WHO DRUG INFORMATION

VOLUME 12 • NUMBER 4 • 1998

PROPOSED INN LIST 80 INTERNATIONAL NONPROPRIETARY NAMES FOR PHARMACEUTICAL SUBSTANCES

WORLD HEALTH ORGANIZATION • GENEVA Volume 12, Number 4, 1998 World Health Organization, Geneva

WHO Drug Information

Contents Isotretinoin: adverse reaction profile 237 Depression with isotretinoin 238 Orlistat sold illegally 238 General Policy Issues Trastuzumab: approved for breast cancer 238 Ritonavir and ecstasy — a fatal combination 238 WHO's Revised Drug Strategy 209 WHO recommendations for influenza virus The World Intellectual Property Organization 209 vaccines — 1999 238 Pharmaceutical patents and the TRIPS Rhabdomyolysis and ritodrine 239 Agreement 211 Flutamide: severe hepatic dysfunction 239 WTO Agreement on Technical Barriers Ebrotidine: liver toxicity 239 to Trade 213 Meloxicam: gastrointestinal and skin South Centre 215 reactions 239 Health Action International 216 Vaccine-associated thrombocytopenic purpura 240 International Federation of Pharmaceutical Abortifacients on free sale 240 Manufacturers Associations 219 Illegal and counterfeit sildenafil on sale 240 International Generic Pharmaceutical Alliance 220 Current standards for over-the-counter analgesics 240 Reports on Individual Drugs Safety of leukotriene antagonists 241 Reformulation of flunitrazepam tablets to The life-threatening risks of therapy prevent misuse 241 substitution 222 Nicergoline re-evaluated 241 Revision of HIV treatment guidelines 222 Entacapone for Parkinson disease 242 Levonorgestrel for emergency contraception 223 Chinese herbal medicines and adverse Cancer risk in women exposed to reactions 242 diethylstilbestrol in utero 224 Zidovudine for mother-to-child transmission of HIV 225 Essential Drugs WHO Model Formulary: General Information Ophthalmological preparations 243 Recommendations from the Expert Committee Anti-infective agents 243 on Drug Dependence 227 Gentamicin 243 Insulin: availability, affordability, Idoxuridine 244 and harmonization 230 Silver Nitrate 244 Tetracycline 244 Anti-inflammatory agents 244 Regulatory Matters Prednisolone 245 Bruising and bleeding with new Local anaesthetics 245 antidepressants 235 Tetracaine 245 Reports of death in sildenafil users 235 Miotics and antiglaucoma drugs 245 Lipodystrophy and HIV protease inhibitors 235 Acetazolamide 246 Cisapride: new contraindications 236 Pilocarpine 246 Cisapride: risk of arrhythmias 236 Timolol 246 Mibefradil: instructions for therapy substitution 237 Mydriatics 246 Mibefradil suspended in Germany 237 Atropine 247 Epinephrine 247

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i World Health Organization, Geneva WHO Drug Information Vol. 12, No. 4, 1998

Contents (continued)

Antiparkinsonism drugs Levodopa/carbidopa 248 Biperiden 248

Recent Publications and Documents Guidelines for HIV and infant feeding 249 Symptom relief in terminal illness 249 Guidance modules on antiretroviral treatments 249 Re-evaluating the safety profile of marketed drugs 250 Interventions to improve antimalarial use 250

Proposed International Nonproprietary Names: List 80 251

ii40 WHO Drug Information Vol. 12, No. 4, 1998

General Policy Issues

WHO's Revised Drug Strategy

WHO's Revised Drug Strategy was conceived in the mid-1980s to foster unity among governments, industry, consumers, academia, nongovernmental organizations, and specialized agencies. Its aim is to ensure equity of access to safe drugs of proven quality by all peoples of the world and to promote their rational use. At the same time, it seeks to remind each party of its responsibilities in the manufacture and provision of drugs.

In compliance with the terms of the Strategy, WHO has supported governments in the formulation and implementation of national drug policies and essential drugs programmes, expanded its normative activities, intensified the dissemination of information, conducted operational research on key drug issues, developed innovative training materials and programmes, and promoted collaboration. Since the original drafting of the Strategy, various World Health Assembly resolutions have addressed related topics such as access to essential drugs, quality assurance, drug safety, medicinal drug promotion, drug donations, provison of independent drug information and consumer education and protection. WHO has also been requested to report on the impact of the work of the World Trade Organization (WTO) with respect to national drug policies and essential drugs and make recommendations for collaboration between WTO and WHO.

In May 1998, the World Health Assembly considered a Resolution on the Revised Drug Strategy* which led to extensive debate among members of the Assembly. It was agreed that an open-ended ad hoc working group should be established to review the complex issues raised by the Resolution, particularly in relation to the public health implications of trade agreements and access to essential drugs.

A summary of the presentations made by panelists at the meeting of the ad hoc Working Group on the Revised Drug Strategy held from 13–16 October 1998 is set out below. The presentations represent the policy and views of the World Intellectual Property Organization (WIPO), the World Trade Organization (WTO), the South Centre, Health Action International (HAI), the International Federation of Pharmaceutical Manufacturers Associations (IFPMA), and the International Generic Pharmaceutical Alliance (IGPA).

* Resolution EB101.R24.

The World Intellectual the administration of various multilateral treaties dealing with the legal and administrative aspects of Property Organization intellectual property. Its principal activities are the progressive development of norms in intellectual Mr Richard Wilder, Director-Advisor, Office of property, and the administration of certain treaties Legal and Organization Affairs, World for global protection of intellectual property, in Intellectual Property Organization, Geneva particular for patents, trademarks, industrial designs and development cooperation. The World Intellectual Property Organization (WIPO) is an intergovernmental organization with One of the main tasks of WIPO is to cooperate with headquarters in Geneva, Switzerland. It is one of developing countries in their efforts to develop the 16 specialized agencies of the United Nations intellectual property. Its main objectives in this system. As of 21 September 1998, there are 171 regard are: States members of the Convention establishing WIPO. Through cooperation among States, WIPO • To encourage and increase, in quantity and is responsible for the promotion of protection of importance, the creation of patentable inventions intellectual property throughout the world and for

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by nationals and national enterprises in develop- patent system. Furthermore, many patent systems ing countries in order to enhance their technologi- require the payment of fees to keep both applica- cal self-reliance and competitiveness in interna- tions and granted patents in force. tional markets. A patent, to be valid, must meet certain conditions. • To improve the conditions of acquisition of foreign First, it must relate to subject matter that is not patented technology, making these conditions excluded from patent protection. A diminishing more favourable than they are today. number of countries still exclude pharmaceutical products from patent protection. WIPO advice is not • To increase the competitiveness of developing to exclude such subject matter. Furthermore, the countries in international trade through better invention for which protection is sought must be protection and more effective use of trademarks novel and involve an inventive step. That is, it must and service marks in such trade and in commerce. not be an invention that is obvious to persons who are skilled in that area of technology. The invention • To facilitate access to technological information must be useful or be applicable in some area of contained in patent documents and disseminate industry. In addition, the patent application must such information to users. disclose the invention in such a way that persons If these objectives are to be met, most developing skilled in the relevant area of technology can also countries will need to do one or more of the follow- make and use the invention. ing: enact or modernize national legislation, streng- Many offices require that a patent application, once then governmental institutions, accede to interna- filed, be subject to search and examination to tional treaties, acquire more specialists in govern- determine if it meets the requirements for patent- ment, industry and the legal profession, and acquire ability. A search involves looking for "prior art", i.e. better access to and make better use of industrial prior patent documents or other literature that may property information including patent documents. be relevant to the invention. Following the search, WIPO provides training and technical assistance to the invention is examined to compare it with the developing countries in all of these areas and has prior art to determine if it meets the requirements been doing so for many years. Recently, these for patentability. If these conditions are met, the activities have been expanded to include matters patent is granted and will have effect for a limited relating to implementation of the TRIPS Agreement. period of time — at least 20 years from the filing date. There is no requirement that every patent Patent protection and procedures office should do such a search and examination for application and legal effect itself. For example, many offices rely on the work In respect to patent protection, there are several that has already been done in respect of the same key points to be borne in mind in gauging the invention by other offices. Moreover, some offices economic impact of the patent system. These grant protection without a search and examination points apply equally to patent protection for phar- having been performed. It should be noted that maceutical processes and products. Firstly, the WIPO administers an assistance programme patent system encourages people to invent. Be- whereby searches and examinations can be per- cause they are granted exclusive rights to an inven- formed for patent offices that do not have the tion, for a limited period of time, individuals or facilities to do so themselves. commercial enterprises are more willing to invest in the resources necessary to make and commercial- The patentee has the right to prevent others from ize the invention. The patent system also encour- using the invention without his permission. This is a ages people to disclose inventions rather than negative right. The grant of a patent does not give retain them as trade secrets. the patentee a positive right to use the patented invention. Thus, other laws, such as those for the An application for patent protection must be filed in protection of the environment or human or animal every country, or region, where protection is de- health may constrain the use to which the patentee sired. The decision to file or not is a business may put the invention. Such constraints include, for decision based upon the cost of obtaining protec- example, the requirement in many countries to tion versus the value of that protection in a given obtain marketing approval for pharmaceutical country. It is rare that a person or company will file products from a health ministry. In respect of pre- for patent protection in every country having a venting others from using the invention, the paten-

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tee is limited to the scope of the claim contained in available so that rights holders can enforce their the patent. The claim is a formal part of the patent rights effectively. which clearly indicates the scope of the patent. It is the claim against which the patentability of an What pharmaceutical inventions must be invention is judged and against which infringement patentable under the TRIPS Agreement? by others of the patent is determined. The main rule relating to patentability is that patents shall be available for any invention, whether a The exercise of the right to exclude others from product or process, in all fields of technology with- using a patented invention may be subject to limita- out discrimination, where those inventions meet the tions in some countries, including the right of the standard substantive criteria for patentability — government to use the invention or by the grant of namely, novelty, inventive step and industrial compulsory licenses. Moreover, countries may put applicability. In addition, Members are required to in place legislation that specifies practices in the make grant of a patent dependent on adequate licensing of patents that have an anti-competitive disclosure of the invention and may require infor- effect. mation on the best mode for carrying it out. Dis- closure is a key part of the social contract that the A patent system, to function properly, should be grant of a patent constitutes, since it makes publicly balanced. On the one hand, the patentee must be available important technical information which may granted effective protection for an invention to be of use to others in advancing technology in the induce further research and encourage the disclo- area, even during the patent term, and ensures sure of inventions to the public. On the other hand, that, after expiry of the patent term, the invention national law may take cognizance of the con- truly falls into the public domain because others straints, as noted above, that may be imposed on have the necessary information to carry it out. the grant and exercise of the patent right. Three types of exception to the above rule on patentable subject-matter are allowed. These may Pharmaceutical patents be of interest from a public health perspective. and the TRIPS Agreement • Inventions the prevention of whose commercial Mr A. Otten, Director, Intellectual Property and exploitation is necessary to protect public order or Investment, World Trade Organization, morality, including to protect animal or plant life or Geneva health. The purpose of this note is to describe provisions of • Diagnostic, therapeutic and surgical methods for the Agreement on Trade-Related Aspects of Intel- the treatment of humans or animals. lectual Property Rights (TRIPS Agreement) that relate to the standards of patent protection to be • Certain plant and animal inventions. accorded to inventions in the area of pharmaceuti- cals. To set this discussion in context, it is useful to What are the rights conferred by a patent recall three basic features of the TRIPS Agreement: under the TRIPS Agreement? The minimum rights that must be conferred by a 1. The TRIPS Agreement, together with some 25 patent under the TRIPS Agreement follow closely other legal texts, is an integral part of the Agree- those that were to be found in most patent laws, ment Establishing the World Trade Organization namely the right for the patent owner to prevent (WTO) (and is therefore subject to the WTO dispute unauthorized persons from using the patented settlement system). process and from making, using, offering for sale, or importing the patented product or a product 2. It covers not only patents but all the other main obtained directly by the patented process. areas of intellectual property rights. Term of protection 3. It lays down not only the minimum substantive Under the TRIPS Agreement, the term of protection standards of protection that should be provided for must be at least 20 years from the date of filing the in each of these areas of intellectual property but patent application. It should be noted that, although also the procedures and remedies that should be the issue of patent term extension to compensate

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for regulatory delays in the marketing of new phar- sory licences where a practice has been deter- maceutical products was raised in the negotiations, mined after due process of law to be anti-competi- the TRIPS Agreement does not contain an obliga- tive. For example, each of the conditions specifi- tion to introduce such a system1. cally referred to above for the grant of compulsory licences may be relaxed in these circumstances. Limitations/exceptions to these rights The Agreement also provides for consultation and Under the TRIPS Agreement, patent rights are not cooperation between Members in taking action absolute but can be subject to limitations or excep- against anti-competitive practices. tions. These can be put into three categories. Transition provisions • The Agreement allows limited exceptions to be The TRIPS Agreement lays down some rather made by Members provided that such exceptions complicated transition provisions which give coun- do not unreasonably conflict with a normal exploi- tries time to adapt their legislation and practices to tation of the patent and do not unreasonably their TRIPS obligations. These periods differ ac- prejudice the legitimate interests of the patent cording to the type of obligation in question and the owner, taking account of the legitimate interest of stage of development of the country concerned. third parties. Thus, for example, many countries Here we will limit the discussion to those transition allow third parties to use a patented invention for provisions which relate to the application of the research purposes where the aim is to understand obligations on substantive standards for the protec- more fully the invention as a basis for advancing tion of pharmaceutical inventions. For these pur- science and technology. poses, the obligations should be divided into two categories: • The Agreement also allows Members to authorize use by third parties (compulsory licences) or for (i) The obligations relating to the introduction of public non-commercial use (government use) product patent protection for pharmaceutical without the authorization of the patent owner. products in those developing and least devel- Contrary to the desire of some countries in the oped countries which do not yet grant it. Since negotiations, the grounds on which this can be most developing and least developed country done are not limited by the Agreement but the Members of the WTO already provide for prod- Agreement contains a number of conditions that uct patent protection for pharmaceuticals, a have to be met in order to safeguard the legiti- relatively small number of countries are con- mate interests of the patent owner. There is not cerned. 2 space to discuss all of these here, but two of the main such conditions are that, as a general rule, (ii) Obligations regarding process patents for this an effort must first have been made to obtain a group of countries and all patent protection voluntary licence on reasonable commercial terms obligations for other developing and least devel- and conditions and that the remuneration paid to oped countries. the rights holder shall be adequate in the circum- stances of each case, taking into account the With respect to the second category above, the economic value of the licence. basic rule is that developing and least developed countries have until 1 January 2000 and 1 January • The Agreement recognizes the right of Members 2006 respectively to meet the obligations in ques- to take measures, consistent with its provisions, tion. At that time, the rules of the TRIPS Agreement against anti-competitive practices and provides will apply not only to new patent applications but to more flexible conditions for the grant of compul- patents still under protection in their territories.

1. The effective period of patent protection for inventions of new chemical entities is much less than the full 20 2. Thirteen WTO Members (Argentina, Brazil, Cuba, years, because a large part of that period will have Egypt, India, Kuwait, Morocco, Pakistan, Paraguay, expired before marketing approval is obtained from the Tunisia, Turkey, United Arab Emirates and Uruguay) public health regulatory bodies. For this reason, most of have notified "mailbox "systems to the TRIPS Council, the major developed countries have introduced systems thus indicating that they do not yet grant patent protection whereby a prolonged period of protection can be obtained to pharmaceutical products. (It cannot be excluded that to compensate, at least in part, for this loss of the there are a few other WTO Members who should have effective period of protection. notified this but have not done so).

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With respect to the first category of situations in the basic underlying balance related to disclosure referred to above, the developing countries in and providing an incentive for research and devel- question have until 1 January 2005 to apply product opment (R & D), but also in the limitations and patent protection to pharmaceutical products and exceptions to rights that are permitted in the transi- the least developed countries until 1 January 2006. tion provisions. Notwithstanding proposals to the contrary, the It should also be appreciated that the protection of TRIPS Agreement does not require the bringing pharmaceutical inventions is one aspect of a much under protection of pharmaceutical inventions that wider agreement, covering not only the protection were in the "pipeline" in these countries on 1 Janu- of intellectual property in general in a coherent and ary 1995 — the time of entry into force of the non-discriminatory way, but also further liberaliza- WTO.3 However, with effect from the entry into tion and strengthening of the multilateral trading force of the WTO (1 January 1995), these countries system as a whole. While it is true that some coun- have been under an obligation to provide a system tries put particular emphasis on TRIPS matters in whereby applications for patents for pharmaceutical the Uruguay Round negotiations, it is also true that product inventions can be filed (often referred to as other countries attached great importance to other the "mailbox" system). These applications do not areas, for example textiles and agriculture. have to be examined until after 1 January 2005 (or 1 January 2006 in the case of least developed It is our belief, and a belief shared by all WTO countries). If found to be patentable by reference to Members, that a strong and vibrant multilateral their filing (or priority) date, a patent would have to trading system is essential for creating conditions of be granted for the remainder of the patent term economic growth and development worldwide. This, counted from the date of filing. In the event that a in turn, will generate the resources required to pharmaceutical product that is the subject of a address health care needs. "mailbox" application obtains marketing approval prior to the decision on the grant of a patent, an exclusive marketing right of up to five years will WTO Agreement on have to be granted provided that certain conditions Technical Barriers to Trade are met. Concluding remarks Doaa Abdel Motaal It will be noted that most developing and least World Trade Organization, Geneva developed countries already grant patent protection The World Trade Organization's Agreement on for pharmaceutical products. In these countries, the Technical Barriers to Trade (TBT) entered into force TRIPS Agreement will therefore not lead to funda- in 1995, with the establishment of the WTO. It was mental changes in this regard, although a certain developed in response to the proliferation of non- amount of adjustment in legislation, for example in tariff barriers to trade and focuses on product respect of patent term and compulsory licensing, technical requirements. may be necessary. With respect to the fairly limited number of countries that did not provide patent The TBT Agreement acknowledges the right of protection for pharmaceutical products at the time WTO Members to develop technical requirements of entry into force of the WTO Agreement, some, as long as these do not create unnecessary obsta- including Brazil and Argentina, have decided to cles to international trade. It lays out a number of bring such protection into effect more quickly than principles which technical requirements must is required under the TRIPS Agreement. respect, including the principles of nondiscrimina- tion, harmonization, equivalence, mutual recogni- It will also be noted that the TRIPS Agreement pays tion and transparency. It also delineates a number considerable attention to the need to find an appro- of legitimate objectives for which mandatory techni- priate balance between the interests of rights cal requirements may be developed. The scope of holders and users and that this was an important the Agreement extends to central and local govern- theme in the negotiations. This is not only reflected mental as well as nongovernmental standardization bodies.

3 The pipeline refers to the backlog of inventions of new Coverage and definitions pharmaceutical products that were no longer patentable on The TBT Agreement divides technical requirements that date, because disclosed, but not yet on the market into either technical regulations or standards. because they are awaiting marketing approval.

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According to the Agreement a technical regulation between imported and locally produced products. In is a "document which lays down product character- accordance with GATT Article I — the most- istics or their related processes and production favoured nation "MFN" clause — WTO Members methods, including the applicable administrative are bound to grant to the products of other Mem- provisions with which compliance is mandatory. It bers treatment which is no less favourable than that may also include or deal exclusively with terminol- accorded to the products of any other country. ogy, symbols, packaging, marking or labelling Thus, no country is to give special trading advan- requirements as they apply to a product, process or tage to another, or to discriminate against it. Ac- production methods." cording to GATT Article III — the national treatment NT clause — Members must treat imported prod- A standard is defined as a "document approved by ucts no less favourably than domestically produced a recognized body, that provides for common and products. The TBT Agreement embraces the GATT repeated use, rules, guidelines or characteristics of principle of nondiscrimination. It states that techni- products or related processes and production cal regulations, standards and conformity assess- methods, with which compliance is mandatory. It ment procedures must be prepared, adopted and may also include or deal exclusively with terminol- applied without discrimination. ogy, symbols, packaging, marking or labelling requirements as they apply to a product, process or Avoidance of unnecessary obstacles to production method." international trade The avoidance of unnecessary obstacles to interna- Compliance with technical regulations is manda- tional trade is the principal objective of the TBT tory, while compliance with standards is voluntary. Agreement. The Agreement states that technical While technical regulations are addressed through regulations, standards and conformity assessment the main body of the Agreement, standards are procedures must not be prepared, adopted or addressed separately through a Code of Good applied with a view to or with the effect of creating Practice contained in an annex to the Agreement. unnecessary obstacles to trade. Technical regula- Many of the principles applied by the Agreement to tions and conformity assessment procedures must technical regulations apply to standards through the not be more trade-restrictive than necessary to fulfil code. The code is open to acceptance by central, a legitimate objective, taking into account the risks local and nongovernmental (whether national or that non-fulfilment or non-conformity would create. regional) standardization bodies. The Agreement also covers conformity assessment procedures, Harmonization which it defines as "any procedure used, directly or The TBT Agreement encourages WTO Members to indirectly, to determine if relevant requirements in base their technical regulations, standards, and technical regulations or standards are fulfilled". conformity assessment procedures on international Legitimate objectives standards, guides and recommendations when these exist, and when they are deemed to be Under the Agreement, technical regulations may appropriate and effective. The call for harmoniza- only be developed for one or more of the objectives tion is designed to avoid the emergence of undue considered legitimate by the Agreement. Legitimate layers of technical requirements and assessment objectives include inter alia, national security re- procedures, and to encourage the use of those quirements, the prevention of deceptive practices, adopted by the international community. To com- or protection of human health or safety, animal or plement this requirement, the Agreement calls upon plant life or health, or the environment. The risks Members to participate in the work of international associated with legitimate objectives are assessed standardizing and conformity assessment bodies. against a number of factors, including, inter alia , However, it recognizes that there may be instances available scientific and technical information, re- in which Members would need to derogate from this lated processing technology or intended end-users obligation and, for certain specific instances, allows of products. them to do so. Nondiscrimination The principle of nondiscrimination constitutes the Equivalence and mutual recognition backbone of the international trading system. In The TBT Agreement calls upon Members to recog- general, it is a principle which outlaws discrimina- nize other Members' technical regulations as equi- tion among the products of WTO Members, and valent to their own, even when they differ, provided

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they are satisfied that they adequately fulfil their South Centre objectives. As international harmonization is a time- consuming process, and is sometimes difficult to Mr Carlos M. Correa, University of Buenos achieve, the Agreement encourages Members to Aires, Argentina accept each other's regulations as equivalent to their own until full-fledged international harmoniza- The TRIPS Agreement contains a number of provi- tion becomes possible. The Agreement also en- sions that are likely to affect access to medicines in courages Members to mutually recognize the developing countries. This is particularly the case in results of each other's conformity assessment countries under the obligation to introduce patent procedures. protection for pharmaceuticals. However, the effects may also be felt in countries that already Transparency offer patent protection. Transparency is a central feature of the TBT Agree- The TRIPS Agreement includes several provisions ment, and is achieved through notification obliga- that are bound to strengthen the protection con- tions, the establishment of enquiry points, and the ferred on pharmaceutical products and processes, creation of the WTO TBT Committee. Notification such as the provisions relating to the duration of means the circulation of information by a WTO patent protection (minimum 20 years from the Member to other Members on matters relating to application date); extension of the protection to the the Agreement. Notification obligations include products directly obtained by a protected process; notifying the measures taken to implement the reversal of the burden of proof in the case of civil provisions of the TBT Agreement nationally, such procedures relating to process patents; and protec- as how its provisions have been incorporated into tion of confidential data submitted in applications for domestic legislation, notifying draft technical regula- the approval of pharmaceuticals. tions, conformity assessment procedures and standards, and providing other Members with However, the TRIPS Agreement does not constitute sufficient time to comment on them — with the a uniform law and WTO Members have some obligation of taking these comments into account. flexibility in their implementation of the provisions at Draft technical regulations and conformity assess- national level. In particular, Article 8 makes a ment procedures only have to be notified when an specific reference to the protection of public health international standard, guide or recommendation as one of the elements to be considered when does not exist, of they are not in accordance with formulating or amending national laws. In addition, existing ones, or if they may have a significant Article 27 contains two health-related possible effect on the trade of other WTO Members. This exceptions to patentability : "Members may exclude includes notifying entry into any bilateral or multilat- from patentability inventions, the prevention within eral agreements regarding technical regulations, their territory of the commercial exploitation of standards or conformity assessment procedures. which is necessary to protect ... health". This may also exclude diagnostic, therapeutic and surgical The TBT Agreement stipulates that each WTO methods for the treatment of humans. Member must establish an enquiry point that can respond to questions on technical regulations, Likewise, under Article 30, Member countries may standards and conformity assessment procedures, provide several exceptions (such as the so-called whether proposed or adopted, and supply relevant Bolar exception), and under Article 31 may estab- documents. The Agreement has also established a lish compulsory licences, for example, based on TBT Committee in the WTO which is a standing health-related grounds. Under Article 6, parallel body that acts as a forum for consultations on all imports may also be admitted on the basis of the issues pertaining to the Agreement. Participation in principle of exhaustion of rights. the Committee is open to all WTO Members. The possible effects of the changes in pharmaceuti- Developing countries cal patent protection in the health sector may be Under the TBT Agreement, special and differential seen from different perspectives. The likely impact treatment for developing countries is authorized, of the new rules on the prices of medicines has and developed countries are encouraged to provide been addressed by a number of studies, under- developing countries with technical assistance on taken before and after the adoption of the TRIPS all matters pertaining to the Agreement. Agreement.

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For instance, in the pre-TRIPS period, Nogués (a Finally, from a public policy perspective, the possi- World Bank economist) estimated consumer ble effects of changes in patent protection on other misallocation in developing countries and found that aspects, such as local innovation, foreign direct the introduction of pharmaceutical patents would investment and transfer of technology, should also entail significant welfare losses for consumers and be assessed. So far, the available evidence indi- income gains for patent owners. cates that, in general, a reinforced and expanded protection is not likely to increase the local rate of After the adoption of the TRIPS Agreement, pharmaceutical research and development or the Subramanian, an International Monetary Fund flow of technology and investments to developing economist, examined the likely impact of introduc- countries. ing pharmaceutical product patents in small and large countries, in cases where either a perfectly Following the adoption of the TRIPS Agreement, competitive market or a Nash-Cournot duopolistic the likely impact of introducing pharmaceutical market becomes a monopoly under patents. The product patents into small and large countries was same author later applied this model to the particu- examined by a World Bank economist. Welfare and lar case of Asian countries, such as India, Indone- price effects were found to be negative in a market sia, Pakistan, the Philippines and Thailand. He introducing patent monopoly — such as India, investigated annual price, welfare and profit effects Indonesia, Pakistan, the Philippines or Thailand — for these countries consequent upon the TRIPS although the effects would not be felt immediately. Agreement. Welfare and price effects were found to Of course, estimating the likely impact of changes be negative for these countries, though given the is methodologically problematic since there are transitional periods provided for by the Agreement important differences from country to country and it and the extensive time required for the approval of is difficult to estimate the market share that would new medicines, the effects would not be felt imme- be covered by patented products. However, there diately. The same methodology, when applied to is no doubt that patents lead to prices higher than Argentina, also indicated a significant price in- those prevailing when patent protection is not crease of 71% and a fall in consumption of 50% enforced. when monopoly follows a competitive situation, and 16% and –25% respectively in the duopolistic- monopoly scenario. Health Action International There are several methodological problems in Dr Zafar Mirza, Association for Rational Use of estimating the likely impact of changes in patent Medicines in Pakistan, Islamabad law on pharmaceuticals as a result of the imple- mentation of the TRIPS Agreement since — among Health Action International (HAI) believes that other reasons — there are important differences global trade liberalization can and does have a from country to country in respect to patent laws, negative impact on public health, especially in the characteristics of the local pharmaceutical developing countries. Globalization is promoted and industry, income levels and patterns of consump- protected by a range of international trade agree- tion. In addition, it is difficult to estimate the market ments, most notably the Uruguay Round of the share that would be covered by patented products, General Agreement on Tariffs and Trade (GATT) and estimates on price increases and welfare being implemented within the World Trade Organi- effects require assumptions on price elasticity for zation (WTO). Most, if not all, countries are ex- which only scant evidence is available. pected to join the WTO in the coming years. The adoption of the TRIPS Agreement has significant Although the results of the various studies under- implications for pharmaceuticals. taken on possible price increases for medicines Certainly, the commercial interests of pharmaceuti- vary significantly, there is no doubt that patents cal corporations can complement public health lead to prices higher than those prevailing without goals. But just as importantly, they can conflict. HAI protection. The generation of monopolistic rents is, believes that national governments must maintain in fact, the very purpose and essence of the patent the ability to regulate trade in the public interest. system. Hence, while introducing or strengthening HAI also believes that WHO has an important role patent protection, in conformity with the TRIPS in assisting countries to comply with trade agree- Agreement, its possible social effects, particularly ments, while protecting public health, and in provid- on a low-income population, should be explicitly ing health expertise to the WTO, particularly in the and carefully considered. settlement of trade disputes.

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HAI's public health principles concerning intellectual providing national treatment (NT) to the pharma- property protection (IPP) are as follows: ceutical transnational companies, it is doubtful that there will be fair competition between local and • IPP is granted for developing a product or process foreign companies. Furthermore, there is no evi- to provide incentives to make that product or dence to date documenting a positive impact of the process available to the public. TRIPS Agreement concerning the transfer of tech- nology and foreign direct investment in developing • A patent is not an absolute right or an end in itself; countries in the pharmaceutical area. public health is an end in itself. • IPP for pharmaceuticals should always promote Trade agreements reinforce justifications and be consistent with public health goals. for commercial secrecy to the detriment of transparency and drug regulation • Public health goals and commercial interests of The positive connection between the rational use of companies sometimes coincide and sometimes drugs and public health is clear, as is the connec- diverge. They are not identical. When they con- tion between access to adequate drug information flict, government should always have the ability to and rational drug use. Therefore, it is disturbing to choose public health as a legitimate reason for note that TRIPS has been used recently to argue limiting or conditioning commercial interests and that access to the full clinical trial data would rights. breach the intellectual property rights of an appli- cant for a marketing licence in Europe. Patents lead to higher drug prices and restrictiveness Strategies for complying with trade Patent protection increases the likelihood that agreements while protecting public health prices for a patented product will be higher, espe- In debates on trade and public health, it is very cially if competition is limited. Price data also sug- important not to lose sight of the realities that (i) gest that pharmaceutical corporations often set countries do have alternatives on how they choose prices according to what the market can bear, not in to comply with agreements and (ii) they have the order to recuperate development costs with reason- right to pursue them in their best interests, which able profits. Finally, pricing data clearly show that may conflict with the interests of other countries or prices of a patented drug drop quickly and dramati- corporations without being illegal under WTO, and cally (30%) when the patent expires and a generic (iii) WHO has a mandate to provide Member States equivalent comes onto the market. Moreover, price with technical assistance, information and advice is an important determinant of access to necessary on how best to protect and promote health for all, drugs. Whenever patents allow companies to price which includes addressing the public health implica- any drug out of the reach of those who need it, tions of trade policies, legislation, regulations and public health suffers. agreements.

Trade agreements do not promote research Furthermore, the WTO is only three years old. and development on diseases prevalent in Countries are still in the process of joining, includ- developing countries ing many developing countries. Countries should One of the main arguments for strong patents is have impartial technical advice about deciding on that they are necessary for research and develop- compliance with TRIPS. The number of disputes ment. However, 75% of the world's population in involving public health issues is still limited. In such developing countries consume only 14% of the cases, the WTO needs to have impartial advice world's drug supply. Free trade policies and trade from public health experts. agreements are not addressing the obvious market failure to develop and make available affordable Recommendations at national level drugs for diseases most prevalent in poorer re- Develop an effective national drug policy and gions, such as tuberculosis, malaria and HIV/AIDS. promote the adoption of an essential drugs list A noteworthy study of international drug pricing Trade agreements dismantle local done in the 1980s showed that the presence of pharmaceutical industry and limit successful national drug policies was a major factor transfer of technology in lowering drug prices. Furthermore, countries that The majority of developing countries have a rela- adopt essential drugs lists will have a mechanism tively weak pharmaceutical industrial base. After for determining what drugs are needed according to

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the disease patterns in their own countries and can ments must be negotiated and interpreted in ways base approvals or government procurement on that will permit the adequate redress of that market need, efficacy and price. failure. Use compulsory licences Recommendations for WHO to achieve public health goals Promote WHO input into understanding TRIPS Under TRIPS, Member Countries have the right to and other trade agreements issue compulsory licences on patents based on WHO, as a UN Agency, is well placed to be an various public health grounds, such as making honest broker in offering guidance, information and essential drugs available at lower cost, subject to advice to Member States on how to best protect several safeguards and limitations. public health while implementing trade agreements. For example, WHO has produced a clear and Permit parallel imports of pharmaceuticals informative document entitled Globalization and Global free trade should include the right to shop Access to Drugs: Implications of the WHO/TRIPS globally for the best prices. Parallel imports are Agreement (WHO/DAP/98.9)*, which gives useful particularly important for smaller economies that guidance for implementing WTO obligations. The suffer from inadequate competition. Where allowed, document should be made widely available. parallel imports have been shown to be effective in lowering drug prices. A study of the price of anti- Secure a role in providing HIV drugs in the United Kingdom showed that expertise in WTO trade disputes parallel imports offer an average saving of 41% WTO panels are comprised of trade experts that from the list price and 30% savings over the best can and should benefit from WHO opinion on contract price. issues of public health. A few years ago, the United States challenged Thailand's import restrictions Ensure that trademark protection does not and strict tobacco advertising ban. In weighing its interfere with public health policies decision, the WTO relied heavily on submissions Protection of trademark rights should not interfere from WHO and on World Health Assembly resolu- with sound public health policies to promote the tions. greater use of generic drugs or to regulate market- ing. It should be clear that countries can require Public health first generic drug substitution, substitution by generic National governments have a vital role to play in name or the printing of the generic name on the ensuring the protection and promotion of public packaging of the product. health. Although trade agreements limit how they can regulate trade, governments retain a range of Promote the production alternatives they can pursue to maximize public and use of generic drugs health goals in a globalized economy. WHO is well Bioequivalence testing, allowed close to the expira- placed to advise Member States in these matters. tion of a patented drug does not violate a patent. Likewise, WHO is well placed to provide expertise Preventing testing until the end of the patent has to the WTO, particularly in the settlement of dis- the same effect as granting an extension on the putes involving health issues. patent by forcing a delay in the introduction of a generic, which means extended higher prices for consumers. International Federation of Promote access to drug information Pharmaceutical Manufacturers IPP in national legislation or through international Associations trade agreements should not be used to unjustifi- ably maintain corporate control over drug informa- Dr Harvey Bale, Director-General, tion. Specifically, access to clinical trial data is International Federation of Pharmaceutical necessary for the public and health care profession- Manufacturers Associations (IFPMA), als to make rational decisions on drugs. Geneva, Switzerland Focus on alternatives that promote research The International Federation of Pharmaceutical and development for drugs needed locally Manufacturers Association (IFPMA) represents Patents are not the only means for promoting over 55 national industry associations from both research and development nor do they ensure that needed drugs are brought to market. Trade agree- * Ed. note: See footnote page 221.

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developed and developing countries. Member new drugs are profitable, and it is impossible to companies of the IFPMA are major global research- know whether a given compound will be successful. based pharmaceutical companies and companies producing a large volume of both generic and non- Because many drugs are relatively inexpensive to prescription drugs. We appreciate the efforts of this copy, and counterfeiting is even cheaper, it is working group and the dedication of WHO and its important that strong intellectual property rights staff to evidence-based decision-making. This is the apply to pharmaceuticals and vaccines in both first time that a meeting has taken place which developed and developing countries. The TRIPS involves WHO Member States, experts and inter- Agreement goes far to assure that new medicines ested parties in a discussion on the health aspects will be forthcoming to patients in both developed of trade issues. We trust that our discussions will and developing countries. Patient access to effec- have value not only in consideration of the subject tive therapies is lacking today in countless disease of the debate, but also in establishing a basis for categories, and new diseases are constantly ap- future dialogue on the evolving link between public pearing — twenty or so have been documented health policy and international cooperation on trade over the past two decades. Meanwhile, resistance and related matters. to drugs for older diseases, such as malaria and tuberculosis, is rising. Stronger worldwide patent, One of the most profound effects of globalization as trademark and trade secret protection promises to far as pharmaceuticals are concerned is that more increase access to new therapies which will ad- research will be carried out on a global basis than is dress the incurable diseases of today. the case today. This is a result of international agreements, including TRIPS. Ironically, while the Stronger intellectual property protection applied to threat and burden of many diseases have been the products of pharmaceutical research should, global, pharmaceutical research efforts have, until when applied with vigour at the national level, now, been concentrated in relatively few countries. increase research efforts by local companies which In the future, TRIPS rules can be expected to have thus far been engaged in copying drugs. spread the burden of research more globally and There is evidence of this happening where laws involve local companies and countries which have have changed or are anticipated. Further, with thus far not been part of the process to discover patents protected, global companies will have more new treatments, cures and preventive vaccines. incentives to do research in diseases prevalent in International companies can be expected to in- developing countries and to license technology. crease investment and partnership with local com- This is not feasible where new compounds are panies where this has not been possible until now copied or where counterfeiting prevails. Also, due to the lack of patent protection and prevalence stronger worldwide patent protection will increase of counterfeiting. the already strong competitive pressures on com- panies. Patents do not create 20-year "monopo- The majority of new medicines are discovered and lies". Instead, companies face old and new com- developed by the research industry. This means petition in therapeutic categories and have far less that industry takes the risk of carrying out multi-year than 20 years to exploit their patents. tests on dose-finding, proper indications and safety profile of new chemical and biological compounds, Beyond these factors, individual companies with and designing quality assurance systems for the new research capabilities, and which have been manufacture of the product. All of this takes place founded on the patent system, often enter into before the medicine is either approved or rejected discussion with WHO and governments to provide by regulatory authorities. The failure rate is high: donations and other collaborative programmes to only one medicine receives marketing approval out assist specialized problems such as the recent of thousands of compounds screened for therapeu- initiatives with UNAIDS, or with onchocerciasis, tic benefit. Only one in five entering clinical trials is filariasis and trachoma. Objectively, companies with approved for patient use. Given this situation, and an inclination for these kinds of programmes would the fact that it takes, on average, ten years from have much less incentive to dedicate their re- discovery of a compound to delivery to patients, the sources to such programmes if medicines are drug research and de-velopment process is not internationally diverted through parallel trade — only risky but expensive. In developed countries, which is a windfall benefit for traders, but a hidden the average cost of a new drug today is in the tax on poor countries as well as a regulatory night- neighbourhood of $500 million. Only a minority of mare which can lead to the introduction of sub-

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standard and counterfeit medicines into the drug associations and companies from Africa, Asia and chain. Common sense dictates that a company will Latin America. not want to offer a major concession to a country that wishes cheaper drugs, if those drugs are going IGPA's principal objective is to promote affordable to be diverted to wealthier countries through parallel quality pharmaceutical care for all consumers. More trade. Parallel trade is inconsistent with public specifically it: health. • Supports the development of the international and What effect will new international agreements have regional policies which seek to ensure access to on local companies and on prices of pharmaceuti- medicinal care for all consumers. cals? No generalization can ever apply to every situation but it can be stated that potential concerns • Promotes balanced and generic-friendly intellec- here are often not matched by reality. In addition to tual property laws in the pharmaceutical sector the benefits that can be expected from increased that ensure timely access to the market for research at local level, evidence and the experi- generic products. ence of developing countries which have adopted stronger patent protection over the past decade • Encourages the scientific development and pro- indicate that local industry is not made redundant. A fessional awareness and general knowledge of strong local or international generic company needs generic medicines. good manufacturing quality assurance programmes and the flow of new products coming from strong • Promotes the global harmonization of regulations patent protection. Local industry needs to worry related to generic products. more about good manufacturing practices than patent protection, because patient safety and global • Provides guidance to international organizations competition dictate higher standards. and national governments in improving regulatory and legal expertise relating to the regulation and Regarding price effect of patent changes, there is marketing of generic products. empirical evidence that this is very low for a number of reasons. These relate to the lack of retroactive • Promotes uniform and effective GMP standards application of patents, therapeutic competition from and quality control for generic pharmaceuticals patented and off-patent drugs, the low proportion of and APIs. patented products on the WHO Model List of Es- sential Drugs and in consumption patterns. Access • Seeks strict and effective control to prevent the to medicines is, however, greatly restricted in many production and trade of counterfeit versions of countries by the poor level of public expenditure on original and generic products. health care and the lack of adequate infrastructure. • Supports the development of competition in the pharmaceutical sector. In conclusion, there is much misunderstanding. However, we hope that dialogue with experts and IGPA believes that all pharmaceutical and health interested parties will continue over the coming legislation worldwide should have the protection of years. Without decisions based on dialogue, both public health as its primary aim. However, this does industry's ability to service public health and public not mean that this is the only aim of a global phar- health itself, could suffer. maceutical policy. Encouraging innovation, ensur- ing affordability and access to medicines, and International Generic reducing barriers to trade in pharmaceuticals are also aims that need to be promoted to ensure Pharmaceutical Alliance effective care for patients. In order to promote these Mr G. Perry, Director, European Generic aims, there needs to be a balanced approach, Medicines Association, Brussels, Belgium which takes into account various, and often conflict- ing, interests. The need for a balanced approach is The International Generic Pharmaceutical Alliance particularly important in the area of intellectual (IGPA) was established in 1997 and represents property of pharmaceuticals. generic industry associations from Europe, the United States and Canada. The Organization is Intellectual property rights clearly contribute to the also considering granting observer status to local development of new pharmaceutical products. The

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TRIPS Agreement will enable innovators of phar- The development of generic medicines is one of the maceuticals to benefit from substantial improve- important balances to be ensured in any analysis of ments in protection. The increased financial stability pharmaceutical intellectual property policy. Two and rewards should lead to new revenues for new major instruments exist within TRIPS to promote innovations in the future. this: (i) a system of compulsory licences, and (ii) a system that permits development and registration of However, one of the basic principles of intellectual generic products in advance of patent expiry so as property protection is that patents are limited in to enable the products to enter the market immedi- nature and that the invention, after a period of ately after the end of patent expiry. Within the market protection, is placed in the public domain. In TRIPS Agreement, provision is made for these the pharmaceutical sector, the end of patent protec- policies. For example, Article 30 provides for the tion leads to the development and marketing of advance development and registration of generic generic or multi-source versions of the original medicines. Legislation in Australia, Canada, Hun- brand. This is important for (i) ensuring lower-priced gary, Israel and the United States of America medicines, (ii) encouraging competition in the provides for these activities. The situation in the pharmaceutical sector, and (iii) providing room in European Union is currently under discussion. national or personal budgets to pay for more expen- sive new products. There is clearly a need for greater guidance and discussion on the limitations of TRIPS. The WHO Even in advanced countries, generic medicines can initiative in this area is therefore welcome. The account for up to 40–60% of the pharmaceutical document entitled Globalization and Access to market in volume. In the case of developing coun- Drugs: Implications of the WHO/TRIPS Agreement tries, the creation of an off-patent market also (WHO/DAP/98.9)* is an example of how WHO can opens opportunities for the development of local assist its Member States. In particular, the docu- pharmaceutical industries that can help reduce ment highlights the importance of Article 30. economic dependence on advanced countries.

To date, however, most of the discussion on TRIPS * Ed. note: Globalization and Access to Drugs Ð Implica- has focused on how the provisions must be imple- tions of the WHO/TRIPS Agreement", is classified as a mented to support intellectual property rights. There technical document in the general distribution category. It is not a formal publication of WHO. has been little guidance concerning the agreed limitations of TRIPS. Similarly, there has been little In the light of views expressed subsequent to the emphasis given to the balance of interests and the document being issued, it has been decided to revise and rights of third parties which the TRIPS agreement is re-issue it. The target release date is December 1998, expected to embrace. subject to final review being completed, and will be available from the Action Programme on Essential Drugs, World Health Organization, 1211 Geneva 27, Switzerland.

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Reports on Individual Drugs

The life-threatening risks One case resulted in death, and the other three cases required intensive care. of therapy substitution The long half-life of mibefradil may explain these When a pharmaceutical product is withdrawn from severe reactions (2). It has been proposed that a the market for safety reasons, it is normal to prolonged wash-out period lasting from three days propose a replacement therapy and to give advice to two weeks after mibefradil discontinuation may and instructions on substitution of a similar be necessary before other hypertensives such as product. However, as recently demonstrated follow- beta-adrenoreceptor antagonists and other calcium ing the withdrawal of mibefradil (Posicor®), a channel blockers can be introduced. The manufac- change in treatment can sometimes prove to be turer has now issued amended instructions for life-threatening. initiating substitution therapy (see page 237). In mid-1997, mibefradil was introduced as a new It is often the case that postmarketing surveillance nondihydropyridine calcium channel blocker for the of a new drug will disclose previously unexpected management of hypertension and chronic stable adverse drug reactions or interactions. However, angina. The drug was long-acting, with a half-life of any subsequent withdrawal of the product and between 17 and 25 hours, blocking both the T-type recommendations for substitution therapy also (transient) and the L-type (long-acting) calcium require careful and considerable reflection. channels (1, 2). Because other available calcium channel blockers acted upon the L-type channel References only, mibefradil was unique in terms of mechanism of action, although the rationale for this character- 1. Mibefradil: a new calcium channel blocker. Medical istic remains less well documented (3). As a result Letter, 39: 103–105 (1997). of this selective T-type calcium channel blocker activity, mibefradil was classified as a new category 2. Mullins, M.E., Horowitz, Z., Linden, D.H.J. et al. Life- of calcium antagonist in the expectation that it threatening interaction of mibefradil and beta-blockers would hold advantage over older calcium channel with dihydropyridine calcium channel blockers. Journal of blockers. the American Medical Association, 280: 157–158 (1998). 3. Po, A.L.W, Zhang, W.Y. What lessons can be learnt In June 1998, following reports of serious interac- from withdrawal of mibefradil from the market? Lancet, tions with some 25 commonly used drugs, the 351: 1829–1830 (1998). manufacturer voluntarily withdrew mibefradil from some 38 countries worldwide (4). Since mibefradil 4. WHO Drug Information, 12(3): 145 (1998) was not demonstrated to offer specific benefits over other drugs in the same therapeutic category, its 5. Dear Doctor letter from Roche Laboratories, 8 June complicated drug interaction profile was assessed 1998. to be an unreasonable risk to patients. The manu- facturer urged physicians to contact patients, discontinue treatment and arrange an alternative Revision of HIV treatment therapy (5). guidelines

However, upon introduction of alternative therapy, When the British HIV-1 Association (BHIVA) guide- some new and unexpected life-threatening reac- lines on antiretroviral treatment of HIV-positive tions occurred (2). Four cases of cardiogenic shock individuals were first published in April 1997 (1), it in patients previously taking mibefradil and beta- was already acknowledged that they would require adrenoreceptor antagonists were reported after a updating on a regular basis given the rapid devel- change to substitute dihydropyridine calcium chan- opment of HIV therapies. nel blockers (nifedipine, felodipine or nisoldipine).

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As more experience is gained and newly docu- With sustained monitoring, it will be possible to mented evidence becomes available, treatment evaluate the long-term implications and prolonged regimens undergo modification. In this respect, data use of HIV regimens and determine future dosages. from two large clinical endpoint studies have re- Adverse reactions to HIV protease inhibitors re- cently been presented which demonstrate superior ported so far include hyperglycaemia, hyperlipidae- clinical benefit in the use of triple combination mia, peripheral fat redistribution (lipodystrophy) and therapy compared to dual combination therapy in visceral fat accumulation. Thus, the optimal long- HIV-positive individuals who have either been term treatment approaches to management of HIV treated with zidovudine or are treatment naive. still need to be defined.

The revised criteria for initiation of antiretroviral References therapy in HIV-infected adults, as presented in the latest BHIVA guidelines (2) are the following: 1. WHO Drug Information, 11(3): 134 (1997).

Therapy should be initiated: 2. 1998 revision to the British HIV Association guidelines When the patient agrees to treatment; for antiretroviral treatment of HIV seropositive individuals. Lancet, 352: 314–316 (1998). When benefit outweights the possible risks of therapy; 3. Antiretroviral therapy for HIV infection in 1998. Journal When the CD4 count is >350 cells/ml; of the American Medical Association, 280: 78–86 (1998). When the viral load value is associated with risk of disease progression. Levonorgestrel for Therapy should consist of: emergency contraception <50 000 RNA copies/ml: two nucleoside analogues plus a non-nucleoside reverse transcriptase inhibi- The most commonly used emergency contraception tor or HIV protease inhibitor. until now, the Yuzpe method, was developed in the >50 000 RNA copies/ml: two nucleoside analogues early 1980s. It is based on a modified regimen of plus one or two HIV protease inhibitors. combined oral contraceptive pills containing ethinylestradiol 100 µg plus levonorgestrel 0.5 mg The aim of therapy in treatment-naive patients or dl-norgestrel 1.0 mg, repeated 12 hours later. will be: This regimen prevents about 75% of pregnancies To reduce plasma viral load to less than 400–500 that would have occurred without this treatment. copies/ml (and preferably <50 copies/ml) by 24 However, about 50% of treated women report weeks of therapy. nausea and more than 20% vomiting. There is thus To improve and extend the length and quality of life. a need for a more effective and better tolerated method. In July 1998, the International AIDS Society — USA Panel has also updated its recommendations for Researchers working with the UNDP/UNFPA/WHO/ antiretroviral therapy in HIV infection to bring them World Bank Special Programme of Research, in line with currently available information (3). The Development and Research Training in Human Panel reviewed clinical and basic scientific studies, Reproduction (HRP) confirm that the use of levo- information from phase III clinical trials, and clinical, norgestrel alone for emergency contraception is virological and immunological endpoint data. It also more effective and produces side effects in consid- evaluated presentations made at research confer- erably fewer users than the Yuzpe regimen (1) ences. The Panel concluded that, overall, these data continue to support early introduction of potent Levonorgestrel is a synthetic derivative of the antiretroviral therapy in patients with HIV infection. hormone progesterone. It is one of two active The variety of combination regimens which now compounds present in combined oral contraceptive demonstrate potency will allow a wider choice when pills. In the regimen proposed for emergency con- initiating therapy. traception, two pills each containing 0.75 mg of The Panel recognized the important contribution of levonorgestrel were administered at an interval of plasma HIV RNA assays of increased sensitivity in 12 hours. In a single WHO-supported study carried monitoring the therapeutic response. However, out in Hong Kong, levonorgestrel was slightly but more data are needed to determine precisely the not significantly more effective than the Yuzpe HIV RNA levels that indicate treatment failure. regimen in preventing pregnancy. In particular, the

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proportion of women experiencing vomiting was pregnancy and the occurrence of clear cell adeno- 2.7% with levonorgestrel compared to 22.4% with carcinoma in exposed female offspring (1). the Yuzpe regimen. In the mid-1970s, several cohorts of DES-exposed A double-blind randomized trial in 21 centres world- daughters and unexposed comparison groups were wide was subsequently designed to compare the followed for the occurrence of cancer, precursor two regimens in women, administered within 72 lesions and reproductive side effects. The result of hours of unprotected sexual intercourse. Among the DES exposure on male offspring is still unknown. 1998 women who took part in the double-blind Animal studies have suggested an increased risk of randomized trial, the crude pregnancy rate was testicular cancer, but results in case-control studies 1.1% (95% CI: 0.6–2.0) in the levonorgestrel group have been inconsistent (2). compared to 3.2% (95% CI: 2.2–4.5) in the Yuzpe regimen group. The proportion of pregnancies Some 30% of girls exposed in utero to DES present prevented compared to the expected number a cervical vaginal adenosis and concern has arisen without treatment was 85% with the levonorgestrel that DES may also result in a higher risk of breast regimen and 57% with the Yuzpe regimen. The cancer (3). A study has been carried out of breast efficacy of both treatments was significantly and and other cancers in women exposed in utero to inversely related to time since unprotected coitus DES by combining the previously identified cohorts (p=0.01). The sooner treatment is initiated, the and extending the follow-up from 1978 to 1994. better it works. A total of 4536 DES-exposed daughters (68110 person years) and 1544 nonexposed women The levonorgestrel regimen was more efficacious (22 599 person years) were identified. The rate and better tolerated than the Yuzpe regimen. ratio for breast cancer was 1.18 (95% CI, 0.56– Women in both groups reported the same side 2.49) and adjustment for known risk factors did not effects: nausea, vomiting, dizziness, fatigue, head- alter this result. Similarly, there was no increased ache, breast tenderness and lower abdominal pain. risk for all cancers or for individual cancer sites, However, for each of these side effects, women in except for clear cell adenocarcinoma of the vagina the levonorgestrel group reported them less fre- and cervix. quently (2). Three cases of vaginal clear cell adenocarcinoma Replacement of the Yuzpe method with levonor- occurred among the exposed daughters, resulting gestrel should improve the acceptability and effi- in a standardized incidence ratio of 40.7 (95% CI, cacy of hormonal emergency contraception. Family 13.1–126.2) in comparison with population-based planning programmes may wish to consider making incidence rates. All these cases occurred among a change based on these findings. 29 111 person years accumulated by the cohort up to 29 years of age. The authors of this study con- References cluded that since the majority of women were currently under 50 years of age, it is still important 1. Task Force on Postovulatory Methods of Fertility to continue to monitor cancer risk as the cohort Regulation. Randomized controlled trial of levonorgestrel versus the Yuzpe regimen of combined oral contracep- ages into the menopausal years. tives for emergency contraception. Lancet, 352: 428–433 (1998). References

2. WHO Press Release, WHO/58, 7 August 1998. 1. Herbst, A.L., Ulfelder, H., Poskanzer, D.C. et al. Adenocarcinoma of the vagina: association of maternal stilbestrol therapy with tumor appearance in young women. New England Journal of Medicine, 284: 878–881 Cancer risk in women exposed to (1971). diethylstilbestrol in utero 2. Guisti, R.M., Iwamoto, K. Hatch, E.E. et al. Diethyl- Diethylstilbestrol (DES) was commonly used before stilbestrol revisited: a review of the long-term health 1970 for the prevention of spontaneous abortion effects. Annals of Internal Medicine, 122: 778–788 (1995). and premature delivery. Several million pregnant 3. Hatch, E.E., Palmer, J.R., Titus-Ernstoff, L. et al. women in the United States of America and Europe Cancer risk in women exposed to diethylstilbestrol in were exposed to DES before a strong association utero. Journal of the American Medical Association, 280: was reported in 1971 between use of the drug in 630–634 (1998).

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Zidovudine for mother-to-child land using zidovudine twice daily from 36 weeks gestation until delivery in women who did not transmission of HIV breastfeed showed a 51% reduction in transmission risk (1). WHO recommends the regimen used in Mother-to-child transmission of HIV infection is a this study for settings where practical and budget- major factor in child health and survival. The aver- ary considerations preclude the use of zidovudine age rate of vertical HIV transmission is around or other therapies for longer periods. 25%, but rates differ significantly between coun- tries. These may vary from 14% in Europe to 45% The following important issues should be consid- in sub-Saharan Africa. Breastfeeding may be ered before implementing antiretroviral therapy for responsible for the higher rates in developing prevention of vertical transmission (2): countries. • It is important to improve access to and quality of Many antiretroviral drugs have been developed to services and to assure adequate and functioning treat HIV infection and the use of zidovudine to antenatal care. Health care workers will require reduce vertical transmission is now standard prac- additional training in the administration of anti-HIV tice in many countries, with a consequent reduction therapies. in perinatally acquired HIV. A clinical trial in Thai-

Table 1. WHO recommended short course zidovudine (ZDV) regimen to reduce mother-to-child transmission – possible schedule

Action 1st visit 2nd visit 3rd visit 4th visit delivery and 16 weeks 24–28 weeks 34–36 weeks antenatal care postnatal care

Screen for observe, Assess Assess Assess risk factors score

Screen and anaemia, blood anaemia anaemia anaemia treat/HIV pressure, rapid blood pressure blood pressure blood pressure testing plasma reagin HIV testing HIV pretest/counsel

Prophylaxis *mebendazole *antimalarial *antimalarial *antimalarial intensive treat- *iron + folate * iron + folate * iron + folate * iron + folate ment with oral *tetanus toxoid *tetanus toxoid zidovudine, oral zidovudine 300 mg twice a 300 mg every day from 36 weeks until delivery 3 h of labour- delivery Individual where to give birth test results and infant feeding birth plan support for counselling results of rapid counselling - if HIV positive, decision on infant decision on plasma reagin refer to support consent for feeding infant feeding inform of voluntary groups/services ZDV therapy compliance with confidential testing regimen Inform obtain clean how to prepare if home delivery receive clean refer HIV+ delivery kit for birth and plan plan steps delivery kit mothers for how to seek care for emergency care/support

Plan for next visit/routine next visit/routine follow-up after family planning follow up * bring partner birth. child *partner immunization counselling

* as necessary

225 Reports on Individual Drugs WHO Drug Information Vol. 12, No. 4, 1998

• Voluntary confidential counselling and testing are depend on the number of women consenting to the cornerstones of an HIV care service. When- testing and returning for the results, on the simplic- ever possible, partners should also be counselled ity of the regimen, and the ease with which they can and offered voluntary confidential testing. return for follow-up. Further information concerning the implementation of anti-HIV therapy is available • A system for distribution and supply of antiretro- from WHO and UNAIDS. viral therapy and breastmilk substitutes must be organized. Regular supply, secure storage, References distribution and accounting need to be organized. Zidovudine (ZDV) is now included in the WHO 1. Centers for Disease Control and Prevention. Adminis- Model List of Essential Drugs. The regimen is set tration of zidovudine during late pregnancy to prevent out in table 1. perinatal HIV transmission — Thailand 1996–1998. Morbidity and Mortality Weekly Report, 47: 151–153 (1998). • Upon introduction of antiretroviral therapy, moni- toring and evaluation of safety and efficacy should 2. World Health Organization. Recommendations on the be in place. Factors of operation and efficacy safe and effective use of short-course ZDV for prevention should also be addressed. of mother-to-child transmission of HIV. Weekly Epidemio- logical Record, 73: 313-320 (1998). The successful implementation of an antiretroviral regimen and a decrease in vertical transmission will

Malaria Researchers!

Letters of interest are invited from researchers conducting projects on the discovery and development of drugs against malaria

Pleast contact: MMV/TDR World Health Organization CH 1211 Geneva 27, Switzerland e-mail: [email protected] fax: 41 22 791 4854

226 WHO Drug Information Vol. 12, No. 4, 1998

General Information

Recommendations from the Expert trolled drug in that country. Based on its pharmaco- logical properties and high dependence potential, Committee on Drug Dependence the Expert Committee estimates that it is equivalent in abuse potential and effects to other drugs al- Efforts to provide an international legal framework ready placed in Schedule I of the 1961 Single for the control of psychoactive drugs have resulted Convention on Narcotic Drugs. in the formulation of the 1961 Single Convention on Narcotic Drugs and the 1971 Convention on Psy- Remifentanil is a selective µ-opioid receptor ago- chotropic Substances. Both are major achieve- nist with an ultra-short duration of action which has ments in the development of coordinated interna- been approved for marketing in 17 countries. It is tional control of dependence-producing drugs. The used medically as an analgesic for induction and international drug control treaties are instruments maintenance of general anaesthesia, for continua- which provide a framework for the regulation of a tion of anaesthesia into the immediate postopera- number of defined narcotic drugs and psychotropic tive period under the direct supervision of an substances, the most dangerous of which are anaesthetist or in an intensive care setting, or as an eliminated from use. Those that are potentially analgesic component of monitored anaesthesia beneficial are subjected to controls in production, care. manufacture, trade and distribution so that their use can be limited exclusively to scientific or medical In terms of review criteria under the 1961 Conven- purposes. Details of the scheduling are set out in tion, opioids are calibrated and ranked against the table on page 228. morphine to determine abuse potential. Based on the pharmacological properties and dependence Each Convention embodies a policy and indicates potential of remifentanil, the Committee agreed that the type of legislation and drug regulatory control to abuse liability and the ill-effects profile are similar to be administered. These controls are intended to those of drugs placed on Schedule I of the Conven- ensure the availability for legitimate use of the tion. It was therefore recommended that controlled substances and prevent their abuse. The remifentanil be placed in Schedule I. Conventions assign to WHO the responsibility for recommending their placement in the appropriate With regard to recommendations for scheduling schedules for control purposes and proposing under the 1971 Convention on Psychotropic Sub- amendments to such schedules. The WHO Expert stances, the Committee reviewed the current status Committee on Drug Dependence is charged with of ephedrine use and abuse. The public health and assessing the dependence liability and therapeutic social problems associated with the abuse of usefulness of each substance. Following evaluation ephedrine appear to be significant, particularly in of the seriousness of the public health and social certain African countries. It was therefore recom- problems related to possible abuse, WHO makes a mended that l-ephedrine and the racemate be recommendation to the Commission on Narcotic placed in Schedule IV of the 1971 Convention. Drugs. The d-isomer is significantly less potent than the l-isomer. At the thirty-first meeting of the WHO Expert Com- mittee on Drug Dependence held in June 1998 a In making this recommendation, the Committee number of dependence-producing psychoactive noted that combination products containing ephe- substances were reviewed in order to decide on drine may be eligible for exemption from scheduling their public health impact and status in relation to under the terms of the 1971 Convention. the Conventions. The following substances were recommended for scheduling or review. A proposal was submitted to the Committee con- cerning the scheduling of isomers, esters, ethers Dihydroetorphine is a potent µ-opioid receptor and pharmacological analogues of the psychotropic agonist. Approved for marketing in China for the substances currently controlled in Schedules I and relief of acute severe pain, it is currently a con- II of the 1971 Convention. With regard to the sched-

227 General Information WHO Drug Information Vol. 12, No. 4, 1998

Conventions, schedules and controlled substances* The 1961 Single Convention on Narcotic Drugs Schedule I Common opioid analgesics, coca all specified controls on manufacture, alkaloids, cannabis trade, distribution, storage, record- keeping and reporting Schedule II Codeine and similar drugs less addictive less strict controls on trade than in Schedule I and retail distribution Schedule III Specified preparations containing limited exempt from some control quantities of drugs in Schedule I and II measures such as prescription requirements Schedule IV Some Schedule I drugs which are in addition to all specified controls, particularly addictive, e.g. heroin prohibition recommended Special Opium and opium poppy, poppy straw, cultivation controls and other Measures coca bush and cannabis plant special measures

The 1971 Convention on Psychotropic Substances Schedule I Hallucinogens and stimulants with no very strict controls, e.g. special medical use, e.g. LSD, Ecstasy authorization for research use Schedule II Addictive psychotropic drugs with limited similar controls to narcotic medical use, e.g. amphetamines. drugs in Schedule I Schedule III Addictive psychotropic drugs in common less strict controls on manufacture, medical use, e.g. barbiturates trade, distribution, storage, record-keeping and reporting Schedule IV Less addictive psychotropic drugs, less strict controls than Schedule III e.g. benzodiazepines, anorectic drugs re trade and record-keeping. Pre- scription still required unless specifically exempted by national authorities.

* Scheduling criteria for the Single Convention on Narcotic Drugs, 1961 and the Convention on Psychotropic Substances, 1971 are given in the 29th Report of the Expert Committee on Drug Dependence, WHO Technical Report Series, No. 856, World Health Organization, Geneva. Information concerning obligations of the parties, controls and exceptions relating to the Conventions is available in: Single Convention on Narcotic Drugs, 1961. United Nations, V.93-88216 (1993) and Convention on Psychotropic Substances, 1971. United Nations, V.93-88220 (1993). uling of analogues, which are understood as "any trial and research activities. The Committee pro- modified chemical compounds producing effects posed that criminal activities involving analogues similar to those produced by the original sub- should be controlled at country level by applying stances", the Committee agreed that extending selective controls. controls to these groups could contradict the sched- uling procedure stipulated in the 1971 Convention With regard to the scheduling of isomers, it was which requires WHO to evaluate substances indi- recommended that the addition of the prefix vidually. "stereo" should be made in the following phrase regarding the substances to be included in Sched- Furthermore, the lack of specificity of such group ule I of the 1971 Convention. designations may lead to disagreement among the "The stereo-isomers, except where expressly parties concerning the precise scope of the control excluded, of psychotropic substances in this Sched- procedures. The same concerns apply to esters ule whenever the existence of such stereo-isomers and ethers: though difficult to evaluate, their control is possible within the specific chemical nomencla- could have a negative impact on legitimate indus- ture in this Schedule."

228 WHO Drug Information Vol. 12, No. 4, 1998 General Information

This addition will render the proposal more consist- bances, unconsciousness, hypotension, brady- ent with the current interpretation of the Schedules, cardia, seizures, severe respiratory depression and and clarify the scope of controlled isomers including coma. A withdrawal syndrome has been described racemates. Nonetheless, interpretation guidelines following discontinuation after long-term use. may need to be developed by an appropriate Severe cases of overdosage have required emer- international body such as the INCB in collaboration gency treatment, including intensive care. Although with WHO for those stereo-isomers appearing in results from preclinical studies did not predict high Schedules II, III and IV. abuse liability, this seems to be increasing in the USA and some European countries. Similarly, a The Committee also discussed the following sub- chemical derivative, gamma butyrolactone (GBL), stances to determine the need for their future is also being abused. The Expert Committee rec- review. Recent literature suggests that some ommended that more information on abuse of GHB substances in the benzodiazepine group may be and GBL should be gathered and that a critical more liable to abuse than others. This has been review should be made. documented, in particular, with flunitrazepam, diazepam and the injectable dosage forms of 4-bromo-2,5-dimethoxyphenethylamine (2C-B) is temazepam. Diazepam has been shown to have an a centrally active hallucinogenic substance. It is abuse liability comparable to that of pentobarbital structurally and pharmacologically similar to which is currently in Schedule III. Of the three phenethylamine hallucinogens. Although it is found benzodiazepines, flunitrazepam has already been in circulation in several countries, it is not registered placed in Schedule III and, in the case of for marketing in any. The ease of clandestine temazepam, the higher abuse liability will only apply synthesis and popularity as a claimed sexual en- to the injectable preparation, which is not easily hancer are likely to encourage its production and available. Thus diazepam alone meets the criterion abuse. For this reason, the Expert Committee for critical review. recommended 2C-B for critical review.

Smoking tobacco is dependence-producing and Although no data exists indicating significant abuse causes grave public health consequences. It has no of N-methyl-1-(3,4-methylenedioxyphenyl)-2- medical use. Although new information indicates butanamine (MBDB), it is structurally and pharma- that health risks are greater than previously cologically similar to MDMA and N-ethyl-MDA. thought, tobacco would not meet the scheduling MBDB has been found in circulation in more than criteria under the existing international drug control 10 countries in Europe, Asia and America. There is treaties. Furthermore, once it is scheduled, total thus a strong likelihood that MBDB will become a prohibition would be the only control measure substance of abuse and will lead to similar public applicable to tobacco because the regulated supply health problems as MDMA. The Expert Committee of controlled substances is not allowed for non- recommended that a review should be carried out. medical and non-scientific purposes. A new con- vention such as the International Framework Con- Although rodent data would suggest that zolpidem vention for Tobacco Control would thus have to be may have less abuse potential than benzodi- developed. azepines, human studies do not support this. In general, when contradictory findings exist between Gamma hydroxybutyric acid (GHB) is a metabo- animal and human studies, the latter should take lite of gamma aminobutyric acid (GABA) which is precedence. There have been no reports of illicit found in the human brain. GHB is used in several activities concerning zolpidem, and spontaneous countries in Europe as an anaesthetic and has reports from countries within Europe have included potential usefulness for the treatment of narcolepsy few adverse effects. Although cases of a discon- and drug abuse disorders. GHB is manufactured tinuation syndrome have also been reported, these using a relatively simple synthesis and inexpensive do not appear serious enough to justify international starting materials. control. However, these cases, which were very few at the time of the previous meeting of the Expert Although GHB gained early favour with health Committee in 1996, have increased significantly enthusiasts in the USA as a natural food supple- and the Committee recommended that data should ment, the medical community reported cases of be gathered for appraisal at the next meeting. overdosage and abuse. GHB has been reported to Critical review of zolpidem was recommended. cause drowsiness, dizziness, nausea, visual distur-

229 General Information WHO Drug Information Vol. 12, No. 4, 1998

Insulin: availability, affordability, incidence and prevalence of type-1 diabetes (Table 2). This article examines some of the factors which and harmonization have brought about this inequity, most of which could be overcome by appropriate interventions, as Hilary King well as some other issues relating to insulin use. Noncommunicable Diseases, World Health Organization, Geneva Availability It is useful to distinguish between acute and chronic Insulin is a hormone produced by the beta-cells of shortages of insulin, since these have different the pancreas. In subjects with diabetes mellitus, causes, and potential remedies (2). insulin production is partly or wholly interrupted, as a result of beta-cell destruction (the type-1 proc- Acute shortages ess), or one or several defects in insulin secretion These can occur in any country as a result of civil —almost always with a major contribution from unrest or natural disasters such as earthquakes, insulin resistance (the type-2 process) (1). In the floods, or fire, as well as the financial crises experi- former case, a continuous supply of insulin is enced by countries in economic transition. There usually required for survival. In the latter, it may be have been recent examples in which the availability required for adequate metabolic control. This will of insulin and other aspects of diabetic care have prevent or delay the long-term complications of been studied and reported. diabetes, such as blindness, kidney failure, neu- ropathy, and infection and gangrene of the lower During the war in Croatia, local industry was able limbs. to maintain adequate supplies of insulin, but equip- Patients who require insulin must take it by injec- ment for monitoring metabolic control — without tion, which is normally self-administered one or which insulin treatment may be ineffective — was in more times each day. Traditionally, porcine or short supply (3). Fortunately, the WHO collaborat- bovine insulin has been used for human patients. ing centre for diabetes in Zagreb had numerous Today, recombinant DNA techniques are used to international contacts and these provided the produce biosynthetic human insulin. Insulin is necessary assistance. available in a variety of strengths, of which IU100 (100 international units per ml) and IU40 (40 inter- Following the 1996 earthquake in Kobe, Japan, the national units per ml) are the most frequently used. needs of people with diabetes received the atten- tion of the rescuing authorities once emergency A brief examination of the use of insulin in the world treatment of trauma victims was accomplished (4). reveals a marked disparity between developed and Despite this, poor metabolic control due to suspen- developing countries, with a more than fourfold sion of treatment caused by the destruction of difference in the percentage of diabetic subjects treatment facilities and lack of drugs and equipment who are treated with insulin (Table 1). This may not was frequently reported and the incidence of dia- entirely be accounted for by differences in the betic complications rose.

Table 1. Worldwide use of insulin (8, 23)

Region Population Insulin used Insulin/ Number Number % treated (million) (units/year) person/year diabetic treated with with insulin (million) insulin (million)

Developed 900 105 000 120 55 7 13 countries Developing 4600 45 000 10 100 3 3 countries

World 5500 150 000 30 155 10 6

230 WHO Drug Information Vol. 12, No. 4, 1998 General Information

Table 2. Estimated prevalence of type-1 diabetes and use of insulin in selected countries (24Ð25)

Country Estimated prevalence Units of insulin used (in order of prevalence) of type-1 diabetes per inhabitant per year per 100 000 population

Bangladesh 2 1 China 6 1–2 Indonesia 10 0.5 Japan 31 40 Malaysia 46 20 India 65 4 United States of America 301 200 Australia 370 100

The most effective way of dealing with acute short- they represent temporary solutions. In order to ages is to be prepared. Similar supplies to those achieve self-sufficiency, reorganization of the health which are normally used in the community should care system and revised prioritization is required. be provided in terms of insulin species and Bearing in mind the rapid rise in the number of strength. Provision of ancillary equipment, such as persons affected by diabetes in the developing appropriate syringes and needles, needed to world (7), there is an urgent need to develop na- ensure effective insulin delivery should not be tional diabetes programmes, whereby insulin and overlooked. Major insulin manufacturers, in col- other essential supplies are provided to all those in laboration with the International Diabetes Federa- need (8). At present, many thousands, perhaps tion, are natural partners in combating such acute millions, of people still suffer because of an inad- shortages. They have developed a plan for deliver- equate supply of insulin. ing insulin supplies in emergency situations, whereby the manufacturer will provide up to three Affordability months supply, if the existing distribution networks The cost of insulin is not uniform around the world. are operational (5). In general, it is most cheaply available in the largest markets, because of economies of scale and the Chronic shortages power of negotiation of the authorities when offering In terms of the number of persons affected, chronic large tenders. Some countries impose taxes on shortages are the most widespread and serious. insulin, which are passed on to the consumer and They are mainly confined to the world’s poor coun- may serve to raise the cost substantially. If ad- tries. Table 2 illustrates the great disparity in insulin equate supplies are not available through the use between countries, and suggests a strong government health sector, patients may be forced association with the level of socioeconomic devel- to seek insulin though commercial retailers. In opment. The 400-fold difference between Indone- addition, there is variability in the price demanded sia and the USA is striking, and would suggest that by the major manufacturers. Recently, four compa- few of those who need insulin in Indonesia are nies were asked to quote for the supply of 10-ml receiving it. vials of IU40 bovine and porcine insulin to three destinations — Jakarta, Indonesia, Ndjamena, Chronic shortages of insulin may arise due to Chad, and La Paz, Bolivia. Three companies of- failure of procurement, ineffective distribution, fered prices in the range US$ 2.10–US$3.80 for inadequate storage systems or simply lack of bovine insulin and US$ 3.00–US$ 4.57 for porcine finance in the health sector. In many developing insulin, whilst a fourth company quoted US$5.00 in countries, insulin may be found in urban centres, each case (9). albeit at a high price, but not at all in rural areas, due to the absence of a distribution system. Philan- Furthermore, per capita income is much lower in thropic organizations, as well as the major manu- developing countries, so that those who can least facturers, have helped alleviate shortages in some afford medication are often faced with the highest countries (6). Such donations can save lives, but expense. Ensuring an adequate supply of insulin

231 General Information WHO Drug Information Vol. 12, No. 4, 1998

can consume a large proportion of a family income facilities included those of butchers’ shops and, in in such circumstances. Difficult decisions regarding an enterprising Nigerian example, a beer parlour family expenditure inevitably arise. Some patients (16). resort to buying a vial of insulin, or even a single injection, only when they feel particularly unwell. It has been known for some time that in the ab- Such treatment is obviously of very little benefit in sence of refrigerator facilities, insulin may be stored terms of long-term outcome. Ignorance may also in porous clay pots filled with water and a bed of lead to the unnecessary prescription of insulin to sand. Thirty-eight per cent of diabetic patients in those who might be adequately controlled by other Malawi and 18% of those in Ethiopia used clay pots and cheaper means, such as oral agents, or diet for storage. When considered in the light of some and exercise regimes. Thus, the insulin which is very inappropriate storage choices (freezer, car, top available may not go to those who need it most. In of television, in bed), the opportunity for better this case, education of the health care provider is information to improve patients’ insulin storage required. practices is clear.

The direct, annual cost of diabetes care at the Social and cultural barriers Muhimbili Medical Centre in Dar es Salaam, United In some communities, widespread misconceptions Republic of Tanzania in 1989–1990 was estimated exist concerning insulin. Because it is injected, at US$ 287 for a person requiring insulin and many believe it is a drug of addiction, and are US$ 103 for a person not requiring insulin (10). unwilling to use it even if it is freely available. Purchases of insulin accounted for US$ 156, or Others associate it with a worsening of disease 68% of average annual outpatient costs. When status, and refuse to accept it on that account. Yet compared to the Tanzanian per capita GNP of US$ others consider it a sign of terminal illness. As with 240 at that time, the financial burden of diabetes, the simple recourse to clay pot storage, a small especially the insulin-requiring form, becomes amount of accurate information from a respected obvious. The total outpatient costs of diabetes in health care worker is often all that is required to Tanzania in the same year were estimated at US$ overcome these problems. 2.7 million, out of a total health care budget of US$ 47.4 million, of which insulin supply accounted for Monitoring metabolic control US$ 800 000. Thus, outpatient usage of insulin, Recent research has clearly demonstrated the alone, amounted to 2% of the entire national health importance of good metabolic control in preventing care budget. and delaying the progression of long-term diabetic complications (17). However, in most of the world’s A questionnaire survey via two medical journals, poor countries the possibility of home blood glucose Practical Diabetes Digest and Tropical Doctor, both monitoring — the most effective form — is remote widely circulated in Africa, indicated that in most indeed. Even a weekly blood glucose estimation cases patients were required to pay for their insulin may be considered a luxury in such circumstances (11). Prices quoted for 1990–1991 ranged from and measures of longer-term control, such as the US$ 1.50 to US$ 20 for a 10-ml vial. The same HbA1c estimation, are rarely available in routine report estimated the total annual cost of insulin care. Thus, the insulin which is provided or pur- treatment in sub-Saharan Africa at US$ 25 million. chased may be ineffective and will not achieve the fundamental aim of maintaining the quality of life of Storage the user. Under such circumstances, urine testing is To retain its potency, insulin should be stored at a a useful and more affordable option which should temperature of 4–8 °C. In tropical countries, this be encouraged, notwithstanding its lower precision. can only be achieved in a refrigerator. Recently, several investigators in Africa have reported pa- Harmonization tients’ insulin storage practices, which appear to Insulin is not only available in a variety of forms, it is reflect both underlying socioeconomic conditions also manufactured in several strengths, ranging and level of diabetic education. Use of a refrigerator from 20 international units/ml (IU20) to 100 interna- was recorded in 77% of cases in Tripoli, Libyan tional units/ml (IU100). For the treatment of diabe- Arab Jamahiriya (12), 69% in Soweto, South Africa tes the current WHO Model List of Essential Drugs (13), 37% in Blantyre, Malawi (14) and only 26% in recognizes IU40 and IU100 soluble and intermedi- Addis Ababa, Ethiopia (15). The refrigerator did not ate-acting insulins, in addition to the oral agents always belong to the patient concerned; reported glibenclamide and metformin (18).

232 WHO Drug Information Vol. 12, No. 4, 1998 General Information

In different countries, different forms and strengths The future predominate. This is especially confusing for the Although it is the minority of diabetic patients who traveller, who may inadvertently use the wrong require regular treatment with insulin, the inconven- dose by drawing up their usual quantity of the ience and discomfort of daily insulin injections has wrong strength. It also requires an array of delivery come to be almost symbolic of the disease itself, systems. For this reason, there have been calls, led causing fear and anxiety about diabetes in the by the International Diabetes Federation, for the public at large. Therefore, there has been harmonization of insulin in all countries to IU100 longstanding interest in delivering insulin in less (19). invasive ways. Recent technological advances are making alterna- While such harmonization has much to recommend tive approaches appear more feasible. Good con- it, there are some difficulties to overcome before trol of both type-1 and type-2 diabetes has been such a plan would be universally acceptable. reported using inhaled insulin and at least two Firstly, a 10-ml vial of IU100 insulin is more expen- multinational companies are seriously involved in sive than its IU40 counterpart, and thus, its pur- product development. There is also interest in oral chase may cause greater short-term financial insulin. However, all such methods are currently in hardship. Secondly, the IU100 vial lasts corre- the research phase and they will not be available to spondingly longer, augmenting storage problems in the large majority of patients for some time. the absence of adequate refrigeration. Conclusions The manufacture of smaller vials might address For a variety of reasons, insulin remains unavail- both of these issues, but since the cost of the vial able or unaffordable to many who need it in devel- would remain much the same, extra expense per oping countries. Consideration of insulin supply is unit of insulin would arise. Thus, these matters are an important ingredient of any national diabetes yet to be satisfactorily resolved. programme, but particularly in developing countries. Many of the barriers may be overcome by meas- Human versus animal insulin ures which are within the means of even the world’s Since the arrival of biosynthetic human insulin on poorer nations. the market in the 1980s, there has been a certain amount of controversy about the relative merits of References human and animal insulins. Clearly, human insulin represents the ideal, in terms of potential antigenic- 1. Alberti, K.G.M.M., Zimmet, P.Z. for the WHO ity, and most “affluent” countries rely on it almost Consultation: Definition, diagnosis and classification of entirely. However, antigenic reactions to either form diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus. Diabetic Medicine, of animal insulin appear to be relatively rare, and 15: 539–553 (1998). animal insulin is generally cheaper than human insulin. Therefore, at present, bovine or porcine 2.. Tan, M.-H. Insulin unavailability – problems and insulin still represents a cost-effective way of solutions. International Diabetes Federation Bulletin, 41: achieving metabolic control for many patients, 8–11 (1996). especially in developing countries. 3. Metelko, Z., Roglic, G., Skrabalo, Z. Diabetes in time of A rather greater controversy was created by a armed conflict: the Croatian experience. World Health report that use of human insulin may be associated Statistics Quarterly, 45(4): 328–333 (1992). with a reduced awareness of hypoglycaemia, with a 4. Baba, S., Taniguchi, H., Nambu, S., Tsuboi, S., consequent risk of coma, or even death (20). The Ishihara, K., Osato, S. The Great Hanshin Earthquake. majority of studies which subsequently addressed Lancet, 347: 307–309 (1996). this issue failed to replicate the findings of the original report (21) and almost all experts now 5. Access to insulin, a report on the IDF task force on discount the theory that human insulin is an impor- insulin 1994–1997. Brussels, International Diabetes tant cause of hypoglycaemia unawareness. How- Federation, 1998. ever, the possibility of this association in a small number of susceptible subjects is acknowledged, 6. Raab R. New developments in a practical programme to help provide insulin and diabetes supplies to nations in and no patient should be denied the opportunity to urgent need. International Diabetes Digest, 6(1): 8–10 use animal insulin if prefered. (1995).

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7. King, H., Aubert, R., Herman W.H. Global burden of 16. Gill, G. Insulin storage by diabetic patients in tropical diabetes, 1995–2025: Prevalence, numerical estimates countries. International Diabetes Digest, 7(2): 25 (1996). and projections. Diabetes Care, 21: 1414–1431 (1998). 17. Diabetes Control and Complications Trial Research 8. World Health Organization. Reiber G., King H. Group. The effect of intensive treatment of diabetes on the Guidelines for the development of a national programme development and progression of long-term complications for diabetes mellitus, WHO/DBO/DM/91.1 (1991). in insulin-dependent diabetes mellitus. New England Journal of Medicine, 329: 977–986 (1993). 9. Krosbein, P., Jörgens, V., Berger, M. The price of insulin. International Diabetes Federation Bulletin, 42(3): 8 18. WHO Model List of Essential Drugs (revised in (1997). December 1997). WHO Drug Information, 12(1): 22–35 (1998). 10. Chale, S.S., Swai, A.B.M., Mujinja, P.G.M., McLarty, D.G. Must insulin be a fatal disease in Africa? Study of 19. Towards one strength of insulin (IU100). WHO Drug costs of treatment. British Medical Journal, 304: 1215– Information, 9(3): 163 (1995). 1218 (1992). 20. Teuscher, A., Berger, W. Hypoglycaemia unaware- 11. McLarty, D.G., Swai, A.B.M., Alberti, K.G.M.M. Insulin ness in diabetics transferred from beef/porcine insulin to availability in Africa: an insoluble problem? International human insulin. Lancet, 2, 382–385 (1987). Diabetes Digest, 5(1): 15–17 (1994). 21. Jørgensen, L.N., Dejgaard, A., Pramming, S.K. 12. Bosseri, S. Insulin storage by diabetic patients in Human insulin and hypoglycaemia: a literature survey. Tripoli, Libya. International Diabetes Digest, 7(2):44 Diabetic Medicine, 11, 925–934 (1994). (1996). 22. Jervell, J. Variations in utilization and cost of 13. Gill, G., Ngubane, T. Insulin storage by diabetic insulin.The insulin issue. International Diabetes patients in Soweto, South Africa. International Diabetes Federation Bulletin, 41: 1–2 (1996). Digest, 6(4):89 (1995). 23. Amos, A., McCarty, D.J., Zimmet, P. The rising global 14. Harries, A.D., Maher, D. Home insulin storage by burden of diabetes and its complications: Estimates and patients with diabetes mellitus in Blantyre, Malawi. projections to the year 2010. Diabetic Medicine, 14, International Diabetes Digest, 5(4):104 (1994). Supplement 5 (1997).

15. Seyoum, B., Abdulkadir, J., Feleke, Y., Worku, Y. 24. Gruber et al. (Eds). The Economics of Diabetes and Insulin storage by diabetic patients in Ethiopia. Diabetes Care. A Report of the Diabetes Health International Diabetes Digest, 9(2):43-44 (1998). Economics Study Group. Brussels, International Diabetes Federation (n.d.).

234 WHO Drug Information Vol. 12, No. 4, 1998

Regulatory Matters

Bruising and bleeding with due to stroke, 46 to cardiovascular events, 3 to coronary artery disease and one to severe hypoten- new antidepressants sion and cardiac arrest.

Australia — Use of selective serotonin re-uptake In the 69 patients, the median age was 64, ranging inhibitors (SSRIs) has increased considerably over from 29 to 87 years of age. Twenty-six patients had the past years and the Adverse Drug Reactions Ad- taken the 50 mg dose and 3 the 100 mg dose. visory Committee has published a comprehensive Twelve patients had been using a concomitant adverse effect profile concerning the new SSRIs, nitrate medication that is contraindicated with silde- fluoxetine, paroxetine and sertraline. nafil. In all, 51 patients had one or more cardio- vascular risk factors or cerebrovascular disease. Bruising and bleeding appeared to be important Twenty-five patients died or had symptoms leading adverse reactions to SSRIs. The most common to death within 4–5 hours of use of sildenafil. Three bleeding sites were vaginal (24 cases), and com- died or developed symptoms later the same day, 7 mon bleeding episodes involved epistaxis (19), the next day and 2 three or four days later. haematuria (10), and rectal haemorrhage (8). The Food and Drug Administration will continue to fluoxetine paroxetine sertraline evaluate adverse events and will monitor the need Total reports 919 1036 2023 for regulatory action.

Purpura/bruising 20 38 16 Reference: FDA Viagra postmarketing report, 24 August Bleeding 10 16 41 1998. Thrombocytopenia 9 10 5 Platelet dysfunction 5 5 4 Lipodystrophy and Paroxetine was most commonly cited as a cause of HIV protease inhibitors purpura. Of the 14 reported platelet abnormalities, 11 occurred in association with purpura or bleed- United Kingdom — Since marketing, spontaneous ing. Five of the reports documented abnormal reporting of suspected adverse effects has shown platelet aggregation, supporting the hypothesis that that hyperlipidaemia, glucose intolerance, and dia- fluoxetine may diminish granular storage of sero- betes mellitus can occur with the HIV protease in- tonin in platelets creating a haemostatic defect with hibitors, ritonavir, indinavir, saquinavir and nelfina- bleeding. vir. More recently, 33 case reports have suggested that HIV protease inhibitors may also cause periph- Reference: Australian Adverse Drug Reactions Bulletin, 17: 10 (1998) eral lipodystrophy, increased abdominal fat, buffalo humps and breast hypertrophy.

Reports of death in sildenafil users Although HIV protease inhibitors are a likely cause, this syndrome of reactions has also occurred in pa- United States of America — The Food and Drug tients treated with a combination of other antiretro- Administration has summarized data on 123 viral drugs for HIV which do not include protease in- patients who died after having been prescribed hibitors. The reports are being evaluated to assess sildenafil (Viagra®). Since introduction onto the how product information can be updated to reflect market in March 1998, more than 3.6 million out- the reactions. This will assist physicians and pa- patient prescriptions have been dispensed. Of the tients in choosing appropriate treatment regimens. 123 deaths reported in the USA, 12 were patients from overseas and 42 could not be verified, leaving Reference: Current Problems in Pharmacovigilance, Vol- 69 fatal cases. Of these, the cause of death could ume 24, August 1998. not be determined in 21 patients. Two deaths were

235 Regulatory Matters WHO Drug Information Vol. 12, No. 4, 1998

Australia — The Adverse Drug Reactions Advisory • In patients with a personal or family history of QT Committee has received reports of adverse reac- interval prolongation. tions to HIV protease inhibitors, including lipodys- trophy (94), hyperglycaemia, development or ag- • In patients with a previous history of ventricular ar- gravation of diabetes (14) and nephrolithiasis. rhythmias or torsades de pointes. The most commonly reported adverse effect is lipo- • In patients with risk factors for arrhythmia such as dystrophy, which involves a mobilization of the lipid second or third degree atrioventricular block, clini- stores in the face, arms and legs. Cases have been cally significant heart disease, uncorrected elec- reported involving indinavir (92), ritonavir (4) and trolyte disturbances, renal or respiratory failure. saquinavir (5). Onset began between 5 days and one year after commencement of treatment, with a Concern has also been expressed about use of cis- mean of 6 months. apride in children for infantile gastro-oesophageal reflux disease following reports of QT interval pro- Adverse effects are estimated to affect about 60% longation in neonates. The pharmacokinetic action of patients taking HIV protease inhibitors. of cisapride in premature neonates is unpredictable and may lead to potentially cardiotoxic blood levels. Reference: Australian Adverse Drug Reactions Bulletin, Cisapride is therefore contraindicated in premature 17: 6 (1998). infants and for up to 3 months after birth. Further- more, insufficient data are available to support cis- Cisapride: new contraindications apride use in children under 12 years of age. United Kingdom — The Medicines Control Agency Reference: Current Problems in Pharmacovigilance, Vol- ume 24, August 1998. has alerted prescribers to an interaction between cisapride, a drug for reflux oesophagitis, and other drugs metabolized by the cytochrome P4503A4 Cisapride: risk of arrhythmias liver enzyme system. Raised blood levels of cis- apride may cause QT interval prolongation and United States of America — The Food and Drug ventricular arrhythmias leading to direct electro- Administration has warned physicians of the car- physiological effects on the heart. diac risks associated with the use of the night-time heartburn drug, cisapride. Between 1993 and 1998 Serious cardiac arrhythmias such as ventricular there have been 38 reports of death including heart tachycardia, ventricular fibrillation and torsades de rhythm disorders, death in patients with particular pointes, resulting in sudden death, have been re- underlying medical conditions, and patients taking ported in patients taking cisapride. Many of these other medications. patients had also taken other drugs suspected of in- creasing cisapride levels in blood by inhibiting liver The drug should not be used in patients taking enzyme metabolism. However, reactions have also certain antibiotics, antidepressants, antifungals, or occurred in the absence of interacting drugs. protease inhibitors. Contraindications now include congestive heart failure, multiple organ failure, It is therefore recommended that cisapride should chronic obstructive pulmonary disease and ad- not be used in the following circumstances: vanced cancer, electrolyte disorders – hypokalae- mia or hypomagnesaemia — severe dehydration, • With CYP3A4-inhibiting drugs, including macrolide vomiting, diarrhoea, malnutrition, those taking antibiotics such as erythromycin or clarithromycin, potassium-wasting diuretics and /or insulin, or azole antifungals such as fluconazole, itracona- those who may experience rapid reduction of zole, or ketoconazole, HIV protease inhibitors plasma potassium. such as ritonavir or indinavir, and nefazadone. It is recommended that drugs other than cisapride, • With drugs known to prolong the QT interval such including lifestyle modification, should be used for as quinine, halofantrine, terfenadine, astemizole, the primary treatment of night-time heartburn due to amiodarone, quinidine, amitriptyline, pheno- reflux oesophagitis. thiazines and sertindole. Reference: FDA Talk Paper, T98–39, 1998.

236 WHO Drug Information Vol. 12, No. 4, 1998 Regulatory Matters

Mibefradil: instructions for This case demonstrates the problem of disharmony therapy substitution in regulatory action between countries and among pharmaceutical companies concerning severe United States of America — Following the world- safety problems involving the same product. wide withdrawal of mibefradil (Posicor®) (1) the manufacturer has issued instructions to physicians Reference: Communication to WHO from the Federal concerning substitute therapy. Unfortunately, a Institute for Drugs and Medical Devices, Germany, small number of patients have experienced life- 4 November 1998. threatening drug interactions caused by the change to alternative therapy. The following precautions Isotretinoin: adverse should be taken to avoid drug-drug interactions (2): reaction profile 1. If either amlodipine or atenolol is to be substi- tuted, the medication should be started two or three United Kingdom — The Medicines Control Agency days prior to mibefradil discontinuation. has received 841 reports of adverse reactions as- sociated with use of isotretinoin since the drug was 2. If another calcium channel blocker (except approved for marketing in 1982. felodipine) or a beta adrenoreceptor blocker (except timolol) is substituted, it should be started 7 days Most frequently reported reactions were skin disor- after mibefradil discontinuation. ders such as rash, dry skin and photosensitivity (18%), musculoskeletal disorders such as myalgia 3. If felodipine or timolol is chosen, it should be and arthralgia (11%), gastrointestinal disorders started 14 days after mibefradil discontinuation. such as cheilitis, abdominal pain and dry mouth (10%), eye disorders such as conjunctivitis, dry 4. No special precautions regarding the timing are eyes and blurred vision (7%), neurological disor- necessary for other antihypertensive or anti-anginal ders such as migraine and convulsions (7%), and medications such as ACE inhibitors, angiotensin II psychiatric reactions, including depression, suicide antagonists, diuretics, or nitrates. and attempted suicide (5%).

References Physicians are reminded that isotretinoin is a tera- togen and is contraindicated in women of childbear- 1. WHO Drug Information, 12(3): 145 (1998). ing age unless the following criteria are respected:

2. Communication to the Food and Drug Administration's • Isotretinoin is only for use in severe, disfiguring Medwatch from Roche Laboratories, dated June 12 1998. cystic acne resistant to standard therapy. • Pregnancy must be excluded before starting Mibefradil suspended therapy and a negative pregnancy test must be in Germany obtained within two weeks prior to therapy. • Effective contraception must be practised for at Germany — In June 1998, Roche withdrew mibe- least 4 weeks before treatment, during the treat- fradil (Posicor 50/100®, Cerate 100®) worldwide ment period and for at least four weeks following for safety reasons. However, mibefradil was still cessation. marketed in Germany by Asta Medica under the brand name Cerate 50. Asta Medica has refused to Isotretinoin should only be given by, or under the follow Roche's decision. It has none the less agreed supervision of, a specialized physician or derma- not to continue selling the drug without the agree- tologist and should not be prescribed by a non- ment of the German drug regulatory authority, specialist. The physician must clearly explain the BfArM. precautions, ensure that the patient understands the risks, and confirm that the warnings have been At the end of August 1998, BfArM ordered a three- understood. month suspension of Asta Medica's marketing au- thorization for mibefradil and recall of the product. Reference: Current Problems in Pharmacovigilance, Vol- Asta Medica does not agree with the reasons for ume 24, August 1998. the withdrawal and has a month in which to appeal.

237 Regulatory Matters WHO Drug Information Vol. 12, No. 4, 1998

the HER2 protein. In the case of metastatic breast Depression with isotretinoin cancer cells, approximately 30% of tumours pro- Australia — A total of 129 reports of adverse reac- duce excess amounts of HER2. Only patients who tions associated with the use of isotretinoin have have tumours with this characteristic have been been received by the Adverse Drug Reaction Ad- shown to benefit from the new targeted approach. visory Committee between 1985 and 1998. Of these, 12 described depression in patients aged Trastuzumab (Herceptin®) is used alone intra- 15–40 years. The median age was 19 years, and all venously for patients where chemotherapy has patients were taking the drug for acne. In 10 re- been abandoned, or as treatment for metastatic ports, this was the first episode of depression: 2 disease in combination with paclitaxel in treatment- cases were severe and 4 cases presented psy- naive patients. chotic features. Three patients had suicidal thoughts, and 2 attempted suicide, with one fatal Trastuzumab is the second monoclonal antibody to outcome. be approved for cancer. The first was approved in 1997 for patients with non-Hodgkin lymphoma. Physicians are advised to be alert for any mood changes in patients taking isotretinoin and to with- Reference: HHS News, P98-27, September 1998. draw the drug if this occurs.

Reference: Australian Adverse Drug Reactions Bulletin, Ritonavir and ecstasy — 17: 11 (1998). a fatal combination Sweden — The Medical Products Agency has is- Orlistat sold illegally sued a warning concerning the potentially fatal out- come of using the HIV protease inhibitor, ritonavir, Switzerland — The authorities in the canton of Zu- with the illicit amphetamine-type drug, ecstasy. In rich have seized several hundred packs of the anti- two fatal cases, the concentration of 3,4- obesity drug orlistat (Xenical®: Roche) from phar- methylendioxymetamfetamin in plasma was more macies and doctors' surgeries. The product has not than ten times higher than that normally detected in yet received marketing authorization and was being users. Ritonavir is one of the most potent inhibitors prescribed and dispensed illegally. of cytochrome P450, including both CYP2D6 and CYP3A4 liver enzymes. Ecstasy is metabolized by Advertisements announcing that the product was CYP2D6 enzymes and it is possible that ritonavir available for sale appeared in local newspapers slows down ecstasy elimination, resulting in highly shortly after it had received marketing authorization toxic levels in plasma. from the European Union Commission earlier this year. Many opiates such as dextromethorphan, codeine, hydrocodon, oxycodon, dihydrocodeine and Meanwhile, the Intercantonal Office for the Control etylmorphine are similarly metabolized by the P450 of Medicines is currently assessing a marketing ap- enzymes mentioned above. Thus, concomitant use plication for orlistat and has requested the company of ritonavir with these opiates can result in a poten- to provide additional information on the possible tiated narcotic effect and risk of toxicity. risks of breast cancer. Reference: Information from the Medical Products Reference: SCRIP, No. 2361, 14 August 1998. Agency, 9: 5 (1998).

Trastuzumab: approved for WHO recommendations for breast cancer influenza virus vaccines — 1999 United States of America — The Food and Drug World Health Organization — Epidemics of influ- Administration has approved a monoclonal antibody enza occur at different times of the year in different as a new biological treatment for metastatic breast parts of the world and the influenza virus is con- cancer, or cancer that has spread beyond the stantly changing. It is therefore appropriate for breast and underarm lymph nodes. Trastuzumab WHO to review recommendations twice a year. inhibits tumour cell growth by the binding action of

238 WHO Drug Information Vol. 12, No. 4, 1998 Regulatory Matters

A recommendation will continue to be made each • Liver function to be monitored at least every February relating to the composition of vaccines in- month. tended for use for the following winter in the north- ern hemisphere and a second recommendation will • If elevated levels of hepatic enzymes or other be made each September relating to vaccines for symptoms of hepatic dysfunction are observed, use the following winter in the Southern hemi- stop medication. sphere. • Prior to taking this medication, patients should be Consequently, vaccines for use in the 1999 season informed of the possibility of hepatic dysfunction in the southern hemisphere should contain the fol- and should be instructed to stop the medication lowing: and to consult their physician immediately if signs of hepatic dysfunction are observed. • an A/Sydney/5/97 (H3N2)-like virus; References • an A/Beijing/262/95 (H1N1)-like virus; 1. Communication from the Ministry of Health and Wel- • a B/Beijing/184/93-like virus. (The most widely fare, Japan, to WHO dated 20 August 1998. used vaccine virus is B/Harbin/7/94.) Ebrotidine: liver toxicity Reference: Weekly Epidemiological Record, 73: 305–308 (1998). Spain — The Medical Products Agency has sus- pended the marketing authorization of ebrotidine, an anti-ulcer H receptor blocker, following reports Rhabdomyolysis and ritodrine 2 of serious liver damage. Japan — The Pharmaceutical and Medical Safety No cases of liver injury were reported during clinical Bureau has received nine reports of rhabdomyoly- trials, but several reports have been received sub- sis associated with ritodrine, used to avoid miscar- sequent to marketing in 1997. Most cases occurred riage and premature birth. in patients using the drug for more than 6 weeks or because of concomitant use of other medications Three of the patients received both tablets and in- known to cause hepatotoxic reactions. jections. Symptoms included myalgia, enervation and elevated creatine phosphokinase levels. The Given the availability of other remedies of equal product information has been revised accordingly. therapeutic value, the company has agreed to with- draw the drug from the Spanish market. Reference: Pharma Japan, 1604, 29 June 1998. Two other countries, Mauritius and Paraguay, have granted a marketing authorization for this product. Flutamide: severe hepatic Reference: Communication from the Ministerio de dysfunction Sanidad y Consumo, Spain, to WHO dated 27 July 1998. Japan — The Pharmaceutical and Medical Safety Bureau has instructed the manufacturer of Meloxicam: gastrointestinal flutamide, an anti-androgen treatment for prostate cancer, to revise the information leaflet and to circu- and skin reactions late a letter to health care professionals indicating United Kingdom — A total of 773 reports were re- that 5 fatal cases of hepatic dysfunction have been ceived by the Medicines Control Agency between associated with use of flutamide this year. Elevated 1996 and 1998 describing 1339 suspected adverse levels of hepatic enzymes have been reported and reactions to meloxicam, a nonsteroidal anti-inflam- deaths occurred during 1995 and 1996. matory drug for osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. The revised information leaflet now includes hepatic dysfunction as a contraindication and a warning has The most frequently reported reactions were gas- been added as follows: trointestinal (41%), dermatological, neurological,

239 Regulatory Matters WHO Drug Information Vol. 12, No. 4, 1998

and cardiovascular, including dizziness, flushing Illegal and counterfeit and fatigue. Although most patients recovered after meloxicam withdrawal, 5 deaths were reported. sildenafil on sale

Of the 193 reports involving skin reactions, the Early in 1998, before sildenafil (Viagra®) was au- most common were pruritus, rash and urticaria. thorized for marketing, several drug regulatory au- Angioedema was reported in 25 patients, photosen- thorities investigated its promotion and illegal sale sitivity in 12, and bullous dermatoses, including ery- (1). In the United Kingdom, faxed messages were thema multiforme and Stevens-Johnson syndrome sent to private individuals offering details of how in 5 patients. and where Viagra could be obtained, either through the internet or by telephone (2). In July, the UK Reference: Current Problems in Pharmacovigilance, Vol- Medicines Control Agency seized 14 boxes of unli- ume 24, August 1998. censed sildenafil openly on sale in London (3).

Sildenafil can be obtained via the internet. Illegal Vaccine-associated sales have also been reported from Austria, thrombocytopenic purpura France, Germany, Hong Kong (Special Administra- tive Region), Republic of Korea, the Russian Fed- Japan — Since 1994, the Pharmaceutical and eration, Spain and Sweden. (4). In addition to this, Medical Safety Bureau has received 13 reports of counterfeits originating in Mexico, Israel and India acute thrombocytopenic purpuras associated with have also appeared on the market in the Russian vaccination. These include 8 cases following rubella Federation (5). vaccine, 3 with measles vaccine and 1 following both diphtheria-tetanus-pertussis (DTP) and These situations not only challenge regulatory con- mumps vaccine. The rubella, measles and mumps trol and legislation on promotional activities, but vaccines were freeze-dried, live attenuated vac- point to the need for appropriate resources for en- cines and the DTP was purified combined. forcement to combat the illegal cross-border sale of medical products. Reference: Pharma Japan, 1604, June 1998. References: Abortifacients on free sale 1. Viagra's licence and the internet. Lancet, 352: 751 (1998). Brazil— Physicians and health authorities are call- ing for new public health measures to reduce the 2. SCRIP, No. 2363, 21 August 1998. risk of birth defects associated with the misuse of 3. Pharmaceutical Journal, 261: 185 (1998). misoprostol, a drug marketed for gastric ulcer, as an abortifacient (1). A recently published study re- 4. SCRIP, No. 2347, 26 June 1998. ports 42 cases of infants exposed in utero to miso- prostol during the first trimester of pregnancy and 5. SCRIP, No. 2360, 12 August 1998. born with abnormalities, mostly limb defects (2). The defects may be caused by vascular disruption due to misoprostol-induced uterine contractions. Current standards for over-the-counter analgesics The authorities are also investigating reports of the illegal sale in pharmacies of an "abortion kit" com- Finland — The National Agency for Medicines has posed of misoprostol and the anticancer drug, reviewed the safety, efficacy and rationale of fixed- methotrexate. dose combinations of analgesics available over-the- counter. The review also assesses the validity of References summary product characteristics and package infor- 1. SCRIP No. 2342, 10 June 1998. mation for the consumer. 2. Gonzalez, C.H., Marques-Dias, M.J., Chong, A.K. et al. It was concluded that the following combinations Congenital abnormalities in Brazilian children associated are irrational, unsafe or insufficiently documented in with misoprostol misuse in first trimester of pregnancy. clinical trials: Lancet, 351: 1624–1627 (1998).

240 WHO Drug Information Vol. 12, No. 4, 1998 Regulatory Matters

• Products containing two or more salicylic acid de- ing agitation/restlessness (15), allergy, including rivatives. anaphylaxis, angioedema and urticaria (10), chest pain (7), tremor (5), mouth dryness (5), vertigo (4) • Products containing acetylsalicylic acid plus and arthralgia (3). phenazone or phenazone salicylate. Reference: Current Problems in Pharmacovigi- • Codeine in combination with caffeine. lance, Volume 24, August 1998.

The Agency recommends the following single- component products for the symptomatic relief of Reformulation of flunitrazepam pain, fever and the common cold: acetylsalicylic tablets to prevent misuse acid, ibuprofen, ketoprofen or paracetamol. Re- moval of the above-mentioned inappropriate combi- Sweden — The Medical Products Agency has is- nations will improve the efficacy and safety of self sued information concerning the reformulation of medication. Rohypnol® tablets containing the benzodiazepine, flunitrazepam. Reference: Drug Information from the National Agency for Medicines (TABU), 6: 39–41 (1998). Since the drug has been subject to misuse, the new tablet is harder and film coated to make it difficult to Safety of leukotriene antagonists dissolve in injections or to smoke. Additionally, the new tablet is green, with a core of indigo that will in- United Kingdom — The Medicines Control Agency stantly colour any liquid it is placed in. This will alert has published a review of adverse drug reactions to the consumer that flunitrazepam has been added to a new class of asthma drugs, leukotriene antago- the drink. nists. Zafirlukast and moltelukast, competitive cys- teinyl leukotriene type-1 receptor antagonists, were Reference: Information from the Medical Products both marketed for the first time in 1998. Agency, 9: 6 (1998).

Cysteinyl leukotrienes are inflammatory mediators Nicergoline re-evaluated and potent constrictors of bronchial smooth muscle that attract human eosinophils and cause airway Japan —The Ministry of Health and Welfare has oedema, mucus hypersecretion and reduced limited the indications for nicergoline based on a mucociliary clearance. By blocking this action, leu- decision by the Committee on New Drug Re- kotriene antagonists can improve respiratory func- examination and Re-evaluation. Nicergoline has tion and lessen symptoms in patients with asthma. been used for the improvement of cerebral circula- tion and metabolism with indications that it will "im- The pharmacological action of leukotrienes is quite prove hyperbulia and emotional disorders due to complex and varying side effects have been chronic cerebral circulatory disorders associated reported. Zafirlukast inhibits the hepatic cytochrome with sequelae of cerebral infarction and cerebral P4502C9, and interacts with warfarin, theophyllin, haemorrhage". terfenadine, acetylsalicylic acid and erythromycin. Montelukast is metabolized by hepatic cytochrome The Ministry has cancelled the marketing authoriza- P450CYP3A4 and co-administration of such drugs tion of nicergoline and ordered the 18 generic as phenytoin, phenobarbitone and rifampicin, which manufacturers to discontinue production and sale of induce this enzyme, result in a marked reduction in 23 nicergoline products and recall all batches from plasma levels. medical institutions and pharmacies within two weeks. Side-effects identified during clinical trials were headache, abdominal pain, nausea, diarrhoea, Following the re-evaluation of new clinical trials car- gastro-enteritis, influenza, pharyngitis, sinusitis, ried out independently by the company, on the one cough, nasal congestion, dizziness, fatigue and in- hand, and the generics manufacturers on the other, somnia. Since marketing of montelukast, 173 re- the original product, Sermion® was re-granted mar- ports of 317 suspected adverse drug reactions keting approval. However, all generics were de- have been received in the United Kingdom. These listed as a result of insufficiently demonstrated effi- include oedema (50), psychiatric reactions, includ- cacy. The revised indication is "improvement of

241 Regulatory Matters WHO Drug Information Vol. 12, No. 4, 1998

hyperbulia due to chronic cerebral circulatory dis- References orders associated with the sequelae of cerebral infarction". 1. CPMP Press Release, 28 May 1998, CPMP/1150/98. WHO Drug Information This unusual case involving the refusal of an origi- 2. , 11: 251 (1997). nal product manufacturer to cooperate in clinical trials with generic manufacturers may make the re- Chinese herbal medicines evaluation of generics a major issue for discussion in health care reform. and adverse reactions

Reference: Pharma Japan, Number 1604, June United Kingdom — In analyses carried out by 1998. King's College Hospital in London, 7 out of 10 creams prescribed to children and adults by herbal practitioners were found to contain dexamethasone, Entacapone for Parkinson disease a corticosteroid. European Union — The Committee for Proprietary The creams were prescribed for eczema, eczema Medicinal Products has given a positive opinion for herpeticum, and scaly scalp. Children had received marketing of entacapone, a catechol-O-methyl higher doses than adults. In one case application of transferase (COMT) inhibitor. Entacapone prevents the cream resulted in severe eczema herpeticum the peripheral breakdown of levodopa and in- requiring hospitalization. creases the amount of dopamine transmitted to the The Pharmaceutical Journal brain (1). This is the second COMT inhibitor ap- Reference: , Volume 261, 8 August 1998. proved for Parkinson disease. The first was tolcapone (2).

242 WHO Drug Information Vol. 12, No. 4, 1998

Essential Drugs

WHO Model Formulary

As described in previous issues of this journal, work is now under way on the WHO Model Formulary, and draft texts will be published regularly to obtain comments on the material proposed for publication. Observations concerning the following sections should be addressed to: Drug Selection and Information (DSI), Division of Drug Management & Policies, World Health Organization, 1211 Geneva 27, Switzerland.

Ophthalmological preparations Silver nitrate is a topical anti-infective. Its germicidal activity is attributed to precipitation of bacterial pro- teins by silver ions. It is available in a 1% ophthal- Anti-infective agents mic solution and is used for prophylaxis of gono- Blepharitis, conjunctivitis, keratitis and endophthal- coccal ophthalmia neonatorum. mitis are common acute infections of the eye, and can be treated topically. However, in some cases Tetracycline is a broad-spectrum antibiotic with ac- — for example gonococcal conjunctivitis — both tivity against Gram-positive and Gram-negative topical and systemic anti-infective treatment may be bacteria including N. gonorrhoeae, and most necessary. Blepharitis and conjunctivitis are often chlamydia, rickettsia, mycoplasma and caused by staphylococcus, while keratitis and en- spirochaetes. Ophthalmic tetracycline is used in dophthalmitis may be bacterial, viral or fungal. blepharitis, conjunctivitis, and keratitis produced by susceptible bacteria. It is also used in the treatment Bacterial blepharitis is treated with an antibacterial of trachoma caused by Chlamydia trachomatis and eye ointment or drops to the conjunctival sac or to in the prophylaxis of ophthalmia neonatorum the edges of the eyelid. Although most cases of caused by N. gonorrhoeae and C. trachomatis. acute bacterial conjunctivitis may resolve spontane- ously, anti-infective treatment shortens the infec- tious process and prevents complications. Acute in- GENTAMICIN fective conjunctivitis is treated with antibacterial eye Solution (eye drops): 0.3% drops by day and eye ointment at night. A poor re- sponse may indicate viral or allergic conjunctivitis. Uses: Blepharitis, conjunctivitis Keratitis requires immediate specialist treatment. Dosage: Mild to moderate infection Gentamicin is a broad-spectrum bactericidal anti- Apply 1 drop to the affected eye every 2 hours until biotic with particular activity against Pseudomonas infection is under control. Thereafter, apply less fre- aeruginosa, Neisseria gonorrhoeae and other bac- quently, but continuing for 48 hours after infection teria that may be implicated in blepharitis or con- has cleared. junctivitis. Topical application can however lead to systemic absorption, and possible adverse effects. Severe infection 1 drop every hour. Idoxuridine is used in the treatment of keratitis due to herpes simplex virus. Idoxuridine is effective Contraindications: Hypersensitivity to gentamicin against initial epithelial infections. These may and to any related antibiotic. respond to treatment within a week and resolve Precautions: Prolonged use may result in over- completely in 1–2 weeks. Eye drops must be ap- growth of non-susceptible organisms including plied frequently to keep the concentration high and fungi. Discontinue if there is purulent discharge, in- achieve a successful therapeutic outcome. flammation or exacerbation of pain.

243 Essential Drugs WHO Drug Information Vol. 12, No. 4, 1998

Adverse effects: Burning or stinging sensation. Precautions: Avoid contact with the skin to prevent staining. Avoid use of old solutions: the concentra- Drug interactions: These will appear in tabulated tion will increase as a result of solvent evaporation. form in the appendix of the published edition of the WHO Model Formulary. Adverse effects: Mild conjunctivitis. Repeated ad- ministration may cause corneal cauterization and blindness. Skin and mucous membrane irritations IDOXURIDINE may occur. Solution (eye drops): 0.1% Eye ointment: 0.2% Drug interactions: These will appear in tabulated Uses: Keratitis or keratoconjunctivitis caused by form in the appendix of the published edition of the herpes simplex virus. WHO Model Formulary.

Dosage: TETRACYCLINE Ophthalmic solution: Initially, apply 1 drop to each Ointment: 1% (hydrochloride) eye every hour and every two hours at night until there is significant improvement. Thereafter, apply Uses: Superficial ocular bacterial infections, pro- 1 drop every two hours during the day and every phylaxis of ophthalmia neonatorum due to N. four hours at night. Treatment should be continued gonorrhoeae or C. trachomatis. Mass treatment of for up to 5 days after complete healing. trachoma in endemic areas.

Ophthalmic ointment: 1 application to the conjunc- Dosage: tival sac every 4 hours and at bedtime (5 applica- Adults: Ointment should be applied to the affected tions daily). Treatment should be continued for up eye 3–4 times daily. In the case of C. trachomatis to 5 days after complete healing. infection, treatment should continue for at least 3 weeks. Contraindications: Hypersensitivity to idoxuridine or any of its components. Concurrent use of corti- Ophthalmia neonatorum costeroids. Apply a thin layer of the ointment to the conjunctival sac. Lower the neonate’s eyelids and massage Precautions: Do not exceed the frequency and du- gently to spread the ointment. Treatment should be ration of treatment. If there is no relief after 7 days, undertaken within one hour of delivery to achieve discontinue treatment. maximum effect.

Adverse effects: Burning, pain, inflammation and Contraindications: Hypersensitivity to tetra- itching occur occasionally, and allergic reactions cyclines. rarely. Photophobia may occur. Precautions: Prolonged use may result in over- Drug interactions: These will appear in tabulated growth of non-susceptible organisms including form in the appendix of the published edition of the fungi. WHO Model Formulary. Adverse effects: Dermatitis, transient stinging or burning sensation occur rarely and increased lacri- SILVER NITRATE mation has been reported. Solution (eye drops): 1% Uses: Prophylaxis of gonococcal ophthalmia neo- Drug interactions: These will appear in tabulated natorum. form in the appendix of the published edition of the WHO Model Formulary. Dosage: The neonate’s eyes should be cleaned with sterile gauze before applying 2 drops of the solution to the lower conjunctival sac. Excess solu- Anti-inflammatory agents tion around the eye should be removed to avoid Topical ophthalmic corticosteroids such as pred- staining. nisolone are useful in inflammatory conditions such as uveitis and scleritis. They are also used for post- Contraindications: Hypersensitivity. operative ocular inflammation. The duration of treat-

244 WHO Drug Information Vol. 12, No. 4, 1998 Essential Drugs

ment depends on the type and severity of infection Contraindications: Hypersensitivity to tetracaine and may range from a few days to several weeks. and other ester-type local anaesthetics. Ocular in- However, long-term use should be avoided. Cessa- flammation or infection. tion should be gradual to avoid exacerbation of the condition. Precautions: Prolonged use may result in severe keratitis, permanent corneal opacification, scarring Topical corticosteroids should only be prescribed by and delayed corneal healing. The anaesthetized qualified ophthalmologists as they may aggravate eye should be protected from dust and bacterio- ocular inflammation due to underlying herpes sim- logical contamination until sensation is fully plex or open-angle glaucoma. restored.

Adverse effects: PREDNISOLONE Burning sensation, stinging, and redness occur frequently. Allergic reactions are re- Eye drops: 0.5% ported rarely. Uses: Short-term treatment of ocular inflammation. Drug interactions: These will appear in tabulated Dosage: Apply 1–2 drops to the eye every 1–2 form in the appendix of the published edition of the hours until inflammation subsides. WHO Model Formulary.

Contraindications: Hypersensitivity to cortico- steroids. Pre-existing glaucoma. Miotics and antiglaucoma drugs Glaucoma is often associated with abnormally Precautions: Use with caution in patients with high intra-ocular pressure and may result in blind- cataract, diabetes, corneal thinning disease or in- ness. The rise in pressure is almost always due to fections of the cornea or conjunctiva. reduced outflow of aqueous humour, the inflow re- maining constant. It can be treated by application Adverse effects: Corneal thinning, which may of eye drops containing beta adrenoreceptor an- impair corneal healing. Increased intra-ocular pres- tagonist, miotics or epinephrine. sure, which may precipitate glaucoma, optic nerve damage, or cataract. Secondary ocular infections. The commonest condition is chronic, simple glau- Burning or stinging sensations may occur rarely coma where the obstruction is in the trabecular meshwork. This is treated initially with a topical Drug interactions: These will appear in tabulated beta adrenoreceptor antagonist. Epinephrine or form in the appendix of the published edition of the pilocarpine is added to control the intra-ocular WHO Model Formulary. pressure as necessary. Miotics, through their parasympathomimetic action, Local anaesthetics contract the iris sphincter and the ciliary muscle Topical local anaesthetics are employed for simple and widen the trabecular meshwork, thereby facili- ophthalmological procedures and for short opera- tating outflow of the aqueous humour and lowering tive procedures involving the cornea and conjunc- intra-ocular pressure. However, systemic absorp- tiva. Tetracaine, available in 0.5% ophthalmic solu- tion may occur, producing muscarine-like toxicity. tion, provides a rapid local anaesthesia which lasts for 15 minutes or more. Prolonged or unsupervised Acetazolamide, a carbonic anhydrase inhibitor, use of tetracaine is not recommended. reduces intra-ocular pressure by reducing the pro- duction of aqueous humour. Carbonic anhydrase inhibitors are used as adjuncts for prolonged TETRACAINE therapy in patients with open-angle glaucoma not Solution (eye drops): 0.5 % (hydrochloride) responsive to miotics alone. They should be admin- istered concurrently with pilocarpine or epine- Uses: Short-acting local anaesthesia of the cornea phrine, to enhance their antiglaucoma effects. and conjunctiva. Timolol is a non-selective beta adrenoreceptor an- Dosage: tagonist with an intra-ocular pressure lowering ef- One to two drops instilled into the conjunctival sac. fect. However, since systemic absorption may oc-

245 Essential Drugs WHO Drug Information Vol. 12, No. 4, 1998

cur, ophthalmic beta adrenoreceptor antagonists Contraindications: Hypersensitivity. should be used with caution in certain individuals. Precautions: Use with caution in patients with bronchial asthma or retinal disease. ACETAZOLAMIDE Tablet: 250 mg Adverse effects: Parasympathomimetic effects Uses: As an adjunct to other agents in the treat- have been reported following systemic absorption. ment of open-angle glaucoma and secondary glau- Eye pain, transient blurring of vision, bradycardia, coma resulting from anterior uveitis, iritis, herpes sweating, increased salivation, intestinal spasm and zoster infections, trauma or the granulomatocyclitic bronchospasm also occur. crisis syndrome. Closed-angle glaucoma.Pre- operative treatment for some types of glaucoma. Drug interactions: These will appear in tabulated form in the appendix of the published edition of the Dosage: Initially, 250 mg 4 times daily. Dosage WHO Model Formulary. should be adjusted according to patient response and may be reduced to 250 mg twice or even once TIMOLOL daily. Solution (eye drops): 0.25%, 0.5% (maleate) Contraindications: Hypersensitivity to sulfona- Uses: Alone or in combination with other antiglau- mides. Pregnancy. Severe renal or hepatic impair- coma agents in ocular hypertension. Open-angle ment. glaucoma. Aphakic glaucoma. Secondary glau- coma. Precautions: A blood count is necessary when used for prolonged periods. May impair mental Dosage: awareness. Use with caution in diabetic patients. Adults: Apply one drop of 0.25% or 0.5% solution 1–2 times daily. Adverse effects: Paraesthesia, hypokalaemia, lack of appetite, nausea, vomiting, diarrhoea, polyuria, Children: Apply 1 drop of 0.25% solution, 1–2 times metabolic imbalance, transient myopia, drowsiness daily. and depression have been reported. Adverse ef- fects related to sulfonamide use can also occur. Contraindications: Heart failure, bradycardia, heart block, asthma or obstructive airways disease. Drug interactions: These will appear in tabulated form in the appendix of the published edition of the Precautions: May precipitate myasthenia gravis in WHO Model Formulary. susceptible patients.

PILOCARPINE Adverse effects: Local allergic blepharitis and Solution (eye drops): 2%, 4% transient dryness of eyes have been reported. (hydrochloride or nitrate). Visual disturbances, decreased corneal sensitivity, diplopia and ptosis are rarely reported. If absorbed Uses: Open-angle glaucoma or closed-angle to a large extent systemically, allergic reactions, glaucoma. Non-uveitic secondary glaucoma, miosis chest pain, difficulty in breathing, arrhythmias, dizzi- following surgery or ophthalmoscopic examination. ness, confusion or mental depression, nausea, vomiting, diarrhoea and muscle weakness may Dosage: occur. Chronic glaucoma Adults: Apply 1 drop of a 2% or 4% solution 4 times Drug interactions: These will appear in tabulated daily. form in the appendix of the published edition of the WHO Model Formulary. Acute closed-angle glaucoma Apply 1 drop of a 2% solution every 10 minutes 3 to 6 times, then 1 drop every 1 to 3 hours until intra- Mydriatics ocular pressure subsides. Mydriatics are used to dilate the pupil and paralyse the ciliary muscle in ophthalmological procedures.

246 WHO Drug Information Vol. 12, No. 4, 1998 Essential Drugs

Atropine produces mydriasis by relaxing the sphinc- EPINEPHRINE ter muscle of the iris and cycloplegia by paralysing Solution (eye drops): 2% (as hydrochloride) the ciliary muscle. It produces these effects by blocking the cholinergic effects of acetylcholine. At- Uses: Open-angle glaucoma, for use alone or in ropine is also used for the treatment of iridocyclitis combination with miotics, beta adrenoreceptor an- mainly to prevent posterior synechia. tagonists or carbonic anhydrase inhibitors.

Ophthalmic atropine is useful in refraction proce- Dosage: Apply eye-drops 1–2 times daily. dures in children, but not in adults because of its prolonged duration of action. Higher concentrations Contraindications: Hypersensitivity, closed-angle of the mydriatic agents are usually required in pa- glaucoma. tients with dark iridic pigmentation. Care should be taken to avoid overdosing in this situation. Mydria- Precautions: Hypertension and heart disease. sis may rarely precipitate acute closed-angle glau- Hyperthyroidism. Diabetes coma particularly in patients over 60 years of age. Adverse effects: Pigmentation of conjunctiva and Epinephrine produces mydriasis by contracting con- reversible macular oedema in aphakia have been junctival blood vessels and the dilator muscle of the reported after prolonged use. Burning, stinging, pupil. It lowers intra-ocular pressure by reducing the ophthalmalgia and conjunctival hyperaemia fre- rate of production of aqueous humour and increas- quently occur and, less frequently, blurred vision, ing the outflow through the trabecular meshwork. hypertension, headache, arrhythmias, or dizziness.

ATROPINE Drug interactions: These will appear in tabulated Solution (eye drops): 0.1%, 0.5%, 1% (sulfate) form in the appendix of the published edition of the WHO Model Formulary. Uses: Cycloplegic refraction procedures in young children. Treatment of uveitis. Antiparkinsonism drugs Dosage: The use of pharmacotherapy will depend upon the Uveitis degree of incapacity of the patient, but is generally Adults: Apply one drop of a 1% solution to the eye not justified until symptoms compromise working 1–2 times daily. ability and social relationships. Close supervision is then needed to ensure that treatment regimens are Cycloplegic refraction tolerated and that appropriate changes are made to Children: Apply 1 drop twice daily for 1–3 days prior the regimen as the disease progresses. to refraction. The eye drops should be applied in the following concentrations : Infants up to 1 year of The most effective form of therapy is a combination age: 0.1%. Children 1Ð5 years of age: 0.1–0.5%. of levodopa and a peripheral dopadecarboxylase Children 5 years of age and above: 0.5% –1%. inhibitor, carbidopa. The response to levodopa/ carbidopa can be compromised both by tolerance Contraindications: Hypersensitivity. Closed-angle and adverse effects. Tolerance, resulting in pro- glaucoma. gressive shortening of the therapeutic response, in- variably occurs within 2–5 years. Fluctuating Precautions: May precipitate glaucoma. dyskinesias and mental changes — which are most evident during troughs in the plasma drug concen- Adverse effects: Contact dermatitis, systemic anti- trations — disruption of the sleep cycle, vivid cholinergic effects, tachycardia, xerostomia, leth- dreams and hallucinations are characteristic ad- argy, hallucination, mental confusion, blurred vision, verse effects that may occur at any time. Ameliora- skin rash, or dry skin may occur. tion of these effects can sometimes be achieved by administering levodopa in a sustained release Drug interactions: These will appear in tabulated preparation or in a greater number of fractionated form in the appendix of the published edition of the doses throughout the day. Supplementary use of WHO Model Formulary. amantadine, bromocriptine or selegiline can be of value either to enhance the effect of levodopa or to

247 Essential Drugs WHO Drug Information Vol. 12, No. 4, 1998

permit dosage to be reduced to a level where ad- treatment often respond to reduction or fractiona- verse effects are no longer troublesome. tion of dosage.

Anticholinergic drugs such as biperiden are usually Later in the course of the disease, the scope for sufficient in drug-induced pseudo-parkinsonism. dose adjustment is decreased as any dose reduc- They are also used as adjunctive therapy in other tion is increasingly likely to result in akinesia. Pain- forms of parkinsonism where the primary need is ful dystonic spasms and short episodes of akinesia, to stimulate dopaminergic activity in the striatal tremor and rigidity lasting from a few minutes to system. several hours are characteristic of the later phases of treatment. Severe generalized dyskinesias are most likely to occur in patients who have received LEVODOPA/CARBIDOPA high doses over prolonged periods. Sudden with- Tablet: 100 mg + 10 mg, 250 mg + 25 mg drawal in these circumstances has resulted in neu- Uses: All forms of parkinsonism other than drug- roleptic malignant syndrome. induced. Drug interactions: These will appear in tabulated Dosage: Dose is expressed in terms of levodopa. form in the appendix of the published edition of the The optimum daily dose must be determined for WHO Model Formulary. each patient by careful clinical monitoring and should be taken after meals. BIPERIDEN Tablet: 2 mg (hydrochloride) Initial dose 100 mg levodopa + 10 mg carbidopa twice daily in- Uses: Treatment of drug-induced parkinsonism creasing, as necessary, by increments of 100 mg + and adjunctive treatment of all other forms of the 10 mg every few days to a maximum of 1500 mg condition. levodopa daily. Dosage: Initially, 2 mg three times daily or 2–4 mg Contraindications: Known hypersensitivity to levo- once daily up to a maximum of 16 mg daily de- dopa or carbidopa. Concurrent use of monoamine pending on response and tolerance. oxidase inhibitors. Narrow-angle glaucoma. Con- firmed or suspected malignant melanoma. Contraindications: Known hypersensitivity to biperiden. Closed-angle glaucoma. Obstructive Precautions: Close supervision of patients is nec- uropathy. Myasthenia gravis. essary. Mental changes and cardiac conductivity in patients with atrial, nodal or ventricular dysrhyth- Precautions: Elderly patients are highly suscepti- mias, or with a history of myocardial infarction, ble to dose-related adverse effects. Patients should should be monitored. A rapid increase in dosage be warned that their ability to drive or operate may cause adverse effects, particularly in the eld- machinery may be impaired. Close supervision erly. Levodopa/carbidopa is teratogenic in animals, of patients with cardiac dysryhthmias, congestive and pregnant women should be treated only when cardiac failure or coronary heart disease is impor- the needs of the mother outweigh the risk to the tant, since they are at particular risk of atrio- fetus. ventricular block due to vagal stimulation of the sinoatrial node. Adverse effects: Nausea, anorexia and vomiting are sometimes troublesome, particularly at the out- Adverse effects: Drowsiness, dry mouth, consti- set of treatment when postural hypotension may pation, blurred vision, postural hypotension, hesi- also occur, particularly in elderly patients and those tancy of micturition, glaucoma, dizziness, tachycar- receiving antihypertensives. Psychiatric and neuro- dia and dysrhythmias commonly occur. Confusion logical disturbances are the most frequent dose- and psychiatric disturbances, particularly in the eld- limiting adverse effects. About half of all patients erly, can be difficult to manage. treated complain of vivid dreams, hallucinations or delusions. Psychotic symptoms and confusional Drug interactions: These will appear in tabulated states are less common. Mild intermittent dys- form in the appendix of the published edition of the kinesias which occur within a few months of starting WHO Model Formulary.

248 WHO Drug Information Vol. 12, No. 4, 1998

Recent Publications and Documents

Guidelines for gether with advice dealing with side-effects and HIV and infant feeding other problems that may arise. The book complements information contained in the It is now recognized that if an HIV-infected mother WHO guide, Cancer Pain Relief: with a Guide to breastfeeds, there is an additional risk that her Opioid Availability, 2nd ed. Pain management is infant will be infected. In many countries, personnel therefore not covered in this publication. dealing with health, nutrition and welfare are begin- ning to face a demand for information, advice and support from anxious mothers and families. Besides Symptom Relief in Terminal Illness. Available from: World being of intense personal concern, the issue of HIV Health Organization, Geneva, Switzerland. ISBN 92 4 transmission through breastfeeding is also of public 154507 0. Price: Sw.fr. 25 (Sw.fr 17.50 in developing health importance — especially in countries where countries). e mail: [email protected] both fertility rates and HIV-infection of pregnant women are high. AIDS has already doubled the mortality of children under 5 years of age in some Guidance modules on areas. Although only a small proportion of this antiretroviral treatments increase is the result of breastfeeding, there is a pressing need for countries to develop and imple- Tremendous optimism has been generated by the ment sound public health policies on HIV and infant recent development of new antiretrovirals, particu- feeding. larly the triple combination therapies, which promise a longer and better life for people living with HIV/ The guidelines cover policy issues and implementa- AIDS. In response to requests for information on tion, monitoring and evaluation of HIV and infant these treatments and for policy and technical feeding strategies, and include a list of useful guidance for health professionals and governments, resources and reference materials. They also nine guidance modules have been published by summarize knowledge of HIV transmission through WHO in collaboration with UNAIDS. The modules breastmilk cover the following topics:

1. Introduction to antiretroviral treatments. HIV and Infant Feeding: Guidelines for Decision-Makers. UNICEF/UNAIDS/WHO. Document WHO/FRH/NUT/CHD/ 2. Introducing antiretroviral treatments into national 98.1. Available from: World Health Organization, Geneva, health systems: economic considerations. Switzerland. e mail: [email protected] 3. ARV treatments: planning and integration into health services. Symptom relief in terminal illness 4. Safe and effective use of antiretrovirals. This guide explains the management of secondary symptoms commonly seen in patients suffering 5. Laboratory requirements for the safe and effec- from cancer, AIDS, and other terminal diseases. tive use of antiretrovirals. Practical advice is offered on how to evaluate patients and find ways to improve their comfort and 6. The use of antiretroviral drugs to reduce mother quality of life, and emphasis is placed on the need to child transmission of HIV. for individual treatment plans. 7. Treatments following exposure to HIV. Each symptom is covered according to a common approach which outlines possible causes, describes 8. Antiretrovirals: regulation, distribution and con- the steps to follow and explains how to select and trol. implement the best treatment option. For drug 9. Ethical and societal issues relating to antiretro- therapies, information includes recommended viral treatments. drugs, doses, and modes of administration, to-

249 Recent Publications and Documents WHO Drug Information Vol. 12, No. 4, 1998

UNAIDS and WHO are committed to increasing series of in-depth case histories for seven drugs access to new technologies which have been and a model for the quantification of risks. This is shown to be effective in preventing and treating accompanied by a detailed example of how the HIV/AIDS, and to improving the length and quality model works in practice. of life of all those in need. However, enthusiasm for the possibilities of triple therapy is tempered by several concerns. These involve the long-term Benefit-risk balance for marketed drugs: evaluating safety benefit and safety of use and accessibility and signals. CIOMS. Available from: World Health compliance with these expensive and complicated Organization, Geneva, Switzerland. ISBN 92 9036 068 2. treatments. Furthermore, sophisticated laboratory Price: Sw.fr. 15 (Sw.fr 10.50 in developing countries). e-mail: [email protected] and clinical services with qualified care providers are necessary for these therapies and follow-up. Interventions to improve Meanwhile, UNAIDS and WHO will continue to assess progress, and guidance provided in the antimalarial use modules will be regularly updated. A Task Force on Improved Use of Antimalarials was set up in 1993 by the UNDP/World Bank/WHO Guidance modules on antiretroviral treatments. Available Special Programme for Research and Training in from: World Health Organization, Geneva, Switzerland. Tropical Diseases to identify and test ways to WHO/ASD/98.1. e-mail: [email protected] rationalize and improve the home treatment of malaria using existing oral antimalarials. Research interventions were implemented in six South-East Re-evaluating the safety profile Asian countries which had the highest rates of antimalarial multidrug resistance in the world. of marketed drugs Treatment regimens included a 5-day combination Addressed primarily to regulatory authorities and of artesunate + mefloquine and a 7-day course of drug manufacturers, this publication responds to quinine + tetracycline. The Task Force provided a the absence of any harmonized, systematic proce- forum for identifying problem areas and testing the dures for assessing newly detected hazards, bal- effect of small but potentially important changes in ancing risks against benefits, and defining the the delivery of drugs in the private sector. results in terms of action. Several approaches were tested in Cambodia, A group of 24 representatives of government regu- China, Lao People's Democratic Republic, latory authorities and industry offer detailed advice Myanmar, Thailand and Viet Nam. These included on concepts and procedures for determining the subsidies for certain drug combinations, improved magnitude of the safety problem and deciding on packaging of doses, health education interventions, appropriate action. This may involve a routine use of a pharmacological marker to measure com- change in product information or immediate with- pliance, and assessment of drug quality. The drawal of the drug from the market. results are described in a supplement of the Bulletin of the World Health Organization. User-friendly The publication promotes a public health approach packaging of drugs, which included simple and to encourage consistent practices when a major clear patient information, produced the best results. safety problem is identified. Examples are used to illustrate responses when evaluating benefit through scoring the seriousness of different ad- Interventions to improve antimalarial use. Bulletin of the verse reactions. The model standard reporting form World Health Organization,76 (Suppl. 1), 1998. Available from: World Health Organization, Geneva, Switzerland. presented in the publication plays a central role in ISBN 92 4 068751 3. Price: Sw.fr. 20.Ð (Sw.fr. 14.Ð in the recommended procedures. It concludes with a developing countries). e-mail: [email protected]

250 WHO Drug Information, Vol. 12, No 4, 1998 Proposed INN: List 80

International Nonproprietary Names for Pharmaceutical Substances (INN)

Notice is hereby given that, in accordance with article 3 of the Procedure for the Selection of. Recommended International Nonproprietary Names for Pharmaceutical Substances, the names given in the list on the following pages are under consideration by the World Health Organization as Proposed International Nonproprietary Names. The inclusion of a name in the lists of Proposed International Nonproprietary Names does not imply any recommendation of the use of the substance in medicine or pharmacy.

Lists of Proposed (1-73) and Recommended (1-35) International Nonproprietary Names can be found in Cumulative List No. 9, 1996. The statements indicating action and use are based largely on information supplied by the manufacturer. This information is merely meant to provide an indication of the potential use of new substances at the time they are accorded Proposed International Nonproprietary Names. WHO is not in a position either to uphold these statements or to comment on the efficacy of the action claimed. Because of their provisional nature, these descriptors will neither be revised nor included in the Cumulative Lists of INNs

Dénominations communes internationales des Substances pharmaceutiques (DCI) Il est notifié que, conformément aux dispositions de l'article 3 de la Procédure à suivre en vue du choix de Dénominations communes internationales recommandées pour les Substances pharmaceutiques les dénominations ci-dessous sont mises à l'étude par l'Organisation mondiale de la Santé en tant que dénominations communes internationales proposées. L'inclusion d'une dénomination dans les listes de DCI proposées n'implique aucune recommandation en vue de l'utilisation de la substance correspondante en médecine ou en pharmacie.

On trouvera d'autres listes de Dénominations communes internationales proposées (1-73) et recommandées (1-35) dans la Liste récapitulative No. 9, 1996. Les mentions indiquant les propriétés et les indications des substances sont fondées sur les renseignements communiqués par le fabricant. Elles ne visent qu'à donner une idée de l'utilisation potentielle des nouvelles substances au moment où elles sont l'objet de propositions de DCI. L'OMS n'est pas en mesure de confirmer ces déclarations ni de faire de commentaires sur l'efficacité du mode d'action ainsi décrit. En raison de leur caractère provisoire, ces informations ne figureront pas dans les listes récapitulatives de DCI,

Denominaciones Comunes Internacionales para las Sustancias Farmacéuticas (DCI) De conformidad con lo que dispone el párrafo 3 del "Procedimiento de Selección de Denominaciones Comunes Internacionales Recomendadas para las Sustancias Farmacéuticas", se comunica por el presente anuncio que las denominaciones detalladas en las páginas siguientes están sometidas a estudio por la Organización Mundial de La Salud como Denominaciones Comunes Internacionales Propuestas. La inclusión de una denominación en las listas de las DCI Propuestas no supone recomendación alguna en favor del empleo de la sustancia respectiva en medicina o en farmacia.

Las listas de Denominaciones Comunes Internacionales Propuestas (1-73) y Recomendadas (1-35) se encuentran reunidas en Cumulative List No. 9, 1996. Las indicaciones sobre acción y uso que aparecen se basan principalmente en la información facilitada por los fabricantes. Esta información tiene por objeto dar una idea únicamente de las posibilidades de aplicación de las nuevas sustancias a las que se asigna una DCI Propuesta. La OMS no está facultada para respaldar esas indicaciones ni para formular comentarios sobre la eficacia de la acción que se atribuye al producto. Debido a su carácter provisional, esos datos descriptivos no deben incluirse en las listas recapitulativas de DCI.

251 Proposed INN: List 80 WHO Drug Information, Vol. 12, No. 4, 1998

Proposed International Nonproprietary Names: List 80 Comments on, or formal objections to, the proposed names may be forwarded by any person to the INN Programme of the World Health Organization within four months of the date of their publication in WHO Drug Information, i.e., for List 80 Proposed INN not later than 15 May 1999.

Dénominations communes internationales proposées: Liste 80 Des observations ou des objections formelles à l'égard des dénominations proposées peuvent être adressées par toute personne au Programme des Dénominations communes internationales de l'Organisation mondiale de la Santé dans un délai de quatre mois à compter de la date de leur publication dans WHO Drug Information, c'est-à-dire pour la Liste 80 de DCI Proposées le 15 mai 1999 au plus tard.

Denominaciones Comunes Internacionales Propuestas: Lista 80 Cualquier persona puede dirigir observaciones u objeciones respecto de las denominaciones propuestas, al Programa de Denominaciones Comunes Internacionales de la Organización Mundial de la Salud, en un plazo de cuatro meses, contados desde la fecha de su publicación en WHO Drug Information, es decir, para la Lista 80 de DCI Propuestas el 15 de mayo de 1999 a más tardar.

Proposed INN Chemical name or description: Action and use: Molecular formula (Latin, English, French, Spanish) Chemical Abstracts Service (CAS) registry number: Graphic formula

DCI Proposée Nom chimique ou description: Propriétés et indications: Formule brute Numéro dans le registre du CAS: Formule développée

DCI Propuesta Nombre químico o descripción: Acción y uso: Fórmula empírica Número de registro del CAS: Fórmula desarrollada

abaperidonum abaperidone 7-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperídino]propoxy]-3-(hydroxymethyl)- 4H-1 -benzopyran-4-one antipsychotic abapéridone 7-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]propoxy]- 3-(hydroxyméthyl)-4H-chromén-4-one psychotrope abaperidona 7-[3-[4-(6-fluoro-1,2-benzisoxazol-3-il)piperidino]propoxi]-3-(hidroximetil)- 4H-1-benzopiran-4-ona antipsicótico

C25H25FN2O5 183849-43-6

252 WHO Drug Information, Vol. 12, No. 4, 1998 Proposed INN: List 80

alitretinoinum alitretinoin (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)- 2,4,6,8-nonatetraenoic acid antineoplastic alitrétinoine acide (2E,4E,6Z,8E)-3,7-diméthyl-9-(2,6,6-triméthylcyclohex-1-ényl)nqna- 2,4,6,8-tétraénoíque antinéoplasique alitretinoína ácido (2E,4E,6Z,8E)-3,7-dimetil-9-(2,6,6-trimetil-1-ciclohexen-1-il)- 2,4,6,8-nonatetraenoico antineoplásico

C20H28O2 5300-03-8

anecortavum anecortave 17,21 -dihydroxypregna-4,9(11l)-diene-3,20-dione 21-acetate steroid anécortave 21-acètate de 17-hydroxy-3,20-dioxoprégna-4,9(11)-dién-21-yle sféroïde anecortava 21-acetato de 17-hidroxi-3,20-dioxopregna-4,9(11)-dien-21-iIo esteroide

C23H30O5 7753-60-8

artemotilum artemotil (3R,5aS,6R,8aS,9R,10S,12R,12aR)-10-ethoxydecahydro-3,6,9-trimethyl- 3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin antimalarial artémotil (3R,5aS,6R,8aS,9R,10S,12R,12aR)-10-éthoxy-3,6,9-triméthyldécahydro- 3,12-époxypyrano[4,3-j]-1,2-benzodioxépine antipaludique artemotilo (3R,5aS,6R,8aS,9R,10S,12R,12aR)-10-etoxidecahidro-3,6,9-trimetil- 3,12-epoxi-12H-pirano[4,3-j]-1,2-benzodioxepina antipalúdico

253 Proposed INN: List 80 WHO Drug Information, Vol. 12, No. 4, 1998

C17H28O5 75887-54-6

arzoxifenum arzoxifene 2-(p-methoxyphenyl)-3-[p-(2-piperidinoethoxy)phenoxy]benzo[b]thiophene- 6-ol antiestrogen arzoxifène 2-(4-méthoxyphényl)-3-[4-[2-(pipéridin-1-yl)éthoxy]phénoxy]benzo= [b]thiophén-6-ol antioetrogène arzoxifeno 2-(p-metoxifenil)-3-[p-(2-piperidinoetoxi)fenoxi]benzo[b]tiofeno-6-ol antiestrógeno

C28H29NO4S 182133-25-1

atorolimumabum atorolimumab immunoglobulin G3, anti-(human Rh(D) antigen) (human monoclonal clone P3x22914G4 γ3-chain), disulfide with human monoclonal P3x22914G4 κ-chain, dimer immunomodulator atorolimumab immunoglobuline G3, anti-(antigène Rh(D) humain) (chaîne γ3 de l'anticorps monoclonal humain P3x22914G4), dimère du disulfure avec la chaîne Κ de l'anticorps monoclonal humain P3x22914G4 immunomodulateur

atorolirnumab inmunoglobulina G3, anti-(antígeno Rh(D) humano) (cadena γ3 del clon monoclonal humano P3x22914G4), dímero del disulfuro con la cadena Κ del anticuerpo monoclonal humano P3x22914G4 inmunomodulador 202833-08-7

254 WHO Drug Information, Vol. 12, No 4, 1998 Proposed INN List 80

avasimibum avasimibe 2,6-diisopropylphenyl[(2,4,6-triisopropylphenyl)acetyl]sulfamate antihyperlipidaemic avasimibe [[2,4,6-tris(1-méthyléthyl)phényl]acétyl]sulfamate de 2,6-bis- (1-méthyléthyl)phényle antihyperlipidémiant avasimiba [(2,4,6-trisopropilfenil)acetil]sulfamato de 2,6-diisopropilfenilo antihiperlipémico

C29H43NO4S 166518-60-1

bexarotenum bexarotene p-[1-(5,6,7,8-tetrahydra-3,5,5,8,8-pentamethyl-2-naphthyl)vinyl]benzoic acid antineoplastic, antidiabetic bexarotène acide 4-[1-(3,5,5,8,8-pentaméthyl-5,6,7,8-tétrahydronaphtalén-2-yl)éthényl]= benzoïque antinéoplasique, antidiabétique bexaroteno ácido p-[1-(5,6,7,8-tetrahidro-3,5,5,8,8-pentametil-2-naftil)vinil]benzoico antineoplásico, antidiabético

C24H28O2 153559-49-0

carabersatum carabersat N-[(3R,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-4-chromanyl]-p-fluorobenzamide anticonvulsant carabersate N-[(3R,4S)-6-acétyl-3-hydroxy-2,2-diméthyl-3,4-dihydro-2H-chromén-4-yl]- 4-fluorobenzamide anticonvulsivant carabersato N-[(3R,4S)-6-acetil-3-hidróxi-2,2-dimetil-4-cromanil]-p-fluorobenzamida anticonvulsiveo

255 Proposed INN: List 80 WHO Drug Information, Vol. 12, No. 4, 1998

C20H20FNO4 184653-84-7

caspofunginum caspofungin (4R,5S)-5-[(2-aminoethyl)amino]-N2-(10,12-dimethyltetradecanoyl)- 4-hydroxy-L-ornithyl-L-threonyl-trans-4-hydroxy-L-prolyl-(S)-4-hydroxy- 4-(p-hydroxyphenyl)-L-threonyl-threo-3-hydroxy-L-ornithy[-trans-3-hydroxy- L-proline cyclic (6→1 )-peptide antifungal caspofungine N-[(2R,6S,9S,11R,12S,14aS,15S,20S,23S,25aS)-12-[(2-aminoéthyl)amino]- 20-[(1R)-3-amino-1-hydroxypropyl]-23-[(1S,2S)-1,2-dihydroxy- 2-(4-hydroxyphényl)éthyl]-2,11,15-trihydroxy-6-[(1R)-1-hydroxyéthyl]- 5,8,14,19,22,25-hexaoxotétracosahydro-1H-dipyrrolo[2,1-c:2',1'-/]= [1,4,7,10,13,16]hexaazacyclohénicosén-9-yl]-10,12-diméthyltétradécamide antifongique caspofungina (4R,5S)-5-[(2-aminoetil)amino]-N2-(10,12-dimetiltetradecanoil)-4-hidroxi- L-ornitil-L-treonil-trans-4-hydroxy-L-prolil-(S)-4-hidroxi-4-(p-hidroxifenil)- L-treonil-treo-3-hidroxi-L-ornitil-trans-3-hidroxi-L-prolina, péptido cíclico (6→1 ) antifùngico

C52H88N10O15 162808-62-0

256 WHO Drug Information, Vol. 12, No. 4, 1998 Proposed INN: List 80

celecoxibum p-[5-p-tolyl-3-(trifluoromethyl)pyrazol-1-yl]benzenesulfonamide celecoxib cycloxygenase-2 inhibitor 4-[5-(4-méthylphényl)-3-(trifluorométhyI)-1H-pyrazol-1-yl]benzènesulfonamide célécoxib inhibiteur de la cyclooxygénase-2 p-[5-p-toliI-3-(trifluorometil)pirazol-1-il]bencenosulfonamida celecoxib inhibidor de la cicloxigenasa-2

C17H14F3N3O2S 169590-42-5

corifollitropinum alfa corifollitropin alfa follicle-stimulating hormone (human α-subunit reduced), complex with follicle- stimulating hormone (human β-subunit reduced) fusion protein with 118-145-chorionic gonadotropin (human β-subunit) hormone corifollitropine alfa hormone folliculostimulante modifiée formée de deux sous-unités α et β sous-unité α: gonadotropine chorionique (partie protéique réduite de la sous- unité α humaine) sous-unité β: hormone folliculostimulante (partie protéique réduite de la sous-unité β humaine)-112-139-gonadotropine chorionique (partie protéique réduite de la sous-unité β humaine) hormone

corifolitropina alfa Hormona estimulante del folículo modificada, formada por dos subunidades α y β: Subunidad α' gonadotropina corionica (fracción proteica reducida de la subunidad α humana) Subunidad β: hormona estimulante del folículo (fracción proteica reducida de la subunidad β humana)- 112-139-gonadotropina coriónica (fracción proteica reducida de la subunidad β humana) hormona

195962-23-3

APDVQDCPEC TLQENPFFSQ PGAPILQCMG CCFSRAYPTP LRSKKTMLVQ KNVTSESTCC VAKSYNRVTV MGGFKVENHT ACHCSTCYYH KS

NSCELTNITI AIBKEECRFC ISINTTWCAG YCYTRDLVYF DPARPKIQKT CTFKELVYET VPVPGCAHHA DSLYTYPVAT QCHCGKCDSD STDCTVRGLG PSYCSFGEMK ESSSSKAPPP SLPSPSRLPG PSDTPILPQ * glycosylation sites * sites de glycosylation * posiciones de glicosilación

257 Proposed INN: List 80 WHO Drug Information, Vol. 12, No. 4, 1998

darbufelonum darbufelone 5-[(Z)-3,5-di-tert-butyl-4-hydroxybenzylidene]-2-imino-4-thiazolidinone anti-inflammatory agent darbufélone (Z)-5-[3,5-bis(1,1-diméthyéthyl)-4-hydroxybenzylidène]-2-iminothiazolidin- 4-one anti-inflammatoire darbufelona 5-[(Z)-3,5-di-terc-butil-4-hidroxibencilideno]-2-imino-4-tiazolidinona antiinflamatorio

C18H24N2O2S 139226-28-1

depreotidum depreotide cyclo(L-homocysteinyl-N-methyl-L-phenylalanyl-L-tyrosyl-D-tryptophyl-L-lysyl- L-valyl),(1→1')-sulfide with 3-(2-mercaptoacetamido)-L-alanyl-L-lysyl- L-cysteinyl-L-lysinamide diagnostic agent dépréotide (1→1')-sulfure de cyclo[L-homocystéinyi-(N-méthyl-L-phénylalanyl)- L-tyrosyl-D-tryptophyl-L-lysyl-L-valyl] et de[3-[(sulfanylacétyl)amino]-L-alanyl]- L-lysyl-L-cystéinyl-L-lysinamide produit à usage diagnostique depreotida (1→1')-sulfuro de ciclo[L-homocisteinil-(N-metil-L-fenilalanil)-L-tirosil-D-triptofil- L-lisil-L-valilo] y 3-(2-mercaptoacetamido)-L-alanil-L-lisil-L-cisteinil-L-lisinamida agente de diagnóstico

C65H96N16O12S2 161982-62-3

deracoxibum deracoxib p-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)pyrazol- 1 -yl]benzenesulfonamide cycloxygenase-2 inhibitor déracoxib 4-[3-(difluorométhyl)-5-(3-fluoro-4-méthoxyphényl)-1H-pyrazol- 1-yl]benzènesulfonamide inhibiteur de la cyclooxygénase-2 deracoxib p-[3-(difluorometil)-5-(3-fluoro-4-metoxifenil)pirazol-1-il]bencenosulfonamida inhibidor de la cicloxigenasa-2

258 WHO Drug Information, Vol 12, No 4, 1998 Proposed INN: List 80

C17H14F3N3O3S 169590-41-4

desloratadinum desloratadine 8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta- [1,2-b]pyridine histamine-H1 receptor antagonist desloratadine 8-chloro-11-(pipéridin-4-ylidène)-6,11-dihydro-5H-benzo[5,6]cyclohepta- [1,2-b]pyridine antagoniste des récepteurs H1 de l'histamine desloratadina 8-cloro-6,11-dihidro-11-(4-piperidilideno)-5H-benzo[5,6]ciclohepta- [1,2-b]piridina antagonista de los receptores H1 de la histamina C19H19CIN2 100643-71-8

desmoteplasum desmoteplase plasminogen activator (Desmodus rotundus, isoform α1 protein moiety reduced) plasminogen activator desmotéplase activateur du plasminogène (Desmodus rotondus, isoforme α1, partie protéique réduite) activateur du plasminogène desmoteplasa activador del plasminógeno (isoforma α1, fracción proteica reducida de Desmodus rotundus) activador del plasminógeno 145137-38-8

259 Proposed INN: List 80 WHO Drug Information, Vol. 12, No. 4, 1998

dexbudesonidum dexbudesonide (R)-11β,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dione 16,17-acetal with butyraldehyde antiasthmatic dexbudésonide 16α,17-[(1R)-butylidènebis(oxy)]-11ββ21dihydroxyprégna-1,4-diène-3,20- dione antiasthmatique dexbudesonida 16,17-acetal butiraldehídico de (R)-11β,16α,17,21-tetrahidroxipregna- 1,4-dieno-3,20-diona antiasmático

C25H34O6 51372-29-3

ecopipamum ecopipam (-)-(6aS,13bR)-11-chloro-6,6a,7,8,9,13b-hexahydro-7-methyl- 5H-benzo[d]naphth[2,1-b]azepin-12-ol dopamine D1/D5 receptor antagonist ecopipam (-)-(6aS,13bR)-11-chloro-7-méthyl-6,6a,7,8,9,13b-hexahydro- 5H-benzo[d]naphto[2,1-b]azépin-12-ol antagoniste des récepteurs D1/D5 de la dopamine ecopipam (-)-(6aS,13bR)-11-cloro-6,6a,7,8,9,13b-hexahidro-7-metil-5H-benzo[d]naft= [2,1-b]azepin-12-ol antagonista de los receptores D1/D5 de la dopamina

C19H20ClNO 112108-01-7

emtricitabinum emtricitabine 5-fluoro-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine antiviral emtricitabine 4-amino-5-fluoro-1-[(2R,5S)-2-(hydroxyméthyl)-1,3-oxathiolan-5-yl]pyrimidin- 2(1H)-one antiviral emtricitabina 5-fluoro-1-[(2R,5S)-2-(hidroximetil)-1,3-oxatiolan-5-il]citosina antiviral

260 WHO Drug Information, Vol. 12, No. 4, 1998 Proposed INN: List 80

C8H10FN3O3S 143491-57-0

enrasentanum enrasentan (1S,2R,3S)-3-[2-(2-hydroxyethoxy)-4-methoxyphenyl]- 1-[3,4-(methylenedioxy)phenyl]-5-propoxy-2-indancarboxylic acid endothelin receptor antagonist enrasentan acide (1S,2R,3S)-1-(1,3-benzodioxol-5-yl)-3-[2-(2-hydroxyéthoxy)- 4-méthoxyphényl]-5-propoxy-2,3-dihydro-1H-indène-2-carbaxylique antagoniste des récepteurs de l'endothéline enrasentano ácido (1S,2R,3S)-3-[2-(2-hidroxietoxi)-4-metoxifenil]- 1-[3,4-(metilenodioxi)fenil]-5-propoxi-2-indanocarboxilico antagonista de los receptores de la endotelina

C29H30O9 167256-08-8

eplivanserinum eplivanserin (E)-2'-fluoro-4-hydroxychalcone (Z)-O-[2-(dimethylamino)ethyl]oxime serotonin receptor antagonist

éplivansérine (E)-1-(2-fluorophényl)-3-(4-hydroxyphényl)prop-2-énone (Z)-O-[2-(diméthylamino)éthyl]oxime antagoniste de la sérotonine eplivanserina (Z)-O-[2-(dimetilamino)etil]oxima de la (E)-2'-fluoro-4-hidroxicalcona antagonista de los receptores de la serotonina

C19H21FN2O2 130579-75-8

261 Proposed INN: List 80 WHO Drug Information, Vol. 12, No. 4, 1998

ethylcellulosum cellulose ethyl ether ethylcellulose pharmaceutical aid éther éthylique de cellulose éthylcellulose auxiliaire pharmaceutique éter etílico de celulosa etilcelulosa excipiente 9004-57-3

etilevodopum (-)-3,4-dihydroxy-L-phenylalanine, ethyl ester etilevodopa antiparkinsonian (-)-(2S)-2-amino-3-(3,4-dihydroxyphényl)propanoate d'éthyle étilévodopa antiparkinsonian éster etílico de (-)-3,4-dihidroxi-L-fenilalanina etilevodopa antiparkinsoniano

C11H15NO4 37178-37-3

exisulindum exisulind 5-fluoro-2-methyl-1-[(Z)-p-(methylsulfonyl)benzylidene]indene-3-acetic acid antineoplastic exisulind acide 2-[5-fluoro-2-méthyl-1-[(Z)-4-(méthylsulfonyl)benzylidéne]-1H-indén- 3-yl]acétique antinéoplasique exisulind ácido 5-fluoro-2-metil-1-[(Z)-p-(metilsulfonil)bencilideno]indeno-3-acético antineoplásico

C20H17FO4S 59973-80-7

262 WHO Drug Information, Vol. 12, No. 4, 1998 Proposed INN: List 80

fanapanelum fanapanel [[3,4-dihydro-7-morpholino-2,3-dioxo-6-(trifluoromethyl}- 1(2H)-quinoxalinyl]methyl]phosphonic acid AMPA receptor antagonist fanapanel acide [[7-(morpholin-4-yl)-2,3-dioxo-6-(trifluorométhyl)-3,4-dihydroquinoxalin- 1(2H)-yl]méthyl] phosphonique antagoniste des récepteurs de l'AMPA fanapanel ácido [[3,4-dihidro-7-morfolino-2,3-dioxo-6-(trifluorometiI)- 1(2H)-quinoxalinil]metil]fasfónico antagonista de los receptores de AMPA

C14H15F3N3O6P 161605-73-8

galarubicinum galarubicin (8s,10S)-10-[(2,6-dideoxy-2-fluoro-α-L-talopyranosyl)oxy]-8-glycoloyl- 7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione 82-ester with β-alanine antineoplastic, antibiotic galarubicine 3-aminopropanoate de 2-[(2S,4S)-4-[(2-fluoro-2,6-didesoxy- α-L-talopyranosyl)oxy]-2,5,12-trihydroxy-7-méthoxy-6,11-dioxo- 1,2,3,4,6,11-hexahydrotétracén-2-yl]-2-oxoéthyle antinéoplasique, antibiotique galarubicina (8S,10S)-8-(3-aminopropanoiloxiacetiI)-10-[(2,6-didesoxi-2-fluoro-α-L-talopiranosil)= oxi]-7,8,9,10-tetrahidro-6,8,11-trihidroxi-1-metoxi-5,12-naftacenodiona antineoplásico, antibiótico

C30H32FNO13 140637-86-1

263 Proposed INN: List 80 WHO Drug Information, Vol. 12, No. 4, 1998

gantofibanum gantofiban 4-[[(5R)-3-[p-(carboxyamidino)phenyl]-2-oxo-5-oxazolidinyl]methyl]- 1-piperazineacetic acid, 1-ethyl methyl ester fibrinogen receptor antagonist gantofiban 2-[4-[[(5R)-3-[4-[(méthoxycarbonyl)carbamimidoyl]phényl]-2-oxooxazolidin- 5-yl]méthyl]pipérazin-1-yl]acétate d'éthyle antagoniste du récepteur du fibrinogène gantofibán 4-[(5R)-3-[(4-metoxicarbonilaminoiminometil)fenil]-2-oxo-5-oxazolidinilmetil]- 1-piperazinilacetato de etilo antagonista del receptor del fíbrinógeno

C21H29N5O6 183547-57-1

gimeracilum 5-chloro-2,4-pyridinediol gimeracil adjuvant for antineoplastic 5-chloropyridine-2,4-diol giméracil adjuvant d'antinéoplasiques 5-cloro-2,4-piridinadiol gimeracilo coadyuvante del tratamiento con antineoplásicos

C5H4CINO2 103766-25-2

OH hemoglobinum glutamerum hemoglobin glutamer hemoglobin glutamer; the species specifity should be indicated in brackets behind the name, "(bovine)"; the average mass of the polymer is given as e.g., hemoglobin glutamer-250 for 250kD oxygen carrier hémoglobine glutamère produit de la réaction du pentanedial avec l'hémoglobine; l'origine de l'hémoglobine doit être indiquée, "(bovine)"; la masse moléculaire moyenne doit être donnée, par exemple: hémoglobine glutamère-250 pour 250 kD porteur d'oxygène hemoglobina glutámero hemoglobina polimerizada con glutaraldehído; debe indicarse entre paréntesis el origen del material, "(bovino)"; la masa del polímero medio se da como, por ej., hemoglobina glutamero-250 para 250kD portador de oxigeno

264 WHO Drug Information, Vol. 12, No. 4, 1998 Proposed INN: List 80

hyetellosum cellulose 2-hydroxyethyl ether hyetellose pharmaceutical aid éther 2-hydroxyéthylique de cellulose hyétellose auxiliaire pharmaceutique éter 2-hidroxietilico de celulosa hietelosa excipiente 9004-62-0

hymetellosum cellulose 2-hydroxyethyl methyl ether hymetellose pharmaceutical aid éther 2-hydroxyéthylique et méthylique de cellulose hymétellose auxiliaire pharmaceutique éter2-hidroxilico metílico de celulosa himetelosa excipiente 9032-42-2

hyprolosum cellulose 2-hydroxypropyl ether hyprolose pharmaceutical aid éther 2-hydroxypropylique de cellulose hyprolose auxiliaire pharmaceutique éter 2-hidroxipropiIico de celulosa hiprolosa excipiente 9004-64-2

insulinum detemirum 298-(N6-myristoyl-L-lysine)-308-de-L-threonineinsulin (human) insulin determir antidiabetic 298-(N6-tétradécanoyl-L-lysine)-308-dès-L-thréonineinsuline humaine insuline détémir antidiabétique 298-(N6-miristoil-L-lisina)-308-des-L-treoninainsulina (humana) insulina detemir antidiabético

265 Proposed INN: List 80 WHO Drug Information, Vol. 12, No. 4, 1998

C267H402N64O76S6 169148-63-4

itavastatinum itavastatin (3R,5S,6E)-7-[2-cyclopropyl-4-(p-fluorophenyl)-3-quinolyl]-3,5-dihydroxy- 6-heptenoic acid antihyperlipidaemic itavastatine acide (6E)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophényl)quinoléin-3-yl]- 3,5-dihydroxyhept-6-énoïque antihyperlipidémíant itavastatina ácido (3R,5S,6E)-7-[2-cicloclopropil-4-(p-fluorofenil)-3-quinolil]-3,5-dihidroxi- 6-heptenoico antihiperlipémico

C25H24FNO4 147511-69-1

leridistimum leridistim 14-L-alanine-50-L-aspartic acid-14-125-interleukin 3 (human reduced) fusion protein with peptide (synthetic) linked with 17-L-serinegranulocyte colony- stimulating factor (human reduced) immunomodulator léridistim protéine de fusion entre la [14-L-alanine-50-acide L-aspartique]- 14-125-interleukine 3 (humaine, réduite) et le [17-L-sérine]facteur de stimulation des colonies de granulocytes (humain, réduit) immunomodulateur leridistim proteína de fusión de la [14-L-alanina-50-ácido L-aspártico]- 14-125-interleucina-3 (humana reducida) con el [17-L-serina]factor de estimulación de las colonias de granulocitos (humano reducido) inmunomodulador

266 WHO Drug Information, Vol. 12, No. 4, 1998 Proposed INN: List 80

C1550H2463N425O462S12

ANCSNMIDEI ITHLKQPPLP LLDFNNLNGE DQDILMDNNL

RRPNLEAFNR AVKSLQNASA IESILKNLLP CLPLATAAPT

RHPIHIKDGD WNEFRRKLTF YLKTLENAQA QQYVEGGGGS

PGEPSGPIST INPSPPSKES HKSPNMATPL GPASSLPQSF

LLKSLEQVRK IQGDGAALQE KLCATYKLCH PEELVLLGHS

LGIPWAPLSS CPSQALQLAG CLSQLHSGLF LYQGLLQALE

GISPSLGPTL DTLQLDVADF ATTIWQQMEE LGMAPALQPT

QGAMPAFASA FQRRAGGVLV ASHLQSFLEV SYRVLRHLAQ

leteprinimum p-[3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionamido]benzoic acid leteprinim nootropic agent acide 4-[[3-(6-oxo-1,6-dihydro-9H-purin-9-yl)propanoyl]amino]benzoïque leteprinim nootrope ácido p-[3-(1,6-dihidro-6-oxo-9H-purin-9-il)propionamido]benzoico leteprinim nootropo

C15H13N5O4 138117-50-7

lopinavirum lopinavir (αS)-tetrahydro-N-[(αS)-α-[(2S,3S)-2-hydroxy-4-phenyl-3-[2-(2,6-xylyloxy)= acetamido]butyl]phenethyl]-α-isopropyl-2-oxo-1(2H)-pyrimidineacetamide antiviral lopinavir (2S)-N-[(1S,3S,4S)-1-benzyl-4-[[(2,6-diméthylphénoxy)acétyl]amino]- 3-hydroxy-5-phénylpentyl]-3-méthyl-2-(2-oxotètrahydropyrirnidin- 1(2H)-yl)butanamide antiviral lopinavir (αS)-tetrahidro-N-[(αS)-α-[(2S,3S)-2-hidroxi-4-fenil-3-[2-(2,6-xililoxi)= acetamido]butil]fenetil]-α-isopropil-2-oxo-1(2H)-pirimidinacetamida antiviral

267 Proposed INN: List 80 WHO Drug Information, Vol. 12, No. 4, 1998

C37H48N4O5 192725-17-0

lusupultidum lusupultide glycyl-L-isoleucyl-L-prolyl-L-phenylalanyl-L-phenylalanyl-L-prolyl-L-valyl- L-histidyl-L-leucyl-L-lysyl-L-arginyl-L-leucyl-L-leucyl-L-isoleucyl-L-valyl-L-valyl- L-valyl-L-valyl-L-valyl-L-valyl-L-leucyl-L-isoleucyl-L-valyl-L-valyl-L-vaIyl- L-isoleucyl-L-valylglycyl-L-alanyl-L-leucyl-L-leucyl-L-isoleucylglycyl-L-leucine pulmonary surfactant lusupultide glycyl-L-isoleucyl-L-prolyl-L-phénylalanyl-L-phénylalanyl-L-proIyl-L-valyl- L-histidyl-L-leucyl-L-lysyl-L-arginyl-L-leucyl-L-leucyl-L-isoleucyl-L-valyl-L-valyl- L-valyl-L-valyl-L-valyl-L-valyl-L-leucyl-L-isoleucyl-L-valyl-L-valyl-L-valyl- L-isoleucyl-L-valyl-glycyl-L-alanyl-L-leucyl-L-leucyl-L-isoleucyl-glycyl-L-leucine surfactif pulmonaire lusupultida glycil-L-isoleucil-L-prolil-L-fenilalanil-L-fenilalanil-L-prolil-L-valil-L-histidil-L-leucil- L-lisil-L-arginil-L-leucil-L-leucil-L-isoleucil-L-valil-L-valil-L-valil-L-valil-L-valil-L-valil- L-leucil-L-isoleucil-L-valil-L-valil-L-valil-L-isoleucil-L-valilglicil-L-alanil-L-leucil- L-leucil-L-isoleucilglicil-L-leucina tensioactivo pulmonar

C182H310N40O35 200074-80-2

Gly—Ile—Pro—Phe—Phe—Pro—Val—His—Leu—Lys— 10 Arg—Leu—Leu—Ile—Val—Val—Val—Val—Val—Val — 20 Leu—Ile—Val—Val—Val—Ile—Val—Gly—Ala—Leu— 30 Leu—Ile—Gly—Leu maribavirum maribavir 5,6-dichloro-2-(isopropyIamino)-1-β-L-ribofuranosylbenzimidazole antiviral maribavir 5,6-dichloro-N-(1-méthyléthyl)-1-(β-L-ribofuranosyl)-1H-benzimidazol-2-amine antiviral maribavir 5,6-dicloro-2-(isopropilamino)-1-β-L-ribofuranosilbenzimidazol antiviral

268 WHO Drug Information, Vol. 12, No. 4, 1998 Proposed INN: List 80

C15H19Cl2N3O4 176161-24-3

minopafantum minopafant (+)-1-ethyl-2-[[N-[[(2R)-2-methoxy-3-[[[4-octadecylcarbamoyl)oxy]piperidino] carbonyl]oxy]propoxy]carbanyl]-o-anisamido]methyl]pyridiniurn chloride platelet activating factor antagonist minopafant (+)-chlorure de 1-éthyl-2-[[(2-méthoxybenzoyl)[[(2R)-2-méthoxy- 3-[[[4-[(octadécylcarbamoyl)oxy]pipérídin-1-yl]carbonyl]oxy]propoxy]= carbonyl]amino]méthyl]pyridinium antagoniste du facteur activant les plaquettes minopafant (+)-1-etil-2-[[N-[[(2R)-2-metoxi-3-[[[4-[(octadecilcarbamoil)oxi]piperidino]= carbonil]oxi]propoxi]carbonil]-o-anisamido]metil]piridinio antagonista del factor de activación de plaquetas

C46H73ClN4O9 128420-61-1

minretumomabum minretumomab immunoglobulin G1 anti-(human tumor-associated glycoprotein 72) (mouse monoclonal Mab CC-49 γ1-chain), disulfide with mouse monoclonal Mab CC-49-chain, dimer immunomodulator minrétumomab immunoglobuline G1 anti-(glycoprotéine 72 humaine associée aux turneurs) (chaîne γ1 de l'anticorps monoclonal de souris Mab CC-49), dimère du disulfure avec la chaîne Κ de l'anticorps monoclonal de souris Mab CC-49 immunomodulateur minretumomab Inmunoglobulina G1 anti-(glicoproteina 72 humana asociada a los tumores) (cadena γ1 del anticuerpo monoclonal de ratón Mab CC-49), dímero del disulfuro con la cadena Κ del anticuerpo monoclonal de ratón Mab CC-49 inmunomodulador 195189-17-4

269 Proposed INN: List 80 WHO Drug Information, Vol. 12, No. 4, 1998

mivotilatum mivotilate isopropyl N-(4-methyl-2-thiazolyl)-1,3-dithietane-Δ2,α -malonamate hepatoprotectant mivotilate 2-(1,3-dithiétan-2-ylidène)-3-[(4-métriylthiazol-2-yl)amino]-3-oxopropanoate de 1-méthyléthyle hépatoprotecteur mivotilato N-(4-metil-2-tiazolil)-1,3-ditietano-Δ2,α-malonamato de isopropilo hepatoprotector

C12H14N2O3S3 130112-42-4

nesiritidum nesiritide L-seryl-L-prolyl-L-lysyl-L-methionyl-L-valyl-L-glutaminylglycyl-L-serylglycyl- L-cysteinyl-L-phenylalanylglycyl-L-arginyl-L-lysyl-L-methionyl-L-aspartyl- L-arginyl-L-isoleucyl-L-seryl-L-seryl-L-seryl-L-serylglycyl-L-leucylglycyl- L-cysteinyl-L-lysyl-L-valyl-L-leucyl-L-arginyl-L-arginyl-L-histidine cyclic (10→26)-disulfide vasodilator, diuretic nésiritide 1,32-facteur natriurétique (cerveau humain, clone λhBNP57) vasodilatateur, diurétique nesiritida (10→26)-disulfuro cilico de L-seril-L-prolil-L-lisil-L-metionil-L-valil- L-glutaminilglicil-L-serilglicil-L-cisteinil-L-fenilalanilglicil-L-arginil-L-lisil- L-metionil-L-aspartil-L-arginil-L-isoleucil-L-seril-L-seril-L-seril-L-serilglicil- L-leucilglicl-L-cisteinil-L-lisil-L-valil-L-leucil-L-arginil-L-arginil-L-histidina vasodilatador, diurético

C143H244N50O42S4 124584-08-3

Ser—Pro—Lys—Met—Val—Gln—Gly—Ser—Gly—Cys— 10 Phe—Gly—Arg—Lys-Met—Asp—Arg—Ile—Ser—Ser— 20 Ser —Ser-Gly—Leu—Gly—Cys—Lys—Val—Leu—Arg— 30 Arg—His oImesartanum olmesartan 2,3-dihydroxy-2-butenyl 4-(1-hydroxy-1-methylethyl)-2-propyl- 1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-carboxylate, cyclic 2,3-carbonate angiotensin II receptor antagonist olmésartan 4-(1-hydroxy-1-méthyléthyl)-2-propyl-1-[4-[2-(1H-tétrazol-5-yl)phényl]benzyl]- 1H-imidazole-5-carboxylate de (5-méthyl-2-oxo-1,3-dioxol-4-yl)méthyle antagoniste du récepteur de l'angiotensine II olmesartán 4-(1-hidroxi-1-metiletil)-2-propil-1-[[2-(1H-tetrazol-5-il)-1,1'-bifenil-4-il]metil]- 1H-imidazol-5-carboxilato de 5(metil-2-oxo-1,3-dioxolen-4-il)metilo antagonista del receptor de angiotensina II

270 WHO Drug Information, Vol. 12, No. 4, 1998 Proposed INN: List 80

C29H30N6O6 144689-63-4

oseltamivirum oseltamivir ethyl (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene- 1-carboxylate antiviral oséltamivir (3R,4R,5S)-4-(acétylamino)-5-amino-3-(1-éthylpropoxy)cyclohex-1-ène- 1-carboxylate d'éthyle antiviral oseltamivir (3R,4R,5S)-4-acetamido-5-amino-3-(1-etilpropoxi)-1-ciclohexeno- 1-carboxilato de etilo antiviral

C16H28N2O4 196618-13-0

oteracilum 1,4,5,6-tetrahydro-4,6-dioxo-s-triazine-2-carboxylic acid oteracil antineoplastic acide 4,6-dioxo-1,4,5,6-tétrahydro-1,3,5-triazine-2-carboxylique otéracíl antinéoplasique ácido 1,4,5,6-tetrahidro-4,6-dioxo-s-triazina-2-carboxílico oteracilo antineoplásico

C1H3N3O4 937-13-3

271 Proposed INN: List 80 WHO Drug Information, Vol. 12, No. 4, 1996

parecoxibum N-[[p-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonyl]propionamide parecoxib cycloxygenase-2 inhibitor N-[[4-(5-méthyl-3-phénylisoxazol-4-yl)phényl]sulfonyl]propanamide parécoxib inhibiteur de la cyclooxygénase-2 N-[[p-(5-metil-3-fenil-4-isoxazolil)fenil]sulfonil]propionamida parecoxib inhibidor de la cicloxigenasa-2

C19H18N2O4S 198470-84-7

pegacaristimum pegacaristim N-(3-hydroxypropyl)-1-163-megakaryocyte growth and development factor (human), monoether with polyethylene glycol monomethyl ether colony stimulating factor pégacaristim N-[3-[[méthylpoly(oxyéthylène)]oxy]propyl]-1-163-facteur de croissance et de développement de mégakaryocyte (humain) facteur stimulant de colonies de mégakaryocytes pegacaristim N-(3-hidroxipropil)-1-163-factor de desarrollo y crecimiento de megacariocitos (humano), monoéter con el éter monometilico de polietilenglicol factor estimulante de colonias 187139-68-0

* pegylation site * site de pégylation * posición de pegilación

272 WHO Drug Information, Vol. 12, No. 4, 1998 Proposed INN: List 80

pegnartograstimum pegnartograstim N-L-methionyl-1-L-alanine-3-L-threonine-4-L-tyrosine-5-L-arginine-17-L-serine colony-stimulating factor (human clone 1034), reaction product with succinic anhydride, esters with polyethylene glycol monomethyl ether immunomodulator pégnartograstim esters entre le produit de réaction du N-L-méthionyl-[1-L-alanine- 3-L-thréonine-4-L-tyrosine-5-L-arginine-17-L-serine] facteur de stimulation de colonie (clone humain 1034) avec l'anhydride succinique et le α-methyl- ω-hydroxypoly(oxyéthylène) immunomodulateur pegnartograstim ésteres con el éter monometilico de polietilenglicol del producto de reacción con anhidrido succinico del N-L-metionil-1 -L-alanina-3-L-treonina-4-L-tírosina- 5-L-arginina-17-L-serina-factor-estimulante de colonias (clon humano 1034) inmunomodulador 204565-76-4

M APTYRASSLP QSFFLKSLEQ VRKIQGDGAA LQEKLCATYK

LCHPEELVLL GHSLGIPWAP LSSCPSQALQ LAGCLSQLHS GLFLYQGLLQ ALEGISPELG PTLDTLQLDV ADFATTIWQQ MEELGMAPAL QPTQGAMPAF ASAFQRBAGG VLVASHLQSF LEVSYRVLRH LAQP * pegylation site * site de pegylation * posición de pegilación

ponazurilum ponazuril 1-methyl-3-[4-[p-[(trifluoromethyl)sulfonyl]phenoxy]-m-tolyl]-s-triazine- 2,4,6(1H,3H,5H)-trione coccidiostatic ponazuril 1-méthyl-3-[3-méthyl-4-[4-[(triflorométhyl)sulfonyl]phénoxy]phényl]- 1,3,5-triazine-2,4,6(1H,3H,5H)-trione coccidiostatique ponazurilo 1-metil-3-[4-[p-[(trifluorometil)sulfonil]fenoxi]-m-tolil]-s-triazina- 2,4,6(1H,3H,5H)-triona coccidiostático

C18H14F3N3O6S 69004-04-2

273 Proposed INN: List 80 WHO Drug Information, Vol. 12, No. 4, 1998

rofecoxibum rofecoxib 4-[p-(methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone cycloxygenase-2 inhibitor rofecoxib 4-[4-(méthylsulfonyl)phényl]-3-phénylfuran-2(5H)-one inhibiteur de la cyclooxygénase-2 rofecoxib 4-[p-(metilsulfonil)fenil]-3-fenil-2(5H)-furanona inhibidor de la cicloxigenasa-2

C17H14O4S 162011-90-7

sarizotanum sarizotan (-)-3-[[[(R)-2-chromanylmethyl]amino]methyI]-5-(p-fluorophenyl)pyridine antipsychotic sarizotan (-)-N-[[(2R)-3,4-dihydro-2H-chromén-2-yl]méthyl][5-(4-fluoropriényl)pyridin- 3-yl]méthanamine psychotrope sarizotán (-)-3-[[[(R)-2-cromanilmetil]amino]metil]-5-(p-fluorofenil)piridina antipsicótico

C22H21FN2O 177975-08-5

satraplatinum (OC-6-43)-bis(acetato)amminedichloro(cyclohexylamine)platinum satraplatin antineoplastic (OC-6-43)-bis(acétato)amminedichloro(cyclohexanamine)platine satraplatine antinéoplasique (OC-6-43)-bis(acetato)aminadicloro(clclohexilamina )platino satraplatino antineoplásico

C10H22Cl2N2O4Pt 129580-63-8

274 WHO Drug Information, Vol. 12, No. 4, 1998 Proposed INN: List 80

semparatidum semparatide L-alanyl-L-valyl-L-seryl-L-α-glutamyl-L-histidyl-L-glutaminyl-L-leucyl-L-leucyl- L-histidyl-L-α-aspartyl-L-lysylglycyl-L-lysyl-L-seryl-L-isoleucyl-L-glutaminyl- L-α-aspartyl-L-leucyl-L-arginyl-L-arginyl-L-arginyl-L-α-glutamyil-L-leucyl-L-leucyl- L-α-glutamyI-L-lysyl-L-leucyl-L-leucyl-L-α-glutamyl-L-lysyl-L-leucyl-L-histidyl- L-threonyl-L-alaninamide hormone analogue semparatide L-alanyl-L-valyl-L-seryl-L-glutamyl-L-histidyl-L-glutaminyl-L-leucyl-L-leucyl- L-histidyl-L-aspartyl-L-lysyi-glycyl-L-lysyl-L-seryl-L-isoleucyl-L-glutaminyl- L-aspartyl-L-leucyl-L-arginyl-L-arginyl-L-arginyl-L-glutamyl-L-leucyl-L-leucyl- L-glutamyl-L-lysyl-L-leucyl-L-leucyl-L-glutamyl-L-lysyl-L-leucyl-L-histidyl- L-thréonyl-L-alaninamide analogue d'hormone semparatida L-alanil-L-valil-L-seril-L-α-glutamil-L-histidil-L-glutaminil-L-leucil-L-leucil-L-histidil- L-α-aspartil-L-lisilglicil-L-lisil-L-seril-L-isoleucil-L-glutaminil-L-α-aspartil-L-leucil- L-arginil-L-arginil-L-arginil-L-α-glutamil-L-leucil-L-leucil-L-α-glutamil-L-lisil- L-leucil-L-leucil-L-α-glutamil-L-lisil-L-leucil-L-histidil-L-treonil-L-alaninamida análogo de hormona

C175H300N56O51 154906-40-8

Ala—Val—Ser —Glu—His—Gln—Leu—Leu—His—Asp— 10 Lys—Gly—Lys—Ser—Ile—Gln—Asp—Leu—Arg—Arg— 20 Arg—Glu—Leu—Leu—Glu—Lys—Leu—Leu—Glu—Lys —

Leu—His—Thr—Ala-NH2 simeticonum simeticone α-(trimethylsilyI)-ω-methylpoly[oxy(dimethylsilylene)], mixture with silicon dioxide antiflatulent siméticone mélange de α-(triméthylsilyl)-α-méthylpoly[oxy(diméthylsilylène)] et de dioxyde de silicium antiflatulent simeticona α-(trimetilsilil)-ω-metilpoli[oxi(dimetilsilileno)], mezcla con dióxido de silicio antiflatulento 8050-81-5

sitamaquinum 8-[[6-(diethylamino)hexyl]amino]-6-methoxy-4-methyiquinoline sitamaquine antiprotozoal N,N-diéthyl-N'-(6-méthoxy-4-méthylquinoléin-8-yl)hexane-1,6-diamine sitamaquine antiprotozoaire 8-[[6-(dietilamino)hexil]amino]-6-metoxi-4-metilquinolina sitamaquina antiprotozoario

275 Proposed INN: List 80 WHO Drug Information, Vol. 12, No. 4, 1998

C21H33N3O 57695-04-2

solimastatum solimastat (2S,3R)-3-[[(1S)-2,2-dimethyl-1-(2-pyriclylcarbamoyl)propyl]carbamoyl]- 2-methoxy-5-methylhexanohydroxamic acid matrix metalloproteinase inhibitor solimastat (2R,3S)-N1-[(1S)-2,2'-dimethyl-1-[(pyridin-2-yl]carbamoyl]propyl]-N4-hydroxy- 3-méthoxy-2-(2-méthylpropyl)butanediamide inhibiteur de la métalloprotéinase de la matrice solimastat ácido (2S,3R)-3-[[(1S)-2,2-dimetil-1-(2-piridilcarbamoil)propil]carbamoil]- 2-metoxi-5-metilhexanohidroxámico inhibidor de la metaloproteinasa de matriz

C20H32N4O5

sonepiprazolum sonepiprazole (-)-p-[4-[2-[(S)-1-isochromanyl]ethyl]-1-piperazinyl]benzenesulfonamide antipsychotic sonépiprazole (-)-4-[4-[2-[(1S)-3,4-dihydro-1H-isochromén-1-yl]éthyl]pipérazin- 1-yl]benzènesulfonamide psychotrope sonepiprazol (-)-p-[4-[2-[(S)-1-isocromanil]etil]-1-piperazinil]bencenosulfonamida antipsicótico

C21H27N3O3S 170858-33-0

276 WHO Drug Information, Vol. 12, No. 4, 1998 Proposed INN: List 80

tabimorelinum tabimorelin (R)-α-[(E)-5-amino-N,5-dimethy[-2-hexenamido]-N-methyl- /V-[(R)-α-(methylcarbamoyl)phenethyl]-2-naphthalenepropionamide growth hormone release stimulating peptide tabimoréline (5)-5-amino-N-[(1R)-2-[[(1R)-1-benzyl-2-(méthylamino)-2-oxoéthyl]= èthylamino]-1-(naphtalén-2-ylméthyl)-2-oxoéthyl]-N,5-diméthylhex-2-énamide peptide stimulant la libération de l'hormone de croissance tabimorelina (R)-α-[(E)-5-amino-N,S-dimetil-2-hexenamido]-N-metil- N-[(R)-α-(metilcarbamoil)fenetil]-2-naftalenopropionamid péptido estimulante de la liberación de la hormona del crecimiento

C32H40N4O3 193079-69-5

tafenoquinum tafenoquine (±)-8-[(4-amino-1-methylbutyl)amino]-2,6-dimethoxy-4-methyl- 5-[(α,α,α-trifluoro-m-tolyl)oxy]quinoline antimalarial tafénoquine (4RS)-N4-[2,6-diméthoxy-4-méthyl-5-[3-(trifluorométhy])phénoxy]quinoléin- 8-yl]pentane-1,4-diamine antipaludique tafenoquina (±)-8-[(4-amino-1-metilbutil)amino]-2,6-dimetoxi-4-metil-5-[(α,α,α-trifluoro- m-tolil)oxi]quinolina antipalúdico

C24H28F3N3O3 106635-80-7

and enantiomer et énantiomère y enantiómero

277 Proposed INN: List 80 WHO Drug Information. Vol. 12, No. 4, 1998

talampanelum talampanel (R)-7-acetyl-5-(p-aminophenyl)-8,9-dihydro-8-methiyl-7H-1,3-dioxolo= [4,5-h] [2,3] benzodiazepine AMPA receptor antagonist talampanel (8R)-7-acétyl-5-(4-aminophényl)-8-méthyl-8,9-dihydro-7H-1,3-dioxolo= [4,5-h][2,3]benzodiazépine antagoniste des récepteurs de l'AMPA talampanel (R)-7-acetil-5-(p-aminofenil)-8,9-dihidro-8-metil-7H-1,3-dioxolo= [4,5-h][2,3]benzodiazepina antagonista del receptor AMPA

C19H19N3O3 161832-65-1

telithromycinum telithromycin (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-4-ethyloctahydro-11-methoxy- 3a,7,9,11,13,15-hexamethyl-1-[4-[4-(3-pyrrdyl)imidazol-1-yl]butyl]- 10-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]- 2H-oxacyclotetradecino[4,3-d]oxazole-2,6,8,14(1H,7H,9H)-tetrone antibiotic télithromycine (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-10-[[3-(diméthylamino)- 3,4,6-tridésoxy-β-D-xylo-hexopyranosyl]oxy]-4-ethyl-11-méthoxy- 3a,7,9,11,13,15-hexaméthyl-1-[4-(pyridin-3-yl)-1H-imidazol-1-yl]butyl]= octahydro-2H-oxacyclotétradécino[4,3-d]oxazole-2,6,8,14(1H,7H,9H)-tétrone antibiotique telitromicina (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-4-etiloctahidro-11-metoxi- 3a,7,9,11,13,15-hexametil-1-[4-[4-(3-piridil)imidazol-1-il]butil]- 10-[ [3,4,6-tridesoxy-3-(dimetilamino)-β-D-xilo-hexopiranosil]oxi]- 2H-oxaciclotetradecino[4,3-d]oxazol-2,6,8,14(1H,7H,9H)-tetrona antibiótico

C43H65N5O10 173838-31-8

278 WHO Drug Information, Vol 12, No. 4, 1998 Proposed INN: List 80

tenatoprazolum tenatoprazole (±)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]- 1H-imidazo[4,5-b]pyridine antiulcer agent ténatoprazole 5-méthoxy-2-[(RS)-[(4-méthoxy-3,5-diméthylpyridin-2-yl)méthyl]sulfinyl]- 1H-imidazo[4,5-b]pyridine antiulcéreux tenatoprazol (±)-5-metoxi-2-[[(4-metoxi-3,5-dimetil-2-piridil)metil]sulfinil]- 1H-imidazol[4,5-b]piridina antiulceroso

C16H18N4O3S 113712-98-4

and enantiomer et énantiomère y enantiómero

teriflunomidum teriflunomide (Z)-2-cyano-α' α' α-trifluoro-3-hydroxy-p-crotonotoluidide antirheumatic tériflunomide (Z)-2-cyano-3-hydroxy-N-[4-(trifluorométhyl)phényl]but-2-énamide antirhumatismal teriflunomida (Z)-2-ciano-α' α' α-trifluoro-3-hidroxi-p-cratonotoluidida antirreumático

C12H9F3N2O3 108605-62-5

timcodarum timcodar (S)-N-benzyl-p-chloro-α-[N-methyl-2-(3-trimethoxyphenyl)glyoxylamido]- N-[3-(4-pyridyl)-1-[2-(4-pyridyI)etriyl]propyl]hydrocinnamamide multidrug resistance inhibitor, antineoplastic timcodar (2S)-N-benzyl-3-(4-chlorophényl)-2-[méthyl[2-oxo- 2-(3,4,5-triméthoxyphényl)acétyl]amino]-N-[3-(pyridin-4-yl)-1-[2-(pyridin- 4-yl)éthyl]propyl]propanamide inhibiteur de la multirésistence aux médicaments, antinéoplasique timcodar (S)-N-bencil-p-cloro-α-[N-metil-2-(3,4,5-trimetoxifenil)glioxilamido]= N-[3-(4-piridil)-1-[2-(4-piridil)etil]propil]hidrocinamamida inhibidor de la resistancia a multiples fármacos, antineoplástico

279 Proposed INN; List 80 WHO Drug Information, Vol. 12, No. 4, 1998

C43H45CIN4O6 179033-51-3

tipranavirum tipranavir 3'-[(1R)-1-[(6R)-5,6-dihydro-4-hydroxy-2-oxo-6-phenethyl-5-propyl-2H-pyran- 3-yl]propyl]-5-(trifluoromethyl)-2-pyridinesulfonanilide antiviral tipranavir N-[3-[(1R)-1-[(6R)-4-hydroxy-2-oxo-6-(2-phényléthyl)-6-propyl-5,6-dihydro- 2H-pyran-3-yI]propyl]phényl]-5-(trifluorométhyl)pyridine-2-sulfonamide antiviral tipranavir 3'-[(1R)-1-[(6R)-5,6-dihidro-4-hidroxi-2-oxo-6-fenetil-6-propil-2H-piran- 3-il]propil]-5-(trifluorometil)-2-piridinasulfonanilida antiviral

C31H33F3N2O5S 174484-41-4

tonabersatum tonabersat N-[(3S,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-4-chromanyl]-3-chloro- 4-fluorobenzamide anticonvulsant tonabersate N-[(3S,4S)-6-acétyl-3-hydroxy-2,2-diméthyl-3,4-dihydro-2H-chromén-4-yl]- 3-chIoro-4-fluorobenzamide anticonvulsant tonabersato N-((3S,4S)-6-acetil-3-hidroxi-2,2-dimetil-4-cromanil]-3-cloro- 4-fluorobenzamida anticonvulsivo

280 WHO Drug Information, Vol. 12, No. 4, 1998 Proposed INN: List 80

C20H19CIFNO4 175013-84-0

tositumomabum tositumomab immunoglobulin G2a anti-(human antigen CD 20) (mouse monoclonal clone B1R1 γ2a-chain), disulfide with mouse monoclonal clone B1R1 λx-chain, dimer immunomodulator tositumomab immunoglobuline G2a anti-(antigène CD 20 humain) (chaîne γ2a de l'anticorps monoclonal de souris B1R1), dimère du disulfure avec la chaîne λx de l'anticorps monoclonal de souris B1R1 immunomodulateur tositumomab Inmunoglobulina G2a anti-(antigeno CD 20 humano) (cadena γ2a del anticuerpo monoclonal de ratón B1R1),dímero del disulfuro con la cadena λx del anticuerpo monoclonal de ratón B1R1 inmunomodulador 192391-48-3

travoprostum travoprost isopropyl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(1E,3R)-3-hydroxy- 4-[(α,α,α-trifluoro-m-toiyl)oxy]-1-butenyl]cyclopentyl]-5-heptenoate prostaglandin travoprost (5Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(1E)-(3R)-3-hydroxy- 4-[3-(trifluorométhyl)phénoxy]but-1-ényl]cycIopentyl]hept-5-énoate de 1-méthyléthyle prostaglandins travoprost (Z)-7-[(1R,2R,3R,5S)-3,5-dihidroxi-2-[(1E,3R)-3-hidroxi-4-[(α,α,α-trifluoro- m-tolil)oxi]-1-butenil]ciclopentil]-5-heptenoato de isopropilo prostaglandina

C26H35F3O6 157283-68-6

281 Proposed INN: List 80 WHO Drug Information, Vol. 12, No. 4, 1998

upidosinum upidosin N-[3-[4-(o-methoxyphenyl)-1-piperazinyl]propyl]-3-methyl-4-oxo-2-phenyl- 4H-1-benzopyran-8-carboxamide α1-adrenoreceptor antagonist upidosine N-[3-[4-(2-méthoxyphényl)pipérazin-1-yl]propyl]-3-méthyl-4-oxo-2-phényl- 4H-chromène-8-carboxamide antagoniste α1-adrénergique upidosina N-[3-[4-(o-metoxifenil)-1-piperazinil]propil]-3-metil-4-oxo-2-fenil- 4H-1 -benzopirano-8-carboxamida antagonista de los receptores α1-adrenérgicos

C31H33N3O4 152735-23-4

valdecoxibum p-(5-methyl-3-phenyl-4-isoxazolyl)benzenesulfonamide valdecoxib cycloxygenase-2 inhibitor 4-(5-méthyl-3-phénylisoxazol-4-yl)benzènesulfonamide valdécoxib inhibiteur de la cyclooxygénase-2 p-(5-metil-3-fenil-4-isoxazolil)bencenosulfonamida valdecoxib inhibidor de la cicloxigenasa-2

C16H14N2O3S 181695-72-7

vangatalcitum vangatalcite dialuminum tetramagnesium carbonate dodecahydroxide trihydrate antacid vangatalcite carbonate et dodécahydroxyde de dialuminium et de tétramagnésium trihydraté antiacide vangatalcita dodecahidróxido carbonato de dialuminio y tetramagnesio trihidrato antiácido

Al2Mg4(OH)12CO3, 3H20

282 WHO Drug Information, Vol. 12, No 4, 1998 Proposed INN: List 80

vepalimomabum vepalimomab immunoglobulin M (mouse monoclonal 1B2 µ-chain anti-human vascular adhesion protein VAP-1), disulfide with mouse monoclonal 1B2 light chain, dimer immunomodulator vépalimomab immunoglobuline M anti-(protéine d'adhésion vasculaire humaine VAP-1) (chaîne µ de l'anticorps monoclonal de souris 1B2), dimère du disulfure avec la chaîne légère de l'anticorps monoclonal de souris 1B2 immunomodulateur vepalimomab inmunoglobulina M (cadena µ del anticuerpo monoclonal de ratón 1B2 dirigido contra la proteína humana de adhesión vascular VAP-1), dímero del disulfuro con la cadena ligera del anticuerpo monoclonal de ratón 1B2 inmunomodulador 195158-85-1

vilazodonum vilazodone 5-[4-[4-(5-cyanoindol-3-yl)butyl]-1-piperazinyl]-2-benzofurancarboxamide antidepressant 5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]pipérazin-1-yl]benzafurane- vilazodone 2-carboxamide antidépresseur 5-[4-[4-(5-cianoindol-3-il)butil]-1-piperazinil]-2-benzofurancarboxamida vilazodona antidepresivo

C26H27N5O2-HCI 163521-12-8

283 Proposed INN: List 80 WHO Drug Information, Vol. 12, No. 4, 1998

volpristinum (3R,4R,5E,105,12E,14S,26aR)-8,9,14,15,24,25,26,26a-octahydro- 14-hydroxy-3-isopropyl-4,12-dimethyl-3H-21,18-nitrilo-1H,22H-pyrrolo= [2,1-c][1,8,4,19]dioxadiazacyclotetracosine-1,7,16,22(4H,17H)-tetrone volpristin antibacterial (5E,10E,12E)-(3R,4R,14S,26aR)-14-hydroxy-4,12-diméthyl-3-(1-méthyléthyl)- 3,4,8,9,14,15,24,25,26,26a-décahydro-7H-21.18-nitrilo-1H,22H-pyrrolo= [2,1-c][1,8,4,19]dioxadiazacyclotétracosène-1,7,16,22(17H)-tétrone volpristine antibactérien (3R,4R,5E,10E,12E,14S,26aR)-8,9,14,15,24,25,26,26a-octahidro-14-hidroxi- 3-isopropil-4,12-dimetil-3H-21,18-nitrilo-1H,22H-pirrolo= [2,1-c][1,8,4,19]dioxadiazaciclotetracosina-1,7,16,22(4H,17H)-tetrona volpristina antibacteriano

C28H37N3O7 21102-49-8

284 WHO Drug Information, Vol, 12, No. 4, 1998 Proposed INN: List 80

AMENDMENTS TO PREVIOUS LISTS MODIFICATIONS APPORTÉES AUX LISTES ANTÉRIEURES MODIFICACIONES A LAS LISTAS ANTERIORES

Proposed International Nonproprietary Names (Prop. INN): List 18 (WHO Chronicle, Vol. 21, No. 11, 1967) p. 12 hypromellosum hypromellose replace the chemical name by the following: a mixed methyl and 2-hydroxypropyl ether of cellulose

Dénominations communes internationales proposées (DCI Prop.): Liste 18 (Chronique OMS, Vol. 21, No. 11, 1967) p. 11 hypromellosum hypromellose remplacer le nom chimique par le suivant: mélange d'éthers méthyliques et 2-hydroxypropyliques de cellulose

Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 1B (Crónica de la OMS, Vol. 21, No. 11, 1967) p. 132 hypromellosum hipromelosa sustitúyase el nombre quimico por el siguiente: mezcla de éteres metilicos y 2-hidroxipropilicos de celulosa

Proposed International Nonproprietary Names (Prop. INN): List 31 (WHO Chronicle, Vol. 28, No. 3, 1974) p. 22 calcitoninum calcitonin replace the description by the following: a polypeptide hormone that lowers the calcium concentration (the species specificity should be indicated in brackets behind the name) e.g.

calcitonin (human)

C151H226N40O45S3

Cys— Gly—Asn— Leu—Ser—Thr—Cys— Met—Leu—Gly—Thr—Tyr—Thr— 10 Gin—Asp—Phe—Asn—Lys—Phe—His—Thr-Phe—Pro—Gin—Thr—Ala — 20

Ile—Gly—Val—Gly—Ala—Pro-NH2 30

285 Proposed INN: List 80 WHO Drug Information, Vol. 12, No. 4, 1998

calcitonin (salmon)

C145H240N44O48S2

Cys— Ser—Asn—Leu—Ser—Thr—Cys—Val—Leu—Gly—Lys—Leu—Ser­ ­­ Gin—Glu—Leu—His—Lys—Leu—Gin—Thr—Tyr—Pro—Arg—Thr—Asn — 20

Thr—Gly—Ser—Gly—Thr—Pro-NH2 30

Dénominations communes internationales proposées (DCI Prop.): Liste 31 (Chronique OMS, Vol. 28, No. 3, 1974)

p. 22 calcitoninum calcitonine remplacer la description par la suivante: hormone polypeptideque qui abaisse le taux de calcium (la spécifité de l'espèce doit être indiquée entre parenthèses derrière la dénomination), ex.: calcitonine (humaine)

C151H226N40O45S3

Cys— Gly— Asn— Leu—Ser— Thr— Cys— Met—Leu— Gly— Thr— Tyr—Thr— 10 Gin—Asp—Phe—Asn—Lys—Phe—His—Thr—Phe—Pro—Gln—Thr—Ala— 20

Ile—Gly—Val—Gly—Ala—Pro-NH2 30

calcitonine (saumon)

C145H240N44O48S2

Cys—Ser—Asn—Leu—Ser—Thr—Cys—Val—Leu—Gly—Lys—Leu—Ser­ ­­ Gin—Glu—Leu—His—Lys—Leu—Gin—Thr—Tyr—Pro—Arg—Thr—Asn— 20

Thr—Gly—Ser—Gly—Thr—Pro-NH2 30

Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 31 (Crónica de la OMS, Vol. 28, No. 3, 1974)

p. 22 calcitoninum calcitonina sustitúyase la descripción por la siguiente: hormona polipeptídica que disminuye la concentración del calcio (la especifidad de especie debe estar indicada entre paréntesis después de la denominación) p. ej.

286 WHO Drug Information, Vol 12, No. 4, 1998 Proposed INN: List 80

calcitonina (humana)

C151H226N40O45S3

Cys—Gly—Asn—Leu—Ser—Thr—Cys—Met—Leu—Gly—Thr—Tyr—Thr— 10 Gln—Asp—Phe—Asn—Lys—Phe—His—Thr-Phe—Pro—Gln—Thr—Ala— 20

Ile—Gly—Val—Gly—Ala—Pro-NH2 30

calcitonina (salmón)

C145H240N44O48S2

Cys—Ser—Asn—Leu—Ser—Thr—Cys —Val—Leu—Gly—Lys—Leu—Ser­ ­­ Gin—Glu—Leu—His—Lys—Leu—Gin—Thr—Tyr—Pro—Arg—Thr—Asn— 20

Thr—Gly—Ser—Gly—Thr—Pro-NH2 30

Proposed International Nonproprietary Names (Prop. INN): List 68 (WHO Drug Information, Vol. 6, No. 4, 1992)

p. 2 altumomabum altumomab replace the description by the following: immunoglobulin G1, anti-(human carcinoembryonic antigen) (mouse monoclonal ZCE025 γ1-chain), disulfide with mouse monoclonal ZCE025 light chain, dimer

p. 16 satumomabum satumomab replace the description by the following: immunoglobulin G1, anti-(human tumor-associated glycoprotein 72) (mouse monoclonal B72.3 light chain), disulfide with mouse monoclonal B72 3 light chain, dimer

Dénominations communes internationales proposées (DCI Prop.): Liste 68 (Informations Pharmaceutiques OMS, Vol. 6, No. 4, 1992)

p. 2 altumomabum altumomab remplacer la description par la suivante. immunoglobuline G1, anti-(antigène associé aux carcinomes embryonnaires humains) (chaîne γ1 de l'anticorps monoclonal de souris ZCE025), dimère du disulfure avec la chaîne légère de l'anticorps monoclonal de souris ZCE025

287 Proposed INN: List 80 WHO Drug Information, Vol. 12, No. 4, 1998

p. 16 satumomabum satumomab remplacer la description parla suivante: immunoglobulins G1, anti-(glycoprotéine 72 humaine associée aux tumeurs) (chaîne légère de l'anticorps monoclonal de souris B72.3), dimère du disulfure avec la chaîne légère de l'anticorps monoclonal de souris B72.3

Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 68 (Información Farmacéutica OMS, Vol. 6, No. 4, 1992) p. 2 altumomabum altumomab sustitúyase la descripción por la siguiente: inmunoglobulina G1, anti-(antigeno carcinoembrionario humano) (cadena γ1 del anticuerpo monoclonal de ratón ZCE025), dimero del disulfuro con la cadena ligera del anticuerpo monoclonal de ratón ZCE025 p. 16 satumomabum satumomab sustitúyase la descripción por la siguiente: inmunoglobulina G1, anti-(glicoproteína 72 humana asociada al tumor) (cadena ligera del anticuerpo monoclonal de ratón B72.3), dímero del disulfuro con la cadena ligera del anticuerpo monoclonal de ratón B72.3

Proposed International Nonproprietary Names (Prop. INN): List 69 (WHO Drug Information, Vol. 7, No. 2, 1993) p. 3 edobacomabum edobacomab replace the description by the following. immunoglobulin M, anti-(endotoxin) (mouse monoclonal XMMEN-0E5 µ-chaín), disulfide with mouse monoclonal XMMEN-0E5 light chain, pentameric dimer p. 9 zolimomabum aritoxum zolimomab aritox replace the description by the following. immunoglobulin G1, anti-(human CD5 (antigen) heavy chain) (mouse monoclonal H65-RTA γ1-chain), disulfide with mouse monoclonal H65-RTA light chain, dimer, disulfide with ricin (castor bean A-chain)

Dénominations communes internationales proposées (DCI Prop.): Liste 69 (Informations Pharmaceutiques OMS, Vol. 7, No. 2, 1993) p. 3 edobacomabum édobacomab remplacer la description par la suivante: immunoglobuline M, anti-(endotoxine) (chaîne m de l'anticorps monoclonal souris XMMEN-0E5), dimère pentamérique du disulfure avec la chaîne légère de l'anticorps monoclonal de souris XMMEN-0E5

288 WHO Drug Information, Vol 12, No. 4, 1998 Proposed INN: List 80

p. 9 zolimomabum aritoxum zolimomab aritox remplacer la description par la suivante: immunoglobuline G1, anti-(chaîne lourde de l'antigène CD5 humain) (chaîne γ1 de l'anticorps monoclonal de souris H65-RTA), dimère du disulfure avec la chaîne légère de l'anticorps monoclonal de souris H65-RTA, disulfure avec la chaîne A de la ricine

Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 69 (Información Farmacéutica OMS, Vol. 7, No. 2, 1993) p. 3 edobacomabum edobacomab sustitúyase la descripción por la siguiente: inmunoglobulina M, anti-(endotoxina) (cadena µ del anticuerpo monoclonal de ratón XMMEN-0E5), dímero pentamérico del disulfuro con la cadena ligera del anticuerpo monoclonal de ratón XMMEN-0E5 p. 9 zolimomabum aritoxum zolimomab aritox sustituyase la descripción por la siguiente: inmunoglobulina G1, anti-(cadena pesada del antígeno humano CD5) (cadena γ1 del anticuerpo monoclonal de ratón H65-RTA), dímero del disulfuro con la cadena ligera del anticuerpo monoclonal de ratón H65-RTA, disulfuro con ricina (cadena A de la judía de ricino)

Proposed International Nonproprietary Names (Prop. INN): List 70 (WHO Drug Information, Vol. 7, No, 4, 1993) p 1 abciximabum abciximab replace the description by the following: immunoglobulin G1, anti-(human integrin αllbβ3) Fab fragment (human-

mouse monoclonal c7E3 clone p7E3VHhCγ1 γ1-chain), disulfide with human-

mouse monoclonal c7E3 clone p7E3VκhCκ κ-chain p. 3 capromabum capromab replace the description by the following: immunoglobulin G1, anti-(human prostatic carcinoma cell) (mouse mono­ clonal 7E11-C5.3 γ1-chain), disulfide with mouse monoclonal 7E11-C5.3 light chain, dimer p 4 detumomabum detumomab replace the description by the following: immunoglobulin G1, anti-(human B lymphoma cell) (mouse monoclonal SPECIFID heavy chain), disulfide with mouse monoclonal SPECIFID light chain, dimer p. 5 enlimomabum enlimomab replace the description by the following: immunoglobulin G2a, anti-(human CD54 (antigen)) (mouse monoclonal BI- RR-1 γ2a-chain), disulfide with mouse monoclonal BI-RR-1 light chain, dimer

289 Proposed INN: List 80 WHO Drug Information, Vol. 12, No. 4, 1996

p. 13 votumumabum votumumab replace the description by the following: immunoglobulin G3, anti-(human carcinoma-associated antigen) (human monoclonal 88BV59 γ3-chain), disulfide with human monoclonal 8SBV59 κ-chain, dimer

Dénominations communes internationales proposées (DCI Prop.): Liste 70 (Informations Pharmaceutiques OMS, Vol. 7, No. 4, 1993) p. 1 abciximabum abciximab remplacer la description par la suivante: immunoglobuline G1, anti-(intégrine αllbβ3 humaine) fragment Fab (chaîne γ1 de l'anticorps monoclonal chimérique homme-souris c7E3 clone

p7E3VHhCγ1), disulfure avec la chaîne K de l'anticorps monoclonal

chimérique homme-souris c7E3 clone p7ESVKhCK p. 4 capromabum capromab remplacer la description par la suivante: immunoglobuline G1, anti-(cellules du carcinome prostatique humain) (chaîne γ1 de l'anticorps monoclonal de souris 7E11-C5.3), dimère du disulfure avec la chaîne légère de l'anticorps monoclonal de souris 7E11- C5.3 p. 5 detumomabum détumomab remplacer la description par la suivante: immunoglobuline G1, anti-(cellules de lymphome B humain) (chaîne lourde de l'anticorps monoclonal de souris SPECIFID), dimère du disulfure avec la chaîne légère de l'anticorps monoclonal de souris SPECIFID p 5 enlimomabum enlimomab remplacer la description par la suivante: immunoglobuline G2a, anti-(antigène CD54 humain) (chaîne γ2a de l'anticorps monoclonal de souris BI-RR-1 ), dimère du disulfure avec la chaîne légère de l'anticorps monoclonal de souris BI-RR-1 p. 13 votumumabum votumumab remplacer la description par la suivante: immunoglobuline G3, anti-(antigène associé aux carcinomes humains) (chaîne γ3 de l'anticorps monoclonal humain 88BV59), dimère du disulfure avec la chaîne K de l'anticorps monoclonal humain 88BV59

290 WHO Drug Information, Vol. 12, No. 4, 1998 Proposed INN: List 80

Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 70 (Información Farmacéutica OMS, Vol. 7, No. 4, 1993) p 1 abciximabum abciximab sustitúyase la descripción por la siguiente inmunoglobulina G1, anti-(integrina αllbβ3 humana) fragmento Fab (cadena

γ1 del anticuerpo monoclonal hombre-ratón c7E3 clon p7E3VHhCγ1), disulfuro con la cadena Κ del anticuerpo monoclonal hombre-ratón c7E3 clon

p7E3VxhCκ p.4 capromabum capromab sustitúyase la descripción por la siguiente inmunoglobulina G1, anti-(células de carcinoma prostático humano) (cadena Γ1 del anticuerpo monoclonal de ratón 7E11-C5.3), dímero del disulfuro con la cadena ligera del anticuerpo monoclonal de ratón 7E11-C5.3 p.5 detumomabum detumomab sustitúyase la descripción por la siguiente: inmunoglobulina G1, anti-(celulas de linfoma B humano) (cadena pesada del anticuerpo monoclonal de ratón SPECIFID), dímero del disulfuro con la cadena ligera del anticuerpo monoclonal de ratón SPECIFID p 5 enlimomabum enlimomab sustitúyase la descripción por la siguiente: inmunoglobulina G2a, anti-((antigeno) CD54 humano) (cadena γ2a del anticuerpo monoclonal de ratón BI-RR-1), dimero del disulfuro con la cadena ligera del anticuerpo monoclonal de ratón BI-RR-1 p. 14 votumumabum votumumab sustituyase la descripción por la siguiente: inmunoglobulina G3 anti-(antígeno asociado a los carcinomas humanos) (cadena γ3 del anticuerpo monoclonal humano 38BV59), dímero del disulfuro con la cadena K del anticuerpo monoclonal humano 88BV59

Proposed International Nonproprietary Names (Prop. INN): List 71 Dénominations communes internationales proposées (DCI Prop.): Liste 71 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 71 (WHO Drug Information, Vol. 8, No. 2, 1994) p. 14 inolimomabum inolimomab replace the description by the following: immunoglobulin G1, anti-(human interleukin 2 receptor α-chain) (mouse monoclonal B-B10 γ1-chain), disulfide with mouse monoclonal B-810 κ-chain, dimer

291 Proposed INN: List 80 WHO Drug Information, Vol. 12, No. 4, 1998

inolimomab remplacer la description par la suivante: immunoglobuline G1, anti-(chaîne α du récepteur de l'interleukine 2 humain) (chaîne γ1 de l'anticorps monoclonal de souris B-B10), dimère du disulfure avec la chaîne K de l'anticorps monoclonal de souris B-B10

inolimomab sustitúyase la descripción por la siguiente: inmunoglobulina G1, anti-(cadena α del receptor de interleukina 2 humano) (cadena γ1 del anticuerpo monoclonal de ratón B-B10), dímero del disulfuro con la cadena K del anticuerpo monoclonal de ratón B-B10

p. 17 nacolomabum tafenatoxum nacolomab tafenatox replace the description by the following: immunoglobulin G1, anti-(human colorectal tumor antigen C242) Fab fragment (mouse monoclonal r-C242Fab-SEA clone pkP941 γ1-chain) fusion protein with enterotoxin A (Staphylococcus aureus), disulfide with mouse monoclonal r-C242Fab-SEA clone pkP941 κ-chain

nacolomab tafénatox remplacer la description par la suivante: protéine de fusion entre l'immunoglobuline G1, anti-(antigène C242 associé aux tumeurs colorectales humaines) fragment Fab (chaîne γ1 de l'anticorps monoclonal de souris r-C242Fab-SEA clone pkP941) et l'entérotoxine A (Staphylococcus aureus), disulfure avec la chaîne κ de l'anticorps mono­ clonal de souris r-C242Fab-SEA clone pkP941

nacolomab tafenatox sustitúyase la descripción por la siguiente: inmunoglobulina G1, anti-(antigeno C242 de tumor colorrectal humano) fragmento Fab (cadena γ1 del anticuerpo monoclonal de ratón r-C242Fab- SEA clon pkP941) proteina de fusión con la enterotoxina A (Staphylococcus aureus), disulfuro con la cadena K del anticuerpo monoclonal de ratón r-C242Fab-SEA clon pkP941 p. 19 regavirumabum regavirumab replace the description by the following: immunoglobulin G1, anti-(human herpesvirus 5 glycoprotein B) (human monoclonal γ1-chain), disulfide with human monoclonal κ-chain, dimer

régavirumab remplacer la description par la suivante: immunoglobuline G1, anti-(glycoprotéine B du virus de l'herpès 5 humain) (chaîne γ1 de l'anticorps monoclonal humain), dimère du disulfure avec la chaîne K de l'anticorps monoclonal humain

regavirumab sustitúyase la descripción por la siguiente: inmunoglobulina G1, anti-(glicoproteina B del virus del herpes 5 humano) (cadena γ1 del anticuerpo monoclonal humano), dímero del disulfuro con la cadena K del anticuerpo monoclonal humano

292 WHO Drug Information, Vol. 12, No 4, 1998 Proposed INN: List 80

Proposed International Nonproprietary Names (Prop. INN): List 72 Dénominations communes internationales proposées (DCI Prop.): Liste 72 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 72 (WHO Drug Information, Vol, 8, No. 4, 1994) p. 3 afelimomabum afelimomab replace the description by the following: immunoglobulin G3, anti-(human tumor necrosis factor a) F(ab')2 fragment (mouse monoclonal LU54107 γ3-chain), disulfide with mouse monoclonal LU54107 κ-chain, dimer

afélimomab remplacer la description par la suivante: immunoglobuline G3, anti-(facteur de nécrose tumorale a humain) fragment F(ab')2 (chaîne γ3 de l'anticorps monoclonal de souris LU54107), dimère du disulfure avec la chaîne K de l'anticorps monoclonal de souris LU54107

afelimomab sustitúyase la descripción por la siguiente: inmunoglobulina G3, anti-(factor de necrosis tumoral a humano) fragmento F(ab')2 (cadena γ3 del anticuerpo monoclonal de ratón LU54107), dímero del disulfuro con la cadena K del anticuerpo monoclonal de ratón LU54107 p. 27 priliximabum priliximab replace the description by the following: immunoglobulin G1, anti-(human CD4 (antigen)) (human-mouse monoclonal cm-T412 γl-chain), disulfide with human-mouse monoclonal cm-T412 K-chain, dimer

priliximab remplacer la description par la suivante: immunoglobuline G1, anti-(antigène CD4 humain) (chaîne γ1 de l'anticorps monoclonal chimérique homme-souris cm-T412), dimère du disulfure avec la chaîne K de l'anticorps monoclonal chimérique homme-souris cm-T412

priliximab sustitúyase la descripción por la siguiente: inmunoglobulina G1, anti-((antígeno) CD4 humano) (cadena γ1 del anticuerpo monoclonal hombre-ratón cm-T412), dímero del disulfuro con la cadena K del anticuerpo monoclonal hombre-ratón cm-T412

Proposed International Nonproprietary Names (Prop. INN): List 78 Dénominations communes internationales proposées (DCI Prop.): Liste 78 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 78 (WHO Drug Information, Vol. 11, No. 4, 1997) p. 280 delete/supprimer/suprimase insert/insérer/insértese nelzarabinum nelarabinum nelzarabine nelarabine nélzarabine nélarabine nelzarabina nelarabina

293 Proposed INN: List 80 WHO Drug Information, Vol. 12, No. 4, 1998

Proposed International Nonproprietary Names (Prop. INN): List 79 Dénominations communes internationales proposées (DCI Prop.): Liste 79 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 79 (WHO Drug Information, Vol. 12, No. 2, 1998)

p. 105 eniporidum eniporide add the fallowing CAS registry number: éniporide insérer le numéro dans le registre du CAS suivant: eniporida insértese el número de registro del CAS siguiente: 176644-21-6

p 106 esomeprazolum esomeprazole add the following CAS registry number ésoméprazole insérer le numéro dans le registre du CAS suivant. esomeprazol insértese el número de registro del CAS siguiente: 119141-88-7

p. 112 stannsoporfinum stannsoporfin replace the molecular formula by the following: stannsoporfine remplacer la formule brute par: stannsoporfina sustitúyase la fórmula molecular por:

C34H36CI2N4O4Sn

Procedure and Guiding Principles / Procédure et Directives / Procedimientos y principios generales

The text of the Procedures for the Selection of Recommended International Nonproprietary Names for Pharmaceuti• cal Substances and General Principles for Guidance in Devising International Nonproprietary Names for Pharma• ceutical Substances will be reproduced in uneven numbers of proposed INN lists only.

Les textes de la Procédure à suivre en vue de choix de dénominations communes internationales recommandées pour les substances pharmaceutiques et des Directives générales pour la formation de dénominations communes internationales applicables aux substances pharmaceutiques ont été publiés avec la liste 77 des DCI proposées et seront, à nouveau, publiés avec la prochaine liste.

El texto de los Procedimientos de selección de denominaciones comunes internacionales recomendadas para las sustancias farmacéuticas y de los Principios generales de orientación para formar denominaciones comunes internacionales para sustancias farmacéuticas aparece solamente en los números impares de las listas de DCI propuestas.

294