The Selection and use of Essential Medicines

Publication date: 2003

i WHO Technical Report Series 920 THE SELECTION AND USE OF ESSENTIAL MEDICINES Report of the WHO Expert Committee, 2003 (including the 13th Model List of Essential Medicines) World Health Organization Geneva THE SELECTION AND USE OF ESSENTIAL M EDICINES WHO Technical Report Series — 920 9 789241 209205 This report presents the recommendations of the WHO Expert Committee responsible for updating the WHO Model List of Essential Medicines. The first part contains a progress report on the new procedures for updating the Model List and the development of the WHO Essential Medicines Library. It continues to present a summary of the Committee’s considerations and justifications 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 13th) and a list of all items on the Model List sorted according to their 5-level Anatomical Therapeutic Chemical (ATC) classification codes. ISBN 9 2412 0920 8 ii 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 func- tions is to provide objective and reliable information and advice in the field of human health, a responsibility that it fulfils in part through its extensive programme of publications. The Organization seeks through its publications to support national health strate- gies and address the most pressing public health concerns of populations around the world. 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For further information, please contact Marketing and Dissemination, World Health Organization, 20 avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 2476; fax: +41 22 791 4857; e-mail bookorders@who.int). i 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 920 THE SELECTION AND USE OF ESSENTIAL MEDICINES Report of the WHO Expert Committee, 2003 (including the 13 Model List of Essential Medicines) World Health Organization Geneva 2004 ii WHO Library Cataloguing-in-Publication Data WHO Expert Committee on the Selection and Use of Essential Medicines (13th : 2003: Geneva, Switzerland) The selection and use of essential medicines : report of the WHO Expert Committee, 2003 : (including the 13th model list of essential medicines). (WHO technical report series ; 920) 1.Essential drugs — standards 2.Formularies — standards 3.Drug information services — organization and administration 4.Drug utilization 5.Pharmaceutical preparations — classification 6.Guidelines I.Title II.Title: 13th model list of essential medicines III.Series. ISBN 92 4 120920 8 (LC/NLM classification: QV 55) ISSN 0512-3054 © World Health Organization 2003 All rights reserved. Publications of the World Health Organization can be obtained from Marketing and Dissemination, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel: +41 22 791 2476; fax: +41 22 791 4857; email: bookorders@who.int). Requests for permission to reproduce or translate WHO publications — whether for sale or for noncommercial distribution — should be addressed to Publications, at the above address (fax: +41 22 791 4806; email: permissions@who.int). 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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 Hong Kong Printed in Singapore 2004/15757 — SNPBest-set/SNP — 6000 iii Contents 1. Introduction 1 2. Open session 1 3. Update on current activities 3 3.1 Dissemination of the previous report of the Expert Committee (including the 12th Model List) 3 3.2 The twenty-fifth anniversary of the WHO Model List of Essential Medicines 4 3.3 The WHO model formulary 4 3.4 Review of the New Emergency Health Kit 5 3.5 Review of essential medicines for reproductive health 5 3.6 Report of an ad hoc Advisory Committee on priority vaccines 5 3.7 The WHO Essential Medicines Library 6 3.8 Promoting rational use of essential medicines 6 3.8.1 Update on activities to contain antimicrobial resistance 6 3.8.2 Guidelines for drugs and therapeutic committees 8 3.8.3 WHO database on rational drug use studies 9 4. Changes made in revising the Model List 10 4.1 Applications for additions 10 4.1.1 Amodiaquine 10 4.1.2 Azithromycin 11 4.1.3 Ibuprofen (pediatric formulation) 12 4.1.4 Insulin semilente 13 4.1.5 Miconazole nitrate buccal tablets 14 4.1.6 Misoprostol 15 4.1.7 Valaciclovir 16 4.2 Applications for deletions 17 4.2.1 Ethinylestradiol + levonorgestrel tablets (50mg + 250mg, pack of four) 17 4.2.2 Nonoxynol 19 4.3 Applications for addition of information 20 4.3.1 Antileprosy medicines 20 4.4 Other changes 21 4.4.1 Oral rehydration salts 21 4.4.2 Streptokinase 23 5. Reviews of sections of the Model List 23 5.1 “Fast-track” procedure for deleting items from the Model List 24 5.2 Review of core versus complementary listing of medicines 27 5.3 Review of the use of the square box symbol (including a review of the corticosteroids) 30 5.4 Review of the antihypertensive medicines 36 6. Priorities for future reviews 42 iv 7. Recommendations 45 7.1 Additions, deletions and other changes to the Model List 45 7.2 Core versus complementary listing of medicines 46 7.3 Use of the square box symbol (including review of the corticosteroids) 47 7.4 Review of the antihypertensive medicines 49 7.5 Future priorities 50 References 50 Annex 1 The 13th WHO Model List of Essential Medicines 54 Annex 2 The Anatomical Therapeutic Chemical (ATC) classification system 101 Alphabetical list of essential medicines (with ATC classification code numbers) 120 v WHO Expert Committee on the Selection and Use of Essential Medicines Geneva, 31 March–3 April 2003 Members* Professor P.M. de Buschiazzo, Department of Pharmacology, School of Medicine, University of La Plata, La Plata, Argentina Professor A. Helali, Director, Centre National de Pharmacovigilance et Matériovigilance, Ministère de la Santé et de la Population, Algiers, Algeria Professor R. Laing, School of Public Health, Boston University, Boston, MA, USA Professor J.-R. Laporte, Director, Fundacio Institut Català de Farmacologia, Department of Pharmacology and Therapeutics, Universitat Autonoma de Barcelona, Barcelona, Spain (Chairman) Professor D. Ofori-Adjei, Director, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana Dr E.M.A. Ombaka, Director, The Pharmaceutical Programme of Community Initia- tives Support Services, World Council of Churches, Nairobi, Kenya Dr M.M. Reidenberg, Chief, Division of Clinical Pharmacology, The New York Hospital — Cornell Medical Centre, New York, NY, USA (Vice-Chairman) Professor S. Suryawati, Centre for Clinical Pharmacology and Drug Policy Studies, Gadjah Mada University, Yogyakarta, Indonesia (Rapporteur) Dr L. Wannmacher, Department of Clinical Pharmacology, School of Medicine, University of Passo Fundo, Rio Grande do Sul, Brazil Representatives of other organizations†‡ International Paediatric Association (IPA) Professor T.I. Bhutta, IPA, Lahore, Pakistan Joint United Nations Programme on HIV/AIDS (UNAIDS) Dr F. Renaud-Théry, Care and Support Network Adviser, UNAIDS, Geneva, Switzerland United Nations Children’s Fund (UNICEF) Ms T. Huong Ha, Technical Officer, Supply Division, UNICEF, Copenhagen, Denmark Mr M.W. Young, Senior Health Advisor, UNICEF Headquarters, New York, NY, USA * Each Member of the Committee signed a statement that he or she agreed not to participate in the review of any other matter under consideration in which there was a real or perceived conflict of interest. † Unable to attend: The World Bank. ‡ Each representative of other organizations signed a statement that he or she agreed not to participate in the review of any other matter under consideration in which there was a real or perceived conflict of interest. vi * Each Temporary Adviser of the Committee signed a statement that he or she agreed not to participate in the review of any other matter under consideration in which there was a real or perceived conflict of interest. United Nations Population Fund (UNFPA) Dr G. Walker, Specialist in Reproductive Health Commodities, Country Services Team, UNFPA, Bratislava, Slovakia WHO Collaborating Centre for International Drug Monitoring (Uppsala, Sweden) Professor C.J. van Boxtel, Professor of Clinical Pharmacology, University of Amsterdam, Amsterdam, The Netherlands Secretariat* Dr A. Asamoa-Baah, Executive Director, Health Technology and Pharmaceuticals, WHO, Geneva, Switzerland Dr R.C.F. Gray, Medical Officer, Policy, Access and Rational Use, Department of Essential Drugs and Medicines Policy, WHO, Geneva, Switzerland Professor U. Gupta, Delhi Society for Promotion of Rational Use Of Drugs, New Delhi, India (Temporary Adviser) Dr S. Hill, Faculty of Medicine and Health Sciences, University of Newcastle, Waratah, NSW, Australia (Temporary Adviser) Dr H.V. Hogerzeil, Coordinator, Policy, Access and Rational Use, Department of Essential Drugs and Medicines Policy, WHO, Geneva, Switzerland (Secretary) Dr Y. Li, Chinese Cochrane Centre, West China Hospital, Sichuan University, Sichuan, China (Temporary Adviser) Mr D.K. Mehta, Executive Editor, British national formulary, Royal Pharmaceutical Society, London, England (Temporary Adviser) Dr L. Offerhaus, Bussum, Netherlands (Temporary Adviser) Mr A. Pillay, Faculty of Medicine and Health Sciences, University of Newcastle, Waratah, NSW, Australia (Temporary Adviser) Dr J.D. Quick, Director, Department of Essential Drugs and Medicines Policy, WHO, Geneva, Switzerland Mr P.J. Wiffen, Pain, Palliative and Supportive Care Group, The Cochrane Collabo- ration, Pain Research Unit, Churchill Hospital, Oxford, England (Temporary Adviser) Professor L.E. Ziganshina, Department of Clinical Pharmacology and Pharmaco- therapy, Kazan State Medical University, Kazan, Russian Federation (Tempo- rary Adviser) 1 1. Introduction The WHO Expert Committee on the Selection and Use of Essential Medicines met in Geneva from 31 March to 3 April 2003. The meeting was opened on behalf of the Director-General by Dr J.D. Quick, Director, Department of Essential Drugs and Medicines Policy, WHO, who expressed appreciation for the rapid dissemination during 2002 of the report of the previous meeting and the first edition of the WHO model formulary (1). In referring to the recent twenty-fifth anniversary of the essential medicines concept, Dr Quick stressed that despite widespread acceptance of the global relevance of the concept, many challenges still remain, especially with regard to ensuring equi- table access to essential medicines. 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 is to allow all stakeholders to participate in the discussions and to comment on issues relating to the WHO Model List of Essential Medicines (the Model List). Further- more, for Expert Committee members it provides an opportunity to receive, at first-hand, additional information and opinions on matters under consideration. Participants were assured that the discussions and considerations of the open session would be reflected in the report of the meeting. A summary of the Committee’s meeting report would be submitted to the WHO Executive Board in January 2004, together with a statement on the public health implications of its recommendations. The Committee decided to maintain the reporting format adopted at its previous meeting whereby the updated version of the Model List, including explanatory notes and supporting background information relating to the use and development of the Model List, is presented as an annex to the meeting report (Annex 1). Similarly, a list of items on the Model List ordered by their corresponding Anatomical Therapeutic Chemical (ATC) classification code number(s) is again attached as annex (Annex 2). 2. Open session The session was opened by Dr A. Asamoa-Baah, Executive Director, Health Technology and Pharmaceuticals, WHO, who informed par- ticipants that WHO is justly proud of the success of the essential medicines concept, as evidenced by its recent twenty-fifth anniver- sary. He stressed that careful selection of essential medicines for the 2 Model List remains at the heart of the programme, given that the Model List provides not only the moral basis for national drug poli- cies but also a technical basis for the procurement, quality assurance and promotion of the rational use of medicines. The future success of the essential medicines programme depends on the credibility of the work of its Expert Committee, which, in turn, depends very much on the implementation of the new procedures for updating and dissemi- nating the Model List, outlined at the previous meeting of the Com- mittee (2). Dr Asamoa-Baah reminded participants that all comments made during the open session would be noted and taken into account by the Committee when formulating their final recommendations in subsequent private sessions. As part of the open session, participants were briefed about various activities relating to the Model List (see section 3). Presentations outlining the simplified or “fast-track” deletion procedure adopted for selected items on the Model List (see section 5.1) and the results of various review exercises that had been undertaken since the previ- ous meeting — including a review of the definition of “core” and “complementary” list medicines (see section 5.2) and a review of the use of the square box symbol (see section 5.3) — were also made. Comments made during the open session on these matters were noted and are reported under the appropriate sections of the meeting report. A number of issues not on the agenda were raised and debated during the open session. The International Federation of Pharmaceutical Manufacturing Associations (IFPMA) made a statement of concern about the lack of transparency in the Committee’s decision-making process, which it felt was, in part, related to the way in which members of the Committee are selected. It was suggested that potential con- flicts of interest should be publicized and applied to all members of the Committee, including special advisors. The breadth of expertise should also be expanded. It was also suggested that technical advice from industry had not been effectively sought during the preparation period for the present meeting and thus industry’s expertise had effectively been excluded from the Committee’s deliberations. The IFPMA welcomed WHO’s efforts to promote the provision of quality drugs through its new pre-qualification system, but cautioned against the promotion of untested fixed-dose regimens, for example, selected combinations of antiretroviral medicines that may actually harm some patients. A representative of the United States Mission expressed satisfaction with the principle of the open session, and requested that it be estab- 3 lished as a permanent part of the procedure. He also stressed the need for the Committee to have permanent access to expertise in drug regulation and quality assurance. In the ensuing discussion, the Committee cited the case of tuberculo- sis, where the advice of WHO had led to full standardization in the dosage of fixed-dose combination medicines, now followed by most manufacturers; it is anticipated that the WHO clinical guidelines for the treatment of HIV/AIDS with antiretroviral therapy will serve the same purpose. The Committee commented on the lack of technical contributions from pharmaceutical companies despite having posted information about the formal applications for changes to the Model List, together with details of relevant systematic reviews, on the WHO web site well in advance of the meeting. Finally, with regard to the matter of potential conflicts of interest by members of the Com- mittee, the Secretary explained the standard procedure for declara- tions of interest, which is rigorously applied. Dr Asamoa-Baah added that the credibility of the Committee is, to a large extent, derived from the scientific basis and transparency of its recommendations. 3. Update on current activities 3.1 Dissemination of the previous report of the Expert Committee (including the 12th Model List) Following approval by its members on Friday 19 April 2002, the report of the meeting of Expert Committee was approved for publica- tion by the Director-General and posted on the WHO web site on Monday 22 April, just ten working hours after the meeting had closed. The rapid dissemination of the meeting report, together with the revised version of Model List and the summary of recommendations was widely appreciated, especially in view of the important recom- mendations the Committee had made on the selection of essential medicines for the treatment of HIV/AIDS and malaria. Within weeks of the meeting, the 12th Model List (including the introductory text and explanatory notes) had been translated into Arabic, Chinese, French, Russian and Spanish and posted on the WHO web site. These web pages in the six official languages of WHO were also disseminated in large numbers as hard copy. During the remainder of 2002, the full report was edited for formal publication in the WHO Technical Report Series. However, the amount of work involved in separating the Model List into core and complementary lists and introducing the ATC classification for all items on the Model List meant that the meeting report was not published in final form 4 until early 2003. In January 2003, a summary of the Committee’s report and a statement on its public health implications were sub- mitted to the WHO Executive Board. The 12th Model List was also incorporated into the WHO Essential Medicines Library (see section 3.7). It was noted that changes in the name of the Expert Committee since its inception in 1977 had given rise to some confusion over the num- bering of the various Committees and their corresponding meeting reports. For the sake of clarity, it was decided that the practice of numbering the meetings of the Committee should be abandoned in favour of referring simply to the number of the Model List. 3.2 The twenty-fifth anniversary of the WHO Model List of Essential Medicines On 21 October 2002, exactly 25 years since the first Expert Committee approved the first WHO Model List of Essential Drugs (3), a techni- cal seminar was held in Geneva to celebrate the achievements of the global application of the concept of essential medicines. Regional anniversary seminars were held on the same day in Cambodia and Brazil. The text of the presentations given at these events, including an important speech by the Director-General, is available on CD- ROM (4); alternatively these can be accessed through the Internet at the WHO web site1. 3.3 The WHO model formulary In order to make the WHO model formulary compatible with the Model List, entries for the antiretroviral medicines and the other additions to the 12th Model List were prepared immediately after the 2002 meeting of the Expert Committee in time for the release of the first edition of the WHO model formulary at the Annual Congress of the International Pharmaceutical Federation held in Nice, France, in September 2002. The publication was generally very well received. All 7000 printed copies were rapidly disseminated, either by free distribution or through commercial channels, necessitating a second printing in November 2002. A searchable version can be accessed via the WHO web site1 and a CD-ROM version, for use by national and institutional committees, is nearing completion (5). Agreement has been reached with the Royal Pharmaceutical Society of Great Britain for editing and printing future editions of the WHO model formulary. 1 http://www.who.int/medicines. 5 3.4 Review of the New Emergency Health Kit All of the 55 essential medicines that are listed in the New Emergency Health Kit (6) are included in the list of 88 medicines recommended for emergency relief by the United Nations (7), all of which, in turn, are on the Model List. Following consultation with the partners in- volved in its development, it was decided that the New Emergency Health Kit is in need of updating, especially with regard to the anti- malarial medicines, emergency contraception and injection materials. A review meeting will be convened by WHO in Spring 2004 to address these issues. 3.5 Review of essential medicines for reproductive health It was noted that a draft interagency list of essential medicines for reproductive health and a Core List of Essential Medicines for Repro- ductive Health drawn up by the United Nations Population Fund (UNFPA) are not fully consistent with the Model List. For instance, 22 items on the draft interagency list and 6 medicines on the UNFPA list do not appear on the Model List. Work is under way to analyse these discrepancies; the analysis will take into account the relevant clinical guidelines and the evidence that supports the selection of items on the other two lists. This information will be used to stream- line the three different lists and will become part of the WHO Essen- tial Medicines Library. 3.6 Report of an ad hoc Advisory Committee on priority vaccines The Committee was informed of the work of an ad hoc Advisory Committee on priority vaccines convened as a result of a recommen- dation made by the Strategic Advisory Group of Experts (SAGE) in 2002 to “establish an expert advisory committee with worldwide rep- resentation to develop a mechanism for prioritisation of vaccines for a model essential vaccine list for immunisation programmes”. The Advisory Committee recommended the establishment of na- tional lists of essential vaccines and suggested that the construction of such lists would be facilitated by the creation of a Global Model List of Essential Vaccines as well as an evidence-based library of essential vaccines. In addition, the Advisory Committee considered that, as there are fundamental differences between medicines and vaccines, an evidence-based Global Model List of Essential Vaccines should be separate from the Model List of Essential Medicines. It was also proposed that, once a list of essential vaccines had been established, vaccines should be taken off the Model List, although the two lists should refer to each other. Whereas the traditional children’s vaccines 6 would be included in the new list automatically, all other vaccines should be subjected to evaluation by an Expert Committee before inclusion. It was anticipated that a procedure similar to that used for updating the Model List of Essential Medicines could be followed. The Advisory Committee also considered that while the creation of a Global Model List of Essential Vaccines would be of great value, the emphasis should remain on the development of national and/or re- gional lists based on the information provided in an essential vaccines library. The Advisory Committee therefore recommended that cri- teria for prioritizing vaccines for inclusion in national lists be devel- oped. A draft list of such criteria has been prepared, and will be subjected to external review and tested before use. The recommenda- tions of the Advisory Committee will be presented to SAGE in July 2003. 3.7 The WHO Essential Medicines Library Work on the WHO Essential Medicines Library is continuing. In its current format, it contains searchable versions of the 12th Model List and the WHO model formulary, and links to the Management Ser- vices for Health (MSH) International Drug Price Indicator Guide and the web site of the WHO Collaborating Centre on Drug Statistics Methodology, Oslo, Norway. A central “Medicine link page” (giving the International Nonproprietary Name (INN), dosage(s), ATC classification code number(s) and justification for inclusion) has been prepared for each item in the Model List and links to key indications, disease summaries, systematic reviews and WHO clinical guidelines. These will supplement the links to the Model List, the WHO model formulary and the INN web site, and to external web sites such as that containing details of the ATC classification system. It is expected that the developmental version will be available for public access during the course of 2003. 3.8 Promoting rational use of essential medicines 3.8.1 Update on activities to contain antimicrobial resistance Antimicrobial resistance occurs when a strain of a micro-organism is able to multiply in the presence of antimicrobial medicine concentra- tions that are higher than in the concentrations in humans receiving therapeutic doses. The development of resistance is a natural biologi- cal phenomenon and has followed the introduction into clinical prac- tice of every antimicrobial agent. Increases in antimicrobial use have been associated with increases in rates of resistance, so much so that irrational overuse of antimicrobials is generally assumed to be a major 7 contributing factor to the escalating global problem of antimicrobial resistance. Currently, antimicrobials are being overused in all world regions and at all levels of the health care system, in amounts that are perhaps as much as double those that are clinically indicated. Resis- tance rates vary locally depending upon local antimicrobial use. The World Health Assembly has recognized antimicrobial resistance as a serious public health problem and in 1998, with resolution WHA51.17, urged Member States to develop measures to encourage appropriate and cost-effective use of antimicrobials (8). Nevertheless, the problem of antimicrobial resistance, including multidrug resis- tance, has since continued to grow while the rate at which new anti- microbials are introduced has decreased. WHO’s Global Strategy for the containment of Antimicrobial Resistance addressed this chal- lenge by providing a framework of interventions aimed at slowing the emergence and reducing the spread of antimicrobial resistant micro- organisms (9). More than 60 interventions were identified and priori- tized on the basis of invited expert opinion and peer review. An adequately funded multi-sectoral task force and reference laboratory for conducting surveillance of both antimicrobial resistance and use were, however, considered fundamental to any national containment programme. The interventions that were deemed to be the most important are: — patient education on preventing infection (e.g. immunization, use of bednets) and reducing transmission (e.g. hand washing, food hygiene); — education on antimicrobial use, antimicrobial resistance contain- ment, disease prevention and infection control; — targeted undergraduate and postgraduate education for all health workers and veterinary practitioners on accurate diagnosis and management of common infections; — development, updating and use of clinical guidelines and treat- ment algorithms; — establishment of infection control programmes in hospitals; — good quality diagnostic laboratories; — limitation of availability of antimicrobials to prescription-only; — granting marketing authorization only to antimicrobials which meet international standards of quality, safety and efficacy. Very few countries currently have national antimicrobial resistance containment programmes in place. Furthermore, many countries do not base their choice of antimicrobials for an essential medicines list or standard treatment guidelines on epidemiologically sound anti- microbial resistance data, even though this has been shown to be 8 crucial to ensuring best patient outcome and efficient use of antimi- crobials. Nevertheless, reductions in antimicrobial resistance have been observed in a few countries that have succeeded in significantly reducing antimicrobial consumption and improving infection control. Containing antimicrobial resistance and ensuring that patients are treated with the most effective antimicrobial requires the linked surveillance of antimicrobial resistance and consumption. WHO is currently supporting pilot projects to develop a new model and meth- odology for the linked surveillance of antimicrobial resistance and consumption and the local containment of antimicrobial resistance in developing countries. However, much more political and financial commitment will be necessary in the future. 3.8.2 Guidelines for drugs and therapeutic committees Drugs and therapeutics committees (DTCs) — sometimes called pharmacy and therapeutics committees — are designated to ensure the safe and effective use of medicines in the facility or area under their jurisdiction. Such committees are well established in most indus- trialized countries as a successful way of promoting a more rational, cost-effective use of medicines in hospitals. WHO promotes the es- tablishment of DTCs through its international training courses (which are run in collaboration with MSH), the preparation of a manual on DTCs and various other research projects. The main responsibilities of a DTC are: — developing, adapting or adopting clinical guidelines for the health institution or health facilities under its jurisdiction; — selecting cost-effective and safe medicines (hospital/health facil- ities’ drug formulary); — implementing and evaluating strategies to improve medicine use (including drug use evaluations, and liaison with antibiotic and infection control committees); — providing ongoing staff education (training and printed materials); — controlling access to staff by the pharmaceutical industry and its promotional activities; — monitoring and taking action to prevent adverse drug reactions and medication errors; — providing advice about other drug management issues, such as quality and expenditure. Governments should encourage all hospitals to set up a DTC (e.g. by making it an accreditation requirement to various professional soci- eties) with a membership that represents all the major specialities and 9 the administration. DTC members should be independent and de- clare any conflict of interest. A senior doctor would usually be the chairperson and the chief pharmacist, the secretary. Factors critical to success include: clear objectives, a firm mandate, support from the senior hospital management, transparency, wide representation, technical competence, a multidisciplinary approach and sufficient re- sources to implement the DTC’s decisions. The WHO manual on establishing and running a DTC will be issued in 2003 (10); international 2-week training courses are ongoing in Asia and Africa. 3.8.3 WHO database on rational drug use studies In 1985, WHO defined rational use of medicines as requiring that “patients receive medications appropriate to their clinical needs, in doses that meet their own requirements, for an adequate period of time, and at the lowest cost to them and their community” (11). Since then, the International Network for the Rational Use of Drugs (INRUD) has been formed and much work has been undertaken by WHO, INRUD and other organizations in order to develop and use indicators for monitoring medicine use and to initiate intervention studies to promote rational use. The impact of these efforts is, however, not very well known. WHO is currently developing a database on the rational use of medicines, the main objective of which is to provide a general overview of existing drug use patterns in primary health care settings in developing coun- tries over time, and to study the impact of different types of interven- tions on improving the use of medicines. This type of information is vital for developing a global multifaceted strategy for the promotion of rational use of medicines and for assisting regions and countries seeking to prioritize their own activities in this area. Work has already started on identifying relevant published and un- published studies from both INRUD and WHO sources, and entering the pertinent data (e.g. prescriber and facility type, disease pattern, methodology, outcome indicators) into the database. The data will be analysed by country and region, and over time (1990–2003), and then used to assess the impact of different kinds of interventions to pro- mote the rational use of medicines. The database has been designed so as to be compatible with other WHO databases; this will allow future analysis of the impact of health systems and policies on the rational use of medicines. At the time of the present meeting, 1160 articles from the INRUD bibliography covering the period 1997–2001 had been screened, and 10 from these, 92 data records extracted and entered into the database. A preliminary analysis of the data will be presented at the Interna- tional Conference on Improving Use of Medicines (ICIUM) in 2004 and is intended as an advocacy tool for promoting rational use of medicines in the developing world. Future work includes entering data for earlier years and a systematic analysis of the full data set. There are also plans to expand the scope of the database to include such information as hospital-based drug use, self-medication, pa- tients’ adherence to treatment and diagnostic accuracy. The database will be made available to interested researchers and policy makers through the Internet. 4. Changes made in revising the Model List Proposals for amendments to the Model List, including applications for additions and deletions, received by the Committee for considera- tion at its present meeting are summarized below. 4.1 Applications for additions 4.1.1 Amodiaquine The Committee reviewed the re-application for the inclusion of amo- diaquine, an antimalarial, having deferred a decision regarding this medicine at its previous meeting (2). Amodiaquine has been on the Model List since 1977 (3), was removed in 1979 (12), reinstated in 1982 (13) and removed again in 1988 (14) in view of safety concerns in prophylactic use. In 2002, the Committee reviewed an application for its inclusion for therapeutic use. At that time, the Committee con- cluded that as amodiaquine had been removed twice for safety rea- sons, a careful review of the safety information was needed before any decision about its future inclusion could be taken. The Committee had also noted with concern the results of a trial of amodiaquine in children that appeared to show a high rate of neutropenia (2). The Committee noted the information supplied with the re- application, which included a systematic review of adverse events (prepared by the Cochrane Infectious Diseases Group) and a review of the effects of amodiaquine treatment on white blood cell and neutrophil counts (presented by Roll Back Malaria, WHO). The Committee agreed that antimalarial drug treatment with amodi- aquine (either alone or in combination with sulfadoxine + py- rimethamine or artesunate), chloroquine and sulfadoxine + pyrimethamine may be associated with a decline in the total white cell 11 and neutrophil counts. Although both counts remained within the normal range in the majority of cases, a small proportion of patients were found to have developed neutropenia when assessed during follow-up. The clinical significance of this finding is, however, un- known. Other publications reviewed by the Committee suggest that peripheral neutropenia is a part of the natural course of malaria itself (15, 16). The Committee concluded that the above findings generally support the conclusions of the systematic review of adverse events submitted by the Cochrane Infectious Diseases Group namely that, relative to other commonly used antimalarial drugs, therapeutic use of amodi- aquine does not appear to be associated with an increased risk of neutropenia. The Committee therefore recommended that amodi- aquine (as tablets, 153 mg, 200mg (base)) be added to the Model List as a core list medicine, with the following footnote: Amodiaquine should preferably be used as part of combination therapy. and that the following text be added at the beginning of the relevant section of the Model List, i.e. section 6.5.3(a): Medicines for the treatment of P. falciparum malaria cases should be used in combination. The Committee also recommended that amodiquine’s place in cura- tive treatment be further defined by WHO guidelines and expressed an interest in reviewing the results of more clinical trials on the comparative efficacy and safety of fixed-dose combinations in the treatment of malaria. 4.1.2 Azithromycin The Committee reviewed two applications for the addition of azithromycin to the Model List. One application was submitted by Médecins sans Frontières (MSF), Brussels, Belgium, for inclusion as an individual core list medicine for the treatment of chlamydial infec- tion and trachoma; the second application was made by the Depart- ment of Reproductive Health and Research, WHO, for inclusion as an individual core list medicine for the treatment of genital chlamy- dia. The MSF application was reviewed and supported by the Depart- ment of Reproductive Health and Research, WHO. The Committee noted that azithromycin, a macrolide antibiotic, has antimicrobial activity against a wide variety of microbes. Its effective- ness against Chlamydia trachomatis genital infection with a single dose has been demonstrated in studies cited in the applications. Cited studies also show that azithromycin is safe for use in both growing 12 adolescents and in pregnancy, both contraindications for tetracycline, the main alternative. The Committee acknowledged that the safety of this medicine in these sectors of the population, combined with the advantages offered by a single-dose curative regimen, support the selection of azithromycin for the treatment of this particular disease. The MSF application also cited studies that indicate that oral azithromycin is as effective in treating trachoma as antibiotic oint- ments. The Committee recognized the advantage of a single oral dose treatment of an infection, especially when it is directly observed, over a prolonged course of prescribed medication. The Committee thus recommended that azithromycin (as capsules, 250 mg, 500mg and as a oral suspension, 200mg/5 ml) be added to the Model List as a core list medicine (in section 6.2.2), for the single dose treatment of genital C. trachomatis infection and of trachoma only. This recommendation was made in view of the effectiveness and safety of azithromycin as documented in the applications, and be- cause of its ease of use relative to the principal alternatives (i.e. doxycycline twice daily for a week, or tetracycline ophthalmic oint- ment for 6 weeks). The Committee recommended that the entry be annotated with the following footnote: Only listed for single dose treatment of genital C. trachomatis and of trachoma. 4.1.3 Ibuprofen (paediatric formulation) The Committee reviewed an application submitted by Boots Healthcare International, Nottingham, England, for the inclusion of a paediatric formulation of ibuprofen in the Model List1. Comments on the application were received from the Department of Child and Adolescent Health, WHO, the United Nations Children’s Fund (UNICEF) and the Cochrane Pain Research Group, Oxford, England. The Committee noted that the application proposes the use of ibuprofen suspension and suppositories in children younger than 12 years and makes reference to evidence relating to the antipyretic effect of ibuprofen. Ibuprofen is used in the management of mild to moderate pain and inflammation; the latter property is, however, generally considered to be the weaker of the two. In its assessment of the application, the Committee paid particular attention to evidence on the efficacy and effectiveness of ibuprofen as an antipyretic agent. 1 Details of the full application (including comments received) are available via the Internet from the WHO web site (http://www.who.int/medicines). 13 The Committee agreed that the application was incomplete in that important information regarding efficacy, safety and cost of ibuprofen in relation to its antipyretic effect was missing. In the opinion of the Committee, the application did not constitute a systematic review; confounding variables such as age, bacterial infection, positive culture and antimicrobial therapy prior to taking the antipyretic were not always taken into account. The Committee considered that there was insufficient evidence to conclude that ibuprofen provides a superior antipyretic effect to paracetamol. Data on the comparative safety and cost-effectiveness of ibuprofen and paracetamol were also lacking. On these grounds, the Committee recommended that the application for the addition of a pediatric form of ibuprofen be rejected, although it would consider a re-application provided it was submitted in the required format and supplied the missing information as mentioned above. In considering the use of paracetamol in adults, the Committee rec- ommended the addition of the following footnote to the entry for paracetamol in section 2.1 (Non-opioid analgesics and antipyretics and non-steroidal anti-inflammatory medicines) of the Model List: Not recommended for anti-inflammatory use due to lack of proven benefit to that effect. 4.1.4 Insulin semilente The Committee reviewed an application submitted by the Patient Association for the Preservation of Natural Animal Insulin Switzer- land, Bern, Switzerland, the Insulin Forum Switzerland, Bern, Switzerland, the Insulin Dependent Diabetes Trust International, Northampton, England, and the Swiss Tropical Institute, Swiss Cen- tre for International Health, Basel, Switzerland, for the inclusion of intermediate amorphous (100%) porcine insulin suspension (insulin “semilente”). Comments on the application were received from The Diabetes Programme, Division of Noncommunicable Diseases and Mental Health, WHO. The Committee noted that the Model List currently includes an intermediate-acting and a short-acting (soluble) insulin, but that nei- ther the origin (i.e. human or animal) nor the type (i.e. zinc suspension or isophane insulin) are specified. Arguments for the inclusion of the intermediate-acting “semilente” form were summarized as follows: — it has more favourable pharmacokinetic properties than other intermediate-acting insulins and the incidence of both nocturnal hypoglycaemia and early morning hyperglycaemia is lower; 14 — it is the only prompt intermediate-acting insulin with added zinc ions and not bound to fish protamine; — human insulins were introduced without any proof of superiority over animal insulins; — some patients present loss of hypoglycaemia warning symptoms after transfer to human insulin; — animal insulins are cheaper than the corresponding human insulins. The Committee agreed that a number of points regarding the intro- duction of human insulins merit attention: — human insulins were introduced without any proof that they are less immunogenic than animal insulins; — the number of patients participating in randomized trials has been limited (2156 in the recent Cochrane Review (17)) and the mean duration of such trials short (5.8 months); — the frequency of insulin resistance has not been assessed. Furthermore, the transfer to human insulins has been associated with a higher risk of severe hypoglycaemia in some studies; however, this finding is not universal. According to the Cochrane Review, the frequency of hypoglycaemic episodes is similar with both types of insulins (17). In the light of the conclusion of the 2003 Cochrane Review, namely that there are no clinically relevant differences between animal and human insulins (17), the Committee concluded that the choice be- tween the two types of insulin should be made on the basis of cost. Noting that intermediate-acting insulin was already on the Model List, the Committee further concluded that insufficient evidence had been presented to justify a decision to single out a species-specific insulin. 4.1.5 Miconazole nitrate buccal tablets The Committee reviewed the re-application, submitted through Family and Community Health, WHO, to include miconazole nitrate buccal tablets for the treatment of oropharyngeal and oesophageal candidiasis in the Model List1. The application to add miconazole nitrate buccal tablets was first considered by the Committee at its previous meeting. At that time, the Committee had been concerned about the lack of comparative data on the efficacy and safety of miconazole nitrate buccal tablets and nystatin lozenges and, thus, on 1 Details of the full application (including comments received) are available via the Internet from the WHO web site (http://www.who.int/medicines). 15 the grounds of insufficient evidence of any additional benefit, had decided not to add miconazole nitrate buccal tablets to the Model List (2). The Committee reviewed the new evidence provided with the re- application and concluded that the efficacy of miconazole nitrate buccal tablets is no worse than that of ketoconazole given systemically and nystatin used locally. The Committee also noted that adverse effects were rarely reported on an estimated 552381 patient exposure worldwide. Assuming therapeutic equivalence, the appropriate eco- nomic evaluation would be a cost-minimization analysis, comparing treatment with miconazole nitrate buccal tablets, ketoconazole tab- lets and nystatin lozenges. On this basis, the total cost for 100 patients was similar for the miconazole nitrate- and ketoconazole-based medi- cations, and lower that that for the nystatin-based preparation. In a secondary analysis, cumulative costs at week 3 were approximately one-third less for patients treated with miconazole nitrate buccal tablets when compared with ketoconazole- and nystatin-treated patients. The Committee considered that the comparison of the effectiveness of miconazole nitrate formulations and nystatin formulations was inadequate; that comparative safety data for miconazole nitrate buc- cal tablets and nystatin lozenges were lacking; and that evidence for clinical benefits arising from a possibly improved adherence to treatment had not been provided. Furthermore, the application was not specifically supported by Family and Community Health. The Committee therefore recommended that the application to add miconazole nitrate buccal tablets to the Model List be rejected. 4.1.6 Misoprostol The Committee reviewed an application from the Department of Obstetrics and Gynaecology, Medical School, Makarere University, Kampala, Uganda, to include misoprostol for obstetric and gynaecological indications. The Committee noted that misoprostol, a synthetic prostaglandin E1 analogue, is only approved for the prevention and treatment of non- steroidal anti-inflammatory drug (NSAID)-associated peptic ulcers; a 25mg vaginal tablet has, however, been registered for hospital use in Brazil (18). Nevertheless, misoprostol has been extensively studied and is widely used for a number of obstetric and gynaecological indications, such as pre-induction cervical ripening (3rd trimester), labour induction (3rd trimester, especially at low Bishop scores), evacuation of the uterus after pregnancy failure or for various 16 other medical reasons (2nd trimester) and primary postpartum haemorrhage. It has been shown to be an effective myometrial stimu- lant of the pregnant uterus, even at the beginning of pregnancy. Thus, it is also an effective abortive agent. Concern about the widespread use of misoprostol as a self-medication has justified its non-approval for marketing in various countries, mainly where abortion is con- sidered illegal. For instance, the use of misoprostol for obstetric indications is not approved by the United States Food and Drug Administration (USFDA). In view of the limited registration for obstetric and gynaecological indications, the Committee decided that the application to add misoprostol to the Model List could not be considered at this meeting. However, if more widespread registration were to be achieved, a full application — supported by a review of available data on efficacy and safety — would be considered. 4.1.7 Valaciclovir The Committee reviewed an application from the Department of Reproductive Health and Research, WHO, for the inclusion of valaciclovir as a better example within a therapeutic group than aciclovir (currently listed in section 6.4.1 Antiherpes medicines) on the grounds of superior bioavailability and a simpler treatment regi- men (valaciclovir can be administered as twice daily doses rather than as 4–6 doses per day as required with aciclovir). In the case of sexually transmitted infections (STIs), compliance is a key issue in ensuring the effectiveness of treatments. Successful treatment is important for reducing the transmission of HIV and for promoting the credibility and acceptance of the syndromic approach to treatment. The Committee noted the comprehensive review of studies on the comparative efficacy and safety of valaciclovir and aciclovir that was provided as part of the application. The studies compared the two medicines as treatments for the first clinical episode of genital herpes, as treatments for recurrent infections or as suppressive therapy, and presented the dosage regimen for each indication. The Committee recognized that none of the randomized controlled trials and studies of comparative effectiveness revealed significant differences between the two medicines and that both valaciclovir and aciclovir are effective when compared with a placebo. However, none of the trials reported adherence to treatment or patient preferences as an outcome measure. The Committee also noted that the treatment regimens for some of the indications involved twice-daily dosing for both medicines. 17 Given the assessment of comparative clinical performance and the lack of evidence of any benefit from better adherence to treatment, the appropriate economic evaluation would be a cost-minimization analysis. On this basis, the cost per course (i.e. 5 days treatment) with aciclovir is in the range US$ 1.46–31.69 whereas the cost per course (i.e. of 5 days treatment) with valaciclovir is higher, at US$ 36.72. Such a cost differential could only be justified if other direct and indirect non-medicine costs (e.g. physician visits, hospitalization, adverse events, productivity losses) associated with use of aciclovir are substantially greater than those associated with treatment with valaciclovir. Based on the available clinical trial evidence, this is un- likely to be the case. The Committee also noted the scarcity of published data on the cost- effectiveness of treatment of herpes simplex with valaciclovir and aciclovir in HIV-infected patients. According to the results of one trial (19), in which the cost-effectiveness of the two medicines for the treatment of herpes simplex virus were compared, relative to aciclovir, the use of valaciclovir reduced direct medical costs by an average of 17% (US$ 60.01) and indirect medical costs by an average of 25% (US$ 46.54). However, this particular analysis was based on a cost-consequence approach and was not a true cost-effectiveness analysis. Moreover, as the analysis was highly system specific, the Committee did not consider it necessarily applicable to other settings. The Committee concluded that valaciclovir could only be considered cost-effective if its price were to be reduced sufficiently, or if evidence were to be presented that adherence to treatment and treatment outcomes are considerably better than those achieved with aciclovir. In the absence of such information, the Committee recommended that valaciclovir should not be added to the Model List, but that aciclovir should take a box symbol for this indication, with valaciclovir identified as one of the alternatives in the same pharma- cological class. 4.2 Applications for deletions 4.2.1 Ethinylestradiol + levonorgestrel tablets (50mg + 250mg, pack of four) The Committee considered a request submitted by the Department of Reproductive Health and Research, WHO, to delete the emergency contraceptive, ethinylestradiol + levonorgestrel (tablets, 50mg + 250mg (pack of four)) from the Model List. The Committee was informed that a levonorgestrel-only regimen is associated with significantly fewer side-effects (20, 21) and, according to a large ran- 18 domized double-blind multinational study organized by the Special Programme of Research, Development and Research Training in Human Reproduction, WHO, more effective as an emergency contra- ceptive than the combination regimen based on ethinylestradiol + levonorgestrel (four-pill pack) (22). Since the publication of the re- sults of the WHO multinational trial in 1998, the levonorgestrel-only regimen has been registered in over 90 countries and some manu- facturers have taken the combined emergency contraceptive pill (four-pill pack) off the market. The Committee was also informed about the results of a more recent randomized, double-blind trial which demonstrated that one dose of 1.5mg levonorgestrel has the same efficacy, and without an increase in side-effects, as two 0.75mg doses of levonorgestrel taken at an interval of 12 hours (23). In the light of this finding, one dose of 1.5mg levonorgestrel is now the recommended regimen for emergency con- traception. At the present time, commercial packs contain two tablets of 0.75mg levonorgestrel, but it is likely that single tablets of 1.5mg levonorgestrel will be available for this indication in the future. The Committee noted that the Model List currently contains two dosage forms for emergency contraception, namely: ethinylestradiol + levonorgestrel tablet, 50mg + 250mg (pack of four) and levonorgestrel tablet, 750mg (pack of two). The Committee considered that the application for the deletion of the former, that is the combination four-pill pack, is supported by a high level of clinical evidence of its inferiority relative to the levonorgestrel-only regimen, as summarized in the Cochrane Review (21). The Committee also acknowledged the better safety profile of the levonorgestrel-only regimen, confirmed statistically and clinically, and with fewer side effects. The relative risk of pregnancy (RR) for the levonorgestrel-only regimen compared with the four-pill combination was 0.80 with a 95% confidence inter- val (CI) of 0.74–0.86. Nausea (16.1% vs 46.5% and 23.1% vs 50.5%) and vomiting (2.7% vs 22.4% and 5.6% vs 18.8%) occurred less frequently with the levonorgestrel-only regimen (P < 0.01) (22). The Committee also considered the results of the recent WHO multicentre randomized trial of the two levonorgestrel-only based regimens (i.e. a single dose of 1.5mg as opposed to two doses of 0.75 mg taken 12 hours apart), involving 4071 women in 15 family- planning clinics in 10 countries, which has demonstrated a high and equal efficacy of both regimens if taken within 5 days of unprotected coitus. The pregnancy rates were 1.5% (or 20 out of 1356) in women assigned single-dose levonorgestrel and 1.8% (or 24 out of 1356) in those prescribed the two-dose levonorgestrel regimen (no statistical 19 difference, p = 0.83). The relative risk of pregnancy for single-dose levonorgestrel compared with two-dose levonorgestrel was 0.83 with 95% CI = 0.46–1.50 (23). The Committee concluded that there is good evidence in favour of the substitution of the two-dose regimen (0.75 mg 12 hours apart) with the single 1.5mg dose of levonorgestrel; the use of a single dose simplifies the use of levonorgestrel for emer- gency contraception without an increase in side effects. On the basis of the evidence before it, the Committee recommended that a 1.5 mg tablet be added as a new dosage form of levonorgestrel and that ethinylestradiol + levonorgestrel (tablet, 50mg + 250mg, pack of four) be deleted from the Model List. 4.2.2 Nonoxynol The Committee considered an application submitted by the Depart- ment of Reproductive Health and Research, WHO, to delete nonoxynol as a condom-additive vaginal spermaticide and virucidal. In addition, a safety analysis was received from the WHO Collaborat- ing Centre for International Drug Monitoring, Uppsala, Sweden, along with a copy of the USFDA proposed rule on the labelling of over-the-counter vaginal contraceptive drug products containing nonoxynol-9. In the application, reference was made to a large multicountry study sponsored by WHO, the former Global Programme on AIDS (GPA) and the Joint United Nations Programme on HIV/AIDS (UNAIDS), results of which indicated that, contrary to expectation, there is a higher incidence of HIV infection in women using nonoxynol-9 than in women using a placebo gel. Prompted by this finding, the Depart- ment of Reproductive Health and Research, WHO, in partnership with the CONRAD Program, convened a technical consultation in October 2001 to review the implications of the new data on the use of nonoxynol-9 as a spermicide. All available evidence regarding the use of nonoxynol-9 as a contraceptive, its effectiveness in preventing infection with gonorrhoea or Chlamydia trachomatis, and its effec- tiveness in preventing HIV infection was summarized in the report of the consultation (24). The main conclusions reached are as follows: — although nonoxynol-9 has been shown to increase the risk of HIV infection when used frequently by women at high risk of infection, it remains a contraceptive option for women at low risk; — nonoxynol-9 offers no protection against STIs such as gonorrhoea or chlamydia; — there is no evidence that condoms lubricated with nonoxynol-9 are any more effective in preventing pregnancy or infection than 20 condoms lubricated with silicone, and such condoms should no longer be promoted; however, it is better to use a nonoxynol-9 lubricated condom than no condom at all; — nonoxynol-9 should not be used rectally. In 2002, and subsequent to the consultation, the final results of the WHO/GPA/UNAIDS-sponsored study (the COL-1492 study) were published in the Lancet (25); a systematic review of the use of nonoxynol-9 for STI and HIV prevention was also published (26). In light of the presented evidence, the Department of Reproductive Health and Research proposed that the specific mention of condoms lubricated with nonoxynol should be removed from the Model List, but that condoms themselves should be retained. The role of condoms in the prevention of pregnancy and HIV transmission is well proven; condoms are also the mainstay of HIV and STI prevention programmes. A silicone-oil lubricant is recommended in the joint WHO-UNAIDS publication The Male Latex Condom (27). The Committee, on the basis of the evidence before it, recommended to maintain condoms on the Model List but to delete the mention of nonoxynol in view of the increased risk of transmitting HIV infection. As there is insufficient evidence to suggest an alternative spermicide to nonoxynol, the Committee recommended that the reference to spermicides be deleted as well. The Committee acknowledged the continued need to offer dia- phragms as part of the contraceptive mix in family planning, despite their moderate contraceptive effect, and thus recommended that they too should be maintained on the Model List. With regard to the use of nonoxynol with a diaphragm, the Committee noted that most obser- vational studies are conducted with spermicide and that one random- ized study reported a statistically non-significant additional beneficial effect of the spermicide in preventing pregnancy (28). The Committee therefore recommended the removal of the reference to spermicides, including nonoxynol, in the entry for diaphragms, in view of the lack of evidence of any additional benefit of spermicides and the strong suggestion of the potential of nonoxynol to increase the risk of trans- mission of HIV infection. 4.3 Applications for addition of information 4.3.1 Anti-leprosy medicines The Committee reviewed a request submitted by the Department of Communicable Diseases Prevention, Control and Eradication, WHO, to modify the Model List so as to better reflect the fact that anti- 21 leprosy medicines should be used exclusively in combination (i.e. as multidrug therapy (MDT)) and be presented in colour-coded blister packs (i.e. MDT blister packs) in order to (i) prevent antimicrobial resistance, (ii) improve patient adherence to treatment and (iii) facili- tate logistics and inventory control; and that MDT blister packs can be obtained free of charge through WHO. To this end, the Committee recommended that the following text be inserted at the head of the appropriate section of the Model List (section 6.2.3 Antileprosy medicines): Medicines used in the treatment of leprosy should never be used except in combination (i.e. as multidrug therapy (MDT)). Combination therapy is essential to prevent the emergence of drug resistance. Colour-coded blister packs (MDT blister packs) containing standard two-medicine (pauciba- cillary leprosy) or three-medicine (multibacillary leprosy) combinations for adult and childhood leprosy should be used. MDT blister packs can be supplied free of charge through WHO. The Committee also recommended that the same information be included in the WHO Essential Medicines Library and the WHO model formulary. 4.4 Other changes 4.4.1 Oral rehydration salts The Committee reviewed an application submitted by the Depart- ment of Child and Adolescent Health, WHO, to change the formula of oral rehydration salts (ORS). The current formula, which provides a solution containing 90 mEq/l of sodium with an osmolarity of 311 mOsm/l, has proven effective, without apparent adverse effects, in worldwide use, and has contributed substantially to the dramatic global reduction in mortality from diarrhoeal disease. The Committee was informed that, over the past 20 years, numerous studies have been undertaken with a view to developing an “im- proved” ORS formulation. The goal has been a product that is at least as safe and as effective as the standard ORS solution for preventing or treating dehydration from all types of diarrhoea but which would, in addition, reduce stool frequency or have other important clinical benefits. One approach that was adopted involved decreasing the osmolarity of the standard ORS solution to avoid possible adverse effects of hypertonicity on net fluid absorption. This was achieved by reducing the solution’s glucose and salt (NaCl) concentrations. Studies evaluating this approach were reviewed at a consultative technical meeting held in New York in July 2001; as a result, technical recommendations were made to WHO and UNICEF regarding the 22 efficacy and safety of a reduced-osmolarity ORS solution in children with acute non-cholera diarrhoea, and in adults and children with cholera (29). The studies showed that the efficacy of ORS treatment in children with acute non-cholera diarrhoea is improved by reducing the sodium concentration to 75mEq/l, the glucose concentration to 75mmol/l, and the total osmolarity to 245mOsm/l. Compared with the established ORS solution, the need for unscheduled supplemental intravenous therapy is reduced by 33% (NNT = 20). In addition, a combined analysis of the studies reviewed at the New York meeting and other studies involving reduced-osmolarity ORS solutions of dif- fering composition (osmolarity 210–268mOsm/l, sodium 50–75 mEq/ l), reported a reduction in stool output of about 20% and a decrease in the incidence of vomiting of about 30%. The 245mOsm/l solution also appeared to be as safe, and at least as effective, as the standard ORS solution for use in children with cholera (29). The application also mentioned the fact that the reduced-osmolarity ORS solution containing 75mEq/l sodium, 75 mmol/l glucose (total osmolarity = 245mOsm/l) has been shown to be as effective as stan- dard ORS in treating adults with cholera, but is associated with an increased incidence of transient, asymptomatic hyponatraemia. Thus, the reduced osmolarity ORS may be used in place of the standard ORS solution for treating adults with cholera, but careful monitoring is advised for significant hyponatraemia. In its discussions, the Committee noted that the new reduced- osmolarity ORS formulation has already been officially released by WHO and its partners during the United Nations General Assembly Special Session on Children that was held in New York, and that UNICEF, USAID and MSF are supporting this application. The Committee further noted that WHO and UNICEF have recently published criteria for acceptable ORS formulations (29). These crite- ria are summarized in Table 1. The Committee concluded that the evidence supporting the superior- ity of the new reduced osmolarity ORS solution for the treatment of acute non-cholera diarrhoea in children was convincing, with a 5% absolute risk reduction (NNT = 20) in the need for unplanned intra- venous infusions, and on this basis recommended that the formula for ORS in the Model List (section 17.7.1 Oral hydration) be changed to 75mEq/l sodium (sodium chloride 2.6g/l) and 75mmol/l (13.5 g/l) glucose. The Committee also recommended the addition of the following footnote: In cases of cholera a higher concentration of sodium may be required. 23 4.4.2 Streptokinase The Committee reviewed an application submitted by Aventis Behring, GmbH, Marburg Germany, to remove the 100000 IU do- sage form of streptokinase from the Model List1 (section 12.5 Antithrombotic medicines). The Committee noted that the recommended standard dosage for streptokinase’s main indication, the treatment of acute myocardial infarction, is 1.5 million IU. The Committee recommended that the dosage form for streptokinase be changed to: powder for injection, 1.5 million IU in vial and that the note, “For use in rare or exceptional circumstances.” be removed since its value in treating acute myocar- dial infarction is now well established and its use is no longer reserved for exceptional situations. 5. Reviews of sections of the Model List At the previous meeting of the Committee, a number of issues relat- ing to the listing and presentation of medicines on the Model List, such as the use of the square box symbol, the classification of medi- cines as either core or complementary and the possibility of initiating a simplified procedure for deleting items, were identified as being in need of detailed consideration and/or re-evaluation (2). Thus during the period between the previous and present meetings, a series of Table 1 Recommended composition of oral rehydration saltsa Substance Concentration Total substances (including 200–310mmol/l that contributed by glucose) Individual substances Glucose At least equal that of sodium, but not exceeding 111mmol/l Sodium 60–90mEq/l Potassium 15–25mEq/l Citrate 8–12mmol/l Chloride 50–80mEq/l a The listed criteria specify the desired characteristics of the solution after it has been prepared according to the instructions on the packet. Source: reference 30. 1 Details of the full application (including comments received) are available via the Internet from the WHO web site (http://www.who.int/medicines). 24 reviews were undertaken by several small groups of international experts formed from the 2002 Expert Committee and the WHO Sec- retariat. The results of these reviews were reported at the present meeting for approval by the full Expert Committee. In addition, and following a recommendation to that effect made by the Committee at its previous meeting, the medicines for the treatment of hypertension (section 12.3 of the Model List) were subjected to a full review. 5.1 “Fast-track” procedure for deleting items from the Model List At its previous meeting, the Expert Committee recognized that, for certain items on the Model List at least, a simplified or “fast-track” deletion procedure may be appropriate and recommended that such a procedure be developed (2). The rationale for this recommendation was that selected items on the Model List, for which no systematic reviews or sufficient evidence of efficacy and safety are available, were probably now obsolete, but the fact that they were probably obsolete (or not essential) did not justify the costly investment of a full systematic review. A consultation technique, which included the use of two question- naires, was used to identify those medicines most in need of a full systematic review on the basis of doubtful safety and/or efficacy or which could be proposed for fast-track deletion. The first question- naire comprised a list of medicines compiled from a number of sources; some were considered by the full Committee to be question- able in terms of safety and/or efficacy, some were identified by means of a survey that compared medicines on the Model List with a sample of 12 national essential medicine lists, and others were identified by the WHO Secretariat. Respondents were asked to indicate which items they thought should be deleted, which should be retained and which should be subjected to a systematic review. The second ques- tionnaire was a simple list of the pharmacological section headings used in the Model List, with a request to rank those sections consid- ered to be in need of revision. In addition, the other reviews — of core versus complementary listing (see section 5.2) and of the use of the square box symbol (see section 5.3) — led to several proposals for medicines for fast-track deletion or for full review; these proposals were subjected to peer review and also to review by the WHO Secretariat. The first questionnaire was sent to a group of 81 individuals proposed by the Secretariat, consisting of Expert Panel members, members of a wider advisory group and relevant WHO staff, including regional advisers. In addition, a message was sent out via the e-drug electronic 25 discussion group on the Internet, which resulted in another 27 expres- sions of interest. In response to the total of 104 forms sent out, 28 (or 24%) completed forms were received from 20 countries. On the basis of the questionnaire responses received, the Committee recommended to retain the following three medicines on the Model List: — codeine for analgesic use (section 2.2 Opioid analgesics); — pyrantel (section 6.1.1 Intestinal anthelminthics); — verapamil tablets (section 12.1 Antianginal medicines). The Committee also recommended, on the basis of the questionnaire responses and other arguments as detailed below, to delete, or to make changes to, the following medicines: • Chloral hydrate (section 1.3 Preoperative medication and sedation for short-term procedures). The Committee noted that chloral hy- drate was included in only 2 of 25 national essential medicines lists. It further noted that this medicine is described in the 1996 WHO publication on cancer pain relief as the “drug of choice for painless procedures” (30), but concluded that there are many as effective and safe alternatives, such as promethazine syrup. The Committee thus recommended that chloral hydrate be deleted from the Model List. • Clomifene (section 18.6 Ovulation inducers). The Committee noted that subfertility is a common problem which can cause considerable distress, that there is a Cochrane Review (31) that demonstrates the effectiveness of clomifene (NNT = 2.74) but no WHO clinical guidelines on infertility treatment, and thirdly, that clomifene is listed on 20 of 25 national essential medicines lists. The Committee recommended that clomifene be retained on the Model List but moved to the complementary list (in view of the need for specialist care) and its square box symbol removed. • Dextromethorphan (section 25.2 Antitussive medicines). The Com- mittee noted the conclusions of WHO clinical guidelines that state, “Given the conflicting nature of the evidence, no clear recommen- dation can be made in favour of its use.” (32), and also those of a recent Cochrane Review which was unable to find good evidence in support of the use of over-the-counter medications against cough (33). The Committee concluded that there was insufficient evi- dence to support the listing of dextromethorphan (oral solution) as an essential medicine and recommended that the item be deleted. • Fludrocortisone (section 18.1 Adrenal hormones and synthetic sub- stitutes). The Committee noted that although fludrocortisone is a 26 life-saving medicine in cases of adrenal insufficiency (which is con- sidered to be a rare condition), it features in only 9 of 25 national essential medicines lists, is not listed in the MSH drug price indica- tor guide and is not currently being supplied by UNICEF and the International Dispensary Association (IDA). The Committee con- cluded that there is no need for this item to be on the Model List and recommended that it be deleted (see also section 5.3). • Folic acid, injection (section 10.1 Antianaemia medicines). The Committee noted that there was no identified need for this presen- tation and therefore recommended that folic acid injections be deleted from the Model List. • Immunoglobulin, human normal (section 19.2 Sera and immuno- globulins). The Committee noted that there is no need for this item in view of the availability of suitable vaccines, that there are no WHO clinical guidelines recommending its use, and that quality control of this blood product poses a problem. The Committee thus recommended that immunoglobulin, human normal be deleted. • Ipecacuanha (section 4.1 Non-specific antidotes and other sub- stances used in poisonings). The Committee noted the lack of need for an emetic in the treatment of poisoning due to the risk of aspiration pneumonia, and the absence of evidence on the efficacy and safety of ipecacuanha in the management of poisoning. The Committee further noted that ipecacuanha is not included in the International Programme for Chemical Safety (IPCS) INTOX databank and thus recommended that it be deleted from the Model List. The Committee noted that selected medicines, such as fludro- cortisone, were deleted from the Model List because, on reflection, the Committee considered the diseases for which they are needed are too rare for these items to meet the selection criteria, “. . . satisfy the priority health care needs of the population”. The Committee fully recognized the essential and even life-saving nature of certain medicines for patients with rare but treatable diseases. While the treatment of such diseases, on reflection, falls outside its remit, the Committee nevertheless urged that effective treatments for serious uncommon diseases be made available whenever possible. At the national level, special arrangements for specific individuals may need to be made in this regard. Finally, the Committee agreed that the sections of the Model List dealing with anaesthetics (section 1) and dermatological medicines (section 13) should be subject to a full systematic review before any 27 further deletions could be recommended in these medicine groups. Recommendations for deletions in section 12.3 of the Model List (Antihypertensive medicines) are covered separately (see pages 36– 41). 5.2 Review of core versus complementary listing of medicines The 12th Model List of Essential Medicines (revised April 2002) is presented as two separate lists: a “core” list and a “complementary” list, which are described as follows: • The core list presents a list of minimum medicine needs for a basic health care system, listing the most efficacious, safe and cost- effective medicines for priority conditions. Priority conditions are selected on the basis of current and estimated future public health relevance, and potential for safe and cost-effective treatment. • The complementary list presents essential medicines for priority diseases which are efficacious, safe and cost-effective but not neces- sarily affordable, or for which specialized health care facilities or services may be needed. At the meeting of the Committee in 2002, there was considerable debate about whether the system of two lists should be retained or whether they should be combined into a single list. This discussion was prompted in part by the observation that the existing criteria for core or complementary listing had become blurred and had been misapplied to those medicines that are for priority conditions but are thought to be expensive. Moreover, as the prices of pharmaceuticals are variable and changing, it did not seem reasonable to use “cost- effective but not necessarily affordable” as the main criterion for the placement of an item on the complementary list (2). During the course of 2002, and in the wake of this debate, the desig- nation of all medicines on the 12th Model List as “core” or “comple- mentary” was reviewed according to the following general principles: 1. All essential medicines should be placed on the core list, unless there is a specific reason for them to be on the complementary list. 2. If there is uncertainty about the classification, the medicine should be put on the core list. The following criteria were used for putting items on the complemen- tary list: • Primary criterion. Use of the medicine requires specialized diag- nostic or monitoring facilities, and/or specialist medical care, and/or specialist training. 28 • Secondary criterion (to be used only in cases of doubt). Consistently higher cost or less attractive cost-effectiveness in a variety of settings. Seventy-nine (or 24%) of the total 325 medicines included in the 12th Model List are listed as complementary; some appear on both the core and the complementary list. For each of these medicines the indications and specifications for use as described in the WHO model formulary were evaluated: if, according to the WHO model formulary, there is always a need for specialist medical care or facilities for use of a medicine for a given indication, the medicine was classified as “complementary” for that indication; where there was uncertainty, evidence of consistently higher cost or less attractive cost-effectiveness in most settings was used as the secondary criterion for putting the medicine on the complementary list. In cases where there was still doubt, the medicine was classified as a core list medicine. At its present meeting, the Committee agreed to define the criteria for core and complementary listing as follows: • The core list presents a list of minimum medicine needs for a basic health care system, listing the most efficacious, safe and cost- effective medicines for priority conditions. Priority conditions are selected on the basis of current and estimated future public health relevance, and potential for safe and cost-effective treatment. • The complementary list presents essential medicines for priority diseases, for which specialized diagnostic or monitoring facilities, and/or specialist medical care, and/or specialist training are needed. In cases of doubt, medicines may also be listed as complementary on the basis of consistently higher costs or less attractive cost- effectiveness in a variety of settings. The Committee recommended that core and complementary medi- cines, previously presented in two separate lists, be combined into one list, with the complementary medicines printed in italics or otherwise identified (see Annex 1). In reviewing the proposals for changes to the classification of medi- cines as “core” or “complementary”, the Committee decided not to make recommendations for changes to items in those sections of the Model List which were also recommended for systematic review; changes of this nature would be recommended as part of such reviews (e.g. see section 5.4 Review of the antihypertensive medicines (section 12.3 of the Model List)). 29 The Committee recommended that the following medicines be moved from the core list to the complementary list: — aminophylline (section 25.1 Antiasthmatic medicines); — amphotericin B (section 6.3 Antifungal medicines); — azathioprine (in section 2.4 Disease-modifying agents used in rheumatoid disorders); — clomifene (section 18.6 Ovulation inducers); — diethylcarbamazine (section 6.1.2 Antifilarials); — dopamine (section 12.4 Medicines used in heart failure); — ethosuximide (section 5 Anticonvulsants/antiepileptics); — hydrocortisone (rectal preparations in section 17.4 Gastrointesti- nal anti-inflammatory medicines); — intraperitoneal dialysis solution (section 23 Peritoneal dialysis solution); — methotrexate (in section 2.4 Disease-modifying agents used in rheumatoid disorders); — penicillamine (in section 2.4 Disease-modifying agents used in rheumatoid disorders), — pentamidine (in section 6.5.2 Anti-leishmaniasis medicines, in sec- tion 6.5.4 Antipneumocystosis and antitoxoplasmosis medicines and in section 6.5.5a Antitrypanosomal medicines — African trypanosomiasis), — pyridostigmine (section 20 Muscle relaxants (peripherally-acting) and cholinesterase inhibitors); — sulfadiazine (section 6.2.2 Other antibacterials); — sulfasalazine (in section 2.4 Disease-modifying agents used in rheumatoid disorders). The Committee recommended that the following medicines be moved from the complementary list to the core list: — amoxicillin + clavulanic acid (section 6.2.1 b-lactam medicines); — chloramphenicol (oily suspension for injection in section 6.2.2 Other antibacterials); — epinephrine (adrenaline) (in section 12.2 Antiarrhythmic medicines); — levonorgestrel (30mg tablets in section 18.3.1 Hormonal contraceptives); — mannitol (section 16 Diuretics); — norethisterone enantate (section 18.3.1 Hormonal contraceptives). The Committee also recommended that the following items be de- leted from the Model List for the reason(s) stated: 30 • Cyclophosphamide (section 2.4 Disease-modifying agent in rheumatoid arthritis). The Committee noted the findings of a recent Cochrane Review (34) on the efficacy and safety of cyclophosphamide as a disease-modifying agent in rheumatoid ar- thritis, and recommended that this item be deleted for this particu- lar indication. • Desmopressin (section 10.2 Medicines affecting coagulation). The Committee recommended the deletion of this item on the grounds of the rarity of the indication. • Iron dextran (section 10.1 Antanaemia medicines). The Committee recommended the deletion of this item on the basis of its unfavourable benefit–risk ratio. • Pethidine (section 2.2 Opioid analgesics). The Committee noted that pethidine was listed on 19 out of 25 national essential medicine lists; that pethidine was considered inferior to morphine due to its toxicity on the central nervous system; and that it is generally more expensive than morphine. The Committee concluded that there was insufficient justification to keep pethidine on the Model List and recommended that it be deleted. The Committee stressed that all national programmes should ensure that sufficient quantities of morphine are always available for those who need it. • Trimethoprim (injection in section 6.2.2 Other antibacterials). The Committee recommended that the injectable form of trimethoprim be deleted because of the lack of need of this particular administra- tion route for this medicine. 5.3 Review of the use of the square box symbol (including a review of the corticosteroids) The 12th Model List contains 113 items that are marked with a “square box” symbol; this symbol is used to indicate that “a listed medicine should be seen as a representative example from a group of clinically equivalent medicines with wide experience of use, within a pharmacological class. The medicines listed on the Model List would generally be the least costly therapeutic equivalent within the group. National lists should not use a similar symbol and should be specific in their final selection, which would depend on local availability and price.” (2). At its previous meeting, the Expert Committee acknowledged that there had been some inconsistency in the way the symbol had been used in the past. For example, in the 12th Model List neostigmine is listed with a square box, yet has no pharmacological or therapeutic 31 equivalent; in the case of the corticosteroids, of which there are sev- eral in various sections of the Model List, some are marked with boxes for some indications while others are not. The Committee therefore recommended that a review of the use of the square box symbol be undertaken with a view to restricting its use (2). As a precursor to the review of the use of the square box symbol, it was necessary to reassess the meaning of the square box symbol, and in particular to consider the definitions of the terms “equivalence” and “interchangeability” as they apply to medicines. In this context, there are three possible ways of defining equivalence and inter- changeability, as outlined below. The first definition of equivalence is based on the notion of generic equivalence, where products contain the same chemical compound. In this respect, the Committee recommended the use of the existing WHO description which states: The term “generic product” has somewhat different meanings in different jurisdictions and in this document use of the term is avoided as much as possible, and the term “multisource pharmaceutical product” has been applied. Generic products may be marketed either under the nonproprietary approved name or under a new brand (proprietary) name. They may sometimes be marketed in dosage forms and/or strengths different from those of the innovator products. However, where the term ‘generic product’ has to be used it means a pharmaceutical product, usually intended to be interchangeable with the innovator product, which is usually manufactured without a licence from the innovator company and marketed after expiry of patent or other exclusivity rights (35).” Generic substitution was assumed to be acceptable for medicines on the Model List as it is constructed by chemical compound, not by brand name. However, it was proposed that square boxes should not be used to indicate substances for which there are known to be mul- tiple suppliers of acceptable products. The second definition of interchangeability is at the level of pharma- cological class (e.g. angiotensin-converting enzyme (ACE) inhibi- tors). There has been some considerable debate in the scientific literature about “class effects” of medicines and whether efficacy and safety can be assumed to be interchangeable throughout a class of medicines; this debate has yet to be concluded. There is some evi- dence to suggest that efficacy can be assumed across a class of medi- cines if equipotent doses of the medicines can be established, but that safety cannot necessarily be generalized in the same way. From a policy point of view, it can be useful to specify those pharmacological items that are deemed to be clinically similar within a class on the basis of the best comparative evidence, and then to set medicine reimbursement levels accordingly. 32 It was agreed that for the purposes of the Model List, the square box symbol should be used primarily to indicate similar clinical perfor- mance within a pharmacological class. Thus, the medicine listed should be that member of a given pharmacological class for which there is the best evidence for effectiveness and safety. In some cases, this may be the first medicine that is licensed for marketing; in others, subsequently licensed compounds may be safer or more effective. Where there is no difference between medicines in terms of efficacy and safety, the listed medicine should be the one that is generally available at the lowest price, based on international drug price infor- mation sources. The third definition of interchangeability is based on therapeutic indication. However, determining therapeutic equivalence is a com- plex matter: for example, to claim therapeutic equivalence would be tantamount to saying that all classes of medicines used to treat hyper- tension are therapeutically interchangeable (i.e. a beta-blocker has the same therapeutic effect as a calcium-channel blocker), a sugges- tion that has been hotly contested. Defining therapeutic groups of medicines for specific indications demands detailed and comprehen- sive review of clinical data on comparative effectiveness and safety, and is often the subject of considerable controversy. In light of the above considerations, the description of the square box symbol was modified as follows: The square box symbol is primarily intended to indicate similar clinical performance within a pharmacological class. The listed medicine should be the example of the class for which there is the best evidence for effectiveness and safety. In some cases, this may be the first medicine that is licensed for marketing; in other instances, subsequently licensed compounds may be safer or more effective. Where there is no difference in terms of efficacy and safety data, the listed medicine should be the one that is generally available at the lowest price, based on international drug price information sources. Therapeutic equivalence is only indicated on the basis of reviews of efficacy and safety and when consistent with WHO clinical guidelines. National lists should not use a similar symbol and should be specific in their final selection, which would depend on local availability and price. The review of the use of the square box symbol in the Model List was conducted using the following principles: 1. As far as possible, items on the Model List should be listed without a square box symbol; the symbol should only be used if there is at least one other member of its pharmacological class that can be considered to be clinically similar; such item(s) should be identified and listed in the WHO Essential Medicines Library and/or the WHO model formulary. 33 2. If for any item there is uncertainty about the clinical similarity of any potential alternatives, a square box symbol should not be used. Based on the outcome of the square box review, the Committee recommended that the square box symbol be removed from the fol- lowing items on the Model List: — amiloride (section 16 Diuretics); — amoxicillin (section 6.2.1 b-Lactam medicines); — amoxicillin + clavulinic acid (section 6.2.1 b-Lactam medicines); — antitetanus immunoglobulin (section 19.2 Sera and immunoglobulins); — azathioprine (in section 8.1 Immunosuppressive medicines), — chloramphenicol (capsule, oral suspension and powder for injec- tion in section 6.2.2 Other antibacterials); — chloroquine (in section 6.5.3a Antimalarial medicines for curative treatment); — ciclosporin (section 8.1 Immunosuppressive medicines); — clomifene (section 18.6 Ovulation inducers); — charcoal, activated (section 4.1 Non-specific antidotes and other substances used in poisonings); — codeine (in section 2.2 Opioid analgesics and section 17.7.2 Antidiarrhoeal (symptomatic) medicines); — cycloserine (section 6.2.4 Antituberculosis medicines) — dexamethasone (in section 3 Antiallergics and medicines used in anaphylaxis); — diloxanide (section 6.5.1 Antiamoebic and antigiardiasis medicines); — doxorubicin (section 8.2 Cytotoxic medicines); — doxycycline (6.5.3a Antimalarial medicines for curative treat- ment) — epinephrine (adrenaline) (in section 25.1 Antiasthmatic medicines); — ethionamide (section 6.2.4 Antituberculosis medicines); — glibenclamide (section 18.5 Insulins and other antidiabetic agents); — ibuprofen (section 2.1 Non-opioid analgesics and antipyretics and non-steroidal anti-inflammatory medicines); — mannitol (section 16 Diuretics); — DL-methionine (section 4.2 Specific antidotes and other substances used in poisonings); — morphine (in section 1.3 Preoperative medication and sedation for short-term procedures and 2.2 Opioid analgesics); — neostigmine (section 20 Muscle relaxants (peripherally-acting) and cholinesterase inhibitors); 34 — promethazine (in section 1.3 Preoperative medication and sedation for short-term procedures and section 17.2 Antiemetic medicines); — quinine (section 6.5.3a Antimalarial medicines for curative treatment); — sodium nitroprusside (section 12.3 Antihypertensive medicines); — retinol (section 27 Vitamins and minerals); — sulfadiazine (6.2.2 Other antibacterials); — sulfadoxine + pyrimethamine (section 6.5.3a Antimalarial medicines for curative treatment), — sulfamethoxazole + trimethoprim (in section 6.2.2 Other antibacterials); — verapamil (section 12.1 Antianginal medicines). In making its recommendations the Committee noted the following: • The square box on ibuprofen was removed because there are significant differences in efficacy and safety within this pharmaco- logical class. • The square box on morphine was removed because of the lower benefit–risk ratio and higher price of the alternatives. The Com- mittee urged all national programmes to ensure that sufficient quantities of morphine are always available to those who need it. In the following cases, the Committee recommended that the square box symbol be retained but the listed medicine be changed (for the reasons stated in parentheses): • Captopril (section 12.3 Antihypertensive medicines) to be replaced by enalapril (enalapril has a simpler dosing regimen and is available as a generic). • Cimetidine (section 17.1 Antacids and other antiulcer medicines) to be replaced by ranitidine (ranitidine has a simpler dosing regimen and less potential for pharmacokinetic interactions, and is available as a generic). The Committee also recommended that examples of possible alternatives for the medicines listed with a square box symbol should not be included in the Model List itself, but that they should be mentioned in the WHO Essential Medicines Library and the WHO model formulary. The corticosteroids During the course of the review of the use of the square box symbol, it was noted that the present Model List is not very consistent in its 35 recommendations regarding the selection of, and the use of the square box symbol with, the corticosteroids. The Committee there- fore recommended that the listing of these medicines for systemic use be reviewed. In reviewing the corticosteroids, the Committee com- mented on the scarcity of systematic data for comparing the safety and efficacy of various corticosteroids in human use and also on the fact that only a limited amount of information on the relationship between dose and effect in the treatment of various conditions is currently available. Nevertheless, the Committee recommended that the listing of the corticosteroids for systemic use be simplified as follows: • Section 3 (Antiallergics and medicines used in anaphylaxis). Dexam- ethasone tablets (500mg, 4 mg) should be removed and a 25mg prednisolone tablet added. The injectable dosage forms, dexam- ethasone (injection, 4mg dexamethasone phosphate (as disodium salt) in 1-ml ampoule) and hydrocortisone (powder for injection, 100 mg (as sodium succinate) in vial) should be retained, but nei- ther with a square box symbol. Thus prednisolone tablets (5 mg and 25 mg) become the only oral corticosteroidal preparations in this section of the Model List to have a square box, on account of their slightly lower price per defined daily dose (DDD) and considerably higher turnover by not-for-profit generic suppliers relative to dexamethasone (500mg). In this regard, dexamethasone should be mentioned as the possible alternative, and the entry for predniso- lone annotated with the following footnote: There is no evidence for complete clinical similarity between prednisolone and dexamethasone at high doses. • Section 8.3 (Hormones and antihormones). The injectable forms of dexamethasone (injection, 4 mg dexamethasone phosphate (as disodium salt) in 1-ml ampoule) and hydrocortisone (powder for injection, 100 mg (as sodium succinate) in vial) should be added to this section (as complementary list medicines). The tablet form only of prednisolone should be retained (5mg) and a higher dosage form added (25 mg), and the entry annotated with the same foot- note as in section 3 (see above). • Section 18.1 (Adrenal hormones and synthetic substitutes). All four corticosteroids (dexamethasone in the core list; fludrocortisone in the complementary list, hydrocortisone in the core list and pred- nisolone in the core list) should be deleted for this indication (i.e. the treatment of Addison’s disease) in view of the rarity of the condition; however, the section heading in the Model List should be maintained but with the addition of the following note: 36 Addison’s disease is a rare condition; adrenal hormones for the treatment of this condition are already included in section 3. The Committee also made the following recommendations: • Section 13.3 (Anti-inflammatory and antipruritic medicines). Betamethasone (ointment or cream, 0.1% (as valerate)) and hydro- cortisone (cream or ointment, 1% (acetate)) should be retained, with square box symbols, pending a full review of section 13 (Dermatological medicines) of the Model List. • Section 17.4 (Anti-inflammatory medicines). Hydrocortisone (sup- pository, 25mg (acetate) and retention enema) should be retained, with a square box symbol, but moved to the complementary list. • Section 21.2 (Anti-inflammatory agents). Prednisolone (eye drops, 0.5% (sodium phosphate)) should be retained, with a square box symbol, pending a full review of section 21 (Ophthalmological preparations) of the Model List. Changes to the listing of the individual corticosteroids are summa- rized in Table 2. 5.4 Review of the antihypertensive medicines At its previous meeting, the Committee recommended that the sec- tion 12.3 of the Model List (Antihypertensive medicines) be reviewed in the light of new clinical guidelines for the treatment of hyperten- sion that were being prepared jointly by WHO and the International Society for Hypertension (ISH) (2). The new guidelines update the WHO/ISH clinical guidelines for the treatment of hypertension pub- lished in 1999 (36). At the present meeting, the Committee was informed by the Depart- ment of Cardiovascular Diseases that WHO plans to incorporate the updated WHO/ISH guidelines into a set of guidelines for cardiovas- cular risk assessment and management, so as to bring about a para- digm shift from single risk factor management to comprehensive cardiovascular risk management. It was envisaged that this work would not be completed until the end of 2003. As an interim measure, it had been agreed that a draft statement on the management of hypertension would be prepared by the group of experts assigned to update the 1999 WHO/ISH guidelines that reflected their evidence- based work. The Committee assessed all seven antihypertensive medicines cur- rently included in section 12.3 of the Model List in the light of the draft statement on the management of hypertension. According to 37 Ta b le 2 Su m m ar y of th e Co m m itt ee ’ s re co m m en da tio ns re ga rd in g th e lis tin g of th e co rti co st er oi ds (A pr il 2 00 3) M ed ic in e M od el L is t D os ag e fo rm a nd s tr en g th R ec om m en d at io n se ct io n nu m b er b et am et ha so ne 13 .3 oi nt m en t or c re am , 0. 1% ( as v al er at e) R et ai ne d w ith n o ch an g e p en d in g r ev ie w o f se ct io n 13 o f th e M od el L is t d ex am et ha so ne 3 ta b le t, 50 0 ug , 4 m g O ra l p re p ar at io n re m ov ed f or t hi s in d ic at io n in je ct io n, 4 m g d ex am et ha so ne p ho sp ha te R et ai ne d b ut w ith ou t th e sq ua re b ox s ym b ol (a s d is od iu m s al t) in 1 -m l a m p ou le 8. 3 in je ct io n, 4 m g d ex am et ha so ne p ho sp ha te A d d ed t o th is s ec tio n of t he M od el L is t as a (a s d is od iu m s al t) in 1 -m l a m p ou le co m p le m en ta ry li st m ed ic in e 18 .1 ta b le t, 50 0 ug , 4 m g D el et ed f or t hi s in d ic at io n; n ew f oo tn ot e ad d ed t o se ct io n 18 .1 o f th e M od el L is t: A d d is on ’s d is ea se is a r ar e co nd iti on ; ad re na l h or m on es f or t he tr ea tm en t of t hi s co nd iti on a re a lre ad y in cl ud ed in s ec tio n 3 of t he M od el L is t. in je ct io n, 4 m g d ex am et ha so ne p ho sp ha te D el et ed f or t hi s in d ic at io n (a s d is od iu m s al t) in 1 -m l a m p ou le flu d ro co rt is on e 18 .1 ta b le t, 10 0 ug ( ac et at e) D el et ed f or t hi s in d ic at io n; n ew f oo tn ot e ad d ed t o se ct io n 18 .1 o f th e M od el L is t: A d d is on ’s d is ea se is a r ar e co nd iti on ; ad re na l h or m on es fo r th e tr ea tm en t of t hi s co nd iti on a re a lre ad y in cl ud ed in s ec tio n 3 of t he M od el L is t hy d ro co rt is on e 3 p ow d er f or in je ct io n, 1 00 m g ( as s od iu m R et ai ne d w ith n o ch an g e su cc in at e) in v ia l 8. 3 p ow d er f or in je ct io n, 1 00 m g ( as s od iu m A d d ed t o th is s ec tio n of t he M od el L is t as a su cc in at e) in v ia l co m p le m en ta ry li st m ed ic in e 13 .3 oi nt m en t or c re am , 1% ( ac et at e) R et ai ne d w ith n o ch an g e p en d in g r ev ie w o f se ct io n 13 o f th e M od el L is t Ta b le 2 38 Co nt in ue d M ed ic in e M od el L is t D os ag e fo rm a nd s tr en g th R ec om m en d at io n se ct io n nu m b er 17 .4 su p p os ito ry , 25 m g ( ac et at e) R et ai ne d b ut m ov ed t o th e co m p le m en ta ry li st re te nt io n en em a R et ai ne d b ut m ov ed t o th e co m p le m en ta ry li st 18 .1 p ow d er f or in je ct io n, 1 00 m g ( as s od iu m D el et ed f or t hi s in d ic at io n; n ew f oo tn ot e ad d ed t o su cc in at e) in v ia l se ct io n 18 .1 o f th e M od el L is t: A d d is on ’s d is ea se is a r ar e co nd iti on ; ad re na l h or m on es f or t he tr ea tm en t of t hi s co nd iti on a re a lre ad y in cl ud ed in s ec tio n 3 of t he M od el L is t . p re d ni so lo ne 3 ta b le t, 5 m g R et ai ne d w ith t he a d d iti on o f a 25 m g t ab le t an d t he fo ot no te : Th er e is n o ev id en ce f or c om p le te si m ila rit y b et w ee n p re d ni so lo ne a nd d ex am et ha so ne a t hi g h d os es . 8. 3 ta b le t, 5 m g R et ai ne d w ith t he a d d iti on o f a 25 m g t ab le t an d t he fo ot no te : Th er e is n o ev id en ce f or c om p le te si m ila rit y b et w ee n p re d ni so lo ne a nd d ex am et ha so ne a t hi g h d os es . p ow d er f or in je ct io n, 2 0 m g , 25 m g In je ct ab le d os ag e fo rm d el et ed f or t hi s in d ic at io n (a s so d iu m p ho sp ha te o r so d iu m su cc in at e) in v ia l 18 .1 ta b le t, 1 m g , 5 m g D el et ed f or t hi s in d ic at io n; n ew f oo tn ot e ad d ed t o se ct io n 18 .1 o f th e M od el L is t: A d d is on ’s d is ea se is a r ar e co nd iti on ; ad re na l h or m on es f or t he tr ea tm en t of t hi s co nd iti on a re a lre ad y in cl ud ed in s ec tio n 3 of t he M od el L is t. 21 .2 so lu tio n (e ye d ro p s) , 0. 5% R et ai ne d w ith n o ch an g e p en d in g r ev ie w o f (s od iu m p ho sp ha te ) se ct io n 21 o f th e M od el L is t 39 the draft statement, current evidence indicates that thiazide diuretics, beta-blockers or ACE inhibitors should be used as first-line drug treatment for hypertension. The role of calcium-channel blockers is less certain; they should be used as first-line treatment only in selected populations, for example, in the elderly (where trials have indicated potential benefits in terms of stroke (37)) or in African Americans (38). The Committee noted that the role of the older medicines for the treatment of essential hypertension (i.e. reserpine, hydralazine and methyldopa) is now considered to be questionable. Systematic re- views of trials of each of these three medicines have been carried out and have been submitted for publication, in the Cochrane database (39, 40). On the basis of these reviews, it would appear that: — there are few large randomized trials that report clinical outcomes (e.g. mortality, stroke, acute myocardial infarction) for these medicines (36, 37); — there are no large comparative clinical trials that report compara- tive efficacy and safety; — all of these medicines are associated with significant side effects. The Committee’s attention was also drawn to the findings of a re- cently published study, the Anti-Hypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (the ALLHAT trial), which have also brought into question the role of alpha-blockers in the treatment of hypertension (41). In that study, patients treated with the alpha-blocker, doxazosin, had higher mortality rates than those in other treatment groups (i.e. patients treated with chlorthalidone, amlodipine and lisinopril) and the doxazosin arm of the study was suspended early. There was no significant difference between the chlorthalidone, amlodipine and lisinopril treatment groups in terms of the primary outcome of the study, namely, the development of coronary heart disease. The Committee also noted that hydralazine, reserpine and methyl- dopa are all off-patent and therefore usually relatively inexpensive. However, this alone is no justification to keep these medicines on the Model List as some of the ACE inhibitors and calcium-channel blockers are now also off-patent, and are probably safer and more effective. On the basis of the evidence before it, the Committee recommended that reserpine and hydralazine be deleted from the Model List for the treatment of essential hypertension on the grounds of the lack of evidence of long-term effects on mortality and morbidity and the 40 availability of better and safer alternatives. Subsequent to the meeting Committee Members agreed that hydralazine should remain on the list for the acute treatment of severe pregnancy-induced hyper- tension pending a further evidence review. The Committee also recommended that prazosin be deleted as a complementary list medi- cine, because of the lack of evidence as to its additional benefit and given that the adverse effects of doxazosin on mortality and morbidity may be a class effect. In addition, the Committee recommended that captopril (an ACE inhibitor) be replaced by enalapril as the listed example of the therapeutic group, on the basis of its simpler dosage schedule. With respect to the use of calcium-channel blockers, preliminary evidence was presented to the Committee suggesting that dihydropyridine calcium-channel blockers as a class should not be used as first-line drug treatment for hypertension, because of the potential increased risk of adverse outcomes. The Committee thus recommended that there should be a thorough and critical review of the evidence supporting the use of dihydropyridine calcium-channel blockers as first-line drug treatment for hypertension before its next meeting, at which time a decision about their retention or deletion from the Model List would be made. The Committee considered the question of the appropriate treatment of pregnancy-induced hypertension (PIH), something that is not specifically addressed in the draft statement. Two Cochrane reviews have been published on the topic, one on mild-to-moderate PIH, last updated in 2000 (42) and one on severe PIH, updated in 2002 (43). The former concluded that data were insufficient to determine whether or not drug treatment was worthwhile at all; the second review concluded that treatment should be with a medicine with which the physician was familiar. Subsequent studies have suggested that, in terms of effects on the child, methyldopa is the medicine of choice, as it appears to have least impact on long-term development (44). The Committee therefore recommended that methyldopa be retained on the Model List (as a core list medicine) but with the addition of the following note: Methyldopa is listed for use in the management of pregnancy-induced hypertension only. Its use in the treatment of essential hypertension is not recommended in view of the availability of further evidence of the efficacy and safety of other medicines. The Committee acknowledged that there is only limited evidence for its recommendation regarding the use of methyldopa in pregnancy, but that methyldopa seems to be the safest alternative for the fetus. 41 The Committee recommended that more research be conducted on the treatment of hypertension in pregnancy, especially with regard to long-term outcomes and effects on child development. The Committee reviewed a proposal from the Secretariat to include magnesium sulphate in the Model List as an antihypertensive, specifi- cally for treatment of pre-eclampsia. It was noted that pre-eclampsia is estimated to complicate 2–8% of pregnancies and is a major cause of morbidity and mortality for both the woman and her child. This disorder is usually associated with raised blood pressure. Anticonvul- sant medicines have been used to treat women with pre-eclampsia in the belief that they reduce the risk of seizure. Following a systematic review of existing treatment trials, magnesium sulphate was identified as the most promising agent for further investigation in large-scale trials. According to the recently published results of the MAGnesium sulphate for Prevention of Eclampsia (MAGPIE) trial, covering 10141 women in 33 countries, treatment with magnesium sulphate halves the risk of eclampsia and probably reduces the risk of maternal death (45, 46). The Committee noted that magnesium sulfate is already on the Model List (as a core list medicine in Section 5 Anticonvulsants/ antiepileptics) and recommended that the following footnote be added to this entry: For use in eclampsia and severe pre-eclampsia and not for other convulsant disorders. The Committee also urged that magnesium sulfate be made more generally available in view of the strong evidence demonstrating its benefit in the treatment of eclampsia and severe pre-eclapmsia. With regard to the two remaining medicines in this section of the Model List, nifedipine and sodium nitroprusside, the Committee made the following recommendations: • Nifedipine. Nifedipine should be included in the list of candidate items for fast-track deletion at the next meeting of the Expert Committee (see section 6 below). • Sodium nitroprusside. The square box symbol should be removed. The Committee’s recommendations regarding the listing of the antihypertensive medicines in section 12.3 of the Model List are summarized in Table 3. 42 Table 3 Changes made to the listing of medicines for the treatment of hypertension during the present revision of the Model List (April 2003) Medicine Administration route and Recommendation dosage forms Core list medicines atenolol tablet, 50mg, 100mg Retained with no change captopril scored tablet, 25mg Replaced by enalapril, tablet 25mg hydralazine tablet, 25mg, 50mg Footnote added: For the acute (hydrochloride) treatment of severe hypertension powder for injection, pregnancy-induced 20mg (hydrochloride) in ampoule hydrochlorothiazide scored tablet, 25mg Retained with no change methyldopa tablet, 250mg Footnote added: Methyldopa is listed for use in the management of pregnancy-induced hypertension only. Its use in the treatment of essential hypertension is not recommended in view of the availability of further evidence of the efficacy and safety of other medicines. nifedipine tablet, 10mg Footnote added: The public health sustained-release relevance and/or efficacy and/or formulations safety of this item has been questioned and its continued inclusion in the Model List will be reviewed at the next meeting of the Expert Committee. reserpine tablet, 100mg, 250mg Deleted injection, 1mg in 1-ml ampoule Complementary list medicines prazosin tablet, 500mg, 1mg Deleted sodium nitroprusside powder for infusion, Square box symbol removed 50mg in ampoule 6. Priorities for future reviews The Committee identified a number of sections of the Model List that it considered to be in need of systematic review. These are listed in Table 4, together with an indication of the level of priority of the review. 43 The Committee also recommended that a special review be carried out on the use of medicines in paediatrics. The following medicines were identified as possible candidates for deletion according to the fast-track procedure at the next meeting of the Committee in 2004: — ether (review actual consumption) (section 1.1 General anaesthetics and oxygen); — colchicine (section 2.3 Medicines used to treat gout); — clonazepam (section 5 Anticonvulsants/antiepileptics); — niclosamide (section 6.1.1 Intestinal anthelminthics); — pyrantel (section 6.1.1 Intestinal anthelminthics); — triclabendazole (section 6.1.3 Antischistosomals and other antitrematode medicines); — oxamniquine (section 6.1.3 Antischistosomals and other antitrematode medicines); Table 4 Sections of the Model List recommended for review, with level of priority Section Title Priority (notes) number 1 Anaesthetics (including muscle relaxants High and preoperative medication) 2.4 Disease-modifying agents used in Low rheumatoid disorders 3 Antiallergics and medicines used in Low anaphylaxis 6.2.1 Cefalosporins High 6.3 Antifungal medicines High 7.2 Antimigraine medicines (prophylaxis) Low 8 Antineoplastics, immuno-suppressives and High medicines used in palliative care 11.1 Plasma substitutes High 11.2 Plasma fractions for specific uses High 12.2 Antiarrhythmic medicines High 13 Dermatological medicines Medium 14 Diagnostic agents Medium 15 Disinfectants and antiseptics Low 17.6 Laxatives Low 20 Muscle relaxants (peripherally-acting) With anaesthetics and cholinesterase inhibitors) (see section 1) 21 Ophthalmological preparations High 25.1 Antiasthmatic medicines High 26 Solutions correcting water, electrolyte Medium and acid–base disturbances (intravenous solutions) 44 — imipenem + cilastatin (section 6.2.1 b-Lactam medicines); — nalidixic acid (section 6.2.2 Other antibacterials); — spectinomycin (section 6.2.2 Other antibacterials); — levofloxacin (section 6.2.4 Antituberculosis medicines); — thioacetazone + isoniazid (section 6.2.4 Antituberculosis medicines); — diethyltoluamide (section 6.6 Insect repellents); — ergotamine (section 7.1 Antimigraine medicines for treatment of acute attack); — polygeline (section 11.1 Plasma substitutes); — factor VIII and factor IX concentrates (section 11.2 Plasma frac- tions for specific uses); — isoprenaline (section 12.2 Antiarrhythmic medicines); — procainamide (section 12.2 Antiarrhythmic medicines); — quinidine (section 12.2 Antiarrhythmic medicines); — nifedepine (section 12.3 Antihypertensive medicines); — topical sun protection agent (section 13.7 Ultraviolet-blocking agent); — local anaesthetic, astringent and anti-inflammatory preparations (section 17.3 Antihaemorrhoidal medicines); — atropine (in section 17.5 Antispasmodic medicines); — codeine (in section 17.7.2 Antidiarrhoeal medicines (symptom- atic) medicines); — medroxyprogesterone acetate (in section 18.3.1 Hormonal contra- ceptives and section 18.7 Progestogens); — silver nitrate (section 21.1 Anti-infective agents — Ophthalmo- logical preparations); — ergometrine (section 22.1 Oxytocics); — salbutamol (in section 22.2 Antioxytocics); — aminophylline (section 25.1 Antiasthmatic medicines); — cromoglicic acid (section 25.1 Antiasthmatic medicines); — theophylline (section 25.1 Antiasthmatic medicines); — calcium gluconate (in section 27 Vitamins and minerals); — sodium fluoride (section 27 Vitamins and minerals). The Committee recommended that these items be identified in the present revision of the Model List with the following footnote: The public health relevance and/or efficacy and/or safety of this item or group has been questioned and its continued inclusion in the Model List will be reviewed at the next meeting of the Expert Committee. 45 7. Recommendations 7.1 Additions, deletions and other changes to the Model List 1. The Committee recommended that amodiaquine (tablet, 153mg, 200 mg (base)) be added to the Model List (as a core list medicine) with the following footnote: Amodiaquine should preferably be used as part of combination therapy. The Committee also recommended that the place of amodiaquine in curative treatment be further defined by WHO guidelines and that the following text be added at the beginning of the relevant section of the Model List (section 6.5.3a Antimalarial medicines for curative treatment): Medicines for the treatment of P. falciparum malaria cases should be used in combination. 2. The Committee recommended that azithromycin (capsule, 250mg, 500 mg and oral suspension, 200mg/5 ml) be added to the Model List (as a core list medicine) for the single dose treatment of genital C. trachomatis infection and of trachoma only with the following foot- note: Only listed for single-dose treatment of genital C. trachomatis and of trachoma. 3. The Committee recommended that the applications for the addi- tion of paediatric ibuprofen, porcine insulin suspension (insulin semilente), miconazole nitrate buccal tablets, misoprostol and valaciclovir to the Model List be rejected. 4. The Committee recommended that the following footnote be added to paracetamol in section 2.1 (Non-opioid analgesics and antipyretics and non-steroidal anti-inflammatory medicines): Not recommended for anti-inflammatory use due to lack of proven benefit to that effect. 5. The Committee recommended that levonorgestrel (tablet, 1.5mg) be added as a new dosage form of levonorgestrel and that ethinylestradiol + levonorgestrel (tablet, 50mg + 250mg (pack of four)) be deleted from the Model List. 6. The Committee recommended that the references to nonoxynol and spermicides in the entry for condoms and diaphragms be deleted. 7. The Committee recommended that the following text be inserted at the beginning of section 6.2.3 (Antileprosy medicines): Medicines used in the treatment of leprosy should never be used except in combination (i.e. as multidrug therapy (MDT)). Combination therapy is 46 essential to prevent the emergence of drug resistance. Colour-coded blister packs (MDT blister packs) containing standard two-medicine (paucibacillary leprosy) or three-medicine (multibacillary leprosy) combin- ations for adult and childhood leprosy should be used. MDT blister packs can be supplied free of charge through WHO. The Committee also recommended that the same information be included in the WHO Essential Medicines Library and the WHO model formulary. 8. The Committee recommended that the composition of oral rehy- dration salts be changed to 75 mEq/l sodium (sodium chloride 2.6g/l) and 75 mmol/l (13.5g/l) glucose and that the following footnote be added: In cases of cholera a higher concentration of sodium may be required. 9. The Committee recommended that the dosage form for streptoki- nase be changed to powder for injection, 1.5 million IU in vial and that the existing footnote, “For use in rare disorders or in exceptional circumstances.” be removed. 10. The Committee recommended that chloral hydrate, dextromethorphan, fludrocortisone, folic acid, immunoglobulin, human normal and ipecacuanha be deleted from the Model List on the basis of the fast-track deletion procedure. 11. The Committee recommended that cyclophosphamide in section 2.4 (due to unfavourable benefit–risk ratio), desmopressin (due to rarity of the indication), iron dextran (due to unfavourable benefit– risk ratio), pethidine (due to a higher risk of central nervous toxicity relative to morphine) and the injectable form of trimethoprim (due to lack of need for this administration route) be deleted. 7.2 Core versus complementary listing of medicines 1. The Committee decided to refine the criteria for classifying medi- cines as either core or complementary list medicines as follows: • The core list presents a list of minimum medicine needs for a basic health care system, listing the most efficacious, safe and cost- effective medicines for priority conditions. Priority conditions are selected on the basis of current and estimated future public health relevance, and potential for safe and cost-effective treatment. • The complementary list presents essential medicines for priority diseases, for which specialized diagnostic or monitoring facilities and/or specialist medical care and/or specialist training are needed. In case of doubt, medicines may also be listed as complementary 47 on the basis of consistently higher costs or less attractive cost- effectiveness in a variety of settings. The Committee recommended that the previously separate core and complementary lists be combined to form a single list, with the complementary list medicines printed in italics or otherwise identified. 2. The Committee recommended that the following medicines be moved from the core list to the complementary list: aminophylline, (in section 25.1 Antiasthmatic medicines), amphotericin B (section 6.3 Antifungal medicines), azathioprine (in section 2.4 Disease- modifying agents used in rheumatic disorders), clomifene, diethyl- carbamazine, dopamine, ethosuximide, hydrocortisone (in section 17.4 Gastrointestinal anti-inflammatory medicines), intraperitoneal dialysis solution, methotrexate (in section 2.4 Disease-modifying agents used in rheumatic disorders), penicillamine (in section 2.4 Disease-modifying agents used in rheumatic disorders), pentamidine (in section 6.5.2 Antileishmaniasis medicines section 6.5.4 Antipneumocystosis and antitoxoplasmosis medicines and section 6.5.5a Antitrypanosomal medicines-African trypanosomiasis), pyridostigmine, sulfadiazine and sulfasalazine (in section 2.4 Disease- modifying agents used in rheumatic disorders). 3. The Committee recommended that the following medicines be moved from the complementary list to the core list: amoxicillin + clavulanic acid, chloramphenicol (oily suspension for injection in section 6.2.2 Other antibacterials), epinephrine (adrenaline) (in section 12.2 Antiarrhythmic medicines), levonorgestrel (30mg tablet in section 18.3.1 Hormonal contraceptives), mannitol and norethisterone enantate. 7.3 Use of the square box symbol (including review of the corticosteroids 1. The Committee agreed to use the square box symbol on the basis of the following description: The square box symbol is primarily intended to indicate similar clinical performance within a pharmacological class. The listed medicine should be the example of the class for which there is the best evidence for effectiveness and safety. In some cases, this may be the first medicine that is licensed for marketing; in other instances, subsequently licensed compounds may be safer or more effective. Where there is no difference in terms of efficacy and safety data, the listed medicine should be the one that is generally available at the lowest price, based on international drug price information sources. Therapeutic equivalence is only indicated on the basis of reviews of efficacy and safety and when consistent with WHO clinical guidelines. National lists should not use a similar symbol and should be 48 specific in their final selection, which would depend on local availability and price. 2. The Committee recommended that the square box symbol be removed from the following items: amiloride, amoxicillin, amoxicillin + clavulinic acid, antitetanus immunoglobulin, azathioprine (in section 8.1 Immunosuppressive medicines), chloramphenicol, chloroquine (in section 6.5.3a Antimalarial medicines for curative treatment), ciclosporin, clomifene, charcoal activated, codeine (in section 2.2 Opioid analgesics and section 17.7.2 Antidiarrhoeal (symptomatic) medicines), cycloserine, dexamethasone (in section 3 Antiallergics and medicines used in anaphylaxis), diloxanide, doxorubicin, doxycy- cline (section 6. 5.3a Antimalarial medicines for curative treatment), epinephrine/adrenaline (in section 25.1 Antiasthmatic medicines), ethionamide, glibenclamide, ibuprofen, mannitol, DL-methionine, morphine (in section 1.3 Preoperative medication and sedation for short-term procedures and section 2.2 Opioid analgesics), neostig- mine, promethazine (in section 1.3 Preoperative medication and sedation for short-term procedures and section 17.2 Antiemetic medicines), quinine, sodium nitroprusside, retinol, sulfadiazine, sulfadoxine + pyrimethamine, sulfamethoxazole + trimethoprim (in section 6.2.2 Other antibacterials) and verapamil. 3. The Committee recommended that the square box symbol be retained but that the example within the pharmacological class listed be changed in the following cases: captopril by enalapril and cimetidine by ranitidine. 4. The Committee recommended that for those medicines that are listed with a square box symbol examples of possible alternatives should be included in the Essential Medicines Library and in the WHO model formulary. 5. The Committee recommended the following changes be made to the listing of the corticosteroids currently included in the Model List: • In section 3 (Antiallergics and medicines used in anaphylaxis), the tablet form of dexamethasone (500mg, 4mg) should be removed and a new dosage form added for prednisolone (tablet, 25mg) making prednisolone tablets (5mg and 25 mg) the only oral prepa- ration for this indication. The entry for prednisolone should retain its square box symbol but should be annotated with a new footnote: There is no evidence for complete clinical similarity between prednisolone and dexamethasone at high doses. The Committee also recommended that the two injectable dosage forms, dexamethasone (injection, 4mg dexamethasone phosphate (as 49 disodium salt) in 1-ml ampoule) and hydrocortisone (powder for injection, 100 mg (as sodium succinate) in vial) should be retained in this section, but neither with a square box symbol. • Section 8.3 (Hormones and antihormones) should include the same three corticosteroids as section 3 (i.e. dexamethasone, hydrocorti- sone and prednisolone) in the same dosage forms and strengths, and with the same footnote. • In section 18.1 (Adrenal hormones and synthetic substances) all three corticosteroids (i.e. dexamethasone, hydrocortisone and prednisolone) should be deleted. The section heading should be maintained and the following text inserted: Addison’s disease is a rare condition; adrenal hormones for the treatment of this condition are already included in section 3. 7.4 Review of the antihypertensive medicines 1. The Committee recommended that the following modifications be made to the medicines listed in section 12.3 of the Model List (Antihypertensive medicines): • Reserpine and prazosin should be deleted. • Captopril should be replaced by enalapril as the listed example of the therapeutic group. • Methyldopa should be retained as a core list medicine but with the addition of the following footnote: Methyldopa is listed for use in the management of pregnancy-induced hypertension only. Its use in the treatment of essential hypertension is not recommended in view of the availability of more evidence of efficacy and safety of other medicines. • The square box symbol should be removed from sodium nitroprusside. 2. In sum, the Committee recommended that section 12.3 (Antihy- pertensive medicines) comprise: atenolol (tablet, 50mg, 100 mg) with a square box; enalapril (tablet, 25mg); hydrochlorothiazide (scored tablet, 25 mg) with a square box; methyldopa (tablet, 250mg) and nifedipine (tablet, 10mg and as slow-release formulations) with a square box as core list medicines and sodium nitroprusside (powder for infusion, 50mg in ampoule) as a complementary list medicine. 3. The Committee recommended that more research be done on the treatment of hypertension in pregnancy, in particular on long-term outcomes and effects on child development, and that a thorough and 50 critical review be carried out of the justification of the use of dihydropyridine calcium-channel blockers as first-line treatment drug for hypertension. 7.5 Future priorities 1. The Committee recommended that the following items be pre- sented for fast-track deletion at its next meeting: ether, colchicine, clonazepam, niclosamide, pyrantel, triclabendazole, oxamniquine, imipenem + cilastatin, nalidixic acid, spectinomycin, levofloxacin, thioacetazone + isoniazid, diethyltoluamide, ergotamine, polygeline, factor VIII and factor IX concentrates, isoprenaline, procainam- ide, quinidine, nifedepine, topical sun protection agent, antihaemorrhoidal local anaesthetic, astringent and anti-inflamma- tory preparations, atropine (in section 17.5 Antispasmodic medi- cines), codeine (in section 17.7.2 Antidiarrhoeal (symptomatic) medicines), medroxyprogesterone acetate (in section 18.3.1 Hor- monal contraceptives and section 18.7 Progestogens), silver nitrate, ergometrine, salbutamol (in section 22.2 Antioxytocics), aminophyl- line, cromoglicic acid, theophylline, calcium gluconate (in section 27 Vitamins and minerals) and sodium fluoride. 2. The Committee recommended that these items be marked in the Model List with the following footnote: The public health relevance and/or efficacy and/or safety of this item has been questioned and its continued inclusion in the Model List will be reviewed at the next meeting of the Expert Committee. References 1. WHO model formulary 2002. Geneva, World Health Organization, 2002. 2. The selection and use of essential medicines. Report of the WHO Expert Committee, 2002 (including the 12th Model List of Essential Medicines). Geneva, World Health Organization, 2003 (WHO Technical Report Series, No. 914) (http://www.who.int/medicines/organization/par/edl/trs/trs914.shtml, accessed 3 October 2003). 3. The selection of essential drugs. Report of a WHO Expert Committee. Geneva, World Health Organization, 1977 (WHO Technical Report Series, No. 615). 4. Essential medicines as a global concept: 25 years commemorative event [CD-ROM]. 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Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The MAGPIE Trial: a randomised placebo-controlled trial. Lancet, 2002, 359:1877–1890. 46. Duley L, Gülmezoglu AM, Henderson-Smart DJ. Magnesium sulphate and other anticonvulsants for women with pre-eclampsia [abstract]. In: The Cochrane Library [online database and CD-ROM], Issue 1. Oxford, Update software, 2004:ab000025. (http://212.49.218.202/abstracts/ab000025.htm). 54 © World Health Organization WHO Technical Report Series, No. 920, 2004 Annex 1 The 13th WHO Model List of Essential Medicines Introduction The concept of essential medicines Essential medicines are those that satisfy the priority health care needs of the population. They are selected with due regard to public health relevance, evidence on efficacy and safety, and comparative cost-effectiveness. Essential medicines are intended to be available within the context of functioning health systems at all times in ad- equate amounts, in the appropriate dosage forms, with assured qual- ity and adequate information, and at a price the individual and the community can afford. The implementation of the concept of essen- tial medicines is intended to be flexible and adaptable to many differ- ent situations; exactly which medicines are regarded as essential remains a national responsibility. Experience has shown that careful selection of a limited range of essential medicines results in a higher quality of care, better management of medicines (including improved quality of prescribed medicines), and a more cost-effective use of available health resources (1, 2). The WHO Model List of Essential Medicines Most countries require that a pharmaceutical product be approved on the basis of efficacy, safety and quality before it can be prescribed. The majority of health care and insurance schemes will only cover the cost of medicines on a given list of approved medicines. Medicines on such lists are selected after careful study of the medicines used to treat particular conditions and a comparison of the value they provide in relation to their cost. The WHO Model List of Essential Medicines (the Model List) is an example of such a list. The first WHO Model List was drawn up in 1977 (3) in response to a request from the World Health Assembly (resolution WHA28.66) to the Director-General of WHO to provide Member States with advice on the selection and procurement, at reasonable costs, of essential medicines of established quality corresponding to their national health needs (4). The Model List has since been revised and updated 11 times (excluding the present revision) at intervals of approximately 2 years (5–15). Over the past two decades, the regular updating of the 55 Model List has not only been at the heart of WHO’s revised drug strategy (16) but has also formed a key component of the information required by Member States in relation to their medicine procurement and supply programmes. The Model List was originally intended as a guide for the develop- ment of national and institutional essential medicine lists. It was not designed as a global standard. Nevertheless, since its introduction 25 years ago, the Model List has led to a global acceptance of the concept of essential medicines as a powerful tool for promoting health equity. By the end of 1999, 156 Member States had official essential medi- cines lists, of which 127 had been updated in the previous 5 years. Most countries have national lists; some have provincial or state lists as well. The concept of essential medicines has also been adopted by many international organizations, including the United Nations Children’s Fund (UNICEF) and the Office of the United Nations High Commis- sioner for Refugees (UNHCR), as well as by nongovernmental orga- nizations and international non-profit supply agencies. Many of these organizations base their medicine supply system on the Model List. Lists of essential medicines also guide the procurement and supply of medicines in the public sector, schemes that reimburse medicine costs, medicine donations and local medicine production, and, fur- thermore, are widely used as informational and educational tools by health professionals. Health insurance schemes too are increasingly using national lists of essential medicines for reference purposes. The way in which national lists of essential medicines are developed and used has evolved over time. Initially, lists were drawn up prima- rily as a means to guide the procurement of medicines. More recently, however, greater emphasis has been placed on the development of treatment guidelines as the basis for medicine selection and supply, and on the evidence underlying the development of those treatment guidelines. Consequently, there has been an increasing demand for information on why a particular medicine is included in the Model List and also for references to the underlying evidence. Activities are now underway to strengthen the links between the Model List and the treatment guidelines developed by WHO. In its present form, the Model List aims to identify cost-effective medicines for priority conditions, together with the reasons for their inclusion, linked to evidence-based clinical guidelines and with spe- cial emphasis on public health aspects and considerations of value for money. Information that supports the selection of essential medi- cines, such as summaries of relevant WHO clinical guidelines, system- 56 atic reviews, key references and indicative cost information is being made available via the WHO web site as the WHO Essential Medi- cines Library1. The latter provides links to other relevant sources of information, including the WHO model formulary and information on nomenclature and quality assurance standards. The Essential Medicines Library is under construction and will be expanded over time. Its primary function is to facilitate the work of national and institutional committees in developing national and institutional lists of essential medicines. Medicines on the Model List are classified as either “core” list or “complementary” list medicines. The core list presents a list of mini- mum medicine needs for a basic health care system, listing the most efficacious, safe and cost-effective medicines for priority conditions. Priority conditions are selected on the basis of current and estimated future public health relevance, and potential for safe and cost- effective treatment. The complementary list presents essential medicines for priority diseases, for which specialized diagnostic or monitoring facilities and/or specialist medical care and/or specialist training are needed. In case of doubt, medicines may also be listed as complementary on the basis of consistently higher costs or less attrac- tive cost-effectiveness in a variety of settings. A number of medicines are labelled with a square box symbol. This symbol is primarily intended to indicate similar clinical performance within a pharmacological class. The listed medicine should be the example of the class for which there is the best evidence for effective- ness and safety. In some cases, this may be the first medicine that is licensed for marketing; in others, subsequently licensed compounds may be safer or more effective. Where there is no difference in terms of the efficacy and safety data, the listed medicine should be the one that is generally available at the lowest price, based on international drug price information sources. Therapeutic equivalence is only indi- cated on the basis of reviews of efficacy and safety and when consis- tent with WHO clinical guidelines. National lists should not use a similar symbol and should be specific in their final selection, which would depend on local availability and price. Examples of alternatives for the medicines with a square box symbol are not included in the Model List, but such information is provided in the WHO model formulary and in the Essential Medicines Library. 1 http://www.who.int/medicines. 57 Procedures for updating the Model List The procedures for updating the Model List are in line with the WHO recommended process for developing clinical practice guidelines (17). The key components are a systematic approach to collecting and reviewing evidence and a transparent development process with sev- eral rounds of external review. The procedures are intended to serve as a model for developing or updating national and institutional clini- cal guidelines and lists of essential medicines. Further information on the procedures for updating the Model List, including descriptions of the applications and details of the review process, is available from the WHO web site1. Selection criteria The choice of essential medicines depends on several factors, includ- ing public health relevance and the availability of data on the efficacy, safety and comparative cost-effectiveness of available treatments. Factors such as stability in various conditions, the need for special diagnostic or treatment facilities and pharmacokinetic properties are also considered if appropriate. In adapting the Model List to their own needs, countries often consider factors such as local demography and the pattern of prevalent diseases; treatment facilities; training and experience of available personnel; local availability of individual pharmaceutical products; financial resources; and environmental factors. The selection of essential medicines must be based on valid scientific evidence; only medicines for which sound and adequate data on effi- cacy and safety are available should be selected. In the absence of adequate scientific evidence on current treatment of a priority dis- ease, the WHO Expert Committee on the Selection and Use of Essen- tial Medicines may either defer its decision regarding selection until more evidence becomes available, or choose to make recommenda- tions based on expert opinion and experience. Most essential medicines should be formulated as single compounds. Fixed-dose combination products are selected only when the combi- nation 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. When making cost comparisons between medicines, the cost of the total treatment, not just the unit cost of the medicine, is considered. Cost and cost-effectiveness comparisons may be made among 1 http://www.who.int/medicines. 58 alternative treatments within the same therapeutic group, but are generally not made across therapeutic categories (e.g. between the treatment of tuberculosis and the treatment of malaria). The absolute cost of the treatment does not constitute a reason to exclude a medi- cine from the Model List that otherwise meets the stated selected criteria. The patent status of a medicine is not considered when select- ing medicines for the Model List. Quality assurance Priority should be given to ensuring that available medicines have been made according to good manufacturing practices (18) and are of assured quality. Factors that need to be considered include: — knowledge of, and confidence in, the origin of the product; — the pharmaceutical stability of the product, particularly in the environment that it will be used; — where relevant, bioavailability and bioequivalence information. It is recommended that all medicines be purchased from known manufacturers, their duly accredited agents, or recognized interna- tional agencies known to apply high standards in selecting their suppliers. Promoting rational use of essential medicines The selection of essential medicines is only one step towards the improvement of the quality of health care; selection needs to be followed by appropriate use. Each individual should receive the right medicine, in an adequate dose for an adequate duration, with appro- priate information and follow-up treatment, and at an affordable cost. Within different countries and settings, this is influenced by a number of factors, such as regulatory decisions, procurement, information, training, and the context in which medicines are prescribed or recommended. Training, education and the provision of medicines information To ensure the safe, effective and prudent use of essential medicines, access to relevant, reliable and independent information on medi- cines is vital. Health care professionals should receive education about the use of medicines not only during their training but also throughout their careers. The more highly trained individuals should be encouraged to assume responsibility for educating those with less training. Health care providers and pharmacists who are responsible for dispensing medicines should take every opportunity to inform consumers about the rational use of products, including those for self- medication, at the time they are dispensed. 59 Governments, universities and professional associations have a criti- cal role to play with regard to the improvement of undergraduate, postgraduate and continuing education in clinical pharmacology, therapeutics and medicines information issues. Problem-based phar- macotherapy teaching has been shown to be a particularly effective strategy in this area (19). Well presented and appropriate information about medicines not only ensures that they are used properly but also decreases the inap- propriate use of medicines. Health ministries have a responsibility to arrange for the provision of such information. Independent medicines information activities should also be properly funded and, if neces- sary, financed through health care budgets. Electronic, readily acces- sible sources of medicines information are becoming more widely available and can form the basis of reliable medicines information systems in many settings. Standard clinical guidelines Standard clinical guidelines are an effective tool for assisting health professionals to choose the most appropriate medicine for a given patient with a given condition. They should be developed at national and local levels and updated on a regular basis. In order to be effec- tive, however, standard clinical guidelines require the support of ap- propriate education and training programmes aimed at encouraging their use. Drugs and therapeutic committees Drugs and therapeutic committees can play an important role in the development and implementation of effective essential medicines programmes. Such committees should be encouraged to select prod- ucts for local use from a national essential medicines list, to measure and monitor the use of these products in their own environments and to undertake interventions to improve their rational use. There is good evidence to suggest that involving both drugs and therapeutic committees and prescribers in guideline development can contribute to improved prescribing behaviour (20). Measuring and monitoring medicine use The purpose of drug utilization studies is to examine the develop- ment, regulation, marketing, distribution, prescription, dispensing and use of medicines within a society, with special emphasis on the medical, social and economic consequences. Studies of this type con- sider all levels of the therapeutic chain, from the development of medicines to their use by consumers. Drug utilization studies can be 60 medicine-oriented (i.e. focused on the use of a particular medicine or group of medicines) or problem-oriented (i.e. focused on the treat- ment of a particular condition or disease) and can provide consump- tion indicators for a given country, area or institution. Consumption can be measured in terms of economic expenditure (either in absolute terms or as a percentage of the total health bud- get), the number of units, or as Defined Daily Doses (DDDs) (21). However, it is generally recommended that drug utilization studies be conducted using the Anatomical Therapeutic Chemical (ATC) classi- fication and the DDD as the measuring unit, especially when making international comparisons on the use of medicines. The efficacy of a medicine is best assessed on the basis of randomized clinical trials, which, if well conducted, provide reliable estimates of the treatment effect of a new medicine. However, clinical trials cannot be conducted in all possible populations or settings and therefore their results must be translated into routine clinical practice with care. Given that drug utilization studies generally provide evidence on the use and the effects of medicines in routine conditions, they can pro- vide additional evidence for the evaluation of the effectiveness of a medicine. Drug utilization studies and clinical trials are important tools for identifying those factors or elements of the therapeutic chain in need of improvement or change. The results of such studies should be taken into consideration when taking regulatory action, selecting medicines, or designing information, training and teaching programmes. Monitoring of medicine safety and pharmacovigilance Safety monitoring is an important part of the overall surveillance of medicine use. The aims of the various forms of pharmacovigilance are to identify new, previously unrecognized adverse effects of medicines, to quantify their risks, and to communicate these to drug regulatory authorities, health professionals, and, when relevant, the public. Vol- untary reporting of adverse effects of medicines, on which the Inter- national WHO Programme for Drug Monitoring is based, has been effective in identifying a number of previously undescribed effects. Voluntary reporting schemes, together with other methods for assem- bling case series, can identify certain local safety problems, and thus form the basis for specific regulatory or educational interventions. The magnitude of the risk of adverse effects is generally evaluated using observational epidemiological methods, such as case–control, cohort and case–population studies. Each country and institution 61 should set up simple schemes aimed at identifying problems related to the safety of medicines. Explanatory notes The core list presents a list of minimum medicine needs for a basic health care system, listing the most efficacious, safe and cost-effective medicines for priority conditions. Priority conditions are selected on the basis of current and estimated future public health relevance, and potential for safe and cost-effective treatment. The complementary list presents essential medicines for priority dis- eases, for which specialized diagnostic or monitoring facilities and/or specialist medical care and/or specialist training are needed. In case of doubt, medicines may also be listed as complementary on the basis of consistently higher costs or less attractive cost-effectiveness in a vari- ety of settings. In the present Model List (the 13th), complementary list medicines are distinguished by italicized typeface. When the strength of a medicine is specified in terms of a selected salt or ester, this is mentioned in brackets; when it refers to the active moiety, the name of the salt or ester in brackets is preceded by the word “as”. The square box symbol (�) is primarily intended to indicate similar clinical performance within a pharmacological class. The listed medi- cine should be the example of the class for which there is the best evidence for effectiveness and safety. In some cases, this may be the first medicine that is licensed for marketing; in others, subsequently licensed compounds may be safer or more effective. Where there is no difference in terms of the efficacy and safety data, the listed medicine should be the one that is generally available at the lowest price, based on international drug price information sources. Therapeutic equiva- lence is only indicated on the basis of reviews of efficacy and safety and when consistent with WHO clinical guidelines. National lists should not use a similar symbol and should be specific in their final selection, which would depend on local availability and price. Medicines are grouped according to therapeutic categories. The num- bers preceding the sections and subsections have, in general, been allocated in accordance with English alphabetical order; they have no formal significance. Within sections, medicines are listed in alphabeti- cal order. Certain pharmacological effects have many therapeutic uses. Medi- cines with multiple uses could be listed under several therapeutic categories in the Model List. However, the inclusion of such 62 medicines in more than one therapeutic category has been limited to those circumstances that the Expert Committee wishes to emphasize. Medicines on the Model List are therefore not listed in all of the therapeutic categories in which they are of value. Detailed informa- tion on the therapeutic use of essential medicines is available in the WHO model formulary (22). 63 Medicine Route of administration, dosage forms and strengths 1. Anaesthetics 1.1 General anaesthetics and oxygen ether, anaesthetica inhalation halothane inhalation ketamine injection, 50mg (as hydrochloride)/ml in 10-ml vial nitrous oxide inhalation oxygen inhalation (medicinal gas) � thiopental powder for injection, 0.5g, 1.0g (sodium salt) in ampoule 1.2 Local anaesthetics � bupivacaine injection, 0.25%, 0.5% (hydrochloride) in vial injection for spinal anaesthesia, 0.5% (hydrochloride) in 4-ml ampoule to be mixed with 7.5% glucose solution � lidocaine injection, 1%, 2% (hydrochloride) in vial injection for spinal anaesthesia, 5% (hydrochloride) in 2-ml ampoule to be mixed with 7.5% glucose solution topical forms, 2–4% (hydrochloride) � lidocaine + epinephrine injection, 1%, 2% (hydrochloride) + (adrenaline) epinephrine 1 :200000 in vial dental cartridge, 2% (hydrochloride) + epinephrine 1 :80000 Complementary list medicine ephedrineb injection, 30mg (hydrochloride)/ml in 1-ml ampoule 1.3 Preoperative medication and sedation for short-term procedures atropine injection, 1mg (sulfate) in 1-ml ampoule � diazepam injection, 5mg/ml in 2-ml ampoule tablet, 5mg a The public health relevance and/or efficacy and/or safety of this item has been questioned and its continued inclusion in the Model List will be reviewed at the next meeting of the Expert Committee. b For use in spinal anaesthesia during delivery, to prevent hypotension. � Recommended example within a pharmaceutical class. See Explanatary notes on page 61. 64 Medicine Route of administration, dosage forms and strengths 1. Anaesthetics (continued) morphine injection, 10mg (hydrochloride or sulfate) in 1-ml ampoule promethazine elixir or syrup, 5mg (hydrochloride)/5ml 2. Analgesics, antipyretics, non-steroidal anti-inflammatory medicines, medicines used to treat gout and disease-modifying agents used in rheumatoid disorders 2.1 Non-opioid analgesics and antipyretics, and non-steroidal anti-inflammatory medicines acetylsalicylic acid tablet, 100–500mg suppository, 50–150mg ibuprofen tablet, 200mg, 400mg paracetamola tablet, 100–500mg suppository, 100mg syrup, 125mg/5ml 2.2 Opioid analgesics codeine tablet, 30mg (phosphate) morphine injection, 10mg (hydrochloride or sulfate) in 1-ml ampoule oral solution, 10mg (hydrochloride or sulfate)/5ml tablet, 10mg (sulfate) 2.3 Medicines used to treat gout allopurinol tablet, 100mg colchicineb tablet, 500mg 2.4 Disease-modifying agents used in rheumatoid disorders chloroquine tablet, 100mg, 150mg (as phosphate or sulfate) a Not recommended for anti-inflammatory use due to lack of proven benefit to that effect. b The public health relevance and/or efficacy and/or safety of this item has been questioned and its continued inclusion in the Model List will be reviewed at the next meeting of the Expert Committee. � Recommended example within a pharmaceutical class. See Explanatory notes on page 61. 65 Medicine Route of administration, dosage forms and strengths 2. Analgesics, antipyretics, non-steroidal anti-inflammatory medicines, medicines used to treat gout and disease-modifying agents used in rheumatoid disorders (continued) Complementary list medicines azathioprine tablet, 50mg methotrexate tablet, 2.5mg (as sodium salt) penicillamine capsule or tablet, 250mg sulfasalazine tablet, 500mg 3. Antiallergics and medicines used in anaphylaxis � chlorphenamine tablet, 4mg (hydrogen maleate) injection, 10mg (hydrogen maleate) in 1-ml ampoule dexamethasone injection, 4mg dexamethasone phosphate (as disodium salt) in 1-ml ampoule epinephrine (adrenaline) injection, 1mg (as hydrochloride or hydrogen tartrate) in 1-ml ampoule hydrocortisone powder for injection, 100mg (as sodium succinate) in vial � prednisolonea tablet, 5mg, 25mg 4. Antidotes and other substances used in poisonings 4.1 Non-specific charcoal, activated powder 4.2 Specific acetylcysteine injection, 200mg/ml in 10-ml ampoule atropine injection, 1mg (sulfate) in 1-ml ampoule calcium gluconate injection, 100mg/ml in 10-ml ampoule deferoxamine powder for injection, 500mg (mesilate) in vial dimercaprol injection in oil, 50mg/ml in 2-ml ampoule DL-methionine tablet, 250mg a There is no evidence for complete clinical similarity between prednisolone and dexamethasone at high doses. � Recommended example within a pharmaceutical class. See Explanatory notes on page 61. 66 Medicine Route of administration, dosage forms and strengths 4. Antidotes and other substances used in poisonings (continued) methylthioninium chloride injection, 10mg/ml in 10-ml ampoule (methylene blue) naloxone injection, 400mg (hydrochloride) in 1-ml ampoule penicillamine capsule or tablet, 250mg potassium ferric hexacyano- powder for oral administration ferrate(II)·2H2O (Prussian blue) sodium calcium edetate injection, 200mg/ml in 5-ml ampoule sodium nitrite injection, 30mg/ml in 10-ml ampoule sodium thiosulfate injection, 250mg/ml in 50-ml ampoule 5. Anticonvulsants/antiepileptics carbamazepine scored tablet, 100mg, 200mg � diazepam injection, 5mg/ml in 2-ml ampoule (intravenous or rectal) magnesium sulfatea injection, 500mg/ml in 2-ml ampoule, 500mg/ml in 10-ml ampoule phenobarbital tablet, 15–100mg elixir, 15mg/5ml phenytoin capsule or tablet, 25mg, 50mg, 100mg (sodium salt) injection, 50mg (sodium salt)/ml in 5-ml vial valproic acid enteric coated tablet, 200mg, 500mg (sodium salt) Complementary list medicines � clonazepamb scored tablet, 500mg ethosuximide capsule, 250mg syrup, 250mg/5ml a For use in eclampsia and severe pre-eclampsia and not for other convulsant disorders. b The public health relevance and/or efficacy and/or safety of this item has been questioned and its continued inclusion in the Model List will be reviewed at the next meeting of the Expert Committee. � Recommended example within a pharmaceutical class. See Explanatory notes on page 61. 67 Medicine Route of administration, dosage forms and strengths 6. Anti-infective medicines 6.1 Anthelminthics 6.1.1 Intestinal anthelminthics albendazole chewable tablet, 400mg levamisole tablet, 50mg, 150mg (as hydrochloride) � mebendazole chewable tablet, 100mg, 500mg niclosamidea chewable tablet, 500mg praziquantel tablet, 150mg, 600mg pyrantela chewable tablet, 250mg (as embonate) oral suspension, 50mg (as embonate)/ml 6.1.2 Antifilarials ivermectin scored tablet, 3mg, 6mg Complementary list medicines diethylcarbamazine tablet, 50mg, 100mg (dihydrogen citrate) suramin sodium powder for injection, 1g in vial 6.1.3 Antischistosomals and other antitrematode medicines praziquantel tablet, 600mg triclabendazolea tablet, 250mg Complementary list medicine oxamniquinea capsule, 250mg syrup, 250mg/5ml 6.2 Antibacterials 6.2.1 b-Lactam medicines amoxicillin capsule or tablet, 250mg, 500mg (anhydrous) powder for oral suspension, 125mg (anhydrous)/5ml a The public health relevance and/or efficacy and/or safety of this item has been questioned and its continued inclusion in the Model List will be reviewed at the next meeting of the Expert Committee. � Recommended example within a pharmaceutical class. See Explanatory notes on page 61. 68 Medicine Route of administration, dosage forms and strengths 6. Anti-infective medicines (continued) amoxicillin + clavulanic acida tablet, 500mg + 125mg ampicillin powder for injection, 500mg, 1g (as sodium salt) in vial benzathine benzylpenicillin powder for injection, 1.44g benzylpenicillin (= 2.4 million IU) in 5-ml vial benzylpenicillin powder for injection, 600mg (= 1 million IU), 3g (= 5 million IU) (sodium or potassium salt) in vial � cloxacillin capsule, 500mg, 1g (as sodium salt) powder for oral solution, 125mg (as sodium salt)/5ml powder for injection, 500mg (as sodium salt) in vial phenoxymethylpenicillin tablet, 250mg (as potassium salt) powder for oral suspension, 250mg (as potassium salt)/5ml procaine benzylpenicillin powder for injection, 1g (= 1 million IU), 3g (= 3 million IU) in vial Complementary list medicines ceftazidimea powder for injection, 250mg (as pentahydrate) in vial � ceftriaxonea powder for injection, 250mg (as sodium salt) in vial imipenem + cilastatina,b powder for injection, 250mg (as monohydrate) + 250mg (as sodium salt), 500mg (as monohydrate) + 500mg (as sodium salt) in vial a Reserve antimicrobial for use only when there is significant resistance to other medicines on the Model List. b The public health relevance and/or efficacy and/or safety of this item has been questioned and its continued inclusion in the Model List will be reviewed at the next meeting of the Expert Committee. � Recommended example within a pharmaceutical class. See Explanatory notes on page 61. 69 Medicine Route of administration, dosage forms and strengths 6. Anti-infective medicines (continued) 6.2.2 Other antibacterials azithromycina capsule, 250mg, 500mg oral suspension, 200mg/5ml chloramphenicol capsule, 250mg oral suspension, 150mg (as palmitate)/ 5ml powder for injection, 1g (sodium succinate) in vial oily suspension for injection, 0.5g (as sodium succinate)/ml in 2-ml ampoule � ciprofloxacinb tablet, 250mg (as hydrochloride) � doxycyclineb capsule or tablet, 100mg (hydrochloride) � erythromycin capsule or tablet, 250mg (as stearate or ethyl succinate) powder for oral suspension, 125mg (as stearate or ethyl succinate) powder for injection, 500mg (as lactobionate) in vial � gentamicinb injection, 10mg, 40mg (as sulfate)/ml in 2-ml vial � metronidazole tablet, 200–500mg injection, 500mg in 100-ml vial suppository, 500mg, 1g oral suspension, 200mg (as benzoate)/ 5ml nalidixic acidc tablet 250mg, 500mg nitrofurantoin tablet, 100mg a Only listed for single-dose treatment of genital Chlamydia trachomatis and of trachoma. b Final selection depends on indication for use. c The public health relevance and/or efficacy and/or safety of this item has been questioned and its continued inclusion in the Model List will be reviewed at the next meeting of the Expert Committee. � Recommended example within a pharmaceutical class. See Explanatory notes on page 61. 70 Medicine Route of administration, dosage forms and strengths 6. Anti-infective medicines (continued) spectinomycina powder for injection, 2g (as hydrochloride) in vial sulfamethoxazole + trimethoprim tablet, 100mg + 20mg, 400mg + 80mg oral suspension, 200mg + 40mg/5ml injection, 80mg + 16mg/ml in 5-ml ampoule, 80mg + 16mg/ml in 10-ml ampoule trimethoprim tablet, 100mg, 200mg Complementary list medicines clindamycin capsule, 150mg injection, 150mg (as phosphate)/ml sulfadiazine tablet, 500mg injection, 250mg (sodium salt) in 4-ml ampoule vancomycinb powder for injection, 250mg (as hydrochloride) in vial 6.2.3 Antileprosy medicines Medicines used in the treatment of leprosy should never be used except in combination (i.e. as multidrug therapy (MDT)). Combination therapy is essential to prevent the emergence of drug resistance. Colour-coded blister packs (MDT blister packs) containing standard two-medicine (paucibacillary leprosy) or three-medicine (multibacillary leprosy) combinations for adult and childhood leprosy should be used. MDT blister packs can be supplied free of charge through WHO. clofazimine capsule, 50mg, 100mg dapsone tablet, 25mg, 50mg, 100mg rifampicin capsule or tablet, 150mg, 300mg 6.2.4 Antituberculosis medicines ethambutol tablet, 100–400mg (hydrochloride) a The public health relevance and/or efficacy and/or safety of this item has been questioned and its continued inclusion in the Model List will be reviewed at the next meeting of the Expert Committee. b Reserve antimicrobial for use only when there is significant resistance to other medicines on the Model List. � Recommended example within a pharmaceutical class. See Explanatory notes on page 61. 71 Medicine Route of administration, dosage forms and strengths 6. Anti-infective medicines (continued) isoniazid tablet, 100–300mg isoniazid + ethambutol tablet, 150mg + 400mg pyrazinamide tablet, 400mg rifampicin capsule or tablet, 150mg, 300mg rifampicin + isoniazid tablet, 60mg + 30mg, 150mg + 75mg, 300mg + 150mg, 60mg + 60mga, 150mg + 150mga rifampicin + isoniazid + tablet, 60mg + 30mg + 150mg, 150mg + pyrazinamide 75mg + 400mg, 150mg + 150mg + 500mga rifampicin + isoniazid + tablet, 150mg + 75mg + 400mg + pyrazinamide + ethambutol 275mg streptomycin powder for injection, 1g (as sulfate) in vial Complementary list medicines amikacinb powder for injection, 1g in vial p-aminosalicylic acidb tablet, 500mg granules, 4g in sachet capreomycinb powder for injection, 1g in vial ciprofloxacinb tablet, 250mg, 500mg cycloserineb capsule or tablet, 250mg ethionamideb tablet, 125mg, 250mg kanamycinb powder for injection, 1g in vial levofloxacinb,c tablet, 250mg, 500mg ofloxacinb tablet, 200mg, 400mg a For intermittent use three times weekly. b Reserve second-line medicine for the treatment of multidrug-resistant tuberculosis which should be used in specialized centres adhering to WHO standards for tuberculosis control. c The public health relevance and/or efficacy and/or safety of this item has been questioned and its continued inclusion in the Model List will be reviewed at the next meeting of the Expert Committee. � Recommended example within a pharmaceutical class. See Explanatory notes on page 61. 72 Medicine Route of administration, dosage forms and strengths 6. Anti-infective medicines (continued) thioacetazone + tablet, 50mg + 100mg, 150mg + 300mg isoniazida 6.3 Antifungal medicines � fluconazole capsule, 50mg injection, 2mg/ml in vial oral suspension, 50mg/5ml griseofulvin capsule or tablet, 125mg, 250mg nystatin tablet, 100000 IU, 500000 IU lozenge, 100000 IU pessary, 100000 IU Complementary list medicines amphotericin B powder for injection, 50mg in vial flucytosine capsule, 250mg infusion, 2.5g in 250ml potassium iodide saturated solution 6.4 Antiviral medicines 6.4.1 Antiherpes medicines � aciclovir tablet, 200mg powder for injection, 250mg (as sodium salt) in vial 6.4.2 Antiretroviral medicines The antiretroviral medicines do not cure the HIV infection, they only temporarily suppress viral replication and improve symptoms. They have various adverse effects and patients receiving these medicines require careful monitoring by adequately trained health professionals. For these reasons, continued rigorous promotion of measures to prevent new infections is essential and the need for this has not been diminished in any way by the addition of antiretroviral medicines to the Model List. Adequate resources and trained health professionals are a prerequisite for the introduction of this class of medicines. Effective therapy requires commencement of three or four medicines simultaneously, and alternative regimens are necessary to meet specific a The public health relevance and/or efficacy and/or safety of this item has been questioned and its continued inclusion in the Model List will be reviewed at the next meeting of the Expert Committee. � Recommended example within a pharmaceutical class. See Explanatory notes on page 61. 73 Medicine Route of administration, dosage forms and strengths 6. Anti-infective medicines (continued) requirements at start-up, to substitute for first-line regimens in the case of toxicity, or to replace failing regimens. The Committee strongly recommends the use of three- or four-medicine combinations as specifically recommended in the WHO treatment guidelines (23). The use of fixed-dose preparations for these combinations is also recommended, with assured pharmaceutical quality and interchangeability with the single products as approved by the relevant drug regulatory authority. (a) Nucleoside reverse transcriptase inhibitors abacavir (ABC) tablet, 300mg (as sulfate) oral solution, 100mg (as sulfate)/5ml didanosine (ddI) buffered chewable dispersible tablet, 25mg, 50mg, 100mg, 150mg, 200mg buffered powder for oral solution, 100mg, 167mg, 250mg packets unbuffered enteric coated capsule, 125mg, 200mg, 250mg, 400mg lamivudine (3TC) tablet, 150mg oral solution, 50mg/5ml stavudine (d4T) capsule, 15mg, 20mg, 30mg, 40mg powder for oral solution, 5mg/5ml zidovudine (ZDV or AZT) tablet, 300mg capsule, 100mg, 250mg oral solution or syrup, 50mg/5ml solution for IV infusion injection, 10mg/ml in 20-ml vial (b) Non-nucleoside reverse transcriptase inhibitors efavirenz (EFV or EFZ) capsule, 50mg, 100mg, 200mg oral solution, 150mg/5ml nevirapine (NVP) tablet, 200mg oral suspension, 50mg/5ml (c) Protease inhibitors Selection of two or three protease inhibitors from the Model List will need to be determined by each country after consideration of local clinical guidelines and experience, as well as the comparative costs of available products. Ritonavir is recommended for use in combination with indinavir, lopinavir and saquinavir as a booster, and not as a medicine in its own right. 74 Medicine Route of administration, dosage forms and strengths 6. Anti-infective medicines (continued) indinavir (IDV) capsule, 200mg, 333mg, 400mg (as sulfate) lopinavir + ritonavir (LPV/r) capsule, 133.3mg + 33.3mg oral solution, 400mg + 100mg/5ml nelfinavir (NFV) tablet, 250mg (as mesilate) oral powder, 50mg/g ritonavir (r) capsule, 100mg oral solution, 400mg/5ml saquinavir (SQV) capsule, 200mg 6.5 Antiprotozoal medicines 6.5.1 Antiamoebic and antigiardiasis medicines diloxanide tablet, 500mg (furoate) � metronidazole tablet, 200–500mg injection, 500mg in 100-ml vial oral suspension, 200mg (as benzoate)/ 5ml 6.5.2 Antileishmaniasis medicines � meglumine antimoniate injection, 30%, equivalent to approximately 8.1% antimony, in 5-ml ampoule Complementary list medicines amphotericin B powder for injection, 50mg in vial pentamidine powder for injection, 200mg, 300mg (isetionate) in vial 6.5.3 Antimalarial medicines (a) For curative treatment Medicines for the treatment of P. falciparum malaria cases should be used in combination. amodiaquinea tablet, 153mg, 200mg (base) a Amodiaquine should preferably be used as part of combination therapy. � Recommended example within a pharmaceutical class. See Explanatory notes on page 61. 75 Medicine Route of administration, dosage forms and strengths 6. Anti-infective medicines (continued) artemether + lumefantrinea tablet, 20mg + 120mg chloroquine tablet, 100mg, 150mg (as phosphate or sulfate) syrup, 50mg (as phosphate or sulfate)/ 5ml injection, 40mg (as hydrochloride, phosphate or sulfate)/ml in 5-ml ampoule primaquine tablet, 7.5mg, 15mg (as diphosphate) quinine tablet, 300mg (as bisulfate or sulfate) injection, 300mg (as dihydrochloride)/ml in 2-ml ampoule Complementary list medicines artemetherb injection, 80mg/ml in 1-ml ampoule artesunateb tablet, 50mg doxycyclinec capsule or tablet, 100mg (hydrochloride) mefloquine tablet, 250mg (as hydrochloride) sulfadoxine + pyrimethamine tablet, 500mg + 25mg (b) For prophylaxis chloroquine tablet, 150mg (as phosphate or sulfate) syrup, 50mg (as phosphate or sulfate)/ 5ml doxycycline capsule or tablet, 100mg (hydrochloride) mefloquine tablet, 250mg (as hydrochloride) proguanild tablet, 100mg (hydrochloride) a Recommended for use in areas with significant drug resistance and not in pregnancy or in children below 10kg. b Reserve antimicrobial for use only when there is significant resistance to other medicines on the Model List. c For use only in combination with quinine. d For use only in combination with chloroquine. � Recommended example within a pharmaceutical class. See Explanatory notes on page 61. 76 Medicine Route of administration, dosage forms and strengths 6. Anti-infective medicines (continued) 6.5.4 Antipneumocystosis and antitoxoplasmosis medicines pyrimethamine tablet, 25mg sulfamethoxazole + trimethoprim injection, 80mg + 16mg/ml in 5-ml ampoule, 80mg + 16mg/ml in 10-ml ampoule Complementary list medicine pentamidine tablet, 200mg, 300mg 6.5.5 Antitrypanosomal medicines (a) African trypanosomiasis melarsoprol injection, 3.6% solution suramin sodium powder for injection, 1g in vial Complementary list medicines eflornithine injection, 200mg (hydrochloride)/ml in 100-ml bottle pentamidine powder for injection, 200mg, 300mg (isetionate) in vial (b) American trypanosomiasis benznidazole tablet, 100mg nifurtimox tablet, 30mg, 120mg, 250mg 6.6 Insect repellents diethyltoluamidea topical solution, 50%, 75% 7. Antimigraine medicines 7.1 For treatment of acute attack acetylsalicylic acid tablet, 300–500mg ergotaminea tablet, 1mg (tartrate) paracetamol tablet, 300–500mg a The public health relevance and/or efficacy and or safety of this item has been questioned and its continued inclusion in the Model List will be reviewed at the next meeting of the Expert Committee. � Recommended example within a pharmaceutical class. See Explanatory notes on page 61. 77 Medicine Route of administration, dosage forms and strengths 7. Antimigraine medicines (continued) 7.2 For prophylaxis � propranolol tablet, 20mg, 40mg (hydrochloride) 8. Antineoplastics, immunosuppressives and medicines used in palliative care 8.1 Immunosuppressive medicines Complementary list medicines azathioprine tablet, 50mg powder for injection, 100mg (as sodium salt) in vial ciclosporina capsule, 25mg concentrate for injection, 50mg/ml in 1-ml ampoule 8.2 Cytotoxic medicines Complementary list medicines asparaginase powder for injection, 10000 IU in vial bleomycin powder for injection, 15mg (as sulfate) in vial calcium folinate tablet, 15mg injection, 3mg/ml in 10-ml ampoule chlorambucil tablet, 2mg chlormethine powder for injection, 10mg (hydrochloride) in vial cisplatin powder for injection, 10mg, 50mg in vial cyclophosphamide tablet, 25mg powder for injection, 500mg in vial cytarabine powder for injection, 100mg in vial dacarbazine powder for injection, 100mg in vial dactinomycin powder for injection, 500mg in vial daunorubicin powder for injection, 50mg (as hydrochloride) a For organ transplantation. � Recommended example within a pharmaceutical class. See Explanatory notes on page 61. 78 Medicine Route of administration, dosage forms and strengths 8. Antineoplastics, immunosuppressives and medicines used in palliative care (continued) doxorubicin powder for injection, 10mg, 50mg (hydrochloride) in vial etoposide capsule, 100mg injection, 20mg/ml in 5-ml ampoule fluorouracil injection, 50mg/ml in 5-ml ampoule levamisole tablet, 50mg (as hydrochloride) mercaptopurine tablet, 50mg methotrexate tablet, 2.5mg (as sodium salt) powder for injection, 50mg (as sodium salt) in vial procarbazine capsule, 50mg (as hydrochloride) vinblastine powder for injection, 10mg (sulfate) in vial vincristine powder for injection, 1mg, 5mg (sulfate) in vial 8.3 Hormones and antihormones Complementary list medicines dexamethasone injection, 4mg dexamethasone phosphate (as disodium salt) in 1-ml ampoule hydrocortisone powder for injection, 100mg (as sodium succinate) in vial � prednisolonea tablet, 5mg, 25mg tamoxifen tablet, 10mg, 20mg (as citrate) 8.4 Medicines used in palliative care The Committee recommended that all the medicines mentioned in the WHO publication, Cancer pain relief: with a guide to opioid availability, 2nd ed., be considered essential (24). The medicines are included in the relevant sections of the Model List, according to their therapeutic use, e.g. as analgesics. a There is no evidence for complete clinical similarity between prednisolone and dexamethasone at high doses. � Recommended example within a pharmaceutical class. See Explanatory notes on page 61. 79 Medicine Route of administration, dosage forms and strengths 9. Antiparkinsonism medicines � biperiden tablet, 2mg (hydrochloride) injection, 5mg (lactate) in 1-ml ampoule levodopa + �carbidopa tablet, 100mg + 10mg, 250mg + 25mg 10. Medicines affecting the blood 10.1 Antianaemia medicines ferrous salt tablet, equivalent to 60mg iron oral solution, equivalent to 25mg iron (as sulfate)/ml ferrous salt + folic acida tablet, equivalent to 60mg iron + 400mg folic acid folic acid tablet, 1mg, 5mg hydroxocobalamin injection, 1mg in 1-ml ampoule 10.2 Medicines affecting coagulation heparin sodium injection, 1000IU/ml, 5000IU/ml, 20000IU/ml in 1-ml ampoule phytomenadione injection, 10mg/ml in 5-ml ampoule tablet, 10mg protamine sulfate injection, 10mg/ml in 5-ml ampoule � warfarin tablet, 1mg, 2mg, 5mg (sodium salt) 11. Blood products and plasma substitutes 11.1 Plasma substitutes � dextran 70 injectable solution, 6% � polygelineb injectable solution, 3.5% 11.2 Plasma fractions for specific use All plasma fractions should comply with the Requirements for the Collection, Processing and Quality Control of Blood, Blood Components, and Plasma Derivatives (Revised 1992) as published in the forty-third report of the WHO Expert Committee on Biological Standardization (25). a Nutritional supplement for use during pregnancy. b The public health relevance and/or efficacy and/or safety of this item has been questioned and its continued inclusion in the Model List will be reviewed at the next meeting of the Expert Committee. � Recommended example within a pharmaceutical class. See Explanatory notes on page 61. 80 Medicine Route of administration, dosage forms and strengths 11. Blood products and plasma substitutes (continued) Complementary list medicines � factor VIII concentratea dried � factor IX complex (coagulation dried factors II, VII, IX, X) concentratea 12. Cardiovascular medicines 12.1 Antianginal medicines � atenolol tablet, 50mg, 100mg glyceryl trinitrate tablet (sublingual), 500mg � isosorbide dinitrate tablet (sublingual), 5mg verapamil tablet, 40mg, 80mg (hydrochloride) 12.2 Antiarrhythmic medicines � atenolol tablet, 50mg, 100mg digoxin tablet, 62.5mg, 250mg oral solution, 50mg/ml injection, 250mg/ml in 2-ml ampoule epinephrine (adrenaline) injection, 1mg (as hydrochloride)/ml in ampoule lidocaine injection, 20mg (hydrochloride)/ml in 5-ml ampoule verapamil tablet, 40mg, 80mg (hydrochloride) injection, 2.5mg (hydrochloride)/ml in 2-ml ampoule Complementary list medicines isoprenalinea injection, 20mg (hydrochloride)/ml in ampoule � procainamidea injection, 100mg (hydrochloride)/ml in 10-ml ampoule � quinidinea tablet, 200mg (sulfate) a The public health relevance and/or efficacy and/or safety of this item has been questioned and its continued inclusion in the Model List will be reviewed at the next meeting of the Expert Committee. � Recommended example within a pharmaceutical class. See Explanatory notes on page 61. 81 Medicine Route of administration, dosage forms and strengths 12. Cardiovascular medicines (continued) 12.3 Antihypertensive medicines � atenolol tablet, 50mg, 100mg � enalapril tablet, 2.5mg hydralazinea tablet 25mg, 50mg (hydrochloride) powder for injection, 20mg (hydrochloride) in ampoule � hydrochlorothiazide scored tablet, 25mg methyldopab tablet, 250mg � nifedipinec sustained-release formulations tablet, 10mg Complementary list medicine sodium nitroprusside powder for infusion, 50mg in ampoule 12.4 Medicines used in heart failure digoxin tablet, 62.5mg, 250mg oral solution, 50mg/ml injection, 250mg/ml in 2-ml ampoule � enalapril tablet, 2.5mg � hydrochlorothiazide scored tablet, 25mg Complementary list medicine dopamine injection, 40mg (hydrochloride)/ml in 5-ml vial 12.5 Antithrombotic medicines acetylsalicylic acid tablet, 100mg Complementary list medicine streptokinase powder for injection, 1.5 million IU in vial a Hydralazine is listed for use in the acute management of severe pregnancy-induced hypertension only. Its use in the treatment of essential hypertension is not recommended in view of availability of more evidence of efficacy and safety of other medicines. b Methyldopa is listed for use in the management of pregnancy-induced hypertension only. Its use in the treatment of essential hypertension is not recommended in view of the availability of further evidence of the efficacy and safety of other medicines. c The public health relevance and/or efficacy and/or safety of this item has been questioned and its continued inclusion in the Model List will be reviewed at the next meeting of the Expert Committee. � Recommended example within a pharmaceutical class. See Explanatory notes on page 61. 82 Medicine Route of administration, dosage forms and strengths 12. Cardiovascular medicines (continued) 12.6 Lipid-lowering agents The Committee recognizes the value of lipid-lowering medicines in treating patients with hyperlipidaemia. b-Hydroxy-b-methylglutaryl-coenzyme A (HMG- CoA) reductase inhibitors, often referred to as “statins”, are a family of potent and effective lipid-lowering medicines with a good tolerability profile. Several of these medicines 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 medicine has been shown to be significantly more effective or less expensive than others in the group, none is included in the Model List; the choice of medicine for use in patients at highest risk should be decided at the national level. 13. Dermatological medicines (topical) 13.1 Antifungal medicines benzoic acid + salicylic acid ointment or cream, 6% + 3% � miconazole ointment or cream, 2% (nitrate) sodium thiosulfate solution, 15% Complementary list medicine selenium sulfide detergent-based suspension, 2% 13.2 Anti-infective medicines � methylrosanilinium chloride aqueous solution, 0.5% (gentian violet) tincture, 0.5% neomycin + �bacitracin ointment, 5mg neomycin sulfate + 500 IU bacitracin zinc/g potassium permanganate aqueous solution, 1 :10000 silver sulfadiazine cream, 1% in 500-g container 13.3 Anti-inflammatory and antipruritic medicines � betamethasone ointment or cream, 0.1% (as valerate) � calamine lotion lotion � hydrocortisone ointment or cream, 1% (acetate) � Recommended example within a pharmaceutical class. See Explanatory notes on page 61. 83 Medicine Route of administration, dosage forms and strengths 13. Dermatological medicines (topical) (continued) 13.4 Astringent medicines aluminium diacetate solution, 13% for dilution 13.5 Medicines affecting skin differentiation and proliferation benzoyl peroxide lotion or cream, 5% coal tar solution, 5% dithranol ointment, 0.1–2% fluorouracil ointment, 5% � podophyllum resin solution, 10–25% salicylic acid solution, 5% urea ointment or cream, 10% 13.6 Scabicides and pediculicides � benzyl benzoate lotion, 25% permethrin cream, 5% lotion, 1% 13.7 Ultraviolet-blocking agents Complementary list medicine topical sun protection agent with cream, lotion or gel activity against ultraviolet A and ultraviolet Ba 14. Diagnostic agents 14.1 Ophthalmic medicines fluorescein eye drops, 1% (sodium salt) � tropicamide eye drops, 0.5% 14.2 Radiocontrast media � amidotrizoate injection, 140–420mg iodine (as sodium or meglumine salt)/ml in 20-ml ampoule a The public health relevance and/or efficacy and/or safety of this item has been questioned and its continued inclusion in the Model List will be reviewed at the next meeting of the Expert Committee. � Recommended example within a pharmaceutical class. See Explanatory notes on page 61. 84 Medicine Route of administration, dosage forms and strengths 14. Diagnostic agents (continued) barium sulfate aqueous suspension � iohexol injection, 140–350mg iodine/ml in 5-ml, 10-ml or 20-ml ampoule � iopanoic acid tablet, 500mg � propyliodone oily suspension, 500–600mg/ml in 20-ml ampoulea Complementary list medicine � meglumine iotroxate solution, 5–8g iodine in 100–250ml 15. Disinfectants and antiseptics 15.1 Antiseptics � chlorhexidine solution, 5% (digluconate) for dilution � ethanol solution, 70% (denatured) � polyvidone iodine solution, 10% 15.2 Disinfectants � chlorine base compound powder (0.1% available chlorine) for solution � chloroxylenol solution, 4.8% glutaral solution, 2% 16. Diuretics amiloride tablet, 5mg (hydrochloride) � furosemide tablet, 40mg injection, 10mg/ml in 2-ml ampoule � hydrochlorothiazide scored tablet, 25mg mannitol injectable solution, 10%, 20% spironolactone tablet, 25mg a For administration only into the bronchial tree. � Recommended example within a pharmaceutical class. See Explanatory notes on page 61. 85 Medicine Route of administration, dosage forms and strengths 17. Gastrointestinal medicines 17.1 Antacids and other antiulcer medicines aluminium hydroxide tablet, 500mg oral suspension, 320mg/5ml magnesium hydroxide oral suspension, equivalent to 550mg magnesium oxide/10ml � ranitidine tablet, 150mg (as hydrochloride) oral solution, 75mg/5ml injection, 25mg/ml in 2-ml ampoule 17.2 Antiemetic medicines metoclopramide tablet, 10mg (hydrochloride) injection, 5mg (hydrochloride)/ml in 2-ml ampoule promethazine tablet, 10mg, 25mg (hydrochloride) elixir or syrup, 5mg (hydrochloride)/5ml injection, 25mg (hydrochloride)/ml in 2-ml ampoule 17.3 Antihaemorrhoidal medicines � local anaesthetic, astringent and ointment or suppository anti-inflammatory medicinea 17.4 Anti-inflammatory medicines � sulfasalazine tablet, 500mg suppository, 500mg retention enema Complementary list medicine � hydrocortisoneb suppository, 25mg (acetate) retention enema a The public health relevance and/or efficacy and/or safety of this item has been questioned and its continued inclusion in the Model List will be reviewed at the next meeting of the Expert Committee. b The square box symbol (�) applies only to hydrocortisone, retention enema. � Recommended example within a pharmaceutical class. See Explanatory notes on page 61. 86 Medicine Route of administration, dosage forms and strengths 17. Gastrointestinal medicines (continued) 17.5 Antispasmodic medicines � atropinea tablet, 1mg (sulfate) injection, 1mg (sulfate) in 1-ml ampoule 17.6 Laxatives � senna tablet, 7.5mg (sennosides) (or traditional dosage forms) 17.7 Medicines used in diarrhoea 17.7.1 Oral hydration oral rehydration salts (for powder, 20.5g/l glucose–electrolyte solution) Components (for 1 litre of glucose– electrolyte solution)b: glucose 13.5g/l sodium chloride 2.6g/l potassium chloride 1.5g/l trisodium citrate dihydratec 2.9g/l These components provide a glucose– elecrolyte solution with the following molar concentrations: glucose 75mEq sodium 75mEq or mmol/l chloride 65mEq or mmol/l potassium 20mEq or mmol/l citrate 10mmol/l osmolarity 245mOsm/l 17.7.2 Antidiarrhoeal (symptomatic) medicines codeinea tablet, 30mg (phosphate) a The public health relevance and/or efficacy and/or safety of this item has been questioned and its continued inclusion in the Model List will be reviewed at the next meeting of the Expert Committee. b In cases of cholera a higher concentration of sodium may be required. c Trisodium citrate dihydrate may be replaced by sodium hydrogen carbonate (sodium bicarbonate) 2.5g/l. However, as the stability of this latter formulation is very poor under tropical conditions, it is only recommended when manufactured for immediate use. � Recommended example within a pharmaceutical class. See Explanatory notes on page 61. 87 Medicine Route of administration, dosage forms and strengths 18. Hormones, other endocrine medicines and contraceptives 18.1 Adrenal hormones and synthetic substitutes Addison’s disease is a rare condition; adrenal hormones for the treatment of this condition are already included in section 3. 18.2 Androgens Complementary list medicine testosterone injection, 200mg (enantate) in 1-ml ampoule 18.3 Contraceptives 18.3.1 Hormonal contraceptives � ethinylestradiol + tablet, 30mg + 150mg � levonorgestrel � ethinylestradiol + tablet, 35mg + 1.0mg � norethisterone levonorgestrel tablet, 30mg, 750mg (pack of two), 1.5mg norethisterone enantate oily solution, 200mg/ml in 1-ml ampoule Complementary list medicine medroxyprogesterone acetatea depot injection, 150mg/ml in 1-ml vial 18.3.2 Intrauterine devices copper-containing device 18.3.3 Barrier methods condoms diaphragms 18.4 Estrogens � ethinylestradiol tablet, 10mg, 50mg 18.5 Insulins and other antidiabetic agents glibenclamide tablet, 2.5mg, 5mg insulin injection (soluble) injection, 40 IU/ml in 10-ml vial, 100IU/ml in 10-ml vial a The public health relevance and/or efficacy and/or safety of this item has been questioned and its continued inclusion in the Model List will be reviewed at the next meeting of the Expert Committee. � Recommended example within a pharmaceutical class. See Explanatory notes on page 61. 88 Medicine Route of administration, dosage forms and strengths 18. Hormones, other endocrine medicines and contraceptives (continued ) intermediate-a

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