effect profi le of ribavirin, the Committee agreed to list ribavirin tablets and injection on the Model List. The Committee noted that even at the nominated prices, access in some country settings would remain a problem. 4.7 Late item: antiviral medicines for pandemic infl uenza Dr Noël Cranswick2 and Dr Thamizhanban Pillay3 excused themselves during discussion of this item. The Committee noted the memo from the WHO Global Infl uenza Programme: GIP, “Possibility of inclusion of infl uenza-specifi c antivirals to the Model List” and acknowledged the problem stated in the paper. The Committee noted that this situation highlights the need for a process for making decisions between meetings and would welcome applications for antivirals for pandemic situations. 1 Dr Lisa Bero, University of California, San Francisco, USA, is a Member of the Expert Committee. 2 Dr Noël Cranswick, Clinical Pharmacology Department, Royal Children’s Hospital, Parkville, Victoria, Australia, is a Member of the Expert Committee. 3 Dr Thamizhanban Pillay, Pharmaceutical Economic Evaluation, National Department of Health, Pretoria, South Africa, participated as Temporary Adviser to the Expert Committee. TRS946.indd 35TRS946.indd 35 19.11.2007 15:29:4319.11.2007 15:29:43 36 4.8 Section 6.5.2: Antileishmaniasis: addition of paromomycin Medicines for treating leishmaniasis have been on the Model List since its fi rst edition and the currently listed medicines are meglumine antimoniate (core list) and pentamidine and amphotericin B (complementary list). The Institute for OneWorld Health, San Francisco, USA, has submitted a new application for a new medicine to be listed for leishmanias, paromomycin. The dosage form and strength proposed is a solution for intramuscular injection containing 375 mg/ml paromomycin base as a 2-ml ampoule (750 mg of paromomycin base present as the sulfate). Paromomycin is an aminoglycoside antibiotic identical to aminosidine (37) which was fi rst shown to have antileishmanial activity in the early 1960s. The application provided a summary of the evidence based primarily on the phase III clinical trial (38), but as noted by the Committee, did not cover all published literature. In the Phase III trial, paromomycin (11 mg/kg paromomycin base for 21 days) was shown to be comparable with amphotericin B (1 mg/kg intravenously every other day for 30 days). The fi nal cure rate in patients treated with paromomycin was equivalent to that of patients treated with amphotericin B. In another study, paromomycin was shown to be more effective that sodium stibogluconate (fi nal cure rates of 93%–97% versus 63%) (39). Combinations of paromomycin with antimony compounds were found to be highly effi cacious (40–42). The application provided a review of safety information. Overall, ototoxicity, nephrotoxicity and elevations of liver enzymes are noted, but do not appear to be clinically relevant and may be reversible. Nephrotoxicity was shown to be less of a problem with paromomycin than with amphotericin B. Currently, a post-approval Phase IV trial is being conducted in India. In summary, paromomycin has been found to be effective in terms of effect on standard end-points, such as initial and fi nal cure, for the treatment of visceral leishmaniasis in children and adults. The Committee considered the additional evidence supporting safety and effi cacy that was not included in the application, as noted above. The safety profi le is well-characterized in randomized trials and during the period of approximately 40 years of its use for treating various bacterial and protozoal infections, including leishmaniasis. Once daily intramuscular administration for 21 days offers greater suitability than sodium stibogluconate (30 days) and amphotericin B (intravenous, 30 days). Paromomycin appears to be the most cost-effective treatment among all available alternatives. Leishmaniasis is a neglected disease. The Committee therefore recommended adding paromomycin to the core Model List. TRS946.indd 36TRS946.indd 36 19.11.2007 15:29:4419.11.2007 15:29:44 37 4.9 Section 6.5.3: Antimalarial medicines 4.9.1 Review of section 6.5.3: Antimalarial medicines Expert reviews of the application were prepared by: Dr Eva M.A. Ombaka and Mr Andy Gray. The WHO Malaria treatment guidelines (43) were published in early 2006. The main change to the treatment recommended in those guidelines was the recommendation that first-line treatment for malaria should be with combinations of medicines rather than monotherapy. Artemisinin combinations were recommended as first-line treatment although other combinations were also noted to be more effective than monotherapy. The Global Malaria Programme, WHO, has therefore proposed several changes to the current Model List of medicines for malaria, to align it with the treatment guidelines. The following combinations are proposed as additions to the core list, for treatment of uncomplicated malaria: — artesunate plus amodiaquine, co-packaged 50 mg + 153 mg — artesunate plus mefl oquine, co-packaged 50 mg + 250 mg — artesunate plus sulfadoxine–pyramethamine, co-packaged 50 mg + 250 mg. The addition of two new artesunate formulations for emergency use in severe malaria: intravenous artesunate (ampoules, containing 60 mg anhydrous artesunic acid with a separate ampoule of 5% sodium bicarbonate solution) and rectal artesunate (capsules containing 100 mg or 400 mg sodium artesunate) was also considered, see Section 4.8.2. The malaria treatment guidelines were based on a number of comprehensive systematic reviews of clinical evidence in relation to treatment of malaria, and these reviews formed the basis of this application. The Committee noted that the evidence in the application had not been updated to include studies published in the last 18 months and that this recent evidence was comprehensively summarized in one of the expert reviews. In summary, the clinical evidence showed that: • Combination therapy for uncomplicated malaria is superior to monotherapy (odds ratio (OR) 0.30, 95% CI, 0.26–0.36). • Artemisinin-containing combination therapy (ACTs) may be superior to other combinations such as amodiaquine plus sulfadoxine–pyramethamine (OR 0.49, 95% CI, 0.27–0.87). • Currently, there do not appear to be any differences in effectiveness between the different ACTs. • 6-dose regimens are superior to 4-dose regimens (based on polymerase- chain-reaction-adjusted cure at 28 days). TRS946.indd 37TRS946.indd 37 19.11.2007 15:29:4419.11.2007 15:29:44 38 The guidelines also include recommendations about treatment of pregnant women and children with ACTs, based on reviews of observational and pharmacokinetic studies. ACTs are recommended as effective and safe in the second and third trimester of pregnancy, and artemether–lumefantrine can be used in children with a body weight > 5 kg rather than > 10 kg. The main safety issues relate to the adverse effects of amodiaquine and mefl oquine; the adverse effects of both products have been well characterized. It is also important to note that the concerns about adverse effects of these products arose when they were being used for prophylaxis. However, there are continuing reports of adverse reactions with both amodiaquine and mefl oquine. The regulatory status of the products proposed for addition was unclear. The Committee noted that the application was primarily for co-blistered pack- aged preparations and no true FDCs currently exist. The Committee also con- sidered several other changes to the list of antimalarial medicines that would be required to ensure consistency of listing with the treatment guidelines, that were not considered in the proposal from the Global Malaria Programme. Having considered the proposal, and in the light of the policy of listing FDC products, the Committee decided to comprehensively amend the list of medicines for malaria as follows: • To include amodiaquine, artemether + lumefantrine, mefl oquine, doxy- cycline, primaquine, quinine and sulfadoxine + pyrimethamine oral dos- age forms on the core list, with notes for each describing the appropriate combinations. • To amend the note regarding the use of artemether + lumefantrine in pregnant women (to restrict use only in the fi rst trimester of pregnancy) and in children (to note that use is possible in children of > 5 kg). • To maintain chloroquine on the core list, but for use only in the treatment of P. vivax, P. ovale and P. malariae infections. • To delete chloroquine injection, on the basis that it is no longer recommended for use in severe malaria. • To amend the list of treatments for prophylaxis to limit the use of chloroquine to central American regions and for prophylaxis of P. vivax, P. ovale and P. malariae infections. The Committee noted that rapid development of high-quality FDCs to meet the treatment needs for malaria would be highly desirable, and it would welcome applications for such products, once they exist. In addition, the Committee recommended rigorous trials of these FDCs as well as noting the potential advice available for drug development and regulatory approvals through existing regulatory procedures such as Article 58 of Regulation (EC) No 726/2004 1. TRS946.indd 38TRS946.indd 38 19.11.2007 15:29:4419.11.2007 15:29:44 39 4.9.2 Addition of artesunate (injectable and suppositories) Expert reviews of the application were prepared by: Dr Youping Li and Mr Andy Gray. Comments on the application were received from Dr John McEwen, Member of the WHO Expert Advisory Panel on Drug Evaluation. Additional statements were received from Médecins Sans Frontières and UNICEF. Artemisinin derivatives – artesunate and artemether – were added to the complementary section of the Model List of Essential Medicines in 2002. Following the publication of the WHO treatment guidelines for malaria (43), the Global Malaria Programme proposed the addition of two new artesunate formulations for emergency use in severe malaria: intravenous artesunate (ampoules, containing 60 mg anhydrous artesunic acid with a separate ampoule of 5% sodium bicarbonate solution) and rectal artesunate (capsules containing 100 mg or 400 mg sodium artesunate). The application provides a short summary of the clinical evidence of effectiveness of intravenous and rectal artesunate compared to intravenous quinine for treatment of severe and moderate-to-severe malaria, but did not include all relevant published studies. Importantly, the application did not refer to the systematic review of artemisinin derivatives in severe malaria published in 2000, although additional trials were cited. The Cochrane systematic review included 16 trials comparing artemisinin derivatives with quinine although not all the derivatives were artesunate. Five of the trials, involving 458 participants, reported effects of intravenous artesunate (44). Intravenous artesunate: The application refers to two randomized trials comparing intravenous artesunate with intravenous quinine. One was conducted in Thailand, in 113 adults with severe malaria, and did not fi nd a signifi cant difference in mortality (RR 0.53, 95% CI, 0.23–1.26) after 300 hours (45). The second study was a large multicentre randomized clinical trial (46), involving 1461 participants with severe malaria, in Bangladesh, India, Indonesia and Myanmar. It found a signifi cantly lower mortality rate in the group treated with artesunate than in the group that received quinine: RR 0.69, 95% CI, 0.54–0.83. The risk difference was 7.8% (95% CI, 3.8– 11.8%), number needed to treat, 13. Including these results with those from the pooled trials in the review gives an overall effect size of RR 0.61 (95% CI, 0.50–0.75), RD 0.11 (95% CI, 0.17–0.05), favouring artesunate. Evidence of the effectiveness of intravenous artesunate in children as presented in the application is limited. One additional small randomized trial (47) was identifi ed which found that intravenous artesunate signifi cantly reduced time to parasite and fever clearance and coma recovery although there was no statistically signifi cant effect on mortality. TRS946.indd 39TRS946.indd 39 19.11.2007 15:29:4519.11.2007 15:29:45 40 Rectal artesunate: The application referred to a study (48) that directly compared the responses to rectally administered artesunate and intravenous quinine in 144 people with moderately severe malaria: 109 children in Malawi and 35 adults in South Africa. It found that in children, artesunate signifi cantly reduced fever clearance time and parasite clearance time compared with quinine. In adults, there was no signifi cant difference in fever clearance time and parasite clearance time. An additional randomized study identifi ed by the expert reviewer, compared rectal artesunate and intramuscular artemether in 79 children in Papua New Guinea. There were statistically signifi cant differences in parasite clearance time with the rectally administered artesunate but this small study did not fi nd differences in clinical outcomes (49). Evidence on safety of rectal and intravenous artesunate was provided. Generally, particularly in the context of severe malaria, artesunate preparations are well tolerated. The Committee noted the potential value of rectal dosage formulations and overall the evidence provided in the application supports the public health need, effectiveness and safety of artesunate formulations for emergency use in adults and children for treating severe malaria. However, the Committee noted that the regulatory status of the products, particularly the rectal capsule, was unclear. The Committee therefore recommended that artesunate ampoules, containing 60 mg anhydrous artesunic acid with a separate ampoule of 5% sodium bicarbonate solution be added to the core list of the 15th WHO Model List with the note: “for use in the management of severe malaria”. The Committee decided, given the uncertainty about currently available rectal products, to refer review of the rectal form to the paediatric subcommittee meeting and recommended further research on rectal dosage forms. 4.10 Review of section 6.5.5: Antitrypanosomal medicines Expert reviews of the application were prepared by: Dr Marcus M. Reidenberg. Additional statements were received from Dr Carmen Pérez-Casas, Access to Essential Medicines Campaign, Médecins Sans Frontières. The Department of Control of Neglected Tropical Diseases, WHO, submitted a proposal for restructuring Section 6.5.5.1 of the Model List by moving pentamidine and efl ornithine to the core list. Pentamidine was added to the core list in 1977, and moved to the complementary list in 2003, when the review of core versus complementary listing of medicines was undertaken. Suramin was added to the core list in 1979. Melarsoprol was added to the core list in 1977 for use only in the second (neurological) phase of Trypanosoma brucei disease. Efl ornithine was added to the complementary TRS946.indd 40TRS946.indd 40 19.11.2007 15:29:4519.11.2007 15:29:45 41 list in 1992 as second-line therapy for late stage African trypanosomiasis due to Trypanosoma brucei gambiense (T .b. g.) and as second-line treatment for those not responding to melarsoprol for treatment of meningoencephalopathy due to T. b. g. Pentamidine, melarsoprol and efl ornithine are produced and donated to WHO by Sanofi -aventis. Pentamidine iseothionate, 300-mg vials are also registered by the US Food and Drug Administration. Suramin is produced and donated by Bayer HealthCare. The Committee noted that there is relatively little high-quality evidence to establish the effectiveness and safety of these medicines, but they have been in use for many years. Two drugs, pentamidine and suramin, have been used for more than 60 years for the treatment of fi rst-stage disease. Treatment of second-stage disease is with melarsoprol and efl ornithine, as these medicines reach therapeutic levels in the central nervous system – these medicines have also been used for many years. All four medicines are given by injection, although pentamidine is administered intramuscularly rather than intravenously. All have signifi cant side-effects. With respect to treatment of fi rst-stage disease, the Committee considered the resistance data provided in the application and the additional clinical evidence summarized by the Secretariat. Pentamidine is used preferentially for T. b. g. infections. Drug resistance in the fi eld has (up to now) had no signifi cant consequences for the treatment, but, owing to a naturally lower susceptibility, it is not used to treat Trypanosoma brucei rhodesiense (T. b. r.) infections. There is no resistance to suramin, which is the medicine of choice for T. b. r. infections (50). The clinical evidence to support the use of these products is limited. The most persuasive evidence is the report of results of the fi rst 5 years (1996– 2001) of a Human African trypanosomiasis (HAT) control programme in northern Angola, run by a nongovernmental organization (51). Thirteen thousand four hundred and twenty-six patients were screened for HAT. Pentamidine isethionate was administered as seven intramuscular injections at a dose of 4 mg/kg body weight every day for patients in stage I. Patients in stage II were treated with melarsoprol, and in cases of relapse after melarsoprol treatment, with efl ornithine (400 mg/kg body weight, given as intravenous infusion at 6-hour intervals over a period of 2 weeks – the second-line treatment). Relapse was defi ned as trypanosomes detected in blood or cerebrospinal fl uid (CSF) within the fi rst year after completion of treatment. Relapse and clinical resistance to melarsoprol reached levels of 25% in M’banza Congo, and remained below 3% in the other study sites. Overall mortality rate of patients in stage II fell from 7.5% to 2.9%. The study demonstrated the effi ciency of a national control programme, and although an observational study, it supports the effi cacy of pentamidine, melarsoprol and efl ornithine. TRS946.indd 41TRS946.indd 41 19.11.2007 15:29:4519.11.2007 15:29:45 42 The application describes adverse effects of pentamidine and suramin noted in several reviews (50, 52, 53). Pentamidine is much better tolerated than sura- min. The major adverse reactions to pentamidine are hypotension and hypogly- caemia. Nausea and vomiting, local reactions at the site of injection including pain, pruritus and rash; tachycardia; hypocalcaemia and abnormal fi ndings in liver function have also been reported. Suramin causes severe adverse effects, including anaphylactic shock, severe cutaneous, neurotoxic reactions and re- nal failure. Polyneuropathy and stomatitis have also been described. With respect to treatment of second-stage disease, the application provides a summary of failure rates for treatment of T.b.g. infection with melarsoprol and efl ornithine, based mainly on observational studies. The failure rates appear to be similar. In addition three studies (54–56), that compared the effi cacy of treatment with efl ornithine and melarsoprol in patients with the second stage of T. b.g., including one randomized trial, were also considered. The trial showed that efl ornithine was an effective treatment for the second stage of Gambian trypanosomiasis and the results of the two comparative studies of efl ornithine versus melarsoprol suggest that efl ornithine is no worse than melarsoprol, and may in fact be less toxic. Based on the clinical information provided, the Committee agreed that pentamidine is the drug of choice for treatment of the fi rst stage of T.b.g. infection, which constitutes 95% of all HAT cases. It is much safer than suramin, is easier to use and the demand for pentamidine is nearly fi ve times greater than that for suramin. The requirements for skills and monitoring for safe and effective use are the same. Cost is not a consideration given that all products are donated to control programmes. Efl ornithine has been demonstrated to be similar to melarsoprol in its effi cacy for treating second-stage HAT in adults and children and to be safer than me- larsoprol. Efl ornithine is currently recommended as an alternative fi rst-line treatment strategy particularly in view of increasing resistance to melarsop- rol. The requirements for special skills or monitoring for safe and effective use of efl ornithine and melarsoprol are essentially the same, although the availability of skilled personnel and equipment for both may be problematic in remote resource-poor rural areas. Recognizing the public health impor- tance of supporting access to the few treatments available for sleeping sick- ness, the Committee recommended that all four products should be included on the core list, with notes indicating their appropriate indications. 4.11 Section 7: Antimigraine medicines 4.11.1 Addition of sumatriptan Expert reviews of the application were prepared by: Dr Liliana de Lima and Dr Rohini Fernandopulle. Comments in support of the application TRS946.indd 42TRS946.indd 42 19.11.2007 15:29:4519.11.2007 15:29:45 43 were received from Dr Benedetto Saraceno, Director, Mental Health and Substance Abuse, WHO. During its meeting in 2005, the Committee recommended that ergotamine be deleted from the Model List because of lack of evidence of effi cacy and the availability of effective and safe alternatives and, that a full application for inclusion of a 5HT1 agonist (triptan) for migraine be submitted at its next meeting in 2007. An application for inclusion of sumatriptan 50-mg tablet was received from the Global Campaign to Reduce the Burden of Headache Worldwide: Lifting the Burden. The Committee noted that the application was generally of poor quality and provided only a limited review of the evidence. Although medicines for man- aging migraine are on the Model List, the information provided did not estab- lish the public health need for an additional medicine. As noted by the expert reviewers, there is high-quality clinical evidence from a Cochrane review (57) that supports the superiority of sumatriptan for the acute management of migraine, compared with placebo. However, there have been few trials com- paring sumatriptan with standard management (aspirin and metoclopramide, or caffeine and ergotamine). In these studies, sumatriptan was found to be superior in effectiveness to caffeine and ergotamine although it caused more adverse events. When compared with aspirin and metoclopramide, sumat- riptan was superior for only one outcome (pain relief at 2 hours) and also caused more adverse events. The Committee noted that it would be helpful to have updated Cochrane reviews to confi rm these fi ndings. Some studies have found that the 50 mg dose of sumatriptan is as effective as the 100 mg dose. Despite the availability of some generic preparations, the current cost of sumatriptan is substantially higher than that of aspirin and metoclopramide. No valid cost-effectiveness evidence was provided. Overall the evidence provided in the application did not support the public health need or comparative effectiveness, safety and cost-effectiveness of sumatriptan. The Committee therefore recommended that sumatriptan not be added to the Model List and will seek high-quality national treatment guidelines to guide a full review of Section 7, Antimigraine Medicines. 4.11.2 Deletion of paracetamol Expert reviews of the application were prepared by: Dr Liliana de Lima and Dr Rohini Fernandopulle. Comments in support of the application were received from Dr Benedetto Saraceno, Director, Mental Health and Substance Abuse, WHO. After review the Committee decided to retain paracetamol on the Model List. During its meeting in 2005, the Committee recommended that ergotamine be deleted from the Model List because of lack of evidence of effi cacy and TRS946.indd 43TRS946.indd 43 19.11.2007 15:29:4619.11.2007 15:29:46 44 the availability of effective and safe alternatives. A proposal for deletion of paracetamol as a medicine for treatment of acute attack of migraine was received from the Global Campaign to Reduce the Burden of Headache Worldwide: Lifting the Burden. The Committee noted that the application was of poor quality, with limited presentation of evidence for the lack of effi cacy of paracetamol. As noted by one of the expert reviewers, a recent systematic review on effi cacy of paracetamol in treating migraine (Damen, 2005) (58) and important studies on comparative effectiveness of paracetamol combinations versus sumatriptan were not included. The additional evidence identifi ed was: one trial that showed paracetamol to be superior to placebo in treatment of acute migraine attack in children (RR 1.5, 95% CI, 1.0–2.1: 1 trial; 106 participants) and two studies comparing paracetamol (combined with other medicines) with sumatriptan, which showed equal or better effi cacy of paracetamol combinations than of sumatriptan 50 mg (ASSET trial) (59) or 100 mg (Freitag, 2001) (60). The study cited in the application (Lipton, 2000) (61) showed the effi cacy of oral paracetamol (100 mg) in treatment of acute migraine attack when compared to placebo. The only study (Leinisch, 2005) (62) which did not show benefi ts of intravenous paracetamol over placebo was small (n = 60) and could not be used alone to support lack of effi cacy of paracetamol. Overall the evidence provided in the application was selective and did not support the claim of lack of effi cacy of paracetamol. Paracetamol may be a useful alternative in children. No signifi cant toxicity was identifi ed, and no evidence for better alternatives was provided. The Committee therefore recommended that paracetamol be retained on the Model List. 4.12 Section 8.2: Cytotoxic drugs 4.12.1 Section 8.2: Cytotoxic medicines The expert review of the application was prepared by: Dr Alar Irs. The Committee welcomed the contribution of the International Network for Cancer Treatment and Research (INCTR) to the review of the cytotoxic drugs for the Model List and noted the letter from Dr Ian McGrath (December 2006) outlining the continuing commitment of the INCTR to the review of the cytotoxic medicines. It is expected that the Network will contribute formal proposals for deletions and additions to the Model List for consideration at subsequent Expert Committee meetings. Two proposals were submitted for consideration at the 15th meeting of the Expert Committee – proposals for deletion of chlormethine (mustine) and levamisole. 4.12.2 Deletion of chlormethine Comments on the proposal were received from: Adamos Adamou, Chairman of the ESMO task force for developing countries; Professor T. Eden; Ben TRS946.indd 44TRS946.indd 44 19.11.2007 15:29:4619.11.2007 15:29:46 45 Anderson and Alex Eniu, The Breast Health Global Initiative; and Professor Ian Olver. The Committee noted that chlormethine (mustine or nitrogen mustard) has been used for the treatment of various lymphomas for more than 50 years, mostly in combination with other agents. The side-effects of the earlier combination therapies (secondary malignancies and infertility) have led to the identifi cation of other, more effective treatment combinations, such that chlormethine is now rarely used in clinical practice. It is not a component of standard therapy for any tumour in current clinical practice. In addition, chlormethine is a vesicant and can cause severe tissue damage and ulceration if it leaks at the site of intravenous administration. Topical mustine has also been replaced by other agents for the treatment mycosis fungoides. Given the availability of more effective and less toxic alternatives, the Committee recommended that chlormethine be deleted from the Model List (Section 8.2 Cytotoxic Medicines). 4.12.3 Deletion of levamisole as an anticancer medicine The Committee noted that levamisole was developed originally as an anthelminthic. It was subsequently recommended for use as adjuvant therapy in colon cancer. However, more recent evidence from large randomized controlled trials has failed to show any benefi t of levamisole in this situation. Levamisole has no place in the treatment of metastatic colon disease, nor is it used in clinical practice in the treatment of other cancers, including melanoma. Therefore, as levamisole has no clearly identifi ed role in the treatment of cancers, the Committee recommended that levamisole be deleted from the section listing cytotoxic medicines (Section 8.2 Cytotoxic Medicines). 4.13 Review of section 8.4: Medicines used in palliative care Expert reviews of the application were prepared by: Dr Eva Ombaka and Dr Abdelkader Helali. The 14th Model List of Essential Medicines lists medicines for palliative care by reference to two WHO treatment guidelines for pain and palliative care (63, 64), which have not been updated since they were published in 1996 and 1998, respectively. Both contain a number of recommendations that would now be regarded as obsolete, as well as not referring to more recently available medicines. In 2005, the International Association for Hospice and Palliative Care (IAHPC), in response to a request from WHO, developed a list of essential medicines for palliative care, in collaboration with other organizations. This was a consensus-based process, and for the fi rst step, the group identifi ed the most common symptoms in palliative care. Based on the symptoms, and TRS946.indd 45TRS946.indd 45 19.11.2007 15:29:4619.11.2007 15:29:46 46 using a Delphi process, the group then listed possible essential medicines. The resulting list of 33 medicines has been announced as the IAHPC List of Essential Medicines. Of the 33 IAHPC essential medicines, 14 are already on the WHO Model List for several indications. Two medicines were added at the present meeting (prolonged-release morphine (Section 2.2) and fl uoxetine (Section 24.2.1). The IAHPC list is based on a holistic approach to treatment of patients with advanced, incurable and progressive diseases. The medicines in this section are included for the treatment of symptoms, not the underlying conditions. The Committee welcomed this initiative and recognized the need for a comprehensive Palliative Care section that lists specifi c medicines. However, there are still a number of unresolved issues. The guidelines remain unchanged, and although WHO is planning to update them, this is still in the preliminary stages. Ideally, the guidelines should be updated fi rst and then changes to the Model List could be proposed. The Committee noted that the consensus process cannot replace consideration of evidence for comparative effectiveness and safety, even allowing for possible evidence gaps, given the diffi culties of carrying out trials in palliative care settings, and that, based on a review of evidence, some of the recommendations may change. For this reason, the Committee decided not to specify any medicines in the Palliative Care Section at this time. In addition, the Committee amended the note in this section to read: “The Committee expects applications for medicines essential in palliative care to be submitted for the next meeting.” 4.14 Section 12.6: Lipid-lowering drugs: addition of simvastatin Expert reviews of the application were prepared by: Dr Alar Irs and Professor Hany Abdel-Aleem.1 Comments in support of the application were received from Dr Shanthi Mendis, Senior Adviser, Cardiovascular Diseases, Chronic Diseases Prevention and Management, WHO. During its meeting in 1997, the Committee added the section on lipid- lowering medicines to the Model List. At that time, no specifi c medicine was recommended at the global level, although it was recommended that the choice should be made at the national level and the class of medicines, “statins” (β-hydroxy-β-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors) was suggested. The following statement has been included in the Model List since that meeting (with minor variations): 1 Professor Hany Abdel-Aleem, Department of Obstetrics and Gynecology, Assiut University Hospital, Assiut, Egypt, participated as Temporary Adviser to the Expert Committee. TRS946.indd 46TRS946.indd 46 19.11.2007 15:29:4619.11.2007 15:29:46 47 “The WHO Expert Committee on the Selection and Use of Essential Medicines recognizes the value of lipid-lowering drugs in treating patients with hyperlipidaemia. HMG-CoA reductase inhibitors, often referred to as “statins”, are a family of potent and effective lipid-lowering drugs with a good tolerability profi le. Several of these drugs have been shown to reduce the incidence of fatal and non-fatal myocardial infarction, stroke and mortality (all causes), as well as the need for coronary by-pass surgery. All remain very costly but may be cost effective for secondary prevention of cardiovascular disease as well as for primary prevention in some very high- risk patients. Since no single drug has been shown to be signifi cantly more effective or less expensive than others in the group, none is included in the Model List; the choice of drug for use in patients at highest risk should be decided at the national level.” An application for inclusion of simvastatin 5, 10, 20 and 40-mg tablet was submitted by the NHS Centre for the Evaluation of Effectiveness of Health Care (CeVEAS), Local Health Unit, Modena, Italy and Universities Allied for Essential Medicines (UAEM). The proposal is to list simvastatin with a square box, with pravastatin, fl uvastatin, atorvastatin and lovastatin as named alternatives. The Committee noted that the application was of high quality and provided a comprehensive review of the existing evidence regarding the effective- ness and safety of statins used for secondary prevention of cardiovascular disease. The public health need for inclusion of a statin on the Model List was fully substantiated. As noted by the expert reviewers, there is high- quality clinical evidence from many large randomized trials and systematic reviews that establish the benefi ts of statins, in conjunction with lifestyle modifi cation, for secondary prevention of cardiovascular disease. For ex- ample, the estimates of benefi t in the UK National Institute for Clinical Excellence (NICE) systematic review (65) are RR 0.80 (95% CI, 0.71– 0.90) for all-cause mortality and RR 0.75 (95% CI, 0.68–0.83) for car- diovascular mortality. These results are consistent with those of the other studies presented. The Committee noted that statins are generally well tolerated (66). However, some of the rare adverse effects of statins are potentially very serious, including rhabdomyolysis. For the statins included in the application, there is no evidence of a difference in adverse effect profi les although adverse effects appear to be dose-related. The Committee noted that one medicine in the statin class, cerivastatin, had been withdrawn from the market due to unacceptably high rates of adverse reactions. Ideally, regular monitoring of liver function should be available if patients are taking long-term statin treatment, but it is also possible to assess safety on the basis of clinical assessment of muscle symptoms such as pain and fatigue. In general the TRS946.indd 47TRS946.indd 47 19.11.2007 15:29:4719.11.2007 15:29:47 48 benefi ts of statins in preventing cardiovascular deaths outweigh the risk of the rare adverse effects. Generic preparations of simvastatin are available worldwide; the current cost of simvastatin is reasonable and its inclusion on the Model List would potentially contribute to further reductions in prices. The application provided a review of the evidence on cost-effectiveness of long-term statin therapy for secondary prevention. The Committee noted that the cost- effectiveness of statin treatment is closely related to the absolute risk for coronary heart disease. There have been many cost-effectiveness analyses of use of statins in developed countries, but few in developing countries. The study by Murray et al. (67) provided modelled estimates of the average cost per disability-adjusted life year (DALY) of statins for secondary prevention in developing countries and suggested that, using the threshold of gross national income per capita, the products are acceptably cost-effective. Overall the evidence provided in the application supports the public health need, effectiveness, safety and cost-effectiveness of simvastatin as an example statin. The Committee therefore recommended that simvastatin be added to the Model List for risk reduction in high-risk populations with a square box symbol denoting pravastatin, lovastatin, fl uvastatin and atorvastatin as possible alternatives, with the choice to be made at the national level. These alternatives were identifi ed on the basis of availability of comparable clinical outcome data. 4.15 Section 18.3: Contraceptives 4.15.1 Review of section 18.03.00.00: Contraceptives Expert reviews of the application were prepared by: Dr Lenita Wannmacher and Mr Dinesh Mehta.1 Comments in support of the application were received from Dr Catherine d’Arcangues, Reproductive Health and Research (RHR), WHO. Additional supporting statements were received from Dr Lindsay Edouard, Senior Adviser, Reproductive Health Branch, United Nations Population Fund, New York, USA. The Section on Contraceptives was noted for review at the 14th Meeting of the Expert Committee on the Selection and Use of Essential Medicines, as the Committee declined to list several contraceptive medicines. In the discussion of the applications, the Committee noted that the approach to provision of contraceptives was a philosophy of choice and therefore required a wide range of options and that this was in contrast to the principles of drug selection applied for the Model List, i.e. the approach is one of identifying the minimum needed to provide health care. 1 Mr Dinesh Mehta, British National Formulary, Royal Pharmaceutical Society of Great Britain, London, England, is a Member of the Expert Committee. TRS946.indd 48TRS946.indd 48 19.11.2007 15:29:4719.11.2007 15:29:47 49 A review of the available evidence was commissioned to provide a stronger evidentiary basis upon which the Committee could make its recommendations. This review sought to answer the question: “Does a policy of providing a wide range of contraceptive methods, as opposed to a limited range, improve health outcomes including contraceptive uptake, acceptability, adherence, continuation and satisfaction, reduction of unintended pregnancy and improved maternal health and well-being?” The review provided was comprehensive, and concluded that based on a limited literature: “It supports the contention that increased choice is associated with increased uptake and with better health outcomes (such as lower pregnancy rates and fewer STIs), and that women given a choice exercise it and continue use of their chosen contraceptives to a greater degree than those denied their choices. There is no evidence to the contrary. Nonetheless, a commitment to expanded choice is pervasive in the literature and has informed global and national policies. Such an approach is consistent with a Human Rights and Essential Medicines approach” (Executive Summary, page 5). However the literature is not particularly helpful in answering a question that has both biosocial and biomedical aspects. Therefore the Committee will need to decide the principles upon which drug selection for contraceptives for the Model List should be based. Should acceptability and suitability be considered, as well as the standard criteria used in identifying medicines for inclusion in the Model List of comparative effi cacy, namely, comparative safety and comparative cost? The competing arguments can be summarized in part as follows: Family planning cannot and should not be considered in the same ways as curative medicine. Data regarding behavioural and psychosocial outcomes such as satisfaction with contraceptive method, persistence with contraceptive choice and desire to try other therapy options are crucial for family planning services. Different methods can be defi ned in a variety of ways, including route of administration, duration, components (e.g., progesterone only versus combined), or perception of the person using the contraceptive. The Department of Reproductive Health and Research in part challenges the commissioned review on the perspective taken, arguing that the review considers the biomedical view, whereas the biosocial science point of view is more relevant to this question. These perspectives frame the questions in different ways. The biomedical view asks whether there is evidence that an increased range of treatment options improves outcomes (health, satis- faction), whereas the biosocial science point of view asks whether limited choices of contraceptive methods act as a barrier to achieving high levels of contraceptive use. The Programme of Action of the International Conference on Population and Development held in Cairo in 1994 recommended the provision of a wide range of contraceptive options. TRS946.indd 49TRS946.indd 49 19.11.2007 15:29:4719.11.2007 15:29:47 50 The approaches adopted by the Expert Committee to the selection of contraceptives are based on the defi nition and selection criteria defi ned in the procedures for the Expert Committee 2002, which defi nes essential medicines as those that satisfy the priority health care needs of the population and where medicines are selected with due regard to disease prevalence, evidence on effi cacy and safety, and comparative cost-effectiveness. Implicit in these criteria is an approach based on parsimonious choice, i.e. a limited list of drugs targeting priority health care needs. After discussion of the review and considering the various arguments, the Committee confi rmed that it would take an evidence-based approach to listing contraceptives. The Committee will assess new products on a case-by- case basis using the accepted criteria of comparative effi cacy, comparative safety and comparative cost, as well as suitability and acceptability. 4.15.2 Addition of levonorgestrel implants In 2005, the Expert Committee rejected the application for two implantable contraceptives (levonorgestrel- and etonogestrel-releasing implants) after consideration of the balance of benefi ts, harm, suitability, the need for the additional choice and the relatively high cost. In particular, the disadvantages noted included the special training required for insertion and removal of the implant and the relatively high cost. A revised application was submitted for the present meeting by The Geneva Foundation for Medical Education and Research, but this time only for inclusion of a two-rod levonorgestrel- releasing implant, each rod containing 75 mg of levonorgestrel (150 mg total). Expert reviews of the application were prepared by: Dr Lenita Wannmacher and Mr Dinesh Mehta. The Committee noted that the application provided an updated review of the existing evidence for the comparative effectiveness and safety of levonorgestrel-releasing implants for reversible contraception. There are reports from studies of four different products: (1) two silastic rods containing levonorgestrel, 70 mg, with contraceptive life of up to 3 years (marketed as Norplant-2®); (2) 6-capsule implant containing 36 mg of levonorgestrel each with a contraceptive life of up to 5 years (marketed as Norplant®); (3 and 4) the proposed formulations (Jadelle® and Sino-implant No. 2). The studies distinguish the different products by brand name. Two trials comparing the proposed formulation of 2-rod implants with the 6-capsule implant have established contraceptive effi cacy (68, 69). The cumulative 5-year pregnancy rate in these studies was 0.7–1 per 100 users for the 2-rod implant versus 0–0.7 per 100 users. For comparison with other methods of contraception, the application referred to a Cochrane systematic TRS946.indd 50TRS946.indd 50 19.11.2007 15:29:4819.11.2007 15:29:48 51 review (70). One randomized controlled trial in family planning clinics in China (71) compared Norplant-2 with intrauterine systems impregnated with levonorgestrel (LNG-20 IUS). Both methods were found to be equally effective in preventing pregnancy, with pregnancy rates of 1/3098 women- months in the group using LNG-20 IUS versus 0/3093 women-months in the group using Norplant-2. The rates for continuation, expulsion and formation of ovarian cysts showed no difference between the two contraception methods. The use of 2-rod levonorgestrel-releasing implants (Norplant-2) was associated with less amenorrhoea and oligomenorrhoea, although there were more reports of spotting and prolonged bleeding. The Committee noted that levonorgestrel-releasing implants are recommended in a number of WHO documents (72, 73) and that there are advantages of implantable contraceptives for women with risk factors for pelvic infl ammatory disease and in cases of problems with adherence to other contraceptive methods. There is now at least one generic preparation and the cost has been reduced substantially. As the evidence provided in the application supports the effectiveness, safety and cost-effectiveness of 2-rod levonorgestrel-releasing implants, the Committee recommended that a 2-rod levonorgestrel-releasing implant, each rod containing 75 mg of levonorgestrel (150 mg total) be added to the core Model List for long-term reversible contraception. 4.15.3 Addition of medroxyprogesterone acetate plus estradiol cypionate Expert reviews of the application were prepared by: Dr Lenita Wannmacher and Mr Dinesh Mehta. In 2005, the Expert Committee rejected the application for two combination injectable contraceptives (medroxyprogesterone acetate plus estradiol cypionate and norethisterone enanthate plus estradiol valerate), questioning the public health need for these preparations in view of the lack of compelling evidence of better effi cacy, convenience and safety. A revised application for inclusion of medroxyprogesterone acetate 25 mg plus estradiol cypionate 5 mg was submitted by the Geneva Foundation for Medical Education and Research. The new application presented the same evidence for comparative effectiveness and safety from a Cochrane systematic review (74) and additional results for comparative safety based on three observational studies. The systematic review included two multicentre studies that directly compared the proposed combination with medroxyprogesterone-only injection. Comparative contraceptive effi cacy was not reported in the review although other evidence from the same systematic review shows that the proposed product is an effective contraceptive. In terms of potential advantages of the proposed combination, the results of the review suggest less menstrual disturbance, better control of bleeding and greater intention to continue contraception TRS946.indd 51TRS946.indd 51 19.11.2007 15:29:4819.11.2007 15:29:48 52 with the combination injectable contraceptive (medroxyprogesterone acetate plus estradiol cypionate) than with medroxyprogesterone-only injections. To address the concerns raised at the previous meeting, the application pre- sented new information from three observational studies (75–77) all of 1 year’s duration. The studies were designed to measure changes in surrogate biochemical markers, but not in cardiovascular events or fracture outcomes. The results generally showed that the injectable combined contraceptive did not have deleterious effects on lipid metabolism, coagulation or bone mineral density. The studies were of insuffi cient duration to identify any effects on clinical outcomes such as cardiovascular events or fractures. Importantly, al- though the application acknowledged the need for a sterile injection technique for administration of this product, it did not provide an assessment of the possible risks associated with a monthly injection regimen. The application did not provide information on the cost-effectiveness of the combination injectable contraceptive. Based on the information provided, the acquisition cost of the product would appear to be substantially more than that of the alternatives. The Committee noted that combination injectable medroxyprogesterone acetate/estradiol cypionate is recommended in WHO guidelines (the WHO Medical eligibility criteria for contraceptive use (78); and the Selected practice recommendations for contraceptive use (73)), although there are currently no such products on the Model List. Notwithstanding the previous inclusion of progestagen-only injectable con- traceptives (POIC), and the similarity in contraceptive effectiveness between them and the combined injectable contraceptive (CIC), the differences in safety profi le and convenience may serve to increase tolerance and continuation rates in women with different organic conditions and preferences. The Committee therefore decided to add medroxyprogesterone acetate plus estradiol cypionate 25 mg + 5 mg combination injectable contraceptive to the Model List of Essential Medicines as a new section, 18.3.5. The Committee also recommended that the Uppsala Collaborating Centre for Drug Monitoring be requested to monitor reports of adverse events in relation to use of this product. 4.16 Section 19.2: Sera and immunoglobulins 4.16.1 Application for antivenom serum: equine immunoglobulin F(ab’)2 fragment Expert reviews of the application were prepared by: Dr Estrella Paje-Villar1 and Dr Noël Cranswick. Additional supporting statements were received from Dr José Manuel Gutiérrez. 1 Dr Estrella Paje-Villar is Professor of Paediatrics and Pharmacology, Faculty of Medicine, University of Sto. Tomas, Sampaloc, Manila, Philippines, and participated as a Temporary Adviser to the Expert Committee. TRS946.indd 52TRS946.indd 52 19.11.2007 15:29:4819.11.2007 15:29:48 53 An application was received from Sanofi Pasteur SA Lyon, France Equine F(ab’)2 antivenoms for the inclusion of four polyvalent antivenoms on the Model List as individual medicines. These are FAVAFRICA for the management of snake bites in sub-saharan Africa, FAVIREPT for the management of snake bites in the Middle-East, VIPERFAV for snake bites in Europe, and SCORPIFAV for scorpion bites in the Middle East. The core Model List (2005) includes antivenom serum, but provides no further specifi cation on type of product beyond a comment that the exact type needs to be defi ned locally. The application from Sanofi Pasteur provides a possible short-term solution for ongoing supply problems identifi ed in Africa and the Middle East for region-specifi c polyvalent antivenoms, and the Committee agreed to add antivenom immunoglobulins to the core list. The Committee decided that it was not appropriate to specifi cally include the individual products as nominated above on the Model List. At its next meeting, the Committee anticipates a full review of this section. 4.16.2 Immunoglobulin Expert reviews of the application were prepared by: Dr Albert Figueras and Dr Noël Cranswick. Comments in support of the application were received from: Dr Neelam Dhingra, Coordinator, Blood Transfusion Safety, Essential Health Technologies, WHO, Dr Ana Maria Padilla Marroquin, Quality and Safety of Plasma Derivatives and Related Substances, WHO and Dr H. Goubran, from Egypt. The Committee acknowledged the receipt of additional supporting statements from the general public and professional organizations. An application was received from the International Union of Immunological Societies (IUIS) and International Patient Organisation for Primary Immunodefi ciencies (IPOPI) for the inclusion of polyvalent human immunoglobulins on the Model List. Human immunoglobulins were listed in Section 19.2 Sera and immunoglobulins, of the Model List in 2002, but deleted by the Expert Committee in 2003. The application seeks listing of polyvalent human immunoglobulins in several places in the Model List: Section 19.2 Sera and immunglobulins; Section 11.2 Plasma fractions for specifi c use; and Section 8.1 Immunosuppressive therapies, under the new subsection 8.1.1 Medicines used in immunomodulation. The Committee noted that the evidence presented in the application does support the claims of effi cacy and safety, and extensive clinical experience underpins the specifi c clinical recommendations to use these products. The costs of these products were noted as a concern. The Committee noted that cost-effectiveness has been assessed, but that this was done in a developed country setting and not found to be cost-effective for all indications. TRS946.indd 53TRS946.indd 53 19.11.2007 15:29:4819.11.2007 15:29:48 54 Two of the specifi c issues that underpinned the decision to remove the product in 2003 were not directly addressed in the application; i.e. that human polyvalent immunoglobulins are not included in any Standard Treatment Guidelines (STGs), and that quality control of the blood product poses a problem. The application does state that improvements in manufacturing practice have reduced infusion-related adverse events, but ensuring that quality products are available in all settings may pose diffi culties. No STGs were identifi ed that included IVIg therapy. The Committee considered that the products may not be cost-effective in many jurisdictions. In addition, however, the Committee considered that these products were part of the blood fractionation process that would yield other blood products for human use. Therefore the products could be seen as part of a package to encourage good manufacturing of plasma- derived products. Because of potential infusion-related adverse events, IVIg would need to be administered in hospital settings where adequate specialist supervision was available. The Committee therefore agreed to list polyvalent human immunoglobulins on the complementary list in Section 11.2, Plasma fractions for specifi c use, in the following forms: — human normal immunoglobulin for intramuscular administration: 16% protein solution; and — human normal immunoglobulin for intravenous administration: 5%, 10% protein solution. However, the Committee noted that unless the prices of the products were substantially reduced, access in developing countries would remain a problem. Countries are advised to acquire human immunoglobulins for specifi c disorders, such as primary immunodefi ciency, Guillain-Barré syndrome and Kawasaki disease. 4.17 Review of section 19.3: Vaccines The Model List of Essential Medicines currently lists vaccines based on the component antigens. This section has not been updated since 1999, when the List was modifi ed to specify antigens rather than vaccines. In reviewing the text for the 2006 WHO Model Formulary, it was noted that several of the vaccine recommendations were out of date and several vaccines that are now recommended by WHO were not listed. The option of undertaking a comprehensive update of the section was considered. In discussions with the Department of Immunization, Vaccines and Biologicals, WHO, however, it was pointed out that there is a separate expert group, the Strategic Advisory Group of Experts (SAGE) that now makes recommendations to the Director-General of WHO on the work of TRS946.indd 54TRS946.indd 54 19.11.2007 15:29:4919.11.2007 15:29:49 55 the Department. A Global Advisory Group of Experts provides scientifi c advice to SAGE on the safety of vaccines. There is also an Expert Committee on Biological Standardization to defi ne standards for prequalifi cation of vaccines. It might be argued therefore that there is already suffi cient WHO advice available to Member States on norms and standards for vaccines, including what vaccines to use. However, although there are several reference sources provided, none of them appear to contain an equivalent to an “essential list of vaccines”. The Committee was advised by Dr David Salisbury, Chair of the SAGE, that there are several problems with the current list and with potentially listing vaccines in the Model List: • The current list is incomplete and out of date. • The current division of the list into vaccines for universal and specifi c use is incorrect. • The recommendations of SAGE and the vaccines listed in the Model List could be inconsistent. The List would need to be continuously updated to keep SAGE recommendations and the Model List harmonized. Countries that use the Model List to guide procurement may not purchase vaccines that are recommended by SAGE. If a vaccine is not listed on the Model List, this can be a disincentive to a country to purchase it. • In making recommendations, SAGE considers trials, studies of safety and effi cacy from industrialized countries, and experience of use in developing countries. An expert subgroup is convened to review this evidence to examine epidemiology of disease, availability of the vaccine, and cost-effectiveness data on the vaccine; this is presented as a WHO position paper on vaccines. One proposed solution discussed was to remove specifi c vaccines from the Model List and refer people to the SAGE recommendations which include a list of pre-qualifi ed vaccines that is updated weekly. This list does not specify which vaccines are universally recommended; it is not a list of “essential” vaccines. Countries could select vaccines from this list based on the epidemiology of disease in that country. Another solution considered was that a procedure for updating the Model List between meetings could be linked to the SAGE process. Thus, the Model List could be updated as the SAGE recommendations are updated. The Secretariat sought comments from regions and countries on the proposal and was advised that the vaccine list should be maintained as part of the Model List. Recognizing that there are several other expert groups that consider vaccines, it would seem unnecessary for the Expert Committee on Selection and Use of Essential Medicines to expect a full application for new vaccines. TRS946.indd 55TRS946.indd 55 19.11.2007 15:29:4919.11.2007 15:29:49 56 However, the other sources of information do not seem to completely replace the function of the Model List. The Committee decided to list all the vaccines for which the SAGE group has a position paper, with a link to the relevant web site. The preamble to the section has been revised to indicate that: Selection of vaccines from the Model List will need to be determined by each country after consideration of international recommendations, epidemiology and national priorities. The list below details the vaccines for which there is either a recommendation from the Strategic Advisory Group of Experts on Immunization (SAGE): (http://www.who.int/immunization/sage_conclusions/en/index.html) and/or a WHO position paper: (http://www.who.int/immunization/documents/positionpapers/en/index. html). This site will be updated as new position papers are published and contains the most recent information and recommendations. All vaccines should comply with the WHO Requirements for Biological Substances. 4.18 Section 21.1: Ophthalmological preparations – Anti-infective agents 4.18.1 Review of section 21: Ophthalmological preparations Expert reviews of the application were prepared by: Dr Lisa Bero and Dr Usha Gupta. In 2006, Sightsavers International, representing the VISION 2020 Technology Working Group approached the Department of Medicines Policies and Standards, WHO, with proposals to review and update the list of medicines for ophthalmic conditions. As the Expert Committee had recommended this in 2005, the proposal was welcomed. The justifi cation for the proposal also notes the WHA resolutions on prevention of blindness, which urge Member States to make available essential medicines for eye care, and the importance of the Model List in infl uencing procurement and tax policies. This proposal was the initial submission, with suggested additional changes requiring applications and/or systematic reviews. The public health importance of providing adequate treatment for the prevention of blindness is clearly established. The major causes of blindness are cataract (in adults and children), viral and fungal infections and glaucoma. All are potentially treatable. The Committee noted that no current WHO treatment guidelines are identifi ed. A “standard list” (79) for a vision service unit exists, which specifi es medicines, equipment, instruments, optical supplies and educational resources needed for effective eye care. As noted in the proposal, several systematic reviews are currently in progress to assess the comparative effectiveness and safety of the additional TRS946.indd 56TRS946.indd 56 19.11.2007 15:29:4919.11.2007 15:29:49 57 medicines suggested. There have been preliminary discussions with WHO about a possible joint grant proposal with the Cochrane group to seek funding to support these reviews. The Committee noted the potential usefulness of the VISION 2020 list, but decided not to add a note to the Model List referring to it until further assessment of the comparative effectiveness and safety of the medicines included on it could be carried out. The Committee expects applications for additional medicines for the Ophthamological preparations section. 4.18.2 Addition of aciclovir and deletion of idoxuridine Expert reviews of the application were prepared by: Dr Lisa Bero and Dr Usha Gupta. In 2005 the Expert Committee requested a review of Section 21 of the WHO Model List of Essential Medicines Ophthalmological preparations. As part of the review, undertaken by Sight Savers International and the VISION 2020 Technology Working Group, an application for inclusion of a new formulation of aciclovir (ophthalmological preparation) and a proposal to delete the listed antiviral ophthalmological medicine idoxuridine was submitted. The proposal was to list aciclovir ointment 3% W/W as a new formulation replacing idoxuridine solution (eye drops), 0.1% and eye ointment, 0.2%. The Committee noted that the application provided a review of the existing evidence for the comparative effectiveness of ophthalmological aciclovir com- pared to idoxuridine and other topical antivirals for treating epithelial keratitis caused by herpes simplex virus. The public health need for inclusion of a new formulation of aciclovir on the Model List was fully demonstrated. As noted by the expert reviewers, the clinical evidence, based on systematic reviews (80), shows that aciclovir ointment is superior to idoxuridine in both adult and child populations, based on improved healing at 7 days (RR 2.10, 95% CI, 1.27– 3.47) and healing at 14 days (RR 1.21, 95% CI, 1.05–1.40). The Cochrane re- view found that aciclovir appeared to be equivalent to other nucleoside antiviral agents (trifl uridine). The Committee noted that aciclovir was well tolerated. The Committee noted that aciclovir ointment has been approved by several stringent regulatory authorities and is available as a generic preparation, while idoxuridine has largely been removed from the market. The current cost of aciclovir ointment is variable (from US$ 0.25 to US$ 23.00 per tube) and its inclusion on the Model List may lead to further reductions in price. As the evidence provided in the application supports the public health need, effectiveness and safety of aciclovir ophthalmological formulation, the Committee recommended that aciclovir ointment 3% W/W be added to the core Model List for treatment of ocular surface disease caused by herpes simplex virus. TRS946.indd 57TRS946.indd 57 19.11.2007 15:29:4919.11.2007 15:29:49 58 4.19 Section 24: Psychotherapeutic medicines – 24.2.1: Medicines used in depressive disorders 4.19.1 Addition of fl uoxetine hydrochloride Expert reviews of the application were prepared by: Dr Liliana de Lima and Dr Rohini Fernandopulle. The antidepressant amitriptyline has been on the Model List since its fi rst edition and is currently listed in Section 24.2.1 Medicines used in depressive disorders: amitriptyline tablet, 25 mg (hydrochloride). Following a Delphi process among it members in 2005–2006, the International Association of Hospice and Palliative Care suggested fl uoxetine be considered for addition to the Model List for use in the context of palliative care as well as in treating depression. An application for inclusion of fl uoxetine 20 mg tablet was prepared for the Department of Medicines Policy and Standards (PSM) by the WHO Collaborating Centre for Research and Training in Mental Health, University of Verona, Italy. The proposal is to list fl uoxetine with a square box as an example selective serotonin reuptake inhibitor (SSRI). The Committee noted that the application was of good quality and provided a comprehensive review of the existing evidence regarding the effectiveness and safety of SSRIs used for acute-phase treatment of moderate-to-severe depression. The public health need for inclusion of an SSRI on the Model List was fully substantiated. As noted by the expert reviewers, there is abundant clinical evidence from many randomized trials and systematic reviews that establish the benefi ts of SSRIs for short-term treatment of depressive disorders. Results from a considerable body of evidence, including a Cochrane Systematic Review (81), show that fl uoxetine is as effective as amitriptyline and may have fewer side-effects. The Committee noted that the major concern with the use of the SSRIs is the potential stimulation of suicidal ideation in high-risk depressive patients, particularly in patients aged 8–18 years. Many studies have attempted to quantify this risk over the past 15–20 years and there is an increased risk of suicidal ideation, but no increased risk of completed suicide. Most recent reviews support the view that the risk is likely to be real, but there is uncertainty about its magnitude, although it appears most likely to be a problem in young, severely depressed patients. This is refl ected in the current labelling of fl uoxetine preparations by the EMEA and FDA, among others. Very recent estimates from the USA suggest that overdose with an SSRI is associated with lower mortality and morbidity than overdose with tricyclic antidepressants (TCAs) (82). Generic preparations of fl uoxetine are available worldwide. The application provided a review of the evidence on cost-effectiveness of SSRI use in TRS946.indd 58TRS946.indd 58 19.11.2007 15:29:5019.11.2007 15:29:50 59 the treatment of depressive disorders which suggested that there are no differences in terms of cost-effectiveness between SSRIs and tricyclics. Overall, the evidence provided in the application supports the public health need, comparable effectiveness and generally more favourable tolerability profi le than amitriptyline. The Committee therefore recommended that fl uoxetine be added to the core Model List for short-term treatment of depressive disorders. A square box was not included, because there may be signifi cant within-class differences in relation to safety. 5. Paediatric medicines 5.1 Section 5: Anticonvulsants/antiepileptics 5.1.1 Carbamazepine – addition of new dosage form An application was prepared by the University of Liverpool, England, at the request of the Department of Medicines, Policy and Standards, WHO, for the addition of carbamazepine oral suspension (100 mg/5 ml) and 100 mg, 200 mg chewable tablets to the Model List for the treatment of childhood epilepsy. The listing is as an individual medicine. Expert reviews of the application were prepared by: Dr Susan Walters.1 Comments in support of the application were received from Dr Benedetto Saraceno, Director, Mental Health and Substance Abuse, WHO. Additional supporting statements were received from DRA. The Committee noted that several Cochrane reviews (83–86) and other ran- domized controlled trials (87–91) were cited in the application to support the effi cacy and safety of carbamazepine in both adults and children. While there is not a substantial body of clinical trial data to establish the superior effi cacy and safety of carbamazepine over other antiepileptic medicines, there are dif- ferences in tolerability and side-effects between available agents and there is a need for a range of antiepileptic drugs for different seizure types. The need for both suspension and chewable tablet formulations is not addressed in the application. There may however be a preference for chewable tablets over syrup formulations because of the additional costs associated with liquid paediatric formulations. The costs for these dosage formulations compared to 100 mg carbamazepine tablets, which are currently included in the Model List, were not provided in the application. The Committee recommended inclusion of carbamazepine suspension 100 mg/5 ml on the core Model List of drugs for the treatment of generalized tonic–clonic and partial seizures. The Committee was concerned that chewable tablets can be expensive and that the stability of liquid forms can 1 Dr Susan Walters is a Member of the Expert Committee. TRS946.indd 59TRS946.indd 59 19.11.2007 15:29:5019.11.2007 15:29:50 60 be problematic. Where a crushable tablet may be specifi ed, a dispersable one may be acceptable. Where an oral liquid is specifi ed, it is possible to make granules. The Committee noted that this may be an issue for the subcommittee on children’s medicines to consider further. 5.1.2 Phenobarbital: addition of new dosage form An application was received from Professor Josemir W. Sander, WHO Collaborating Centre for Research and Training in Neurosciences, London, England, for inclusion of phenobarbital 200 mg/ml injection on the Model List for second-line treatment for status epilepticus refractory to initial treatment with benzodiazepines in both adults and children. Listing is as an individual medicine and formulation. Expert reviews of the application were prepared by: Dr Noël Cranswick and Dr Marcus M. Reidenberg. Comments in support of the application were received from Dr Benedetto Saraceno, Director, Mental Health and Substance Abuse, WHO. The Committee noted that the effi cacy and safety data were derived from a small number of trials, but generally supported the view that phenobarbital injection is both effective and safe for use in status epilepticus. In the largest trial (Treiman et al., 1998) (92), treatment with lorazepam was successful in 64.9% of subjects with overt generalized convulsive status epilepticus, phenobarbital in 58.2%, diazepam plus phenytoin in 55.8%, and phenytoin in 43.6% of subjects. There was no statistically signifi cant difference in the risk of non-cessation of seizures between lorazepam IV and phenobarbital IV (34/97 versus 38/91 participants) or adverse effects (42/97 versus 46/91 participants). The side-effects of phenobarbital such as respiratory and cardiac depression are serious. However, it is not clear whether these side-effects relate to the treatment or to the condition being managed; the evidence suggests that complications occur no more frequently with phenobarbital than other agents. The application suggests second-line listing for status epilepticus refractory to initial treatment with benzodiazepines in both adults and children. Wilmshurst and Newton (2005) (93) suggest third-line use in status epilepticus and that it can be and is used at all levels of hospital care. The Committee recommended inclusion of phenobarbital injection 200 mg/ ml on the core Model List as second-line treatment for status epilepticus refractory to initial treatment with benzodiazepines in both adults and children. The Committee had some concerns about availability across countries and anticipated that listing would stimulate production of these dosage forms and strengths, and thus improve availability. TRS946.indd 60TRS946.indd 60 19.11.2007 15:29:5019.11.2007 15:29:50 61 5.1.3 Phenytoin oral liquid and chewable tablets: addition of new dosage form An application was prepared by the University of Liverpool at the request of the PSM Department, for the addition of phenytoin base syrup (30 mg/ 5 ml) and 50-mg chewable tablets to the Model List for the treatment of childhood epilepsy. Listing is as an individual medicine. Expert reviews of the application were prepared by: Dr Susan Walters and Dr Marcus M. Reidenberg. Comments in support of the application were received from Dr B. Saraceno, Director, Mental Health and Substance Abuse (MSD). Additional supporting statements were received from DRA. The Committee noted that several Cochrane reviews (85, 94– 96) and other randomized controlled trials (97, 98) were cited in the application to support the effi cacy and safety of phenytoin in both adults and children. While there is not a substantial body of clinical trial data to establish the superior effi cacy and safety of phenytoin over other antiepileptic medicines, there are differences in tolerability and side-effects between available agents and there is a need for a range of antiepileptic drugs for different seizure types. The need for both suspension and chewable tablet formulations is not addressed in the application. There may however be a preference for chewable tablets over syrup formulations because of the additional costs associated with liquid paediatric formulations. The comparative costs for these dosage formulations were not provided in the application. The Committee recommended inclusion of phenytoin suspension 30 mg/ 5 ml and the chewable tablet on the core Model List. 5.1.4 Valproic acid (sodium valproate): addition of new dosage form An application was prepared by the University of Liverpool, England, at the request of the PSM Department for the addition of valproic acid oral liquid (200 mg/5 ml) and 100 mg crushable tablets to the Model List for the treatment of childhood epilepsy. Listing is as an individual medicine. Expert reviews of the application were prepared by: Dr Susan Walters. Comments in support of the application were received from Dr B. Saraceno, Director, Mental Health and Substance Abuse (MSD). Additional supporting statements were received from DRA. The Committee noted that several Cochrane reviews (84, 95, 97–99) and other randomized controlled trials were cited in the application to support the effi cacy and safety of valproic acid (91, 100, 101) in both adults and children. No clinical data are presented on use of valproic acid in children younger than 3 years. While there is not a substantial body of clinical trial data to establish the superior effi cacy and safety of valproic acid over other TRS946.indd 61TRS946.indd 61 19.11.2007 15:29:5119.11.2007 15:29:51 62 antiepileptic medicines, there are differences in tolerability and side-effects between available agents, and a need for a range of antiepileptic drugs for different seizure types. Valproic acid has a product licence in Europe and the USA for the treatment of generalized, partial and other seizures in adults and children. No lower age limit is specifi ed for its use as monotherapy or adjunctive therapy. However, because of the risk of liver damage it is not recommended as fi rst- line therapy for children younger than 2 years, in whom its use is reserved for diffi cult cases of epilepsy. The need for both suspension and chewable tablet formulations is not addressed in the application. There may however be a preference for chewable tablets over syrup formulations because of the additional costs associated with liquid paediatric formulations. The comparative costs for the crushable tablet formulation were not provided in the application. The Committee recommended inclusion of valproic acid oral liquid (200 mg/5 ml) and the crushable tablet on the core Model List. 5.2 Section 6.2.4: Antituberculosis medicines 5.2.1 Isoniazid: addition of new dosage form An application was received from the Global Drug Facility (GDF), Stop TB (STB) and the TB Partnership (TBP) for inclusion of isoniazid 50 mg scored tablets on the Model List for the prevention and treatment of tuberculosis in children. Listing is as an individual medicine. Expert reviews of the application were prepared by: Dr Estrella Paje-Villar. Additional supporting statements were received from DRA. The Committee noted that there had been few recent studies of the effi cacy and safety of isoniazid for the treatment of TB in children. However it has been used effectively for many decades and is recommended in the WHO Treatment Guidelines (15). There is recent evidence on the benefi t of isoniazid prophylaxis in HIV-positive adults and children (102–106), and HIV-negative but at-risk adults and children (107–109) in reducing the development of TB. At present, the lack of an appropriate paediatric formulation means that tablets have to be broken and fractionated to approximate intended doses. An appropriate paediatric formulation would minimize these problems. Limited information was provided on potential suppliers of a quality-assured 50 mg isoniazid product. The Committee recommended inclusion of isoniazid 50 mg scored tablets on the core Model List for treatment and chemoprophylaxis of tuberculosis in paediatric populations with concurrent HIV infection or at risk of HIV infection, or others with increased risk of contracting the disease. TRS946.indd 62TRS946.indd 62 19.11.2007 15:29:5119.11.2007 15:29:51 63 5.2.2 Pyrazinamide: addition of new dosage form An application was received from the Global Drug Facility (GDF), Stop TB (STB) and the TB Partnership (TBP) for inclusion of pyrazinamide 150 mg dispersible and scored tablets on the Model List for the treatment of tuberculosis in children. Listing is as an individual medicine. Expert reviews of the application were prepared by: Dr Estrella Paje-Villar. Additional supporting statements were received from DRAs, Japan. The Committee noted that the effi cacy and safety data were derived from a small number of studies (110–112), but generally supported the view that pyrazinamide is safe and effective in children. It has been widely used in children and is recommended in the WHO Treatment Guidelines (15). There have been a small number of studies (113–115) of the pharmacokinetics of pyrazinamide in children, with confl icting results on the clearance and half- life of the drug in children compared to adults. Further work is required to establish whether higher doses of pyrazinamide are needed in children. At present, the lack of an appropriate paediatric formulation means that tablets have to be broken and fractionated to approximate intended doses. Limited information was provided on potential suppliers of a quality-assured 150 mg pyrazinamide product. The Committee recommended inclusion of pyrazinamide 150 mg dispers- ible and scored tablets on the core Model List. 5.3 Section 6.5.3: Antimalarial medicines 5.3.1 Artemether/lumefantrine: addition of new dosage form An application was received from Dafra Pharma (Belgium) for a powder for paediatric suspension of artemether/lumefantrine to be included in the Model List. The powder for suspension contains 7.9 mg β-artemether/47.4 mg lumefantrine per gram. After reconstitution with water the mixture delivers: — 60 ml fi xed-dose combination of 180 mg β-artemether and 1080 mg lumefantrine; — 12 ml fi xed-dose combination of 360 mg β-artemether and 2160 mg lumefantrine, i.e. the same 1:6 ratio as is included in the tablet formulation. The recommended dosage schedule delivers artemether in a daily dosage of approximately 4 mg/kg/day for 3 days. Expert reviews of the application were prepared by Dr Susan Walters and Dr Noël Cranswick. Comments on the application were received from Dr Peter Olumese, Global Malaria Programme. Additional statements were received from DRAs, Japan. The Committee noted that while the application identifi es a need for a paediatric formulation suitable for children with a body weight of less than TRS946.indd 63TRS946.indd 63 19.11.2007 15:29:5119.11.2007 15:29:51 64 10 kg, the current WHO Guidelines for the treatment of malaria, 2006 suggest that tablets can be used for children who weigh ≥ 5 kg. The Committee also expressed some concerns about the recommended doses. For children who weigh 5–10 kg, the population most likely to be prescribed the suspen- sion, the recommended doses of suspension were substantially lower than the currently recommended doses of the tablet formulation. Limited clinical trial data were presented in the application to demonstrate the effi cacy and safety of the suspension at this dose, and these were short-term studies in small numbers of children. None were rigorous randomized controlled trials comparing the combination suspension with the drugs administered in tablet form in the same populations of patients. While the application states that registration has been achieved in 19 countries and is pending in a further eight, none of these are stringent regulatory authorities. The Committee noted the comments from the Global Malaria Programme (WHO), which concluded it could not support the application as the doses for specifi c age groups, the dosage regimen (single daily dose), and dosage ratio recommended in the submitted dossier are at variance with the current recommended WHO schedules (WHO Guidelines for the treatment of malaria, 2006). No evidence was provided to the Global Malaria Programme, nor was there evidence available on the safety and effi cacy of the dosages and regimen recommended in this submission. Although the Committee recognized the need for a suspension formulation for paediatric use, given the uncertainty about the dose, the Committee decided not to include the artemether/lumefantrine suspension on the Model List. 5.5 Section 25: Medicines acting on the respiratory tract 5.5.1 Addition of caffeine citrate Expert reviews of the application were prepared by: Dr Estrella Paje-Villar. During its meeting in 2005, the Committee deferred a decision on listing caffeine citrate for apnoea of prematurity on the Model List because of limited evidence of effi cacy and the lack of longer-term safety data. The Committee was waiting for the results of a large randomized controlled trial then underway. A second application for the inclusion of caffeine citrate was received from the Royal Children’s Hospital, Melbourne, Australia. The Committee noted that the effi cacy data were largely unchanged from those in the previous application and that the long-term safety results of the large randomized controlled trial were still not available. As noted by the expert reviewers, data from two Cochrane reviews (116, 117) are available. Although they are based on small numbers of trials and patients, they support the effi cacy of methylxanthines in managing apnoea in preterm TRS946.indd 64TRS946.indd 64 19.11.2007 15:29:5219.11.2007 15:29:52 65 infants and suggest that while it had similar effi cacy, caffeine citrate was associated with fewer adverse events than theophylline. Limited safety data are provided in these reviews. Schmidt et al. 2006 (118) reported short-term, secondary safety outcomes in the large Caffeine for Apnoea of Prematurity trial. No differences were noted between caffeine citrate and placebo in the incidence of retinopathy of prematurity, necrotizing enterocolitis or ultrasonographic signs of brain injury. However data on the primary study outcome (a composite of death, cerebral palsy, cognitive delay, deafness, or blindness at a corrected age of 18–21 months) are not yet available. The inclusion criteria of the study may have excluded the most vulnerable infants from evaluation i.e. the smallest infants on ventilation for long periods of time. The effi cacy of caffeine in this population remains uncertain. The WHO Pocket book of hospital care for children (2005, p. 55) states that caffeine citrate and aminophylline prevent and treat apnoea in premature babies. Caffeine is preferred if it is available. Dosing recommendations are consistent with this application. No valid cost-effectiveness data were provided and limited cost comparisons are possible for caffeine citrate, aminophylline and theophylline. Neither aminophylline nor theophylline is currently on the Model list. Based on the evidence for effi cacy and safety, the Committee decided to include caffeine citrate on the Model List. 5.6 Section 27: Vitamins and minerals 5.6.1 Vitamin A (retinol palmitate): addition of new dosage strength Expert reviews of the application were prepared by: Dr Estrella Paje- Villar. Additional supporting statements were received from: Dr J. Wiley, Therapeutic Goods Administration, Australia; DRA; Dr K. Misawa, Director, Pharmaceuticals and Medical Devices Agency, Japan; and Mr M. Goddard, Information Centre, Medicines and Healthcare Products Regulatory Agency, London, England. Retinol (vitamin A) was added to the UK Model List in 1987 as 10 000 IU tablets, 200 000 IU capsules and other forms that have not been reviewed since then. Vitamin A is widely promoted as supplementation for prophylaxis and treatment of defi ciency in children including infants of 12 months of age and younger. However, the dose used in younger children is 50–100 000 IU, currently supplied to some extent by UNICEF as 100 000 IU capsules. An application for inclusion of retinol (as palmitate) 50 000 to 100 000 IU per capsule was received from the Clinical Pharmacology Unit, General Medicine, Royal Children’s Hospital, Melbourne, Australia; and the Centre for International Child Health, Department of Pediatrics, University of Melbourne, Australia. TRS946.indd 65TRS946.indd 65 19.11.2007 15:29:5219.11.2007 15:29:52 66 The Committee noted that the application provided a comprehensive review of the evidence of effectiveness of vitamin A supplementation for prophylaxis and treatment of defi ciency in children, including infants of 12 months of age and younger. The public health need for an additional formulation is fully justifi ed. As noted by the expert reviewers, there is high-quality clinical evidence from the Cochrane systematic review (119) involving more than one million very low-birth-weight infants that proved the benefi ts of retinol supplementation in reducing deaths or oxygen use at one month of age (RR 0.93, 95% CI, 0.88–0.99). Additional evidence shows a reduction in death from measles pneumonia in children given supplementary vitamin A (120) and a reduction in all-cause mortality (121). The tolerability of oral retinol in infants is excellent, with no evidence of any permanent or long-term sequelae (122–124). This intervention has been estimated as one of the most cost-effective of all health interventions (125). Overall the evidence provided in the application supports the public health need, effectiveness, safety and cost-effectiveness of retinol lower-strength capsules for infants of 12 months of age and younger. The Committee therefore recommended that retinol 50 000 IU capsule and 100 000 IU capsule be added to the core list of the 15th WHO Model List. 6. Summary of recommendations – additions, changes and deletions to the Model List 1. The Committee updated the following explanatory notes and made the following changes to Sections: The term “oral liquid” was clarifi ed and used to replace “syrup”, “oral elixir”, “oral suspension” and similar terms throughout the Model List. Section 4: The Committee noted that there was no need for a review of Section 4 (Antidotes and other substances used in poisoning) at this time. Section 6.4.2: The note on antiretrovirals was revised. Section 6.4.2.3: The note on protease inhibitors was revised with the section marked for review at the next meeting of the Expert Committee. Section 6.5.3: Antimalarial medicines. The Committee edited the note for antimalarial medicines for curative treatment and comprehensively updated the section to refl ect current treatment guidelines. Artemether injection 80 mg/ml, artesunate tablet 50 mg, doxycycline 100 mg tablets or capsules, mefl oquine 250 mg tablets and sulfadoxine + pyrimethamine tablets 500 mg + 25 mg were moved from the complementary to the core list. This means there is now no complementary list for antimalarials. Section 6.5.5.1: African trypanosomiasis. All medicines are now included in the core list; efl ornithine injection 200 mg and pentamidine powder for injection 200 mg were moved from the complementary list to the core list. TRS946.indd 66TRS946.indd 66 19.11.2007 15:29:5219.11.2007 15:29:52 67 Section 8.2: Cytotoxic medicines were marked for review at the next meeting of the Expert Committee. Section 8.4: The note on medicines used in palliative care was updated. Section 19.3: The Committee revised the note on the selection of vaccines and updated the Model List to include all vaccines for which there is a SAGE recommendation or a WHO position paper. Section 21: This section on ophthalmological preparations was noted for review at the next meeting of the Expert Committee. 2. The Committee recommended the following additions to the Model List: Section 2.2: Addition of prolonged-release morphine tablets 10 mg, 30 mg, 60 mg. Section 5: Addition of carbamazepine chewable tablets 100 mg, 200 mg and oral liquid 100 mg/5 ml. Addition of phenobarbital sodium injection 200 mg/ml. Addition of phenytoin chewable tablet 50 mg and oral liquid 25–30 mg/ 5 ml with a note advising against having both strengths available in the same market. Addition of valproic acid (sodium valproate) crushable 100-mg tablets and oral liquid 200 mg/5 ml. Section 6.2.1: Addition of cefazolin powder for injection 1 gram (as sodium salt) with a

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