WHO DRUG

INFORMATION

VOLUME 3 • NUMBER 2 • 1989

PROPOSED INN LIST 61 INTERNATIONAL NONPROPRIETARY NAMES FOR PHARMACEUTICAL SUBSTANCES

WORLD HEALTH ORGANIZATION • GENEVA WHO Drug Information

WHO Drug Information provides an cerned with the rational use of overview of topics relating to drug drugs. In effect, the journal seeks development and regulation that to relate regulatory activity to are of Current relevance and im­ therapeutic practice. It also aims to portance, and will include the lists provide an open forum for debate. of proposed and recommended In­ Invited contributions will portray a ternational Nonproprietary Names variety of viewpoints on matters of for Pharmaceutical Substances general policy with the aim of sti­ (INN). Its contents reflect, but do mulating discussion not only in not present, WHO policies and ac­ these columns but wherever re­ tivities and they embrace socio­ levant decisions on this subject economic as well as technical mat­ have to be taken. ters. WHO Drug Information is publish­ The objective is to bring issues that ed 4 times a year in English and are of primary concern to drug French. regulators and pharmaceutical manufacturers to the attention of a Annual subscription: Sw.fr. 50.— wide audience of health profes­ Airmail rate: Sw.fr. 60.— sionals and policy-makers con­ Price per copy: Sw.fr. 15.—

© World Health Organization 1989 Authors alone are responsible for views expressed Publications of the World Health Organization in signed contributions. enjoy copyright protection in accordance with the provisions of Protocol 2 of the Universal The mention of specific companies or of certain Copyright Convention. For rights of reproduc­ manufacturers' products does not imply that they are tion or translation, in part or in toto, applica­ endorsed or recommended by the World Health tion should be made to: Chief, Office of Organization in preference to others of a similar na­ Publications, World Health Organization, ture which are not mentioned. Errors and omissions 1211 Geneva 27, Switzerland. The World excepted, the names of proprietary products are Health Organization welcomes such applica­ distinguished by initial capital letters. tions. The designations employed and the presen­ tation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country, territory, city, or area or of its authorities, or concern­ ing the delimitation of its frontiers or boun­ daries.

ISSN 1010-9609 Volume 3, Number 2, 1989 World Health Organization, Geneva

WHO Drug Information

Contents General Policy Topics Potassium chloride voluntary withdrawal 67 Guiding principles for small national Slimming aids 67 drug regulatory authorities 43 Tamoxifen 67

Personal Perspectives Veterinary Drugs Address to Ninth General Assembly of the Amoxicillin 67 World Federation of Proprietary Medicines Carcinogenicity and veterinary drugs 68 Manufacturers 51 Chloramphenicol 68 Reports on Individual Drugs Advisory Notices Oral contraceptives and breast cancer 53 Allergenic extracts: risk of anaphylaxis 69 Efficacy of hepatitis B vaccine 54 Dapsone: severe cutaneous reactions 69 Aerosolized pentamidine in Pneumocystis Floctafenine 69 carinii pneumonia 55 Injectable vitamin preparations: Antihaemophilic factor and AIDS 56 serious allergic reactions 69 Fenoterol and fatal asthma 57 Lofepramine: severe hepatic reactions 70 Ciclosporin enemas in refractory Low osmolar radiocontrast media and shock 70 chronic proctitis 58 Lysine acetylsalicylate injectables and shock 70 Mianserin: blood dyscrasias 70 Nefopam: risk of urinary retention 70 General Information Parenteral nutrition: need forthiamine- Proposed revision of Australian therapeutic containing vitamin supplements 71 goods legislation 59 Propofol: convulsions, anaphylaxis and Epidemiologists at odds 59 delayed recovery from anaesthesia 71 Analgesics and renal disease 59 Sulfonylureas and hypoglycaemia 71 Resistance to antivirals 61 Suxemethonium chloride: severe bradycardia 71 High blood pressure in the elderly 62 Tetracyclines: benign intracranial Volatile anaesthetics and the ozone layer 63 hypertension 72 Disclosure of inactive ingredients 63 Registration of drug products in Malaysia 63 Is multiple sclerosis an immune disease? 64 Essential Drugs Measles virus vaccines: defective Intestinal infections due interfering particles 65 to nematodes 73 Measles/mumps/rubella vaccine: Ascariasis 73 cost benefit 65 Hookworm 74 Salt-induced enhancement of measles Strongyloidiasis 74 virus yield in cultured cells 65 Enterobiasis 75 Trichuriasis 75 Regulatory Matters Trichostrongyliasis 75 Drugs for Human Use Capillariasis 76 76 Erratum: pyrrolizidine alkaloids 66 Albendazole Encainide and flecainide for life-threatening Levamisole 77 dysrhythmias only 66 Mebendazole 77 Fenbufen 66 Imipenem/cilastatin 67 (continued)

i WHO Drug Information Vol. 3, No. 2, 1989

Contents (continued)

Piperazine 78 Pyrantel 79 Tiabendazole 80

Newly Registered Products 81 Recent Publications American Hospital Formulary Service Drug Information: 89 83 Medicines: regulation, research and risk 83 Pyrrolizidine alkaloids 83 Guidelines for improving children's prescription medicine use 84 Predicting carcinogenicity 84 Proposed International Non­ proprietary Names: List 61 85

ii WHO Drug Information Vol. 3, No. 2, 1989

General Policy Topics

Guiding principles for small Pharmaceuticals Newsletter, the quarterly journal WHO Drug Information, and the UN Consolidated national drug regulatory List of products whose consumption and/or sale authorities have been banned, withdrawn, severely restricted or not approved by governments. Moreover, many The elaboration of guiding principles for small difficulties inherent in storing, retrieving and analys­ national drug regulatory authorities is a component ing data that subserve the many facets of the of WHO's Revised Drug Strategy which was regulatory process can now be redressed by the use adopted by the Thirty-ninth World Health Assembly of microcomputers and commercial software pack­ following the WHO Conference of Experts on the ages. Rational Use of Drugs held in Nairobi in November 1985. This consultative document, which is now The scope of drug control being circulated to Member States, is based exten­ sively on the report of a meeting convened in To be effective, a small drug regulatory authority Geneva in November 1987*. It was subsequently needs to operate within the context of a defined reviewed in December 1988 by the Thirty-first WHO national drugs policy and to interrelate with other Expert Committee on Specifications for Pharmaceu­ interested bodies, including organizations respon­ tical Preparations. sible for drug procurement in the public sector and the national formulary committee, where such exists. Small countries which have yet to introduce compre­ Basic responsibilities hensive legal provisions for drug regulation can draw from a diversity of national systems in determining The responsibilities of the regulatory authority are their own requirements. None the less, problems in to ensure that all products subject to its control establishing drug control in developing countries conform to acceptable standards of quality, safety have too often resulted from the adaptation of and efficacy; and that all premises and practices provisions successful elsewhere but of a complexity that precludes their effective implementation in the employed to manufacture, store and distribute country of adoption. It is of paramount importance these products comply with requirements to assure that legislation and administrative practices are the continued conformity of the products to these attuned to available resources and that every standards until such time as they are delivered to the opportunity is taken to obtain and use information end-user. provided by regulatory authorities in other countries on pharmaceutical products and substances moving Licensing functions in international commerce. These objectives can be accomplished effectively Channels of communication between national only if a mandatory system of licensing products, regulatory authorities are improving as is evident manufacturers, importing agents and distributors is from the information contained in WHO's monthly in place. A small authority has strictly limited

*Participants Mr J.Y. Binka, Medical and Health Department, Banjul, The Gambia. Dr J.L. Carrois, Cabinet International Carrois, Paris, France. Dr H. El Sheikh, Ministry of Health, Khartoum, Sudan. Dr G. Lewandowski, Ciba-Geigy, Basle, Switzerland. Mr L. Prescod, Barbados Drug Service. Professor M.D. Rawlins, University of Newcastle-upon-Tyne, United Kingdom. Mr J. Ruberantwari, Ministry of Health, Entebbe, Uganda. Dr P.N. Suwal, Ministry of Forest and Soil Conservation, Kathmandu, Nepal. Mr Tan Kiok K'ng, Ministry of Health, Singapore. Mrs S.S. Tessema, Chief Pharmacist's Office, Nairobi, Kenya

43 General Policy Topics WHO Drug Information Vol. 3, No. 2, 1989

capacity to undertake these tasks. For the assur­ Product licences ances it requires in relation to imported pharmaceu­ tical products and drug substances, it is vitally The issuance of product licences is pivotal to any dependent on authoritative, reliable and independ­ system of drug control. The licence is a legal ent information generated in the exporting country. document that establishes the detailed composition This information is most effectively obtained and formulation of the product, the pharmacopoeial through the WHO Certification Scheme on the or other officially-recognized specifications of its Quality of Pharmaceutical Products moving in ingredients, its clinical interchangeability (in the case International Commerce. of multisource products), its packaging, shelf-life and labelling. Of itself, this goes a long way towards Before a formal licensing system can become establishing the assurances of quality, efficacy and operative, it is necessary: safety to which the system is directed. However, without a viable pharmaceutical inspectorate or • to adopt a precise definition of a drug product access to an independent quality control laboratory and of the various categories of licence holders; operating to standards that will assure its credibility in the event of dispute, licensing provisions cannot • to determine the content and format of licences, be effectively enforced. both for products and for licence holders; Manufacturers and distributors • to detail the criteria on which licence applications will be assessed; and licences

• to provide guidance to interested parties on the The pharmaceutical inspectorate is responsible for content and format of licence applications, and ensuring that pharmaceutical products comply with on the circumstances under which an application conditions set out in the licence up to the time that for renewal, extension or variation of a licence they are delivered to the end user. Its functions are: will be required. • to establish, through periodic formal inspections The definition of a drug product is commonly and spot checks, that all categories of licence- contingent upon the claims that are made for it. holder are operating in accordance with their Ideally, controls need to be applied to any product licensed activities, prevailing standards of good that is offered for sale for administration to human manufacturing practice and other prescribed beings for treating, preventing and diagnosing regulations; disease, for anaesthesia, for contraception and for otherwise altering normal physiological functions. • to maintain oversight of distribution channels, In practice, exemptions may need to be granted to either by inspection and monitoring or by various specific categories of products in order to arranging for pharmacopoeial analysis of address priorities effectively. It might be decided as selected samples, with a view to ensuring that an interim measure, for example, to require products are not subject to unacceptable degra­ licences only for products listed in a national dation during transit and storage at the periphery. formulary. Ultimately, however, control needs to be extended not only to all products moving in the New drug assessments major distribution channels, but to those formulated in pharmacies and hospital dispensaries, to herbal Within highly-evolved national drug regulatory preparations, and to other traditional medicines authorities much effort is directed to establishing the entering into local commerce. efficacy and safety of new drug entities through pharmaceutical, biological and clinical assessment Analogous priorities may also need to be accorded and through subsequent surveillance of their to the registration of licence-holders, although the performance in routine use after marketing. Pre­ ultimate objective should be to embrace all manu­ marketing assessment is dependent upon detailed facturers, importing agents, wholesalers involved in multidisciplinary technical review, and post-market­ repackaging, pharmacies and hospital dispensaries ing surveillance requires a highly-developed health in a system that imposes upon them relevant care infrastructure. Only in exceptional circum­ statutory obligations. stances should a small regulatory authority contem-

44 WHO Drug Information Vol. 3, No. 2, 1989 General Policy Topics

plate allocation of scarce resources to these ends. • secure the subsequent safe and effective use of Reliance must be vested primarily on information each product by controlling, through the terms of notified by other countries through the network of the licence, the content of all labelling, including national Information Officers established by WHO. package inserts, associated prescribing informa­ tion and advertising and the channels through which it may legitimately be supplied; and

Authorization of clinical trials • inspect and license all manufacturing premises, importing agents, wholesalers and distributors, A small authority may occasionally need to consider hospital dispensaries, independent pharmacies an application to conduct a clinical trial of an and other retail outlets to ensure that they comply unregistered drug in the treatment of a condition that with prevailing regulations and guidelines. has a high local prevalence. To provide for this contingency, the registration system should include provision for the importation of the necessary materials, subject to appropriate controls. Such trials Powers of enforcement should only take place after formal clearance has been obtained from the competent registration In order to implement these responsibilities the authority and after assurances have been obtained authority must command powers of enforcement that they will be conducted in conformity with the backed by legal provision for penal sanction against principles contained in the World Medical Associa­ offenders. tion's Declaration of Helsinki and the Proposed Guidelines for Biomedical Research Involving In establishing administrative mechanisms for Human Subjects issued by the Council for Interna­ decision-making, the regulatory authority should not tional Organizations of Medical Sciences. WHO lose necessary flexibility. In particular, it should stands ready to offer independent technical advice make provision for: to national authorities in these circumstances. • implementing decisions regarded as urgent in the Terms of reference of the interest of public safety; regulatory authority •formal consultation (usually through representa­ tive bodies) with pharmaceutical companies and The formal terms of reference of a national drug other interested parties, including pharmacists, regulatory authority are determined by statute and doctors, nurses and patients. regulation. Legislation relating to pharmaceutical products has developed piecemeal in many coun­ Technical competence tries, and there are obvious advantages in bringing matters concerned with their regulation under one A small licensing authority will rarely, if ever, law. For example, it is important to correlate laws undertake comprehensive independent assess­ relating to the control of narcotic and psychotropic ments of the safety and efficacy of individual substances with requirements for product registra­ products. The administrative and technical responsi­ tion. If comprehensive overhaul of the legal system bilities that fall within its ambit are essentially of a is impractical, control within the existing framework pharmaceutical nature and they are directed primar­ through regulations specifically related to the ily to quality assurance. The professional staff must registration of pharmaceutical products offer advan­ include members with a thorough understanding and tages of economy and time-saving. Whichever practical experience of the different facets of this option is chosen, regulatory authorities require the work. flexibility to respond to changing circumstances imposed by the evolution of pharmaceutical science. The responsible officer is accountable for the professional validation and assessment of licence In general terms, the authority should be vested with applications and for the administrative aspects of legal powers to: licensing and, as such, should be involved in determining priorities and developing a timetable for • issue, vary and revoke licences for pharmaceu­ implementation of controls. These activities require tical products on grounds of quality, safety and administrative and clerical support and premises efficacy and safety; sufficient to handle the large volume of documen-

45 General Policy Topics WHO Drug Information Vol. 3, No. 2,1989

tation involved with appropriate confidentiality. day" no medicinal product may lawfully be distrib­ Efficiency of operation is enhanced when the uted or supplied unless its existence has been required information can be retrieved rapidly from a notified to the authority and no new product may be com-puterized data base. introduced until a request for a product licence has been granted by the authority. Advisory bodies Effective administration of the provisonal registration The responsible officer must also have access to a procedure is dependent upon: standing advisory committee (or board) of independ­ ent experts — including academic and practising • prior identification of all interested manufacturers health care professionals — for advice on technical and importers; issues. Consideration should also be given to the need for a multidisciplinary commission to advise on • a precise definition of a notifiable medicinal matters of general policy and administration and to product based primarily on the labelled claims assure effective interrelationships with bodies re­ and the indications for use; sponsible for drug procurement in the public sector and with the national formulary committee. • the issuance of guidelines on the procedure to be followed.

Independence of operation Each notified product must be identified by name (either brand or generic), the names and full To retain public confidence and respect, the addresses of the manufacturer and importing agent, authority must be seen to undertake its tasks in an a description of the dosage form, its composition — independent, authoritative and impartial manner. It including active and inactive ingredients (using should be concerned exclusively with the determina­ international nonproprietary names where tion of standards and the implementation of controls. appropriate) — the therapeutic class, the indica­ Although it will need to work closely with the author­ ity responsible for drug procurement within the tions, a copy of all labelling, including any package public sector, it should not, itself, be responsible for insert, and a copy of any relevant certificates and procurement and it should remain independent and warranties relating to the product or its components. autonomous in its operational activities and decis­ ions. Screening of provisionally-registered products

Administrative aspects A rapid screening of notified products should be of the licensing process undertaken at the earliest opportunity with a view to securing the withdrawal of any products which, simply on the basis of a review of their ingredients Provisional registration and indications, are judged not to meet admissible of existing medicinal products standards of safety. This may be achieved by the withdrawal of permission to trade in specific notified Before any system of control can become effective, products, or the issuance of regulations imposing it is necessary to identify and catalogue all products specified restrictions on precisely-defined groups of already sold or otherwise supplied on the domestic products. market, both in the public and private sectors, that qualify for control. To this end, all manufacturers and After this preliminary review, a set of longer-term importing agencies must be given reasonable notice priorities needs to be set for the definitive assess­ through official gazettes, the trade press and other ment of provisionally-registered products. Consid­ media of their obligation to notify the authority by a eration needs to be given to the resources required, specific date of all medicinal products that they both in manpower and information, if the review is to currently distribute within the jurisdiction of the au­ be adapted to a proposed time-schedule. Standards thority and that they intend to continue to supply must be maintained and calls to accelerate the after a duly "appointed day" on which licensing re­ speed of implementation must be recognized as quirements enter into operation. After the "appointed holding resource implications.

46 WHO Drug Information Vol. 3, No. 2, 1989 General Policy Topics

In planning priorities, consideration must be given to: (a) all herbal ingredients, save for those items classified under (b) below, which may be dis­ • the number of provisionally-registered products to pensed for a specific, named patient by practi­ be processed; tioners of herbal medicine who do not possess a formal medical qualification; • the number of staff and/or consultants to be allocated to the task; (b) ingredients such as digitalis leaf and atropine which, having regard either to their pharmacologi­ • the amount of relevant information available from cal potency or toxicity, need to be subjected to other national authorities; prescription control; and

• the extent to which products can be reviewed in (c) ingredients which, as a result of widespread, groups rather than individually; long-established and apparently innocuous tradi­ tional usage, are included, often within defined • the extent to which a "laisser faire" disposition can permissible limits, in labelled products for which be adopted toward such products as herbal limited claims are made and which are sold remedies and tonics that are without potent directly to the public from retail outlets other than pharmacological activity and carry imprecise pharmacies. claims, but which satisfy an acknowledged public demand. New product licences

Considerations of safety require that particular No product which is first proposed for authorization attention be accorded to: after the "appointed day" should be accorded a product licence without having first been submitted • products that have either been withdrawn or are to technical assessment. Such products may not the subject of restrictive regulatory action in other necessarily contain a new active ingredient: they countries as notified in the United Nations may constitute a new combination of two or more Consolidated List of products whose consumption established substances or they may merely repre­ and/or sale have been banned, withdrawn, sent a new dosage strength, a new dosage form, or severely restricted or not approved by govern­ a generic version of a pre-existing nominally- ments, and in WHO's Pharmaceuticals News­ equivalent licensed product. In no case should the letter to national drug regulatory authorities; requirement for assessment be waived. A rationale for the formulation of every new product should in­ • products representing examples of irrational variably be provided, but the extent of the required poly-pharmacy; and review will vary considerably according to circum­ stances. • products for which exaggerated or spurious promotional claims are made in the labelling. The normal procedure for the authorization of a product is accomplished in three stages: Subsequently, the review needs to be extended in a phased manner, giving priority to drugs that are • the application is received from the manufacturer widely used, listed in nationally-recognized formular­ and is checked and assessed for completeness ies, or of a particularly important therapeutic class. by the authority's technical staff; An adequate documentation and information retrieval system is vital for this purpose. • it is submitted to the competent standing commit­ tee for advice on whether or not to authorize Some traditional products and particularly herbal marketing of the product; preparations, because of their complexity, do not lend themselves to licensing on a product-specific • the formal administrative action to grant or refuse basis. Control is then more readily applied through a licence and to settle its content is then taken by consideration of individual ingredients. Several regulatory authorities have devised administrative the authority. approaches to their licensing which are based on a The assessment of the product must be based trivalent system of classification: primarily on its safety, quality and efficacy having

47 General Policy Topics WHO Drug Information Vol. 3, No. 2, 1989

regard to its intended use. In accordance with Technical aspects locally-determined requirements, the assessment might also impinge upon comparative efficacy and/ of the licensing process or safety and embrace economic factors including price, cost effectiveness, and other considerations General considerations determined by national policy. Although countries vary in their resources and For administrative convenience, the product licence priorities, advantage accrues from harmonizing should be as simple as possible. It should always documentary requirements to the fullest possible describe the product by name, manufacturer and extent since this simplifies registration procedures importing agent, identify the ingredients, (preferably and reduces costs. by their international nonproprietary names), and provide full details of the dosage form. It should also The most important starting-point for imported contain a serial number, the date of issuance of the products is the WHO Certification Scheme on the licence, its date of expiry and any special conditions Quality of Pharmaceutical Products moving in to be observed. It is advisable to cite certain International Commerce. This gives basic informa­ additional items in the licence for easy reference — tion on composition, an assurance that the product is such as shelf-life and sales category — but, in other manufactured in accordance with good manufactur­ particulars, it should refer to the information submit­ ing practices in premises which are subject to in­ ted by the licence-holder in the dated product spection, and information on the regulatory status of application. the product in the country of export. A certificate, issued in compliance with the model format recom­ mended by WHO, should be required whenever Renewal and variation of licences application is made to licence an imported product. Licences should never be regarded as immutable. Products containing long-established Ideally, they should be reviewed at, say, five-yearly intervals. However, many national authorities do not chemical entities have the capacity to undertake this task, particularly for as long as they remain engaged in the initial For products indicated for standard uses and that review of provisionally-licensed products. In these contain established ingredients, the following circumstances many products fall to review on an ad elements of information usually suffice as the basis hoc basis. Sometimes this is inspired by recently for both a product licence and for a computerized generated concern regarding safety. More fre­ data retrieval system: quently, a product attracts attention because the licence-holder has altered the formulation in some name of the product way — by changing, for instance, the source of the active ingredient(s) [by international starting materials, the nature of the excipients, the nonproprietary name(s)] route of synthesis of an active ingredient, or the type of formulation claims made in labelling and promotional material. therapeutic category The precise circumstances in which licence-holders quantitative formula (including excipients) are required to apply for variations in a product quality control specifications licence differ from country to country. These circum­ indications, dosage, method of use stances should be clearly defined in all product contraindications, warnings, precautions licence documents, including provisional licences. bioavailability data (in vitro/in vivo) stability data, shelf-life container, packaging, labelling Licence-holders should be required, in all circum­ intended method of distribution: stances, to inform regulatory authorities immedi­ ately of unanticipated adverse effects which could controlled drug; prescription item; possibly be associated with a licensed product and pharmacy sale; general sale which might call for restrictive licensing action or the manufacturer withdrawal of the product licence. importer/distributor regulatory status in the exporting country.

48 WHO Drug Information Vol. 3, No. 2, 1989 General Policy Topics

If the dosage form is a novel one, such as a delayed- ensure that a monitoring mechanism is put in place release tablet, or if a new route of administration is to detect unanticipated reactions. A mutually- proposed, supporting data from clinical studies will acceptable plan for post-marketing surveillance be required. should be settled in advance and included in the product licence as a condition of approval. Products containing new chemical entities Herbal products

Considerably more extensive information is required The use of herbal and other naturally-occurring sub­ to support a marketing application for a new drug stances is part of the fabric of traditional medicine. substance in order to provide assurance of efficacy Because of the complex, and sometimes imprecise and safety as well as of quality. In particular, detailed nature of the ingredients they contain and the accounts are required of: paucity of scientific information on their properties, products containing these substances, often in chemistry (structure, physical properties, combination, can rarely be reviewed on a rigorously synthesis, specification, impurities, stability scientific basis. Where time-honoured practices do characteristics) no apparent harm, there is no urgency for regulatory intervention other than to set up a system for pharmacological properties provisional registration. (in animals, in man) However, prolonged and apparently uneventful use toxicological data of a substance offers insecure testimony of its (short and long-term studies in animals, safety. In a few instances, recently commissioned including carcinogenicity studies) investigations of the potential toxicity of naturally- occurring substances widely used as ingredients in reproductive and teratological studies in these preparations have revealed previously unsus­ animals pected potential for systemic toxicity, carcinogenicity and teratogenicity. Small regulatory authorities need clinical studies. to be quickly and reliably informed of these findings. They should also have the authority to respond Small regulatory authorities need to adopt caution in promptly to such alerts, either by withdrawing or licensing newly-developed products because they varying the licences of registered products contain­ do not possess the capacity: ing the suspect substance, or by rescheduling the substance in order, for instance, to disallow its use • to undertake the multidisciplinary assessment by non-medically-qualified practitioners. applied to them within large, highly-evolved authorities; All regulatory authorities should also be alert to the practice of incorporating potent pharmacologically- • to monitor their performance in use through post­ active compounds, such as steroids, into herbal marketing surveillance. preparations. When this is done clandestinely it is a manifestly dangerous practice which demands In general, a small authority is best advised to wait immediate withdrawal of the products and a review until this information has been generated and of the manufacturer's licence. assessed elsewhere before authorizing such a product for use. Combinations of potent, In the case of products intended exclusively for therapeutically-active substances tropical parasitic disease, much of this evidence may need to be built up in countries with limited re­ The justifications for formulating fixed combinations sources. The expertise of the World Health Organi­ of potent, therapeutic substances are few. All zation is at hand to offer advice in these circum­ biologically-active substances have a potential to stances. Once a decision is taken to authorize such induce harm as well as therapeutic benefit. The ad­ a product for general use, the regulatory authority ministration of two or more such substances, rather and the manufacturer share a responsibility to than one, increases the potential for adverse

49 General Policy Topics WHO Drug Information Vol. 3, No. 2, 1989

effects. Fixed-ratio combination products are con­ cations. Regulatory authorities consequently need to sequently acceptable only when the dosage of each consider not only the quality, efficacy and safety of ingredient meets the requirements of a defined such products, but also their interchangeability one population group and when use of the combination with another and with the original innovative product. provides a clear advantage over separate admini­ This concept of interchangeability applies not only to stration of the individual active compounds, either the dosage form but also to the instructions for use in therapeutic effect or compliance, or when it and even to the packaging specifications when enhances safety — as in the case of multiple chemo­ these are critical to stability and shelf-life. therapy intended to reduce the emergence of resistant pathogens. Some highly-evolved authorities require that every generic product must satisfy three sets of criteria of therapeutic equivalence. These relate to: Generic products manufacturing and quality control; In many countries, for reasons of economy, drugs destined for use in the public sector are purchased product characteristics and labelling; and on open tender. This favours the use of generic products, and the practice in some countries is for bioequivalence. tenders to be issued, bids examined, and contracts offered by the procurement authority without Others adopt a more pragmatic approach to the reference to the drug regulatory authority. need for experimental demonstration of bio­ equivalence. Study of the bioavailability of a dosage The licensing of generic products poses a challenge form is a costly undertaking that is demanding of to all regulatory authorities, particularly when the human resources. It is clearly not a cost-effective product to be supplied is not registered in the requirement for highly water-soluble substances country of origin. The need for expert assessment is when neither precise dosage nor consistency of accentuated because not all drug-exporting coun­ response is a critical consideration. In developing tries submit drugs intended exclusively for export to countries the in vivo bioavailability testing of all do­ the same rigorous controls as drugs intended for the mestically-manufactured products would be imprac­ domestic market. Nominally equivalent generic ticably costly. The regulatory authority should be in a products should contain the same amount of the position to help local manufacturers by advising same therapeutically-active ingredients in the same them on drugs which pose potential bioavailability dosage form and they should meet required problems. compendial standards. However, they are not necessarily identical and in some instances their In the case of imported products, assurance should clinical interchangeability may be in question. be obtained through WHO's Certification Scheme on Differences in colour, shape and flavour, while obvi­ the Quality of Pharmaceutical Products moving in ous and sometimes disconcerting to the patient, are International Commerce that the product has been often inconsequential to the performance of the produced in accordance with WHO's standards of product, but differences in sensitizing potential due Good Manufacturing Practices and that, in the light to use of different excipients and differences in sta­ of a full assessment, it has been authorized to be bility and bioavailability have obvious clinical impli­ placed on the market in the country of origin.

50 WHO Drug Information Vol. 3, No. 2, 1989

Personal Perspectives

Address to Ninth General Assembly survival against adversity. They gain confidence from the unprecedented technical progress that has of the World Federation of been made in every field of medicine within the Proprietary Medicines experience of a single generation — progress for which the industry, time and again, has provided the Manufacturers* motive force for change. They recognize that they are living longer and their quality of life has been Dr Hiroshi Nakajima transformed beyond all reasonable expectation. Director-General Suddenly, however, they are faced with the realiza­ tion that there is a price to pay: that health, like any World Health Organization other commodity, must be costed. I greatly appreciate the invitation to address your Regardless of the benefit that accrues, every Annual General Assembly today. The industry rep­ medical intervention represents an inevitable resented by this Federation holds the unique pre­ charge, either on the individual or the community. rogative of supplying medicinal products directly to The more that is done to extend and ameliorate the consumers. Each one of us here today — with quality of life, the more we must each expect to greater or lesser frequency — buys your products. contribute financially to society's collective commit­ Wherever there are families, there are household ment. Increasing sophistication in health technology medicines. Whenever temporary illness strikes, continues to extend the horizons of medicine, and there is need for symptomatic relief. this is enabling countless disadvantaged people to live fuller and more productive lives, but it does Forty years ago, when the World Health Organiza­ nothing to relieve the immediate burden of expense tion was founded and at a time of intensive develop­ upon the health care services. Inevitably, doctors ment of public health services in many of the more are suddenly finding themselves under pressure to highly-developed countries, health and health coun­ count the cost of treatment. selling were widely regarded — even within the public mind — as being the preserve of the health professional. Health education was on no political This need for cost-consciousness has been dramati­ agenda. Healthy lifestyle, as a concept, had yet to cally exacerbated, of course, by the advent of AIDS be invented. The art of medicine maintained its and society's desperation to prolong the lives of mystique and was intended to do so. The labels of increasing numbers of young people with greatly medicines, made to individual order within pharma­ lowered resistance to infection. But the dilemma cies, identified the name of the patient rather than was already disconcertingly broadly-based and is the nature of the product. The patient was given now casting a sombre shadow over many potentially dosage instructions, but rarely any other information exciting developments in preventive medicine and or explanation. The transaction was undertaken the care of the chronically sick. What is the cost that exclusively on a basis of trust. society is prepared to countenance for extending a life? Where does the doctor's professional duty begin and end? How can considerations of cost- We now live in a very different world. Life has containment be reconciled with the Hippocratic Oath become more complex, more problematic in many and the legal liabilities that devolve from it? ways, both for individuals and institutions. Better educational opportunities have created societies that are more open and that demand to be better The hapless clinician cannot be left to search his informed. As people become more affluent, their conscience in isolation. A crisis is in the making that expectations are heightened. They begin to view everyone with a responsibility for the provision of health in a positive context, not merely in terms of medical services will be forced, sooner or later, to heed. What can be done? Every option must obviously be explored to increase the efficiency of * Held in Rome from 4 to 7 June 1989 health care without jeopardizing standards. Doctors

51 Personal Perspectives WHO Drug Information Vol. 3, No. 2, 1989

must be seen to be disciplining themselves to A bottle of vitamins offers little to those in search of become cost conscious and they must be prepared food. Research your markets. Maintain a presence to reconsider, in the light of changing circumstances, wherever your products are sold. Learn about the the extent to which their extensive training and skills practices and infrastructure of traditional medicine remain essential to the delivery of primary health where they are widely practicable in order to explore care. Better informed people have more compe­ how you can best complement them, and seek to tence to help themselves. Pharmacists and commu­ exorcise — through the influence of this Federation nity nurses are equipping themselves to provide — unacceptable marketing practices wherever they more comprehensive counselling services. Drug may occur. regulatory bodies are becoming more indulgent in the range of products they are prepared to counte­ Last year, the World Health Assembly adopted a nance as non-prescription items. Your companies further resolution that dispels any excuse for com­ are at hand to support these trends. placency. It makes a plaintive call for the initiation of programmes for the prevention and detection of the Much depends on the way you respond to the export, import and smuggling of falsely-labelled, challenge. I have no doubt that your long-term spurious, counterfeit or substandard pharmaceutical interest lies, not simply in being on the marketplace preparations. This is a brutal reminder of man's as vendors of proprietary medicines, but in being potential for inhumanity to man; of an unflinching ready and waiting to assume a key role in the capability within the criminal subculture to exploit delivery of primary health care. You will be judged even the sick and disadvantaged; of the duty of by the extent to which you are prepared to think each one of us to serve the common cause; and of beyond product promotion to possible ways in which the need to assure universal implementation of the you might use your privileged access to the public to standards and practices embodied within this educational purpose. Your prerogative to address Federation. the consumer directly is not accorded lightly within the field of health. It embodies a trust conferred by We have a long road to travel to assure the universal society never to exploit privilege to commercial availability of necessary drugs of good quality at advantage in a way that runs counter to the public prices that countries can afford. Our dialogue must interest. We depend upon you to use your resources continue. We need your collaboration and support to imaginatively, constructively and dispassionately to root out the cancer that has developed within the facilitate the development of the health care infra­ system; to promote exemplary standards of manu­ structure wherever you establish your markets. facture and trading; to positively support the health infrastructures and the regulatory processes of the countries in which you operate; to further the Those markets are far from homogeneous. The objectives of WHO's Certification Scheme for the "affluence gap" between rich and poor yawns ever Quality of Pharmaceutical Products moving in wider. The World Health Assembly, in 1978, called International Commerce; and to respect and serve upon WHO to develop further the dialogue with with every sensitivity the vital needs and priorities of pharmaceutical industries in order to assure their the collectivity of communities in this world that it is collaboration in meeting the health needs of the our destiny to share. large underserved segments of the world's popula­ tion. It has been estimated that today, in some coun­ tries, the annual per capita sum spent on medicines I recognize the pivotal role of your Federation in this is higher than US$ 100; in others it remains less challenge. I welcome your commitment to become than US$ 2. More than one-third of the human race more broadly representative of industry in develop­ is still denied adequate access to essential drugs ing countries. The issues are clearly defined and and vaccines. Where there is deprivation of this WHO relies upon you to act in a spirit of partnership degree, proprietary medicines are likely to be to address them. Together, we will not only stand, bought, not to safeguard health, but in a desperate we will roll back many of the constraints that, for far attempt to restore it. Our call to you is to respond to too long, have impeded the effective delivery of need where it so obviously exists, never to exploit it. primary health care.

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Reports on Individual Drugs

gously-designed Boston study (4) — involving two Oral contraceptives groups of approximately 400 women —suggests and breast cancer that, by the age of 45, women who have used oral contraceptives for up to 10 years face twice the risk Apprehension that prolonged use of combined oral of developing breast cancer than women who have contraceptives might initiate or promote the develop­ never used them. The association was demon­ ment of breast cancer has existed for more than strated in virtually all subgroups examined and it was twenty years. Notwithstanding intensive epidemio­ even more pronounced among women with more logical investigation and the arrival of early users of than 10 years of exposure. Similarly, a reworking of these products into their fourth and fifth decades, the results of a large study conducted by the Cancer definitive conclusions are still not at hand. Because and Steroid Hormone Group in the USA (5,6) of the considerable scale on which oral contracep­ suggests a positive association may exist that was tive products have been used in many developed previously not identified. In this instance, however, it countries, any significant excess of the disease applies only to women who used oral contraceptives should ultimately be reflected in national or regional for more than four years before their first full-term cancer registries. Thus far no such trends have been pregnancy. reported. But, even if they were to appear, they could well prove difficult to interpret because the As yet, neither the United States Food and Drug basis upon which many registry records are com­ Administration nor the British Committee on the piled has changed appreciably throughout this Safety of Medicines considers that the new evidence period. warrants warning labelling or other regulatory action.

The urgency to resolve the existing uncertainty at An FDA expert panel is sceptical that the studies will the earliest opportunity has provided impetus to ultimately overturn the more reassuring conclusions explore the problems not only prospectively but also drawn in earlier publications, and it points to the retrospectively through case-control studies. Taken possibility that — should the postulated associations together, the latter have failed to provide a consis­ reflect reality — the results may demonstrate a tent message. Instead, indecisive claims and potential of oral contraceptives to promote the counterclaims have generated a pendulum of development of breast cancer, rather than to induce concern that has provided little help to prescribers, it (7). If this is so, a compensatory fall in the inci­ users or drug regulators. Until a few months ago, dence of the disease should occur among long-term the balance of evidence was largely reassuring. oral contraceptive users who survive into the later Indeed, negative studies continue to be published decades of life. The UK Committee on the Safety of (1, 2). Now, however, two new case-control studies Medicines has adopted a similar stance in advising undertaken respectively in the United Kingdom (3) that "there is no need for a change in oral contra­ and the United States of America (4), and a re- ceptive prescribing practice on the evidence analysis of data derived from one of the largest presently available" (8). It emphasizes, in particular, studies previously conducted in the USA (5, 6), have that the marked excess of cases described in the reawakened controversy. British study is not reflected in national cancer statistics and that findings attributable to the effects The British study (3), which is based on data derived of older contraceptive products containing relatively from 755 women who developed breast cancer, high doses of estrogen may not be applicable to together with matched controls, is interpreted by the currently-available preparations. investigators as indicating that oral contraceptives are implicated in about one-fifth of such cancers The Lancet, in commenting that "the pendulum now presenting in women under 36 years of age. The risk seems to be hovering some way from total reassur­ was estimated to be increased by about 40 per cent ance about breast cancer in younger women" strikes among women who had used oral contraceptives for a less defensive note, but with wry pragmatism it 4 to 8 years and by about 70 per cent in women who adds: "If cancer registration data continue to yield had used them for more than 8 years. The analo­ no support for an association of any sort, some day

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the call may soon have to go out not for more Alaska in whom hepatitis B virus infection was previ­ research into oral contraceptives and breast cancer ously hyperendemic. Between November 1981 and but for an inquiry into the basic tenets of the case- May 1982,1630 inhabitants of these villages who control technique, if only in this controversial and were considered to be at high risk of infection, difficult area" (9). including both infants and young adults, received plasma-derived hepatitis B vaccine in three intra­ References muscular 20 µg doses — or 10 µg in children aged 10 years or less. Each individual subsequently 1. Vessey, M.P., McPherson, K., Villard-Mackintosh, L. et remained in the survey for five years, during which al. Oral contraceptives and breast cancer: latest findings time both the concentrations of hepatitis B surface in a large cohort study. British Journal of Cancer, 59:613- 617 (1989). antigen and markers for active infection were monitored annually. 2. Jick, S.S., Walker, A.M., Stergachis, A. et al. Oral contraception and breast cancer. British Journal of Overall, 95 per cent of those vaccinated reacted with Cancer, 59: 618-621 (1989). an immediate immune response of 10 or more sample ratio units and were classified as having 3. UK National Case-Control Study Group. Oral responded positively. After five years the antibody contraceptive use and breast cancer risk in young women. concentration fell below this threshold in approxi­ Lancet, 1: 973-982 (1989). mately 20 per cent of the sample. However, no one 4. Miller, D.R., Rosenberg, L, Kaufman, D.W. et al. Breast developed either clinical hepatitis or hepatitis B cancer before age 45 and oral contraceptive use: new surface antigen during this period, although evi­ findings. American Journal of Epidemiology, 129: 269-280 dence of abortive infection — a spontaneous boost (1989). in the surface antigen, together with the appearance of hepatitis B core antigen — was recorded in four 5. Stadel, B.V., Lai, S., Schlesselman, J.J. et al. Oral persons, including one "non-responder". contraceptives and premenopausal breast cancer in nulliparous women. Contraception, 38: 287-299 (1989). The results of the study are of prime importance because they provide direct confirmation that 6. Peto, J. Oral contraceptives and breast cancer: is the CASH study really negative? Lancet, 1: 552 (1989). hepatitis B vaccine can provide long-lasting protec­ tion against infection during the periods of greatest 7. Ezzell, C. FDA sceptical about link between breast risk, both in infancy and in early adulthood. In a cancer and the pill. Nature, 337:108 (1989). commentary carried in the same issue of the journal in which the survey is published (2), it is emphasized 8. Committee on Safety of Medicines. Oral contraceptives that, globally, hepatitis B virus is a leading cause of and carcinoma of the breast. Current Problems, No. 26 morbidity and mortality, not only from fulminant (1989). hepatitis but also from the long-term sequelae of cirrhosis and hepatocellular carcinoma. These 9. Leading article. Cases/controls, breast cancer, and the diseases are most highly prevalent in Asia and pill. Lancet, A: 1000 (1989). Africa, but even within the United States of America it is estimated that 300 000 persons are infected annually, and that the direct medical costs exceed Efficacy of hepatitis B vaccine US$ 1 million daily (3).

Hepatitis B vaccines have been shown to be The outcome of the study in Alaska will certainly lend immunogenic in several controlled studies, but the momentum to efforts to incorporate hepatitis B duration of the period of protection has remained vaccination in national immunization programmes in uncertain. The need for this information is particu­ Asia and Africa where, in some regions, more than larly important since concentrations of antibody to 90 per cent of the population have been infected by hepatitis B surface antigen have been reported to the age of 15 years. Experience in The Gambia, decline rapidly with time and infection has occasion­ where 60 000 infants have already received the ally been recorded within a few years of vaccination. vaccine, indicates that a four-dose schedule, started within the first month of life, can be conveniently These initial concerns have now been largely integrated into the country's expanded programme redressed by the first population-based study to be of immunization (4). Here, too, the number of non- reported (1). The data were derived from Eskimo responders has been estimated to be low — communities living in remote villages in western probably less than 2 per cent — and it is anticipated

54 WHO Drug Information Vol. 3, No. 2, 1989 Reports on Individual Drugs

that the antibody concentrations achieved will be the risk of bone marrow depression. Pyrimethanine- adequate to provide effective protection throughout sulfadoxine has also been studied but, again, severe the period that they remain at high risk of developing toxicity and treatment failures have been reported persistent infection. This will be evaluated in the (7, 8). Pentamidine has been used intravenously for years ahead using information obtained from a the past five years to treat clinically-evident infec­ cohort of at least 1000 vaccinated children who may tions but it is too toxic when administered by this also, eventually, provide an indication of the route for preventive therapy (9). measure of protection afforded against chronic hepatic disease. Tangible progress has now been achieved through the development of an aerosol formulation of pen­ References tamidine which, it is hoped, might inhibit infection at dosages that do not give rise to serious dose-related 1. Wainwright, R.B., McMahon, B.J., Bulkow, L.R., et al. systemic toxicity. Experience already gained in the Duration of immunogenicity and efficacy of hepatitis B United States of America and France in administer­ vaccine in a Yupic Eskimo population. Journal of the ing pentamidine by this route at doses of up to 300 American Medical Association, 261: 2362-2366 (1989). mg every 4 weeks has resulted in the approval by 2. Francis, D.P., Margolis, H.S. Worldwide elimination of the US Food and Drug Administration of a prepara­ hepatitis B transmission: we have the way, we need the tion of the isoethionate salt manufactured by will. Journal of the American Medical Association, 261: Lyphomed Inc (10). It is indicated for individuals who 2400 (1989). have experienced at least one previous episode of pneumonia, or who have a T4 lymphocyte count of 3. Centers for Disease Control. Changing patterns of 200/mm3 or less. These groups were defined on the groups at high risk for hepatitis B in the United States. basis of a large, long-term epidemiological study Morbidity and Mortality Weekly Report, 37: 429-437 undertaken by the US National Institute of Allergy (1988). and Infectious Diseases which has demonstrated 4. The Gambia Hepatitis Study Group. Hepatitis B vaccine that patients with a severely depressed T4 lympho­ in the Expanded Programme of Immunization: The cyte count are at risk of developing this form of Gambian Experience. Lancet, 1:1057-1060 (1989). pneumonia even if they have no symptoms of HIV infection. The selected dosage, which is higher than has often been used in the past and which induces Aerosolized pentamidine in coughing or wheezing in some patients, is recom­ mended on the basis of a clinical trial sponsored Pneumocystis carinii pneumonia jointly by the manufacturer and a community group in San Francisco that represents the interests of It is estimated that in more than 60 per cent of cases AIDS patients. an opportunistic protozoal infection, Pneumocystis carinii pneumonia, is the first clinical manifestation of Thus far, the results of this study have not been acquired immunodeficiency disease (AIDS). It also reported in detail, but an encouraging account has supervenes in an additional 15 to 20 per cent of recently been published of an analogous study patients in whom AIDS presents in some other way undertaken in France (11). A randomized controlled (1, 2). Approximately 15 to 20 per cent of these comparison between zidovudine alone and pen­ episodes are fatal and there is a high frequency of tamidine taken concurrently with daily zidovudine in relapse. patients who had recovered from an initial attack was terminated prematurely on ethical grounds after Earlier efforts to suppress the infection have been 41 patients had been treated for 6 months or longer. either marginally successful or unacceptably toxic. Of these, infection recurred in 15 of 21 patients who Zidovudine has been claimed to reduce the fre­ had received zidovudine alone, but only in one of 19 quency of relapse, but its effect is rarely sustained patients who had additionally received the aerosol in for more than a few months (3, 4). Trimethoprim- the form of particles with a medium diameter of 4.6 sulfamethoxazole has been claimed to successfully µm at a dose of 4 mg/kg pentamidine base at suppress infection in patients with AIDS first intervals of two weeks for the first month, and then presenting with Kaposi's sarcoma, but adverse monthly. effects are often troublesome (5, 6). Many patients are unable to tolerate this treatment, and zidovudine Further trials are now planned to investigate the cannot be used concomitantly since it potentiates effect and acceptability of these products at even

55 Reports on Individual Drugs WHO Drug Information Vol. 3, No. 2, 1989

higher doses and to assess their longer-term effects Antihaemophilic factor and AIDS on pulmonary function. It is estimated that 60 to 80 per cent of patients with haemophilia who were exposed to factor VIII References concentrates before 1984, when heat-treated preparations were introduced, are seropositive to 1. Murray, J.F., Felton, C.P., Garay, S.M. et al. Pulmonary complications of the acquired immunodeficiency HIV by Western blot assay (1 -3). By mid-1988, syndrome. Report of a National Heart, Blood and Lung within the USA, almost 700 of these patients had de­ Institute workshop. New England Journal of Medicine, veloped clinical evidence of AIDS (4). Cases of sero­ 310:1682-1688 (1984). conversion are now being described following the use of heat-treated lyophilized preparations (5-7), 2. Centers for Disease Control. Update: acquired and the question has been raised as to whether immunodeficiency syndrome — United States. Morbidity these patients are also necessarily infected or and Mortality Weekly Report, 34: 245-248 (1985). whether they might possibly have been immunized by preserved viral proteins (8). It is pointed out that, 3. Fischl, M.A, Richmann, D.D., Grieco, M.H. et al. The in general, microorganisms are killed by heat at efficacy of azidothymidine (AZT) in the treatment of AIDS and AIDS-related complex. New England Journal of temperatures lower than are required to denature Medicine, 317:185-191 (1987). their protein components. HIV-1 cultures and polymerase chain reaction analysis can now rapidly 4. Doumon, E., Matheron, S., Rozenbaum, W. et al. demonstrate whether these patients are infected or Effects of zidovudine in 365 consecutive patients with not, and the University of Minnesota, USA is calling AIDS or AIDS-related complex. Lancet, 2:1297-1302 for serum samples on which to undertake these (1988). investigations (9). Confirmation of active infection would provide a compelling stimulus to develop 5. Fischl, M.A., Dickinson, G.M., La Voie, L Safety and recombinant antihaemophilic factor which is now efficacy of sulfamethoxazole and trimethoprim chemo- prophylaxis for Pneumocystis carinii pneumonia in AIDS. undergoing phase II trials (10) and, should it prove to Journal of the American Medical Association, 259: 1185- be safe and effective, to make it available for daily 1189 (1988). prophylaxis at a cost comparable to that of the currently-available blood-derived products. 6. Kaplan, L.D., Wong, R., Wofsy, C. et al. Trimethoprim- sulfamethoxazole prophylaxis of Pneumocystis carinii References pneumonia in AIDS. Presented at II International Conference on AIDS, Paris, France (1986). 1. Melbye, M. Forebel, K.S., Madhok, R. et al. HTLV-III seropositivity in European haemophiliacs exposed to 7. Fischl, M.A., Dickinson, G.M. Fansidar prophylaxis of factor VIII concentrate imported from the USA. Lancet, 2: Pneumocystis carinii pneumonia in acquired immuno­ 1444-1446 (1984). deficiency syndrome. Annals of Internal Medicine, 195: 629-630 (1986). 2. Goedert, J.J., Sarngadhassan, M.G., Eyster, M.E. et al. Antibodies reactive with human T cell leukemia viruses in 8. Centers for Disease Control. Fansidar-associated fatal the serum of haemophiliacs receiving factor VIII reaction in an HIV-infected man. Morbidity and Mortality concentrate. Blood, 65: 492-495 (1985). Weekly Report, 37: 571-572 (1988). 3. Jackson, J.B., Sannerud, K.J., Hopsicker, J.S. et al. 9. Conte, J.E., Hollander, H., Golden, J.A. Inhaled or Haemophiliacs with HIV antibody are actively infected. reduced dose intravenous pentamidine for Pneumocystis Journal of the American Medical Association, 260: 2236- carinii pneumonia. A pilot study. Annals of Internal 2239 (1988). Medicine, 107: 495-498 (1987). 4. AIDS Monthly Surveillance Report. Medical bulletin No. 10. FDA Talk Paper, T89-25 (1989) 67. Haemophilia Information Exchange. Distributed by: the National Haemophilia Foundation, Room 406, Soho 11. Girard, P.M., Landman, R., Gaudebout, C. et al. Building, 100 Greene St, New York, NY 10012. Prevention of Pneumocystis carinii pneumonia relapse by pentamidine aerosol in zidovudine-treated AIDS patients. 5. White, G.C., Matthews, J.J., Weinhold, K.J. et al. HTLV- Lancet, 1: 1348-1353 (1989). III seroconversion associated with heat-treated factor VIII concentrate. Lancet, 1:611-612 (1986).

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6. Van den Berg, W., ten Cate, J.W., Brederveld, C. et al. During the period at issue, mortality from asthma Seroconversion to HTLV-III in haemophiliacs given heat- within this age group was estimated approximately treated factor VIII concentrate. Lancet, 1: 803-804 (1986). to have doubled from the time that fenoterol was first introduced to New Zealand in 1976. On the basis of 7. Safety of therapeutic products used for haemophilia their data, the authors estimate that fenoterol might patients. Morbidity and Mortality Weekly Report, 29: 441- 450 (1988). have been implicated in approximately 40 per cent of the "excess" deaths. At first sight this conclusion is 8. Damjanovic, V. What makes human immunodeficiency persuasive. It becomes more problematic, however, virus (HIV) resistant to dry heat inactivation? Journal of in the light of information that use of fenoterol — in Hospital Infections, 10: 209-211 (1987). comparison with that of other anti-asthma drugs — remained steady in New Zealand in subsequent 9. Jackson, J.B., Balfour, H.H. Haemophiliacs with HIV years, whereas mortality from asthma is estimated seroconversion associated with heat-treated products: are to have decreased from 4.1 per 100 000 in 1979 to they actively infected? Journal of the American Medical less than 1.8 per 100 000 in 1987 (6). Association, 261:1275 (1989).

10. White, G.C., McMillan, C.W., Kingdom, H.S. et al. Use In the light of this inconsistency, the design of the of recombinant antihaemophilic factor in the treatment of study was bound to become a focus for debate. two patients with classic haemophilia. New England Claims have been made that potentially important Journal of Medicine, 320:166-170 (1989). sources of bias and artefact were either unappreci­ ated or underemphasized (6-8). Whereas the diagnosis in each of the fatal cases had been Fenoterol and fatal asthma verified by the New Zealand Medical Research Council's Asthma Task Force, the control patients A case-control study, undertaken in New Zealand were selected solely on the basis of hospital records. and recently published in the Lancet (1), is inter­ Some, it has been claimed, may not have been preted by the investigators as indicating that asthmatic, others were admitted to hospital for other unsupervised inhalation of the beta-agonist com­ reasons, and it is disputed whether the severity of pound, fenoterol, by patients with severe asthma the disease was as great among the controls as considerably increases the risk of a fatal attack. among the patients who died. Moreover, it is Their suggestion that use of fenoterol may induce questioned whether the available evidence is serious cardiac dysrhythmias or inappropriately sufficient to support the crucial assumption that all delay the admission of patients with severe acute patients prescribed fenoterol inhalers actually used asthma to hospital as a result of its potent bronchodi- them during their terminal attack. lating action, has resurrected controversies that developed in the 1960s over the use of isoprenaline In essence, the critics claim, the study confuses the forte inhalers in the same circumstances (2-5). question of whether fenoterol has an acute toxic effect when used during an attack with the separate The study is founded upon information on 125 question of whether chronic long-term dosage patients aged between 5 and 45 years who died in increases the risk of death. In this study, they argue, hospital between 1981 and 1983 during a severe the severity of the illness was classified, not with exacerbation of asthma. Controls—four for each respect to the acute episode that occasioned the case —were identified from hospital records as admission, but with respect to imprecise and asthmatics admitted and subsequently discharged arguably inappropriate markers for chronic asthma. from hospital close to the time that the matching This defect, they conclude, is fundamental because case died. Fenoterol inhalers had been prescribed it leaves open the possibility that fenoterol was before admission with significantly greater frequency preferentially prescribed for patients who were in those who died than those who survived — odds experiencing the most severe attacks of asthma and ratio 1.55 — and this association became more was then falsely linked with the deaths that subse­ apparent when control patients with less severe quently occurred. grades of asthma were excluded from analysis. No association was demonstrated with any other anti- The last word in this dispute has doubtless still to be asthma drug widely used in New Zealand. printed. But, regardless of the ultimate outcome, it points to a central dilemma in the conduct of

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epidemiological research. To escape criticism 7. Buist, A.S., Burney, P.G.J., Feinstein, A.R. et al. studies need to be meticulously designed and Fenoterol in fatal asthma. Lancet, 1:1071 (1989). implemented. Unfortunately, the pursuit of perfection in this field is immensely costly. Moreover, when 8. O'Donnell, T.V., Sears, M.R., Rea, H.H. Fenoterol and fatal asthma. Lancet. 2: 45 (1989). drug-related hazards are at issue, pressures inevitably emerge to communicate suspicions at the earliest opportunity. Shortcuts may sometimes be taken in generating data and presenting the results. Ciclosporin enemas in refractory With publication, however, these pressures are chronic proctitis immediately transferred to drug manufacturers, to individual prescribes and, not least, to drug Preliminary data presented in the Lancet suggest regulatory authorities. For the latter, the dilemma is that ciclosporin (250 mg in 5 ml) administered as a particularly acute when expert opinion is divided. retention enema can induce sustained improvement The time is, perhaps, fast approaching when a forum in patients with chronic distal ulcerative colitis needs to be provided to enable regulators, epidemi­ refractory to corticosteroids and mesalazine ologists and interested manufacturers to discuss (5-aminosalicylic acid). Six of eight such patients these issues as they arise in an international were improved both clinically and sigmoidoscopi- context. cally after a single enema and, in three of them, improvement was sustained for at least two weeks. References In one instance, a scheduled colostomy was cancelled. There was no indication of drug-induced 1. Crane, J., Pearce, N., Flatt, A. et al. Prescribed fenoterol and death from asthma in New Zealand, 1981- mucosal toxicity, and only on one occasion was ­­: case-control study. Lancet, 1: 917-922 (1989). ciclosporin detected in venous blood samples. Two patients complained of nausea, but no other adverse 2. Inman, W.H.W., Adelstein, A.M. Rise and fall of asthma effect attributable to the drug was encountered, and mortality in England and Wales in relation to use of no deterioration was noted either in renal or hepatic pressurized aerosols. Lancet, 2: 279-285 (1969). function.

3. Jackson, R.T., Beaglehole, R., Rea, H.H. et al. Mortality The enema contained about half the daily oral from asthma: a new epidemic in New Zealand. British Medical Journal, 285: 771-774 (1982). dosage recommended in inflammatory bowel disease, which is limited by the risk of nephrotoxicity. 4. Wilson, J.D., Sutherland, D.C., Thomas, A.C. Has the Whereas oral ciclosporin is usually administered in change to beta-agonists combined with oral theophyllines lipophilic solution, the injectable form used for the increased cases of fatal asthma? Lancet, 1:1235-1237 enema was hydrophilic. This, the authors suggest, (1981). may explain why the drug was not significantly absorbed. 5. Grant, W.B. Asthma in New Zealand. British Medical Journal, 286: 374-377 (1983). Reference: Brynskov, J., Freund, L, Østergaard Thomsen, O. et al. Treatment of refractory ulcerative 6. O'Donnell, T.V., Rea, H.H., Holst, P.E. et al. Fenoterol colitis with cyclosporin enemas. Lancet, 1: 721-722 and fatal asthma. Lancet, 1: 1070-1071 (1989). (1989).

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General Information

demonstrating true dose-responses; and with the Proposed revision of Australian credulous acceptance of erroneous death-certificate therapeutic goods legislation diagnoses.

Australia is planning to revise its legislation dealing Few of his peers are likely to share his scepticism to with therapeutic goods to provide more uniform the extent of continuing to question the existence of controls over imported and locally-manufactured a causal relationship between long-term administra­ products. It is hoped to introduce the changes in tion of exogenous estrogens and endometrial cancer early 1990. and between diethylstilbestrol and vaginal carci­ noma. None the less, a sharp reminder is timely that One of the proposals is to require certification for there is no place for uncritical application of epidemi­ each imported pharmaceutical product as to its ological techniques in the investigation of adverse marketing status in the country of manufacture and drug effects. The field is fraught with difficulties. the standard of the manufacturer. Certification in Feinstein and his colleagues have themselves compliance with the WHO Certification Scheme will identified 56 different situations in which evidence generally be required. Other forms of certification will interpreted as supporting a cause-effect relationship generally not be accepted. Certification will be in at least one epidemiological study has been required for final dosage forms including those for refuted by the results of another (2). Nor is clinical medicinal drugs, herbs, vitamins and minerals. medicine usefully served when, as so often hap­ pens, remote risks of treatment are considered in Countries which may experience difficulties with this dissociation from the perceived benefits. At a time proposal are asked to contact Mr P. Pflaum, First when utility data bases, originally constructed for Assistant Secretary, Therapeutics Division, Depart­ other purposes, are perceived as providing a major ment of Community Services and Health, GPO Box resource for identifying and quantifying drug-related 9848, Canberra ACT 2061, Australia. risks, there is greater need than ever for contempla­ tive reconsideration of how bias and artefact can best be prevented from distorting comparative data Epidemiologists at odds and confounding their interpretation. References Large pharmacoepidemiological studies are difficult to conduct, costly to organize and often fallible in the 1. Feinstein, A. R. Scientific standards in epidemiologic results they provide. Too often, in the opinion of studies of the menace of daily life. Science, 243: 1257- Professor Alvin Feinstein of the University of Yale, 1258 (1988), and 244. 1256 (1989). this fallibility derives from neglect of basic scientific principles. 2. Mayes, L.C., Horwitz, R.I., Feinstein, A.R. A collection of 56 topics with contradictory results in case-control In reviewing the axioms of epidemiological investiga­ research. International Journal of Epidemiology, 17: 680- 685 (1988). tion in a recent issue of Science (1) he complains of the uncertainty that arises when investigators are tempted to use convenient collections of data for testing hypotheses that were not entertained at the Analgesics and renal disease time the information was compiled. More pointedly, he takes issue with those who adjust control groups Habitual use of analgesics has been recognized as a after the results have been analysed; with the large significant cause of chronic renal disease since 1953 number of studies beset with unresolved and (1). In Australia, where much of the early research unreconciled contradictions; with the infrequency was conducted in the 1970s, it was estimated that as with which precautions are taken to exclude many as a quarter of the patients needing chronic ascertainment bias; with questionable statistical dialysis or transplantation were suffering from manoeuvres that are sometimes adopted in lieu of analgesic nephropathy (2). Elsewhere, the disease

59 General Information WHO Drug Information Vol. 3, No. 2, 1989

has seemed to be less prevalent and more unevenly of North Carolina where the regular use of analge­ distributed, but it may none the less account for 15 to sics — in the form of "headache powders" containing 20 per cent of terminal renal disease in both the phenacetin or paracetamol — is estimated to be Federal Republic of Germany (3) and Belgium (4). particularly high. The data were obtained from 554 adults with newly diagnosed chronic renal disease On the basis of both epidemiological and toxicologi- and 516 matched controls. Renal disease was found cal data, habitual use of phenacetin was long to be significantly more prevalent among daily users regarded as the prime factor predisposing to the of analgesics than those who used them infre­ characteristic pathological lesion, renal papillary quently. Whereas the risk was most marked among necrosis, and the risk of cumulative exposure users of phenacetin (odds ratio 5.11; 95% confi­ seemed to be exacerbated when it was taken in dence interval 1.76-14.9), it was similarly and together with acetylsalicylic acid and caffeine in independently increased among users of paraceta­ analgesic mixtures (5). Persuasive biochemical mol (odds ratio 3.21; confidence interval 1.05-9.80). explanations have been advanced to explain the In contrast, daily use of acetylsalicylic acid was mechanisms involved but these have implicated, not without demonstrable risk. The plausibility of the phenacetin itself, but its major metabolite, paraceta­ results was heightened by evidence of a dose- mol. Unless it is efficiently detoxified through an response effect and by showing that the relative oxidative mechanism catalysed by prostaglandin risks remained essentially unchanged when hydroperoxidase, the latter accumulates in the renal adjustments were made for other diseases, includ­ medulla. Acetylsalicylic acid, by inhibiting prosta­ ing diabetes and hypertension, and for the various glandins and also by decreasing the supply of indications for which the analgesics were taken. reduced glutathione, tends to impede this oxidative process (6). This, in turn, may promote medullary An accompanying commentary on the trial (10) necrosis by causing an accumulation of reactive emphasizes that "case-control studies cannot intermediary products capable of binding to cellular determine cause and effect but can only suggest macromolecules. Caffeine, which inhibits adeno­ associations that need to be confirmed by prospec­ sine, might further exacerbate cellular damage by tive observations". At the same time, however, it increasing the demand for oxygen in the renal cites a comparable, but as yet unpublished, study medulla (7). recently completed in the Federal Republic of Germany (11) which provides strong corroboration Because of the coherence of this array of facts and of the results obtained in the American study. In this hypotheses, and in the absence of reports of instance, a review of 517 patients with end-stage habituation to paracetamol, it was confidently renal disease indicated that cumulative lifetime anticipated that the problem of analgesic nephro­ consumption of analgesic mixtures in excess of 1 kg pathy could be overcome by withdrawing phenacetin is associated with a dose-related risk of renal from use and by subjecting all analgesic mixtures to disease. Again, whereas the risk was most strongly prescription control. However, fourteen years after associated with phenacetin, an association was also these measures were taken in Australia, the results demonstrated with paracetamol/acetylsalicylic acid are less decisive than had been expected. During combinations, and particularly those additionally the 12-month period ending in October 1987, anal­ containing caffeine. gesic nephropathy remained the primary diagnosis in 13 per cent of all patients within the country newly The commentary concludes by raising several requiring dialysis (8). Elsewhere, there are few inevitable questions. It asks whether sales of indications of any amelioration of the situation. In analgesics over-the-counter should be limited to Belgium, for example, the proportion of dialysis preparations containing a single ingredient. It patients diagnosed as having analgesic nephro­ suggests that substances more recently marketed pathy has failed to decline with time, even though for such use, including paracetamol and ibuprofen the volume share of phenacetin in the national — which, as nonsteroidal anti-inflammatory drugs, analgesic market is estimated to have fallen from 30 cannot be assumed to be devoid of nephrotoxic per cent in 1970 to less than 1 per cent in 1988 (4). potential (12,13) — should be subjected to particu­ In these circumstances, the outcome of a case- larly careful monitoring. It proposes that more control study recently published in the New England consideration should be given to the importance of Journal of Medicine (9) is of particular interest. It was other possible risk factors, including smoking and conducted in the United States of America in an area the use of alcohol and caffeine. Not least, it makes a

60 WHO Drug Information Vol. 3, No. 2, 1989 General Information

plea for investment in preventative and educational Resistance to antivirals measures commensurate with the scale on which over-the-counter analgesics are advertised and Until recently, reports of resistance to antiviral used, and with the "billion-dollar cost" of the feder­ agents were rare and sporadic. This has now ally-subsidized end-stage renal disease programme changed dramatically. Herpes simplex and cyto­ within the United States. megalovirus resistant to aciclovir and ganciclovir, respectively, are now well established as causes of References progressive opportunistic infection in patients with AIDS (1-4). 1. Spühler, O., Zollinger, H.U. Die chronisch-interstitelle Nephritis Zeitschrift. Klinische Medizin, 151:1-50 (1953). Aciclovir is activated only when it is phosphoryfated 2. Kincaid-Smith, P. Analgesic nephropathy. Kidney by viral thymidine kinase, and mutants of herpes International, 13: 1-4 (1978). simplex deficient in this enzyme have been demon­ strated in unresponsive patients and generated in 3. Pommer, W., Glaeske, G., Molzhan, M. The analgesic vitro. Resistant strains of cytomegalovirus also problem in the Federal Republic of Germany: analgesic develop by mutation and possibly as a result of consumption, frequency of analgesic nephropathy and pressure of selection when patients carrying multiple regional differences. Clinical Nephrology, 26: 273-278 strains are treated. In view of this, it has been (1986). questioned in a recent editorial in the New England 4. Elseviers, M.M., DeBroe, M.E. Is analgesic nephropathy Journal of Medicine (5) whether it is prudent to use still a problem in Belgium? Nephrology, Dialysis and aciclovir and ganciclovir to suppress these diseases Transplantation, 2: 143-149 (1988). in severely immunocompromised patients or whether reliance should be placed in other antivirals, 5. Prescott, L.F. Analgesic nephropathy — the such as foscarnet and vidarabine. international experience. Australian and New Zealand Journal of Medicine, 6 (Suppl 1): 44-48 (1976). More clinical information is needed, it seems, before these questions can be answered with assurance. At 6. Brezis, M., Rosen, S., Epstein, F.H. The patho­ present, ganciclovir is the only drug of proven benefit physiological implications of medullary hypoxia. American Journal of Kidney Diseases, 13: 253-258 (1989). when life or sight are threatened by cytomegalovirus infection, but the therapeutic options may widen with 7. Walker, R.J., Duggin, G.G. Drug nephrotoxicity. Annual the completion of a planned prospective trial of Reviews of Pharmacology and Toxicology, 28: 331-345 foscarnet and vidarabine in patients with resistant (1988). disease. Moreover, it remains unproven that long- term suppressive therapy with antivirals favours the 8. Eleventh Report of the Australia and New Zealand emergence of drug-resistant mutants. Nor is there, combined dialysis and transplant registry, ed Disney, A.P. as yet, any indication that drug-resistant mutants will (1988). tend to establish themselves in immunocompetent 9. Sandler, D.P., Smith, J.C., Weinberg, C.R. et al. patients. Whereas aciclovir-resistant herpes viruses Analgesic use and chronic renal disease. New England have been isolated occasionally from otherwise Journal of Medicine, 320: 1238-1243 (1989). healthy individuals, they have not been reported to be implicated in progressive disease, and isolates 10. Bennett, W.M., DeBroe, M.E. Analgesic nephropathy a obtained from patients in relapse have thus far been preventable renal disease. New England Journal of sensitive to aciclovir. Medicine, 320:1269-1271 (1989). There can be no doubt, however, that surveillance 11. Pommer, W., Bronder, E., Greisner, E. et al. Regular analgesic intake and the risk of end-stage renal failure. for virulent, drug-resistant viruses must be sus­ American Journal of Nephrology (in press). tained, particularly in immunologically incompetent patients, and that the search for yet more novel 12. Champion de Crespigny, P.J., Hewitson, T., Birchall, I. antiviral agents must continue. et al. Caffeine potentiates the nephrotoxicity of mefenamic acid on the rat renal papilla. Nephron (in press). References

13. Adams, D.H., Howie A.J., Michael, J. et al. 1. Schinazi, R. F., del Bene, V., Scott, R. T. et al. Nonsteroidal anti-inflammatory drugs and renal failure. Characterization of acyclovir-resistant and -sensitive Lancet, 1:57-60 (1986). herpes simplex viruses isolated from a patient with an

61 General Information WHO Drug Information Vol. 3, No. 2, 1989

acquired immune deficiency. Journal of Antimicrobial between mortality and blood pressure were estab­ Chemotherapy, 18 (Suppl B): 127-134 (1986). lished for both cardiovascular and non-cardiovascu­ lar events. For any given achieved systolic or 2. Norris, S. A., Kessler, H. A., Fife, K. H. Severe, diastolic blood pressure, mortality was lower in those progressive herpetic whitlow caused by an acyclovir- taking active treatment than those taking placebo. resistant virus in a patient with AIDS. Journal of Infectious Diseases, 157: 209-210 (1988). Overall, however, these differences were not marked: 56 deaths were recorded in the treated 3. Erice, A., Chou, S., Biron, K. K. et al. Progressive group and 65 in the placebo group and, of these, disease due to ganciclovir-resistant cytomegalovirus in one-third were attributed to non-cardiovascular immunocompromised patients. New England Journal of events. Medicine, 320: 289-293 (1989). The authors do not question that an exaggerated 4. Erlich, K. S., Mills, J., Chatis, P. et al. Acyclovir-resistant reduction of blood pressure in response to anti­ herpes simplex virus infections in patients with the hypertensive therapy is harmful if it compromises the acquired immunodeficiency syndrome. New England Journal of Medicine, 320: 293-296 (1989). coronary or cerebral circulation. However, in the light of the information obtained from the control group, 5. Hirsch, M. S., Schooley, R. T. Resistance to antiviral they conclude that other factors must have contrib­ drugs: the end of innocence. New England Journal of uted to the excess mortality among the patients Medicine, 320: 313-314 (1989). within the lower third of the blood pressure range. They note, in particular, that these patients tended to be less heavy and and to have lower blood haemo­ globin levels than the average of the cohort as a High blood pressure in the elderly whole, and they suggest that their increased death rate might simply be an expression of a deterioration in their general state of health. Several large studies of hypertension recently conducted in elderly patients have demonstrated that, whereas the highest cardiovascular mortality is References associated with the highest systolic and diastolic 1. Coope, J., Warrander, T.S. Randomised trial of the pressures, mortality also tends to rise in patients treatment of hypertension in elderly patients in primary whose clinical blood pressures are reduced to care. British Medical Journal, 293: 1145-1151 (1986). readings appreciably below 150 mmHg systolic and 90 mmHg diastolic (1 -3). This has led to the sugges­ 2. Coope, J., Warrander, T.S. Lowering blood pressure. tion that a reduction of pressure induced by drugs Lancet, 1:1380 (1987). may sometimes cause rather than prevent myocar­ dial ischaemia (4-6). Confirmation of the existence of 3. Cruickshank, J.M. Coronary flow reserve and the J- such J- or U-shaped mortality curves among elderly curve relation between diastolic blood pressure and treated hypertensive patients has recently been myocardial infarction. British Medical Journal, 297: 1227- 1230 (1988). obtained in some 700 patients over 60 years of age (mean 71.5 years) organized by the European 4. Green, K.G. The role of hypertension and downward Working Party on High Blood Pressure in the Elderly changes in blood pressure in the genesis of coronary (7). Indeed, for diastolic pressure, the paradoxical atherosclerosis and acute myocardial ischemic attacks. effect of treatment — hydrochlorothiazide and American Heart Journal, 103: 579-582 (1982). triamterene for a period of nine months, with methyldopa added in resistant cases — was even 5. Strandgaard, S., Haunsø, S. Why does more marked than in other published studies in that antihypertensive treatment prevent stroke but not mortality was inversely associated with treated myocardial infarction? Lancet, 2: 658-661 (1987). diastolic pressure throughout the observed range. 6. Beevers, D.G. Overtreating hypertension. British Medical Journal, 297:1212 (1988). The study was particularly notable in that a similar, but U-shaped, relationship was demonstrated 7. Staessen, J., Bulpitt, C, Clement, D. et al. Relation between diastolic blood pressure and mortality in between mortality and treated blood pressure in elderly patients randomly allocated to placebo instead of an patients with hypertension: report of the European active hypotensive regimen. Indeed, in both treated Working Party on High Blood Pressure in the Elderly. British Medical Journal, 298: 1552-1556 (1989). patients and controls, comparable relationships

62 WHO Drug Information Vol. 3, No. 2, 1989 General Information

3. Hutton, P., Kerr, J.A. Anaesthetic agents and the ozone Volatile anaesthetics layer. Lancet, 1:1011 (1989). and the ozone layer 4. Health in the greenhouse (Editorial). Lancet, 1: 819-820 (1989). Correspondents to the Lancet have expressed concern that, because the halogenated anaesthetic gases — halothane, enflurane and isoflurane — are possibly contributing to the destruction of the ozone Disclosure of inactive ingredients layer, there may be a case for reducing this possible source of pollution through encouraging, on environ­ In recent years it has become appreciated that mental grounds, the use of alternative techniques excipients in pharmaceutical products, as well as such as regional and total intravenous anaesthesia active ingredients, can have sensitizing properties. (1). However, it has since been explained that only On occasion, the reported reactions have been chlorofluorocarbons (CFCs) that are fully halo­ severe and, in very rare instances, fatal. Several of genated are regulated under the Montreal Conven­ the substances implicated have already been tion (2). Whereas the latter have atmospheric withdrawn from use by national regulatory authori­ lifetimes of 75 to 100 years, the halogenated ties and in several countries the inclusion of some anaesthetics, which contain C-H groups, should be others must now be declared in labelling. much more susceptible to attack by naturally- occurring hydroxyl radicals in the lower atmosphere. No one contests that a more complete declaration of Indeed, most new CFCs currently under develop­ additives and excipients in foods, cosmetics and ment contain at least one hydrogen atom in the medicines would protect individuals with known expectation that this will render them environmen­ hypersensitivities and assist in the detection and tally acceptable. investigation of chemical allergens, but concerns about confidentiality of intellectual property have It has been assumed from indirect evidence that the tended to impede progress. The initiative of G.D. mean atmospheric lifetime of halothane ranges from Searle & Co of Canada to voluntarily take a lead in one to five years, but it is conceded that these reac­ the matter by disclosing all inactive ingredients in its tions are highly unpredictable and they are now full line of prescription and over-the-counter medica­ subject to further study (3). Confirmation that they tions is consequently not only welcome, but a are relatively innocuous in environmental terms will challenge to manufacturers at large. Complete lists be reassuring, but there are no grounds for compla­ of the ingredients of Searle's products will be cency regarding the problem at large. The total included on the outer labels of over-the-counter amount of halothane used worldwide per annum is products and on packaging and/or patient inserts for less than 1000 tonnes; the annual manufactured prescription drugs. This information will also be tonnage of the "regulated" CFCs is of the order of 1 included in independent drug compendia widely million tonnes. An editorial published in the Lancet used within Canada, and the company has set up a tersely places the situation into perspective (4). permanent telephone service to deal with enquiries Nobody, it contends, really knows how much more for supplementary information. chlorine-loading the atmosphere can withstand. "The only certainty among atmospheric physicists is Reference: Press Release, G.D. Searle & Co., August, that global warming and stratospheric ozone 1988. depletion will interact to destabilize the atmosphere in unpredictable ways, and that a total phase-out of CFCs is not merely desirable but an absolute and urgent requirement for any strategy to combat Registration of drug products climatic change". in Malaysia

References The Drug Control Authority has decided in future not to register any imported product which does not 1. Norreslet, J., Friberg, S., Nielsen, T. M. et al, Halothane demonstrate therapeutic or pharmaceutical advan­ anaesthetic and the ozone layer. Lancet, 1: 719 (1989). tage over similar products already on the market, particularly when five or more such products are 2. Joyner, B.D. Anaesthetic agents and the ozone layer. already manufactured locally. Lancet, 1:1209 (1989).

63 General Information WHO Drug Information Vol. 3, No. 2, 1989

A total of 4144 prescription drug products has been many of the treated patients also underwent registered in Malaysia and it is considered that the plasmapheresis and received adrenocorticotrophic addition of yet more products offering no clear hormone. None the less, possibility that immunosup­ advantages will accentuate difficulties in monitoring pression continues to hold unexplored potential is and ensuring the safety, efficacy and quality of those confirmed by evidence that total lymphoid irradiation currently registered. The resulting liberation of the can arrest the progress of the disease for eighteen regulatory services from licensing functions will months or longer (9, 10). The Lancet commentator enable them to concentrate on inspection and concludes that "although cyclophosphamide is quality control. unpleasant to take, the few late complications represent an acceptable risk when the prognosis for Reference: Letter to WHO from the Ministry of Health, remaining independent is otherwise poor", and he Pharmacy Division, Kuala Lumpur, 21 February 1989. looks forward to the time when molecular immunobi¬ ology will provide a more precisely focused means of inactivating the immune mediators of myelin injury. Is multiple sclerosis an immune disease? References 1. British and Dutch Multiple Sclerosis Trial Group. Multiple sclerosis, which is most prevalent at Double-masked trial of azathioprine in multiple sclerosis. temperate latitudes, strikes about 1 in 800 Northern Lancet, 2: 179-183 (1988). Europeans. Often the disease remains mild but 2. Ellison, G. W., Myers, L. W., Mickey, R. et al. Clinical many foci of demyelination are always demonstrable experience with azathioprine: the pros. Neurology, 38 on imaging by magnetic resonance. The widespread (suppl 2): 20-23 (1988). distribution of these lesions has long raised specula­ tion that they are caused by an immune mechanism. 3. Immunological treatment for multiple sclerosis Interest in immunosuppressive therapy has been (Editorial). Lancet, 1:699-701 (1989). sustained for almost 20 years but most formal trials have been inconclusive because they have lacked 4. Rudge, P., Koetsier, J. C, Meritin, J. et al. Randomised adequate statistical power. double blind controlled trial of ciclosporin in multiple sclerosis. Journal of Neurology, Neurosurgery and Psychiatry (in press). An exception is a recently published British/Dutch multicentre study involving over 350 patients, each 5. Kappos, L, Patzold, U., Dommasch, D. et al. of whom was treated for at least three years with Cyclosporin versus azathioprine in the long-term either a fixed dose of azathioprine or placebo (1). As treatment of multiple sclerosis — results of the German in other studies in which azathioprine was used in multicentre study. Annals of Neurology, 23: 66-63 (1988). conjunction with corticosteroids (2) the treatment had a marginal effect. Despite this setback, a recent 6. Calder, V. L., Bellamy, A. S., Owen, S. et al. Effects of leading article in the Lancet (3) continues to sound a ciclosporin A on expression of IL2 and IL2 receptors in note of optimism by proposing that an undefined normal and multiple sclerosis patients. Clinical and subpopulation of patients may be more responsive Experimental Immunology, 70: 570-577 (1987). or that a higher dose might have been more effec­ 7. Hauser, S. L., Dawson, D. M., Lehrich, J. R. et al. tive. Intensive immunosuppression in progressive multiple sclerosis: a randomized three-arm study of high-dose At first sight, optimism is difficult to countenance intravenous cyclophosphamide, plasma exchange and since similarly disappointing results have been ACTH. New England Journal of Medicine, 308:173-180 obtained with ciclosporin (4,5). This, however, may (1983). simply reflect poor penetration of the drug across the blood-brain barrier (6). More promising is the claim, 8. Carter, J. L, Hafler, D. A., Dawson, D. M. et al. Immunosuppression with high-dose iv cyclophosphamide based on a study of more than 150 patients over six and ACTH in progressive multiple sclerosis: cumulative 6- years, that a high-dose pulse of intravenous cyclo­ year experience in 164 patients. Neurology, 38 (suppl 2): phosphamide can sometimes slow the rate of pro­ 9-14 (1988). gression of the disease for a prolonged period (7,8). Other investigators remain more equivocal in their 9. Cook, S. D., Devereux C, Troiano, R. et al. Effect of assessment of such therapy and objective assess­ total lymphoid irradiation in chronic progressive multiple ment is compromised, in this instance, because sclerosis. Lancet, 1: 1405-1409 (1986).

64 WHO Drug Information Vol. 3, No. 2, 1989 General Information

10. Cook, S. D., Devereux, C, Troiano, R. et al. Total an instructive insight into the immediate and longer- lymphoid irradiation in chronic progressive multiple term consequences of introducing a national sclerosis: relationship between blood lymphocytes and measles/mumps/rubella vaccine programme. It is clinical course. Annals of Neurology, 22: 634-638 (1988). estimated that after defraying the costs of delivering the programme, a net saving to the community in contingent medical care becomes evident only after Measles virus vaccines: 17 years. After 25 years, however, it is projected that cumulative savings in the public health sector defective interfering particles will exceed FFr 1245 million at current value. This is based on an expectation that, by then, the pro­ Defective interfering particles are virus mutants that gramme will have prevented 9 million cases of are deficient in genetic information and that interfere measles, 8 million cases of mumps, 3000 cases of with the growth of the normal virus. Work being congenital rubella, 25 000 cases of meningitis, over undertaken on the measles virus within the Univer­ 3500 cases of encephalitis and some 1500 deaths. sity of Geneva has led to the discovery of such particles in yields derived from the Edmonston- Reference: Weekly Epidemiological Record, 64:142-144 Zagreb strain, but not from two other strains of live (1989). attenuated vaccines. Further studies are in hand to determine whether these particles play a role in the mechanism of attenuation or in any other way modify Salt-induced enhancement of the biological properties. measles virus yield in cultured cells Reference: Calain, P., Roux, L Generation of measles virus defective interfering particles and their presence in a Union of Soviet Socialist Republics — Millimolar preparation of attenuated live virus vaccine. Journal of Virology, 62: 2859-2866 (1988). supplementation of culture media with magnesium sulfate is claimed to result in enhanced yield of measles virus. The effect, which is being studied within the Institute for Viral Preparations in Moscow, Measles/mumps/rubella vaccine: appears to be due to stimulation of intracellular cost benefit events. It is already being used to improve yields in the cell culture system routinely used for measles vaccine production in the USSR. France — Immunization has long been recognized as an outstandingly effective means of controlling Reference: Boriskin, Y.S., Steinberg, L.L., Dorofeeva, communicable diseases, but few precise cost- L.V. et al. Salt-induced enhancement of measles virus benefit analyses of its impact have been published. yields in cultured cells. Archives of Virology, 101: 131-136 Such a study recently undertaken in France provides (1988).

65 WHO Drug Information Vol. 3, No. 2, 1989

Regulatory Matters

Federal Republic of Germany — On the basis of Drugs for Human Use the same data, the Federal Health Office is consider­ ing, together with the manufacturer, the need to Erratum: pyrrolidine alkaloids restrict the approved uses of flecainide to life- threatening supraventricular tachycardia, including In Volume 2, Number 4 of WHO Drug Information it AV re-entry tachycardia and Wolff-Parkinson-White was reported that the Federal Health Office of the syndrome, and to contraindicate its administration to Federal Republic of Germany had suspended patients who have sustained a recent or earlier marketing authorizations for herbal products cardiac infarction. containing pyrrolizidine alkaloids as from 1 October 1988. Reference: Deutsche ApothekerZeitung, 129: 37 (1989).

This is incorrect: the Federal Health Office gave manufacturers 4 weeks as from 10 August 1988 to Fenbufen provide comments and additional information on which to base possible future action with a view to United Kingdom — The data sheet for fenbufen, a the risks of hepato-toxicity and mutagenic and nonsteroidal anti-inflammatory agent, has recently carcinogenic effects associated with these products. been amended to accentuate warnings of adverse To date, the Federal Health Office has not taken any mucocutaneous effects (1). Since the product was decision on changes in approval status. first marketed in the United Kingdom in 1980, more than 6000 notifications have been received. Of these, 80 per cent relate to mucocutaneous reac­ Encainide and flecainide for life- tions, characterized by a generalized and florid erythematous rash of sudden onset, often associ­ threatening dysrhythmias only ated with pruritus. A small proportion of the reports cite more serious conditions, including 178 cases of United States of America — The Food and Drug erythema multiforme and 30 of Stevens-Johnson Administration together with the manufacturers of syndrome, of which two were fatal. encainide (Bristol Myers) and flecainide (Riker) have issued a joint statement urging doctors to reserve In at least seven such cases, the initial reaction was these drugs for the treatment of life-endangering followed by lung disorders, including allergic dysrhythmias, particularly sustained ventricular alveolitis and pulmonary eosinophilia (2). These tachycardia. The warning results from interim data were characterized by cough, fever, malaise and obtained in a multicentre trial intended to determine breathlessness and required admission to hospital. whether these antidysrhythmic agents could A diagnosis of pulmonary eosinophilia was made in improve survival in patients with acute cardiac 5 patients, all of whom had osteoarthritis. The two infarction by preventing or suppressing premature remaining patients — one of whom was seropositive ventricular beats. It was found, after the patients for rheumatoid arthritis — were diagnosed as having had been treated for an average of 10 months, that, an allergic alveolitis. All seven patients recovered of 730 given encainide or flecainide 56 had died, within 4 to 6 weeks of stopping fenbufen. whereas death had occurred in only 22 of 725 given placebo. The trial was immediately terminated. References

Patients currently taking these drugs are advised to 1. Committee on Safety of Medicines, Current Problems consult their doctor since unsupervised adjustment No. 23, (1988). or interruption of treatment may precipitate a fatal dysrhythmia. 2. Committee on Safety of Medicines, Current Problems No. 24, (1989). Reference: Enkaid and Tambocor use in non-life- threatening arrhythmias halted. FDA Talk Paper, T89-22 (1989).

66 WHO Drug Information Vol. 3, No. 2, 1989 Regulatory Matters

• precise directions to be provided on the proper Imipenem/cilastatin use of the product emphasizing that it should not be used for more than six weeks at any one time; Japan — Following reports of convulsions and and disturbances of consciousness in patients taking the broad-spectrum antibiotic, imipenem in combination • a warning that patients with metabolic disorders with the penicillinase inhibitor cilastatin, the Sub­ should consult a doctor before using the product. committee on Adverse Drug Reactions has decided that the approved product information should be Reference: Pharmaceutisch Weekblad, 124: 201 (1989). amended to include a relevant warning. This emphasizes that patients with renal impairment or pre-existing disease of the central nervous system must be treated with particular caution and that the Tamoxifen preparations should be withdrawn immediately, should reactions occur. Federal Republic of Germany — The Federal Health Office is proposing to amend the approved Reference: Pharmaceutical Affairs Bureau, Ministry of product information for the anti-estrogenic com­ Health and Welfare. Information on Adverse Reactions topound , tamoxifen, to indicate that even at low Drugs, No. 93 (1988). dosage and following short periods of treatment occasional cases of visual disturbance, cataract, corneal changes and/or retinopathy have been associated with its use. Statements previously made Potassium chloride voluntary to the effect that such changes occur predominantly in patients with existing eye disease, in elderly withdrawal patients, and those taking high dosages for long periods are now regarded as invalid and will be France — Following eight reports of perforation deleted. ascribed to rapid intestinal release of potassium, the last two brands of rapid-release potassium chloride Reference. Deutsche Apotheker Zeitung, 128: 66 tablets available in France have been withdrawn (1988). from the market with the agreement of the manufac­ turers. References Veterinary Drugs 1. La Revue Prescrire, 8: 492 (1988). Amoxicillin 2. La Revue Prescrire, 9: 59 (1989). United States of America — The Food and Drug Administration has approved an extension of the indications for amoxicillin trihydrate suspension to Slimming aids include treatment of respiratory infections (shipping fever, pneumonia) in lactating cattle with amoxicillin- Netherlands — The Ministry of Welfare, Public susceptible microorganisms (including Pasteurella Health and Cultural Affairs has issued revised multocida, P. haemolytica, Haemophilus spp., guidelines for licensing slimming aids which provide Staphylococci spp. and Streptococci spp.) at a dose dietary bulk with little calorific value. Existing of 3 to 5 milligrams per pound body weight. Milk from authorizations will remain valid until 1 January 1990, treated cows must not be used for human consump­ but from this date all products sold as meal replace­ tion during treatment or for 96 hours (8 milkings) ments must comply with the new labelling regula­ after the last dose. Previously, this antibiotic was tions which require: registered for use only in non-lactating animals. The product has also been additionally approved to treat • the full composition of the product to be displayed acute necrotic pododermatitis (foot rot) due to together with an accompanying assurance that it Fusobacterium necrophorum. fulfils all vital nutritional requirements; Reference: Federal Register, 53: 40058-40059 (1988).

67 Regulatory Matters WHO Drug Information Vol. 3, No. 2, 1989

Carcinogenicity Chloramphenicol and veterinary drugs Hungary — The Ministry of Agriculture and Food has banned the use of chloramphenicol for thera­ United States of America — The Food and Drug peutic purposes in milk and egg-producing animals, Administration has emphasized, on the basis of having regard to its potential to induce aplastic guidance prepared by the Center for Veterinary anaemia in man, and the prolonged period during Medicine, that care is mandatory in the handling of which residues remain demonstrable after discon­ veterinary drugs that have been demonstrated in tinuation. animal studies to possess carcinogenic potential, even when they present no tangible hazard to man Reference: Letter from the National Institute of when used in accordance with the labelled recom­ Occupational Health to IRPTC/UNEP. mendations. A warning of carcinogenic potential, indicating the drug name and species implicated, should be included in the labelling.

Reference: Federal Register, 53: 35562 (1988).

68 WHO Drug Information Vol. 3, No. 2, 1989

Advisory Notices

that it has received 27 reports of adverse effects Allergenic extracts: associated with the use of dapsone in the treatment risk of anaphylaxis of patients with severe acne, lupus erythematosus, pustulous psoriasis and dermatitis herpetiformis. United States of America — The Food and Drug Anaemia, often haemolytic, was most frequently Administration has requested doctors to ensure that reported (12 cases) followed by liver dysfunction (6 it is notified of all fatalities associated with exposure cases), fever, skin reactions and agranulocytosis. to an allergenic extract. Information currently Some of the haemotological reactions became available from reports submitted to the Agency and evident only after several months' treatment. In all from a retrospective survey among members of the but two cases the reaction resulted in a decision to American Academy of Allergy and Immunology discontinue treatment. indicate that at least 14 deaths have resulted from such exposure since 1980, and that a further 4 Reference: Ugeskriftfor Laeger, 150: 2846 (1988). deaths have been attributed to skin tests for allergies. On this basis the Agency estimates that the overall risk of death from such exposure is of the Floctafenine order of 0.2 per million. Belgium — The Adverse Drug Reaction Monitoring Whereas it accepts this risk as extremely small, it is Centre has received six reports of severe anaphy­ concerned that such incidents may be substantially lactic reactions associated with the use of the under-reported and that they might be reduced analgesic, floctafenine. One patient had experi­ further if essential precautions were always fol­ enced a similar reaction previously after taking the lowed. It notes that many of the patients known to have died were asthmatic and it emphasizes that closely-related analgesic, glafenine. The Centre patients with an allergic diathesis are at increased stresses that floctafenine is contraindicated in risk of anaphylaxis. It also reminds doctors that patients who have reacted adversely to glafenine different types of extract cannot be regarded as and that treatment must be discontinued immedi­ allergenically interchangeable; that initial dosage ately should pruritus, urticaria or any other sign should always be based on the results of skin tests; suggestive of a risk of anaphylaxis occur. that patients should always remain under observa­ tion for at least 20 minutes after each injection; that Reference: Folia pharmacotherapeutica, 15: 63 (1988). individuals receiving β adrenoreceptor blocking agents may not be responsive to epinephrine or inhaled bronchodilators; and that the administration Injectable vitamin preparations: of these substances should be undertaken exclu­ sively by physicians experienced in their use and in serious allergic reactions the emergency management of anaphylaxis. United Kingdom — The Committee on Safety of Medicines has informed doctors that between 1970 Reference: From the Food and Drug Administration. and 1988 it received 90 reports of adverse reactions Allergenic extracts: risk of anaphylaxis. Journal of the American Medical Association, 261: 3368 (1989). that had occurred in patients during or immediately after injection of a preparation containing high doses of B-group vitamins, vitamin C and metabisul¬ fite. Many of these — including 41 cases of anaphy­ Dapsone: laxis, 13 cases of dyspnoea or bronchospasm and 22 cases of rash or flushing — were allergic in severe cutaneous reactions character.

Denmark — The Adverse Drug Reaction Committee Reference: Committee on Safety of Medicines. Current of the National Board of Health has advised doctors Problems. No. 24, (1989).

69 Advisory Notices WHO Drug Information Vol. 3, No. 2, 1989

Reference: Pharmaceutical Affairs Bureau, Ministry of Lofepramine: Health & Welfare. Information on Adverse Reactions to severe hepatic reactions Drugs, No. 93 (1988).

United Kingdom — Between 1983 and 1987 the Committee on Safety of Medicines received 57 reports of abnormal liver function associated with the Mianserin: blood dyscrasias use of the tricyclic antidepressant, lofepramine. These include one case of hepatic failure, 9 cases of United Kingdom — Reports of blood dyscrasias jaundice and 5 of hepatitis. Other reports are received by the Committee on Safety of Medicines suggestive of cellular damage and cholestasis. All over the last few years have confirmed concern reactions occurred within 8 weeks of starting about the potential of the antidepressant, mianserin, treatment and all were reversible upon discontinu­ to provoke these effects, particularly in the elderly. ation. The Committee has asked doctors to report in From the time the product was introduced in the detail all suspected hepatic reactions due to United Kingdom in 1976 until 1988, 239 reports of antidepressant drugs and to indicate any possible haematological disturbances were received. These predisposing factors, including use of alcohol. include 68 cases of agranulocytosis and 84 cases of granulocytopenia or leukopenia. Clinicians are Reference: Committee on Safety of Medicines. Current reminded that a full blood count should be requested Problems, No. 23, (1988). routinely every four weeks during the first three months of treatment. Whenever a patient develops fever, sore throat or other signs of infection, treat­ Low osmolar radiocontrast media ment should be immediately suspended and a and shock further count obtained. The Committee has also indicated that it wishes to Japan — Having reviewed reports of shock associ­ receive reports of all haematological adverse ated with the use of low osmolar radiocontrast reactions associated with the use of other anti­ agents, the Subcommittee on Adverse Drug depressant drugs. Reactions has suggested that physicians and medical personnel be advised by circular letter to Reference: Committee on Safety of Medicines. Current exercise the same precautions during the admini­ Problems, No. 25 (1989). stration of these preparations as are required for other contrast media.

Reference: Pharmaceutical Affairs Bureau, Ministry of Nefopam: risk of urinary retention Health & Welfare. Information on Adverse Reactions to Drugs, No. 92 (1988). United Kingdom — The Committee on Safety of Medicines has received 53 reports in which the analgesic, nefopam, was associated with urinary Lysine acetyisalicylate injectables retention, hesitancy, poor stream or dribbling. In only one case was a previous history of prostatism and shock elicited and all cases recovered when nefopam was withdrawn. A further 12 reports cite confusion and 22 Japan —The Pharmaceuticals and Chemical cite hallucinations. The Committee advises that Safety Division has written to all doctors to remind nefopam be used with caution, particularly in the them that cases of shock have been reported in elderly, in patients with symptoms of urinary patients following the administration of an injectable retention and in those taking other medicines with preparation containing lysine acetyisalicylate. This anti-cholinergic properties. preparation, which was first introduced in 1982, is indicated as an analgesic in severe neuralgia and Reference: Committee on Safety of Medicines. Current post-operative pain, and in the emergency manage­ Problems, No. 24, (1989). ment of severe fever.

70 WHO Drug Information Vol. 3, No. 2, 1989 Advisory Notices

Reference: Committee on Safety of Medicines. Current Parenteral nutrition: Problems, No 26 (1989). need for thiamine-containing vitamin supplements Sulfonylureas and hypoglycaemia United States of America — The Food and Drug Administration has advised physicians that patients The Adverse Reaction Monitoring Centre in Belgium being fed intravenously require a preparation that has drawn the attention of doctors to an article in the contains thiamine. Deficiencies that are potentially British Medical Joumal which points out that the use fatal can develop rapidly because thiamine is of chlorpropamide, glibenclamide and other sul­ consumed at a high rate in patients receiving fonylureas in the management of diabetes frequently intravenous glucose. The American Society for results in episodes of hypoglycaemia. Fatal reac­ Parenteral and Enteral Nutrition (ASPEN) has tions are particularly likely to occur in the elderly and alerted its members to three deaths attributed to in patients with cardiac, renal or hepatic insuffi­ thiamine deficiency which occurred during a ciency, and the Centre stresses that these drugs transient period of shortage of intravenous multi­ should only be prescribed when dietary measures vitamin supplements. have failed.

Reference: FDA Press Release, P88-33 (1988). it notes, additionally, that the hypoglycaemic effect may be potentiated by concomitant use of salicyl­ ates, beta adrenoreceptor blocking agents and antibacterial sulfonamides and that similar incidents Propofol: convulsions, have recently been reported in AIDS patients anaphylaxis and delayed recovery receiving high dosages of sulfamethoxazole + trimethoprim for treatment of Pneumocystis carinii from anaesthesia pneumonia.

United Kingdom— The Committee on Safety of References Medicines has advised anaesthetists that it has received reports of serious reactions attributed to 1. Folia pharmacotherapeutica, 15: 95 (1988). the short-acting intravenous anaesthetic, propofol. It emphasizes that particular care be taken in admini­ 2. Ferner, R.E., Neil, H.A.W. Sulphonylureas and stering it to epileptic patients. It is estimated that the hypoglycaemia. British Medical Journal, 296: 949 (1988). product has now been used on some two million occasions from the time it was introduced in the United Kingdom in June 1986. Since then, the Suxamethonium chloride: Committee has received 37 reports of seizures in which the drug is thought to have been implicated, severe bradycardia 13 of which were in known epileptics. Sixteen reports of involuntary movements and 10 reports of Denmark — The Adverse Drug Reaction Committee opisthotonos are also on record. of the National Board of Health has received 29 reports of patients who developed severe Among the remaining reports are 32 anaphylactic bradycardia or asystole after a single injection of the reactions — which in most cases resulted in severe depolarizing neuromuscular blocking agent, bronchospasm and profound hypotension as well as suxamethonium chloride. No predisposing factors in flushing and/or oedema — and 13 cases of were evident but it is suggested that, even though cardiac arrest necessitating emergency resuscita­ suxamethonium chloride does not normally reduce tion. heart rate, its weak parasympathomimetic effect may, in some cases, have potentiated bradycardia induced by fentanyl or other concomitantly admini­ The need for an adequate period of recovery after stered drugs. Anaesthesiologists are requested to minor interventions is also stressed. In some cases provide details of all other drugs administered to the an hour or more had elapsed before consciousness patient when reporting such effects. had been fully reestablished and some of these patients lapsed back into unconsciousness after a short period of wakefulness. Reference: Ugeskrift for Laeger, 150: 2846 (1988).

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Federal Republic of Germany — The Federal cases presented with headache and visual disturb­ Health Office has amended the approved product ances typical of the condition. Papilloedema information for products containing suxamethonium occurred in almost every case and, in some, it was chloride to indicate that it has been associated with unilateral. The visual disturbances included persis­ cases of cardiac dysrhythmia in children. tent blurring of vision, scotomata and diplopia due to Vlth nerve palsy. The onset occurred in some cases Reference: Bundesgesundheitsblatt, 32: 172-173 (1989) within a few weeks of starting treatment, but in others it was delayed for several months. Tetracyclines: In comparison with the scale on which tetracyclines are used, benign intracranial hypertension is benign intracranial hypertension obviously a rare event. However, since half the reported cases may be expected to suffer perma­ United Kingdom — The Committee on Safety of nent loss of vision, doctors have been urged to Medicines has received reports of benign intra­ consider the possibility of raised intracranial cranial hypertension in patients taking prolonged pressure in any young person complaining of courses of oral tetracycline antibiotics for acne. Nine headache or visual disturbances while receiving of these cases were associated with minocycline, 5 tetracyclines. with tetracycline, 2 with demeclocycline and 1 with oxytetracycline. References: Committee on Safety of Medicines. Current Problems, No. 23, (1988). Dosage was within the normal range in most cases and none of the patients was taking any other drug known to be associated with this condition. Most

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Essential Drugs

Intestinal infections due quate and the disease remains endemic in many to nematodes regions of south-east Asia, Africa and Central and South America. Many hundreds of millions of people throughout the world harbour nematodes in the intestine. In their Children are particularly vulnerable since they are at social and economic implications these parasitic risk of ingesting ascaris eggs while playing in soil infections constitute a major public health problem, contaminated with human faeces. Dust and contami­ particularly in developing countries. Infection is nated fruit and vegetables pose a hazard to all transmitted by eggs or larvae which begin their cycle members of the community. of development within the human host when, depending on the species, they either actively Once ingested, the eggs hatch in the small intestine penetrate intact skin or become ingested or, very and motile larvae penetrate the mucosal blood rarely, inhaled. The larvae of the most widely vessels. They are carried first to the liver and then to prevalent species remain dormant but potentially the lungs where they ascend the bronchial tree infective for long periods in contaminated soil; the before being re-swallowed. Eventually they re-enter the small intestine where they mature, over a period larvae or cysts of other species are ingested when of two months, into adult worms. the flesh of reservoir hosts is eaten raw or under­ cooked. This larval migration sometimes induces transient hypersensitivity and inflammatory reactions resulting Control in pneumonitis, bronchial asthma and urticaria. Subsequently, colonization of the gastrointestinal Interruption of transmission is the key to effective tract by adult worms, which survive for about one long-term control. In some instances this is depend­ year, may cause anorexia, abdominal pain and ent simply upon ensuring that meat and fish are discomfort and other gastrointestinal symptoms. adequately cooked. For the soil-borne infections, From time to time, all or part of a worm may be however, major public health initiatives are required, vomited or passed in the stools. including: Obstruction of the small intestine by worms or, less • education in personal, family and community frequently, their migration — often subsequent to hygiene and the use of shoes or sandals; inadequate treatment — into the appendix, the biliary tract, the pancreatic ducts, or even the upper • construction of latrines and efficient sewage respiratory tract, can create a life-threatening disposal systems; and emergency requiring surgery.

• pre-treatment of human faeces destined for use Chemotherapy as fertilizer to destroy all parasites.

Effective and regular community-based chemo­ Ideally, all infections should be treated, since even a therapy will also reduce transmission but, in the single worm can induce serious allergic reactions or absence of other measures, this does not provide a cause life-threatening complications. practicable basis for long-term control. In highly endemic areas mass treatment of entire communities is justified when over half the popula­ ASCARIASIS tion is estimated to be infected. Selective treatment of infected individuals — particularly children —also Over 1000 million people worldwide are estimated to reduces mortality and morbidity, but a demonstrable be infected with Ascaris lumbricoides (roundworm) effect on transmission, as indicated by a reduction in and, of these, at least 20 000 die annually. A risk of the rate of reinfection, can only be expected after at infection exists wherever faecal disposal is inade­ least two interventions 4 to 6 months apart.

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Individual infections are eradicated by a single dose effective in some community-based control pro­ of pyrantel or levamisole. Piperazine is also effec­ grammes but several doses are often needed to tive, but it is less well-tolerated. Broad spectrum eliminate N. americanus infection. anthelminthics hold obvious advantage where other nematode infections are known to be endemic: the Anaemic patients require supplementary iron salts. benzimidazoles (mebendazole, albendazole and They should continue to receive 200 mg ferrous flubendazole) are each effective in a single dose. sulfate daily for at least three months after the haemoglobin concentration has regained the threshold of 12 g/100 ml. HOOKWORM

Over 900 million people in tropical and subtropical STRONGYLOIDIASIS countries are estimated to be infected with either Ancylostoma duodenale or Necator americanus, Some 50 to 100 million people are estimated to be and associated anaemia causes at least 50 000 infected with Strongyloides stercoralis. It is wide­ deaths annually. spread, not only in moist rainy areas of the tropics and subtropics, but also in some areas of southern Eggs shed in large numbers in infected human and eastern Europe and of the United States of faeces develop rapidly in warm, moist soil into America. filariform larvae which are capable of penetrating intact human skin. They pose a hazard to anyone Infective larvae in contaminated soil penetrate intact walking barefoot over contaminated ground. skin and cause an itchy erythematous rash at the Additionally, A. duodenale may be transmitted by point of entry. They are carried in the bloodstream to ingestion of larvae. the lungs where they ascend the bronchial tree before being swallowed. They then enter the small The invasive larvae are first carried in the blood intestine where they penetrate the mucosa and stream to the lungs. They subsequently ascend the mature into adult worms. Eggs shed by female bronchial tree before being carried in the gastro­ worms are transformed into larvae that are excreted intestinal contents to the small intestine where they into the intestinal lumen. Most larvae are excreted in become attached. As they mature into adult worms, the stool, but some may penetrate the mucous they digest considerable quantities of blood and membrane of the lower bowel or the perianal skin. cause further losses by lacerating the mucosa. This results in autoinfection which intensifies and Clinically evident infection is characterized by perpetuates intestinal colonization. abdominal discomfort, peptic ulcer-like pains and eventually by hypochromic, microcytic anaemia Infection may remain asymptomatic, but recurrent which becomes severe in the absence of treatment, cutaneous and gastrointestinal symptoms and signs particularly when iron intake is inadequate or are common. In patients whose immune mecha­ marginal. nisms are depressed either by disease, cytotoxic drugs or irradiation, the larvae may become widely disseminated. This gives rise to severe haemor¬ Chemotherapy rhagic enteritis and pulmonitis, diarrhoea, malab­ sorption, oedema, liver enlargement and paralytic Ideally, all cases should be treated. However, where ileus. Encephalopathy, pyogenic meningitis and the risk of reinfection is high, this may be impracti­ Gram-negative septicaemia are particularly serious cable. In these circumstances high priority should be complications. In endemic areas, vulnerable patients given to women in the second and third trimesters of should be screened regularly and treated promptly pregnancy, children, and patients debilitated by such as need arises. It is particularly important to exclude conditions as malnutrition, tuberculosis or anaemia. infection before immunosuppressive therapy is started. Broad-spectrum anthelminthics should be preferred wherever other nematode infections are endemic and mebendazole, albendazole and flubendazole Chemotherapy are each effective. Levamisole is also promising in the treatment of mixed ascariasis and hookworm All infected patients should be treated. Albendazole infections. Although pyrantel has been highly administered for three consecutive days is well

74 WHO Drug Information Vol.3, No. 2, 1989 Essential Drugs

tolerated and initial reports suggest it may eradicate TRICHURIASIS up to 80 per cent of infections. It is both more effective and better tolerated than tiabendazole which induces disabling nausea and malaise in a Trichuriasis, or whipworm infection, which is caused high proportion of patients. Mebendazole has also by the nematode worm Trichuris trichiura, is been used but, to be effective, it must be admini­ estimated to affect some 500 million people. stered for longer periods. Children aged 5 to 14 years are particularly vulner­ able. Most cases occur in the moist, warm, tropical regions of Asia, Africa, Central and South America and the Caribbean islands. ENTEROBIASIS Eggs, excreted in faeces, can survive for several Enterobius vermicularis (pinworm or threadworm) years in soil. If these are ingested they hatch in the occurs worldwide. Unlike other pathogenic jejunum to liberate larvae which mature into adult helminths, it is highly prevalent in temperate zones worms that lodge mainly in the caecum. and developed countries. Light infections are symptomless and without clinical Enterobiasis is almost exclusively an infection of significance. Since the worms cause focal necrosis man and it occurs most commonly in children. The at their points of attachment in the large intestine, condition is self-limiting within a few weeks if anaemia results if the infection is heavy. Concomi­ reinfection does not occur. Most female worms tant bacterial or protozoal infections are also migrate to the anal region where their eggs, which common and may require additional specific contaminate perianal skin, night clothes and bed treatment. Protracted diarrhoea occasionally results linen, are a source of reinfection to the patient and to in rectal prolapse. room-mates. Chemotherapy Once ingested, the eggs hatch in the jejunum to liberate larvae. Within a few weeks these develop Chemotherapy is required whenever symptoms into mature worms in the colon, particularly in the supervene or when faecal samples are found to be caecal area. Most infections are asymptomatic, but heavily contaminated (up to 10 000 eggs per gram). intense anal pruritus can occur. Scratching may then A single dose of albendazole can be effective in mild lead to eczematous dermatitis and secondary to moderate infections but heavier infections require bacterial infection. The pruritus can result in children a 3-day course of either mebendazole, albendazole becoming hyperactive and emotionally labile. or flubendazole. Sustained reinfection is an occasional cause of vulvovaginitis and appendicitis. Control TRICHOSTRONGYLIASIS Trichostrongyliasis, which results from infection by Prevention of reinfection is dependent upon Trichostrongylus orientalis or other closely-related scrupulous hygiene, including daily washing of the species of nematode worms, affects several million perianal area, regular changes of clothes and people living mainly in rural communities in Asia. nightwear and strategies to prevent infected children from scratching. Dormant eggs can survive for long periods in soil. Once ingested, they release larvae which mature Chemotherapy into adult worms within 25 to 30 days. Most cases are asymptomatic, but heavy infections can cause Worms are readily eradicated by a single dose of mild anaemia and enteritis. mebendazole, albendazole, flubendazole, or pyrantel. However, since reinfection readily occurs, Chemotherapy at least one further dose is required two to four weeks later. Piperazine is also effective if it is taken regularly for at least 7 consecutive days. A single dose of pyrantel or albendazole is highly effective.

75 Essential Drugs WHO Drug Information Vol. 3, No. 2, 1989

CAPILLARIASIS sometimes steatorrhoea. In the absence of effective treatment, it can become fulminant and result in Capillaria philippinensis is endemic in the Philip­ death within four weeks. pines and southern Thailand where fish provide a reservoir of infection. Intestinal colonization occurs Control as a result of eating raw or undercooked fish. Only sporadic cases of intestinal capillariasis are notified Adequate cooking of fresh-water fish would totally each year, although larger epidemics are on record. prevent infection.

The adult worm matures and reproduces in the jejunum. The resulting heavy infection causes an Chemotherapy enteritis characterized by malabsorption and a protein-losing enteropathy. The condition usually Prolonged treatment with mebendazole or alben­ presents with abdominal pain, diarrhoea, and dazole offers the only prospect of cure.

ALBENDAZOLE Strongyloidiasis chewable tablet 200 mg, 400 mg 400 mg daily for 3 consecutive days. If, after three suspension 100 mg/5 mi in bottles of 20 ml, weeks, eggs or larvae are demonstrable in the 200 mg/ml in bottles of 10 ml stools, a second course of treatment should be administered. A benzimidazole derivative which blocks glucose uptake in many intestinal and tissue nematodes and Capillariasis some cestodes. It is poorly absorbed from the gastrointestinal tract and rapidly undergoes exten­ 400 mg in 2 divided doses daily for 10 - 20 days. sive metabolism in the liver. The absorbed fraction, which has a plasma half-life of some 8 hours, is Contraindications largely eliminated in the urine as the sulfoxide. Known hypersensitivity. Uses Use in pregnancy Treatment of ascariasis, hookworm infections, strongyloidiasis, enterobiasis, trichuriasis, tricho- Albendazole has been shown experimentally to strongyliasis and capillariasis. It is widely used in have teratogenic potential. Although high priority community-based control programmes. should be accorded to the treatment of pregnant women, albendazole should not be administered Dosage during the first trimester.

Adults and children over two years: Adverse reactions

Ascariasis, hookworm infections, enterobiasis and Transient gastrointestinal discomfort and headache trichuriasis have occasionally been reported.

400 mg as a single dose. Single infections of ascariasis or enterobiasis may respond to a single Overdosage dose of 200 mg. Heavy trichuris infections generally require treatment for three consecutive days. In Emesis or gastric lavage may be of value if under­ enterobiasis, it is necessary to treat all members of taken within a few hours of ingestion. Otherwise the household concurrently. treatment is symptomatic and supportive. No specific antidote exists.

76 WHO Drug Information Vol.3, No. 2, 1989 Essential Drugs

Storage Adverse effects

Albendazole preparations should be stored in well- Abdominal pain, nausea, vomiting, dizziness and closed containers. headache are occasionally reported. Overdosage

LEVAMISOLE Emesis or gastric lavage may be of value if under­ tablet 40 mg, 50 mg (as hydrochloride) taken within a few hours of ingestion. Treatment is syrup 40 mg/5 ml otherwise symptomatic and supportive. Levamisole, the laevoisomer of tetramisole, acts by Storage paralyzing the musculature of susceptible nema­ todes. Unable to maintain their anchorage, the Levamisole tablets should be stored in well-closed worms are ejected by normal peristaltic action, containers. usually within 24 hours.

Levamisole is rapidly and almost completely absorbed from the gastrointestinal tract. Peak MEBENDAZOLE plasma concentrations occur within 2 hours and chewable tablet 100 mg levamisole has a plasma half-life of about 4 hours. It suspension 100 mg in 5 ml is extensively metabolized in the liver and is excreted mainly in the urine as metabolites and A benzimidazole derivative which blocks glucose unchanged drug. uptake in many intestinal and tissue nematodes. The small amounts absorbed after oral dosage Uses undergo extensive metabolism within the liver to inactive substances. The plasma half-life is usually 2 to 9 hours, but it is considerably lengthened when Treatment of ascariasis and ascariasis/hookworm hepatic function is impaired. Mebendazole is mixed infections. excreted in the faeces as unchanged drug and metabolites. Dosage Uses Adults and children Treatment of ascariasis, hookworm infections, A single dose of 2.5 mg/kg is used widely both for enterobiasis, trichuriasis and capillariasis. individual treatment and community-based cam­ It is widely used in community-based eradication paigns. In cases of severe hookworm infection a programmes. second standard dose may be given 7 days after the first. Dosage Contraindications Adults and children over two years In the doses used for treatment of helminthic Mebendazole should preferably be taken between infections there are no absolute contraindications. meals.

Ascariasis Use in Pregnancy A single dose of 500 mg is effective. Safe use in pregnancy has not been established. Whenever possible, treatment should be deferred Hookworm infections and trichuriasis until after delivery. 100 mg twice daily for 3 consecutive days. A second

77 Essential Drugs WHO Drug Information Vol. 3, No. 2, 1989

course may be given after 3 to 4 weeks if eggs Piperazine is readily absorbed but the plasma half- persist in the faeces. Recently, a single dose of 600 life is highly variable. It is partially metabolized in the mg has been shown to be effective in hookworm liver and the remainder is excreted unchanged in the infections. urine.

Enterobiasis Uses 100 mg as a single dose, repeated at least once after an interval of 2 to 4 weeks. It is advisable to Treatment of ascariasis and enterobiasis. treat all members of the household concurrently. Dosage Capillariasis Ascariasis 200 mg twice daily for 20 to 30 days. The following schedule is commonly used both in Contraindications treating individuals and in community-based campaigns: Known hypersensitivity. Adults and children over 12 years: Use in pregnancy 75 mg/kg to a maximum of 3.5 g Children between 2 and 12 years: Mebendazole has been shown experimentally to have teratogenic potential. Although high priority 75 mg/kg to a maximum of 2.5 g should be accorded to the treatment of pregnant women, mebendazole should not be administered Children under 2 years: during the first trimester. 50 mg/kg to be administered under medical supervision. Adverse effects This amount may be taken in a single dose on an Transient gastrointestinal discomfort and headache empty stomach, but it has been claimed that better have occasionally been reported. results are obtained when the total dose is divided and taken over two consecutive days.

Overdosage Enterobiasis

Emesis or gastric lavage may be of value if under­ 50 mg/kg on each of 7 successive days. This course taken within a few hours of ingestion. Otherwise is repeated after an interval of 2 to 4 weeks. treatment is symptomatic and supportive. No it is advisable to treat all members of the household specific antidote exists. concurrently.

Storage Contraindications

Mebendazole preparations should be stored in well- Known hypersensitivity. closed containers. Patients with epilepsy or impairment of renal or PIPERAZINE hepatic function. tablet 500 mg hydrate (as citrate or adipate) elixir (as citrate) equivalent to 500 mg hydrate/5 ml Precautions

Piperazine may selectively block neuromuscular Treatment should be discontinued if hypersensitivity cholinergic receptors in Ascaris lumbricoides and or severe intolerance develops, or if neurological Enterobius vermicularis, but this has not been signs occur. demonstrated conclusively.

78 WHO Drug Information Vol.3, No. 2, 1989 Essential Drugs

Drug interactions tinal tract. Most is excreted unchanged in the faeces. The absorbed fraction is partially metabolized in the liver and the residuum is excreted in the urine as Piperazine and pyrantel are antagonistic in their unchanged drug and metabolites. mechanisms of action. They should never be ad­ ministered together. Uses Concurrent administration of chlorpromazine has been reported to potentiate the risk of seizures. Treatment of ascariasis, hookworm infections, enterobiasis and trichostrongyliasis. Use in pregnancy Dosage Safe use in pregnancy has not been established. Although high priority should be accorded to the Adults and children treatment of pregnant women, piperazine should not be administered during the first trimester. A single dose of 10 mg/kg is sufficient to eliminate many infections due to ascariasis, hookworm, Adverse effects enterobiasis and trichostrongyliasis. When treating enterobiasis, however, a second Gastrointestinal irritation occasionally occurs. dose should be given routinely after 2 to 4 weeks. Hypersensitivity reactions, including skin rashes, All members of the household should be treated fever and joint pains are not uncommon. When they concurrently. occur, treatment should be withdrawn immediately and the patient warned against taking piperazine Heavy hookworm infections are relatively resistant again. and three further doses should be given on con­ secutive days. Transient neurological symptoms may also occur, particularly dizziness, paraesthesia and slight A single oral dose of 2.5 mg/kg administered incoordination. Epilepsy and neuropsychiatric regularly 3 or 4 times a year in mass treatment conditions may be exacerbated. control programmes has been reported to reduce substantially the prevalence of ascariasis. Overdosage Contraindications Overdosage can result in convulsions, respiratory depression and transient paresis of the limbs. Known hypersensitivity Emesis or gastric lavage may be of value if under­ taken within a few hours of ingestion. Treatment is otherwise supportive and symptomatic. Precautions

Storage Lower doses should be administered when liver function is impaired. Piperazine preparations should be stored, protected from light, in tightly closed containers. Drug interactions

Pyrantel and piperazine have an antagonistic effect. PYRANTEL They should never be given concurrently. chewable tablet 250 mg (as embonate) oral suspension 50 mg (as embonate)/ml Use in pregnancy

A pyrimidine derivative which depolarizes neuro­ Safe use in pregnancy has not been established. muscular junctions of susceptible nematodes. The Although high priority should be accorded to the paralysed worms are subsequently expelled in the treatment of pregnant women, pyrantel should not faeces. It is poorly absorbed from the gastrointes­ be administered during the first trimester.

79 Essential Drugs WHO Drug Information Vol. 3, No. 2, 1989

Adverse effects Use in pregnancy

Mild gastrointestinal disturbance, headache, Tiabendazole has been shown experimentally to dizziness, drowsiness, insomnia and rash are possess teratogenic potential. Although high priority occasionally reported. should be accorded to the treatment of pregnant women, tiabendazole should not be administered during the first trimester. Overdosage Precautions Emesis or gastric lavage may be of value if under­ taken within a few hours of ingestion. Whenever possible, anaemia, dehydration and malnutrition should be corrected before treatment. Storage Patients should be advised not to drive or operate machinery. Pyrantel preparations should be stored in tight, light- resistant containers. Adverse effects

Dizziness, gastrointestinal irritation, drowsiness, pruritus and headache are common, and many TIABENDAZOLE patients are incapacitated for several hours. chewable tablet 500 mg Less commonly, tinnitus, visual disturbances, hyperirritability, numbness, hyperglycaemia, A benzimidazole derivative which inhibits cellular hypotension, collapse, hepatic dysfunction and enzyme systems specific to various helminths. It is transient leukopenia have been reported. associated with a high incidence of acute incapaci­ Hypersensitivity may present as fever, flushing, tating reactions and its systemic use remains chills, conjunctival inflammation, angioedema, justified only in strongyloidiasis when albendazole is anaphylaxis, lymphadenopathy or rashes. Erythema not available. It is rapidly absorbed from the gastro­ multiforme and Stevens-Johnson syndrome may intestinal tract and peak plasma concentrations subsequently occur, particularly if treatment is occur about 1 hour after ingestion. Approximately 90 continued. Crystalluria, sometimes with haematuria, per cent is excreted in the urine, principally as can occur, and the urine may develop an asparagus­ conjugates formed in the liver. like odour.

Uses Drug interactions

Treatment of strongyloidiasis, as an alternative to Serum levels of theophylline and other xanthine albendazole. derivatives may rise above the toxic threshold when tiabendazole is administered concomitantly. Dosage Overdosage 25 mg/kg in three divided doses daily taken for 3 consecutive days preferably after meals. Higher Emesis or gastric lavage may be of value if under­ doses for longer periods may often be required. taken within a few hours of ingestion. Otherwise, treatment is symptomatic and supportive. No Contraindications specific antidote exists.

Known hypersensitivity. Treatment should be Storage suspended immediately should suspicion of allergy arise. Tiabendazole tablets should be kept in tightly closed containers.

80 WHO Drug Information Vol.3, No. 2, 1989

Newly Registered Products

Antithrombin III iopromide anticoagulation factor non-ionic radiocontrast agent Kybernin®: Behring, Italy Ultravist 150, 240, 300, 370®: Schering, injection fluid 50 IU/ampoule Netherlands Indications: prophylaxis and therapy of thrombo­ solution for injection containing iopromide/iodine embolic episodes due to acquired antithrombin-III Indications: various radiographic diagnostic pro­ deficiency. cedures, including myelography and ventriculo­ graphy. Increases contrast in digital substraction angio-graphy, and computerized tomography. butyl methoxydibenzoylmethane + Contraindications: clinically evident hyper -thyroidism. Hypersensitivity. padimate O Warning: not for subarachnoidal application. ultraviolet screen Photoplex®: Herbert Labs, United States of America ipriflavone lotion 3% + 7% Indications: protection against sunburn. metabolic agent Osten®: Takeda, Japan tablet 200 mg cethexonium bromide Indications: loss of bone mass due to osteoporosis. Precautions: safety during pregnancy, lactation not antiseptic established. Inhaxol®: Laboratoires Sauba, France Warning: not to be used concomitantly with estro­ nasal drops 0.5 mg gens. Indications: infections of the nasal mucosa, rhino­ Adverse effects: hypersensitivity, gastrointestinal pharyngitis. symptoms, dizziness. Contraindications: infants under 30 months of age. Precautions: not to be used for more than 10 days. irsogladine maleate gamolenic acid anti-ulcer agent (in evening primrose oil) Gaslon®: Nippon Shinyaku, Japan tablet 2, 4 mg; granules 8 mg/g Indications: gastric ulcer prostaglandin precursor Precautions: safety in children and during pregnancy Epogam®: Scotia Pharmaceuticals, United Kingdom not established. capsule 40 mg Adverse effects: gastrointestinal symptoms, mild Indications: symptomatic relief of atopic eczema. changes in hepatic function. Occasional skin Caution: epileptic patients. eruptions necessitating discontinuation of therapy. Adverse effects: nausea, indigestion, headache

81 Newly Registered Products WHO Drug Information Vol. 3, No. 2, 1989

isradipine oxidronate disodium + calcium channel blocking-agent stannous chloride Prescal®: Ciba Laboratories, United Kingdom tablet 2.5 mg radiodiagnostic agent, carrier for technetium-99 Indications: essential hypertension. Osteoscan®: Mallinckrodt Diagnostics, Precaution: safety in pregnancy, lactation and in United Kingdom children not established. powder for injection 3.0 mg + 0.24 mg Caution: patients with heart disease, particularly Indications: bone and myocardial scintigraphy. aortic stenosis, uncontrolled sick sinus syndrome, Caution: patients should be encouraged to drink and patients with low systolic blood pressure. fluids liberally before and after examination. Adverse effects: headache, flushing, dizziness, Radiopharmaceuticals should not be administered tachycardia and palpitations. to patients under 18 years of age or during preg­ nancy or lactation unless the information to be gained outweighs the potential hazard. nipradilol

beta-adrenoreceptor blocking agent with vaso­ sermorelin dilating properties Hypadil®: Kowa, Japan synthetic growth hormone releasing factor (GHRF) tablet 3 mg Groliberin®: KabiVitrum, Sweden Indications: essential hypertension, angina pectoris. powder for injection 100 µg/ml Contraindications: severe bradycardia, atrioventricu­ Indications: diagnosis of pituitary secretion of growth lar block, sinoauricular block; diabetic ketoacidosis hormone. and metabolic acidosis; cardiogenic shock; bron­ Adverse effects: transient flush. chial asthma, bronchial spasm; heart failure; pregnant and lactating women and other women of childbearing potential. Caution: in the elderly, diabetics, patients with severe hepatic/renal dysfunction. Safety in infants and children has not been established. Warning: pregnancy should be excluded. With­ drawal should be gradual. Adverse effects: bradycardia, circulatory disturb­ ances, shortness of breath, dizziness, headache, drowsiness, insomnia, gastrointestinal symptoms, hypersensitivity, weakness, sweating, tinnitus.

82 WHO Drug Information Vol.3, No. 2, 1989

Recent Publications

American Hospital Formulary ized English-speaking countries and in Japan, together with a brief guide to the European Service Drug Information: 89 Directives concerning medicines as they stood at the end of 1987. The American Hospital Formulary Service Drug Information, which is published by the American As an important bonus it also includes a series of Society of Hospital Pharmacists, prides itself as "the informed essays and commentaries on matters of most comprehensive authoritative source of the moment ranging from the costs of pharmaceuti­ evaluative drug information". It is certainly one of the cal research, product patent life, product liability, and most frequently updated. Every year, for the past orphan drugs, to mechanisms for monitoring mar­ thirty years, a new annual edition has been pub­ keted products. The topics are wide-ranging and the lished to assure the claim that it covers virtually reader will be hard-pressed to find them presented in every single drug entity available in the United a more readily-assimilable form. States. The task, which involves over 250 independ­ ent clinicians and pharmacists in the review process, Reference: Medicines: regulation, research and risk. Ed. is formidable and, since the unwieldy loose-leaf Griffin, J.P., D'Arcy, P.F., Harron, D.W.G. Queen's format was replaced by a single bound volume in University of Belfast, 1989 ISBN 0 85389 325 X 1984, it has become a prime source of reference far beyond North America. Pyrrolizidine alkaloids Its organization, which is determined by a practical, and not overly elaborate, pharmacologic-therapeutic This book disposes of the dogma that herbal and classification, is admirable for the busy clinicians for other traditional medicines may be assumed to be whom it is primarily intended. If the trend to include safe on the basis of long and apparently uneventful introductory commentaries at the beginning of each usage. Many of these preparations contain alkaloids set of individual drug monographs is sustained, it will that are known to be toxic and, among these, the compete strongly with many of the established pyrrolizidines have long been associated with the textbooks on clinical pharmacology. development in man of veno-occlusive hepatic disease and the development of cirrhosis. However, Reference: AHFS Drug Information 89. American Society it is accidental poisoning with these substances that of Hospital Pharmacists, Inc., 4630 Montgomery Avenue, poses the greatest danger. In many regions plants Bethesda, MD 20814. ISBN 0 930530-89-6. containing them in high concentrations contaminate staple crops and constitute a threat to farm animals, particularly during the dry season. A large outbreak Medicines: of human poisoning was recently reported from regulation, research and risk Afghanistan following a prolonged period of drought.

No drug regulator and no executive working in an In experimental studies in animals they have internationally-based pharmaceutical company can produced acute and chronic toxic changes in the operate effectively without a sound working know­ liver, lungs and central nervous system and they ledge of the processes by which medicinal products possess a dose-related potential to induce terato­ are controlled within the major national markets. genic, fetotoxic and mutagenic changes. This book There is no shortage of information of a more or less draws together information cited in over 500 ephemeral nature in the weekly trade press, but it is published studies and it provides the most compre­ not so easy to find comprehensive and readable hensive overview of the biological properties of accounts of how the statutory and regulatory these substances that has yet been compiled. provisions that determine these processes have evolved. This book provides a valuable introduction Reference: Pyrrolizidine alkaloids. Environmental Health to the complexities of relevant law in the industrial­ Criteria, No. 80. World Health Organization, Geneva (1988) ISBN 92 4 15480 2

83 Recent Publications WHO Drug Information Vol. 3, No. 2, 1989

Guidelines for improving children's ments to the classical long-term cancer bioassays performed in rodents. The first phase of the study, prescription medicine use completed in 1985, which was directed to the identification of one or more in vitro eukaryotic tests Ten independent studies of the attitudes of children suitable to complement the Salmonella mutation in the United States of America towards their assays, has resulted in a proposal that a standard­ medicines have shown that, even in the case of ized chromosomal aberration assay should be those on anticancer therapy, almost half of them fail developed for this purpose (1). to comply with instructions. A report entitled "Children and America's Other Drug Problem", The second phase of the study appraises the results which discusses these findings, has been issued by obtained when two structurally-related carcinogen/ the National Council on Patient Information and non-carcinogen pairs of compounds were subjected Education, a body that represents consumers, to a wide range of in vivo assays. The results, now health-care professionals, government and industry, published in two volumes (2), indicate that short- and which receives active support from the Food term in vivo tests are of value, less as primary and Drug Administration and the American Medical screens, but rather to identify genotoxins most likely Association. Its message, issued in the form of to present a carcinogenic hazard to man. guidelines on how to inculcate a more responsible attitude in children towards their medicines, is Much still remains to be explored regarding the directed primarily to clinicians and it draws on much relative advantages and disadvantages of short- expert advice from professionals with extensive term in vivo and in vitro models as indicators of practical experience of the many facets of the genotoxicity. Particularly for those toxicologists problem. concerned primarily with new drug development, the strategies for investigating non-genotoxic Reference: Children and America's Other Drug Problem. mechanisms of chemical carcinogenesis remain National Council on Patient Information and Education, largely open to debate. The work accomplished 666 Eleventh Street, NW, Suite 810, Washington, DC thus far in this project indicates that, if answers are to 20001, USA. be supplied, they are most likely to emerge through organized international collaborative efforts.

Predicting carcinogenicity References

One of the most challenging and complex tasks in 1. Progress in Mutation Research. Vol. 5. Evaluation toxicology today is to determine which of the of short-term tests for carcinogens. Ed. Ashby, J., de Serres, F.J., Draper, M. et al. Elsevier (1985). daunting array of established laboratory models are ISBN 0 444 80615 6 most reliably predictive of the consequences to man of exposure to biologically active substances. In 2. International Programme on Chemical Safety. 1981, the International Programme on Chemical Evaluation of short-term tests for carcinogens. Vols. 1 & 2. Safety, in collaboration with the National Institute of Eds. Ashby, J., de Serres, F.J., Shelby, M.D. et al. Environmental Health Sciences of the USA, initiated Cambridge University Press on behalf of the World Health a large inter-laboratory collaborative study of short- Organization, Geneva (1988). ISBN 0 521 34152 3 term assays proposed as alternatives or supple­ (Vol.1): 0 521 34153 1 (Vol.2).

84 WHO Drug Information Vol. 3, No. 2, 1989

International Nonproprietary Names for Pharmaceutical Substances

In accordance with article 3 of the Procedure for The inclusion of a name in the lists of proposed the Selection of Recommended International international nonproprietary names does not Nonproprietary Names for Pharmaceutical imply any recommendation for the use of the Substances,1 notice is hereby given that the substance in medicine or pharmacy. following names are under consideration by the World Health Organization as Proposed Action and Use International Nonproprietary Names. The statements in italics indicating the action and use are based largely on information sup­ plied by the manufacturer. The information is Comments on, or formal objections to, the pro­ meant to provide an indication of the potential posed names may be forwarded by any use of new substances at the time they are ac­ person to the Pharmaceuticals unit of the World corded proposed INNs. WHO is not in a position Health Organization within four months of the either to uphold these statements or to comment date of their publication in WHO Drug Informa­ on the efficacy of the action claimed. Because of tion, e.g., for List 61 Prop. INN not later than their provisional nature these descriptors will not 30 November 1989. be included in the Cumulative Lists of INNs.

Proposed International Nonproprietary Names (Prop. INN): List 612

Comprehensive information on the INN programme can be found in: WHO Technical Report Series, No. 581, 1975 (Nonproprietary Names for Pharma­ ceutical Substances. Twentieth Report of the WHO Expert Committee), ISBN 92 4 120581 4 (price: Sw. fr. 6.-); an account of this publication will be found in Annex 2 of the present List. All names from Lists 1-47 of Proposed International Nonproprietary Names, together with a molecular formula index, will be found in: International Nonproprietary Names (INN) for Pharmaceutical Substances. Cumulative List No. 7, 1988, World Health Organization, Geneva (ISBN 92 4 056014 9) (price: Sw. fr. 65.-). This publication consists, in the main, of a computer printout which groups together all the proposed and recommended international nonproprietary names (INN) - in Latin, English, French, Russian, and Spanish—published up to March 1988. The printout also indicates in which of the 58 individual lists of proposed names and 27 lists of recommended names each INN was originally published, and gives references to national nonproprietary names, pharmacopoeia monographs, and other sources. In addition, the list contains molecular formulae and Chemical Abstracts Service registry numbers. For easy reference, national nonproprietary names that differ from INN, molecular formulae, and Chemical Abstracts Service registry numbers are indexed in a series of annexes. A final annex describes the procedure for selecting recommended INN and outlines the general principles to be followed in devising these names. All the textual material published in this volume appears in both English and French These publications may be obtained, direct or through booksellers, from the sales agents listed on the back cover of WHO Drug Information. Orders from countries where sales agents have not yet been appointed may be addressed to: World Health Organization, Distribution and Sales Service. 1211 Geneva 27, Switzerland.

1 Text adopted by the Executive Board of WHO in resolution EB15.R7 (Off. Rec. Wld Hlth Org., 1955, 60, 3) and amended by the Board in resolution EB43.R9 (Off. Rec. Wld. Hlth Org., 1969, 173, 10). 2 Other lists of proposed and recommended international nonproprietary names can be found in Cumulative List No. 7, 1988.

85 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number Action and use ablukastum ( ± )-6-acetyl-7-[[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyl]oxy]- ablukast 2-chromancarboxylic acid C28H34O8 96566-25-5 antiallergic, antiasthmatic

acamprosatum 3-acetamido-1-propanesulfonic acid acamprosate C5H11NO4S 77337-76-9 psychotropic 6473

acidum alendronicum (4-amino-1-hydroxybutylidene)diphosphonic acid alendronic acid C4H13NO7P2 66376-36-1 Calcium regulator

acidum neridronicum (6-amino-1 -hydroxyhexyIidene)diphosphonic acid neridronic acid C6H17NO7P2 79778-41-9 Calcium regulator

86 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number Action and use

altoqualinum (3S)-7-amino-4,5,6-triethoxy-3-[(1R)-1,2,3,4-tetrahydro-6,7,8-trimethoxy- altoqualine 2-methyl-1-isoquinolyl]phthalide C27H36N2O8 121029-11-6 antiallergic, antihistaminic

amocarzinum 4-methyl-4'-(p-nitroanilino)thio-1-piperazinecarboxanilide amocarzine C18H21N5O2S 36590-19-9 antifilarial

artemetherum (3R,5aS,6R,8aS,9R,10S,12R,12aR)-decahydro-10-methoxy-3,6,9-trimethyl- artemether 3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin C16H26O5 71963-77-4 antimalarial

artesunatum (3R,5aS,6R,8aS,9R,10S,12R,12aR)-decahydro-3,6,9-trimethyl-3,12-epoxy-12H- artesunate pyrano[4,3-j|-1,2-benzodioxepin-10-ol, hydrogen succinate C19H28O8 88495-63-0 antimalarial

87 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number Action and use atrimustinum estradiol 3-benzoate 17-glycolate, 4-[p-[bis(2- atrimustine chloroethyl)amino]phenyl]butyrate C41H47CI2NO6 75219-46-4 antineoplastic

avobenzonum 1-(p-tert-butylphenyl)-3-(p-methoxyphenyl)-1,3-propanedione avobenzone C20H22O3 70356-09-1 sunscreen

bakeprofenum (± )-2-(m-benzoylphenoxy)propionic acid bakeprofen C16H14O4 74168-02-8 analgesic, nonsteroidal anti­ inflammatory

batanopridum ( ± )-4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[(1-methylacetonyl)oxy]- batanopride benzamide C17H26ClN3O3 102670-46-2 antiemetic

belfosdilum tetrabutyl [2-(2-phenoxyethyl)trimethylene]diphosphonate belfosdil C27H50O7P2 103486-79-9 Calcium antagonist

88 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number Action and use bemoradanum (± )-7-(1,4,5,6-tetrahydrc-4-methyl-6-oxo-3-pyridazinyl)-2H-1,4-benzoxazin- bemoradan 3(4H)-one C13H13N3O3 112018-01-6 positive inotropic agent

calcipotriolum. (5Z,7E,22E,24S)-24-cyclopropyl-9,10-secochola-5,7,10(19),22-tetraene- calcipotriol 1α,3β,24-triol C27H40O3 112828-00-9 antipsoriatic

camonagrelum ( ± )-5-(2-imidazol-1-ylethoxy)-1-indancarboxylic acid camonagrel C15H16N2O3 105920-77-2 platelet aggregation inhibitor

carmoxirolum 3-[4-(3,6-dihydro-4-phenyl-1(2H)-pyridy})butyI]indole-5-carboxylic acid carmoxirole C24H26N2O2 98323-83-2 D1 -dopamine receptor agonist

89 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number Action and use cefdinirum (-)-(6R,7R)-7-[2-(2-amino-4-thiazolyl)glyoxylamido]-8-oxo-3-vinyl-5-thia-1- cefdinir azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 72-(Z)-oxime C14H13N5O5S2 91832-40-5 antibiotic

cilutazolinum 2-[[(6-cyclopropyl-m-tolyl)oxy]methyl]-2-imidazoline cilutazoline C14H18N2O 104902-08-1 nasal vasoconstrictor

clentiazemum ( + )-cis-8-chloro-5-[2-(dimethylamino)ethyl]-2,3-dihydro-3-hydroxy- clentiazem 2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one acetate (ester) C22H25ClN2O4S 96125-53-0 Calcium antagonist

cronidipinum [8-(p-chlorophenyl)-1,4-dioxa-8-azaspiro[4,5]dec-2-yl]rnethyl methyl cronidipine 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate C30H32CIN3O8 113759-50-5 Calcium antagonist

90 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number Action and use

danofloxacinum 1 -cyclopropyl-6-fluoro-1,4-dihydro-7-[ (1S,4S)-5-methyl-2,5-diaza¬ danofloxacin bicyclo[2.2.1]hept-2-yl]-4-oxo-3-quinolinecarboxylic acid C19H20FN3O3 112398-08-0 antibacterial (vet.)

decitabinum 4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)-s-triazin-2(1H)-one decitabine C8H12N4O4 2353-33-5 antineoplastic

deslorelinum 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-tryptophyl-L-leucyl- deslorelin L-arginyl-/V-ethyl-L-prolinamide C64H83N17O12 57773-65-6 LHRH analogue

dexibuprofenum (S)-( + )-p-isobutylhydratropic acid dexibuprofen C13H18O2 51146-56-6 analgesic, nonsteroidal anti-inflammatory

divaplonum 6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidin-2-yl phenyl ketone divaplon C17H17N3O2 90808-12-1 anxiolytic

91 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number Action and use docebenonum 2-(12-hydroxy-5,10-dodecadiynyl)-3,5,6-trimethyl-p-benzoquinone docebenone C21H26O3 80809-81-0 antiallergic, antiasthmatic

doconexentum (a//-Z)-4,7,10,13,16,19-docosahexaenoic acid doconexent C22H32O2 6217-54-5 platelet aggregation inhibitor

ecomustinum methyl 3-[3-(2-chloroethyl)-3-nitrosoureido]-2,3-dideoxy-α-D-arabino- ecomustine hexopyranoside C10H18ClN3O6 98383-18-7 antineoplastic

edatrexatum N-[p-[1-[(2,4-diamino-6-pteridinyl)methyl]propyl]benzoyl]-L-glutamic acid edatrexate C22H25N7O5 80576-83-6 antineoplastic

eflumastum 3'-acetyl-5'-fluoro-2'-hydroxy-1H-tetrazole-5-carboxanilide eflumast C10H8FN5O3 70977-46-7 antiallergic, antiasthmatic

92 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number Action and use

elgodipinum 2-[(p-fluorobenzyl)methylamino]ethyl isopropyl ( ± )-1,4-dihydro-2,6-dimethyl- elgodipine 4-[2,3-(methylenedioxy)phenyl]-3,5-pyridinedicarboxylate C29H33FN2O6 119413-55-7 Calcium antagonist

emonapridum ( ± )-cis-N-(1-benzyl-2-methyl-3-pyrrolidinyl)-5-chloro-4-(methylamino)- emonapride o-anisamide C21H26ClN3O2 93664-94-9 D1-dopamine receptor antagonist

enalkirenum (aS)-a-[(aS)-a-(3-amino-3-methylbutyramido)-p-methoxyhydrocinnamamido]- enalkiren N-[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]imidazole- 4-propionamide C35H56N6O6 113082-98-7 renin inhibitor

epervudinum 2'-deoxy-5-isopropyluridine epervudine C12H18N2O5 60136-25-6 antiviral

93 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number Action and use

famciclovirum 2-[2-(2-amino-9H-purin-9-yl)ethyl]-1,3-propanediol diacetate (ester) famciclovir C14H19N5O4 104227-87-4 antiviral

fasiplonum 6-ethyl-7-methoxy-5-methyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)imidazo- fasiplon [1,2-a]pyrimidine C13H15N5O2 106100-65-6 anxiolytic

fibrinum an insoluble plasma protein obtained by the action of thrombin on fibrin fibrinogen. The source of the product should be indicated, e.g. fibrin (bovine). local haemostatic agent

fludeoxyglucosum (18F) 2-deoxy-2-fluoro-18F-a-D-glucopyranose 18 18 fludeoxyglucose ( F) C6H11 FO5 105851-17-0 radioactive diagnostic agent

flutomidatum ethyl ( ± )-1-(p-fluoro-a-methylbenzyl)imidazole-5-carboxylate flutomidate C14H15FN2O2 84962-75-4 anaesthesic (vet.)

flutrimazolum 1-[o-fluoro-a-(p-fluorophenyl)-a-phenylbenzyl]imidazole flutrimazole C22H16F2N2 119006-77-8 antifungal

94 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number Action and use galamustinum 6-[bis(2-chloroethyl)amino]-6-deoxy-D-galactopyranose galamustine C10H19CI2NO5 105618-02-8 antineoplastic

gedocarnilum isopropyl 5-(p-chlorophenoxy)-4-(methoxymethyl)-9H-pyrido[3,4-6]indole- gedocarnil 3-carboxylate C23H21ClN2O4 109623-97-4 partial benzodiazepine receptor agonist

gevotrolinum 8-fluroro-2,3,4,5-tetrahydro-2-[3-(3-pyridyl)propyl]-1H-pyrido[4,3-6]indole gevotroline C19H20FN3 107266-06-8 antipsychotic

icosapentum (a//-Z)-5,8,11,14,17-eicosapentaenoic acid or (a//-Z)-5,8,11,14,17- icosapent icosapentaenoic acid C20H30O2 10417-94-4 platelet aggregation inhibitor

isaglidolum 4-fluoro-2-(2-imidazolin-2-ylamino)isoindoline isaglidole C11H13FN4 110605-64-6 antidiabetic

95 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number Action and use isosorbidum 1,4:3,6-dianhydro-D-glucitol isosorbide C6H10O4 652-67-5

lactitoium 4-O-β-D-galactopyranosyl-D-gIucitol lactitol C12H24O11 585-86-4 sweetener

laidlomycinum (αS,βR,γS,2S,5R,7S,8R,9S)-β,9-dihydroxy-α,γ,2,8-tetrarnethyl-2-[(2R,5S)- laidlomycin tetrahydro-5-methyl-5-[(2R,3S,5R)-tetrahydro-3-methyl-5-[(2S,3S,5R,6R)- tetrahydro-6-hydroxy-6-(hydroxymethyl)-3,5-dimethyl-2H-pyran-2-yl]-2-furyl]- 2-furyl]-1,6-dioxaspiro[4.5]decane-7-butyric acid, β-propionate C37H62O12 56283-74-0 coccidiostatic (vet.)

letrazurilum ( ± )-[2,6-dichloro-4-(4,5-dihydro-3,5-dioxo-as-triazin-2(3H)-yl)phenyl](p-fluoro- letrazuril phenyl)acetonitrile C17H9CI2FN4O2 103337-74-2 coccidiostatic (vet.)

levobetaxololum (-)-(S)-1-[p-[2-(cyclopropylmethoxy)ethyl]phenoxy]-3-(isopropylamino)- levobetaxolol 2-propanol C18H29NO3 93221-48-8 β-adrenoreceptor antagonist

96 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number Action and use losigamonum (5R*)-5-[(αS*)-o-chloro-α-hydroxybenzyl]-4-methoxy-2(5H)-furanone losigamone C12H11ClO4 112856-44-7 antiepileptic

losmiprofenum (± )-2-[[3-(p-chlorobenzoyl)-o-tolyl]oxy]propionic acid losmiprofen C17H15CIO4 74168-08-4 nonsteroidal anti-inflammatory

miltefosinum choline hydroxide, hexadecyl hydrogen phosphate, inner salt miltefosine C21H46NO4P 58066-85-6 antineoplastic

mirtazapinum 1,2,3,4,10,14b-hexahydro-2-methylpyrazino[2,1-a]pyrido[2,3-c][2]benzazepine mirtazapine C17H19N3 61337-67-5 antidepressant

moguisteinum ethyl ( ± )-2-[(o-methoxyphenoxy)methyl]-β-oxo-3-thiazolidinepropionate moguisteine C16H21NO5S 119637-67-1 antitussive

97 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number Action and use moxidectinum (6R,25S)-5-Odemethyl-28-deoxy-25-[(E)-1,3-dimethyl-1-butenyl]-6,28-epoxy- moxidectin 23-oxomilbemycin B 23-(Omethyloxime) C37H53NO8 113507-06-5 antiparasitic (vet.)

10 10 natrii borocaptas ( B) disodium undecahydromercaptododecaborate(2-)- B12 10 10 sodium borocaptate ( B) Na2 B12H12S 103831-41-0 neutron capture agent

2Na+

ocfentanilum 2'-fluoro-2-methoxy-N-(1-phenethyl-4-piperidyl)acetanilide ocfentanil C22H27FN2O2 101343-69-5 narcotic analgesic

pemirolastum 9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one pemirolast C10H8N6O 69372-19-6 antiallergic

98 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number Action and use penciclovirum 9-[4-hydroxy-3-(hydroxymethyl)butyl]guanine penciclovir C10H15N5O3 39809-25-1 antiviral

pidolacetamolum 5-oxo-L-proline, ester with 4'-hydroxyacetanilide pidolacetamol C13H14N2O4 114485-92-6 analgesic, antipyretic

rebamipidum (±)-α-(p-chlorobenzamido)-1,2-dihydro-2-oxo-4-quinolinepropionic acid rebamipide C19H15CIN2O4 111911-87-6 antiulcer

revospironum 2-[3-[4-(2-pyrimidinyl)-1-piperazinyl]propyl]-1,2-benzisothiazolin-3-one revospirone 1,1-dioxide C18H21N5O3S 95847-87-3 tranquillizer (vet.)

99 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number Action and use rifametanum (2S,12Z,14E,16S,17S,18R,19R,20R,21S,22S,23S,24E)-1,2-dihydro-5,6,9,17,19,21- rifametane hexahydroxy-23-methoxy-2,4,12,16,18,20,22-heptamethyl-1,11-dioxo-2,7- (epoxypentadeca[1,11,13]trienimino)naphtho[2,1-b)]furan-8-carboxaldehyde, 8-azine with N, N-diethylacetamide, 21-acetate C44H60N4O12 94168-98-6 antibiotic

romurtidum 2-acetamido-3-O-[(R)-1-[[(S)-1-[[(R)-1-carbamoyl-3-[[(S)-1-carboxy- romurtide 5-stearamidopentyl]carbamoyl]propyl]carbamoyl]ethyl]carbamoyl]ethyl]- 2-deoxy-D-glucopyranose C43H78N6O13 78113-36-7 immunomodulator

ropinirolum 4-[2-(dipropylamino)ethyl]-2-indolinone ropinirole C16H24N2O 91374-21-9 D2-dopamine receptor agonist

sertindolum 1-[2-[4-[5-chloro-1-(p-fluorophenyl)indol-3-yl]piperidino]ethyl]- sertindole 2-imidazolidinone C24H26CIFN4O 106516-24-9 antipsychotic

100 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number Action and use suronacrinum (± )-9-(benzylamino)-1,2,3,4-tetrahydro-1-acridinol suronacrine C20H20N2O 104675-35-6 cholinesterase inhibitor

taludipinum ( ± )-4-[o-[(E)-2-carboxyvinyl]phenyl]-2-[(dimethylamino)methyl]-1,4-dihydro- taludipine 6-methyl-3,5-pyridinedicarboxylic acid, 4-terf-butyl diethyl ester C28H38N2O6 108687-08-7 Calcium antagonist

taniplonum 6,7,8,9-tetrahydro-5-methoxy-2-(5-methyl-1,2,4-oxadiazol-3-yl)imidazo- taniplon [1,2-a]quinazoline C14H15N5O2 106073-01-2 anxiolytic

technetium (99mTc) teboroximum [bis[(1,2-cyclohexanedione dioximato)(1-)-O][(1,2-cyclohexanedione technetium (99mTc) teboroxime dioximato)(2-)-O]methylborato(2-)-N,N',N",n"',N''",n''''']chloro[99mTc]tech- netium(lll) 99m C19H29BCIN6O6 Tc 104716-22-5 radioactive diagnostic agent

101 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number Action and use tenidapum (±)-5-chloro-2-oxo-3-(2-thenoyl)-1-indolinecarboxamide tenidap C14H9CIN2O3S 100599-27-7 nonsteroidal anti-inflammatory

terflavoxatum 1,1-dimethyl-2-piperidinoethyl 3-methyl-4-oxo-2-phenyl-4W-1-benzopyran- terflavoxate 8-carboxylate C26H29NO4 86433-40-1 antispasmodic

thymotrinanum N-(N2-L-arginyl-L-lysyl)-L-aspartic acid thymotrinan C16H31N7O6 85465-82-3 immunomodulator

toripristonum 17β-hydroxy-11β-[p-(isopropylmethylamino)phenyl]-17-(1-propynyl)estra- toripristone 4,9-dien-3-one C31H39NO2 91935-26-1 antiglucocorticoid

102 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number Action and use troquidazolum N'-(3-nitro-4-quinolyl)-4-morpholinecarboxamidine troquidazole C14H15N5O3 108001-60-1 radiosensitizing agent

velnacrinum (± )-9-amino-1,2,3,4-tetrahydro-1-acridinol velnacrine C13H14N2O 112964-98-4 cholinesterase inhibitor

vintoperolum (-)-(1S,12bS)-1-ethyl-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine- vintoperol 1-methanol C18H24N2O 106498-99-1 peripheral vasodilator

voxergolidum ( ± )-(6aR,9R,10aR)-4,6a,7,8,9,10a-hexahydro-7-methyl-9-[(methylthio)methyl]- voxergolide 6H-indolo[3,4-gh][1,4]benzoxazine C16H20N2OS 89651-00-3 dopamine receptor agonist

103 Names for Radicals and Groups

Some substances for which may be of complex composi­ and groups have been de­ a proposed international non­ tion and it is then inconvenient vised or selected, and they are proprietary name has been to refer to them in systematic suggested for use with the established may be used in chemical nomenclature. Con­ proposed international non­ the form of salts or esters. The sequently, shorter nonpropri­ proprietary names. radicals or groups involved etary names for some radicals

butepras butyrate propionate buteprate

crobefas (±)-(E)-6-hydroxy-4'-rnethoxy-3-(p-rriethoxybenzylidene)flavanone, crobefate phosphate, ion(2-) C24H19O8 P

farnesilum (2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrienyl

farnesil C15H25

104 AMENDMENTS TO PREVIOUS LISTS

WHO Chronicle, Vol. 36, No. 5, 1982 Proposed International Nonproprietary Names (Prop. INN): List 48

p. 13 delete insert loxtidinum lavoltidinum loxtidine lavoltidine

WHO Chronicle Vol. 37, No. 5, 1983 Proposed International Nonproprietary Names (Prop. INN): List 50 p. 17 levocabastinum replace the chemical name and the graphical formula by: levocabastine (-)-(3S,4R)-1-[cis-4-cyano-4-(p-fluorophenyl)cyclohexyl]-3-methyl-4- phenylisonipecotic acid

WHO Drug Information Vol. 1, No. 3, 1987 Proposed International Nonproprietary Names (Prop. INN): List 58 p. 186 pemedolacum replace the chemical name, the CAS registry number and the graphic formula pemedolac by the following: (±)-cis-4-benzyl-1-ethy 1-1,3,4,9-tetrahydropyrano[3,4-b]indole-1 -acetic acid 114716-16-4

WHO Drug Information Vol. 2, No. 4, 1988 Proposed International Nonproprietary Names (Prop. INN): List 60 p. 4 delete insert mequitazii iodidum mequitamii iodidum mequitazium iodide mequitamium iodide p. 6 cefprozilum replace the chemical name and the graphical formula by the following: cefprozil (6R,7R)-7-[ (R)-2-amino-2-(p-hydroxyphenyl)acetamido]-8-oxo-3-propenyl-5- thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

105 Annex 1 PROCEDURE FOR THE SELECTION OF RECOMMENDED INTERNATIONAL NONPROPRIETARY NAMES FOR PHARMACEUTICAL SUBSTANCES*

The following procedure shall be B. Such notice shall: 6. Where there is a formal objection followed by the World Health Organ­ (i) set forth the name under con­ under article 5, the World Health Or­ ization in the selection of recom­ sideration; ganization may either reconsider the mended international nonproprietary (ii) identify the person who sub­ proposed name or use its good names for pharmaceutical substan­ mitted a proposal for naming offices to attempt to obtain with­ ces, in accordance with the the substance, if so requested drawal of the objection. Without preju­ World Health Assembly resolution by such person; dice to the consideration by the WHA3.11: (iii) identify the substance for World Health Organization of a sub¬ stitut name or names, a name shall 1. Proposals for recommended inter­ which a name is being consid­ ered; not be selected by the World Health national nonproprietary names shall Organization as a recommended in­ (iv) set forth the time within which be submitted to the World Health Or­ ternational nonproprietary name while comments and objections will ganization on the form provided there exists a formal objection thereto be received and the person and therefor. filed under article 5 which has not place to whom they should be been withdrawn. 2. Such proposals shall be submitted directed; by the Director-General of the World (v) state the authority under which 7. Where no objection has been filed Health Organization to the members the World Health Organization under article 5, or all objections previ­ of the Expert Advisory Panel on the is acting and refer to these ously filed have been withdrawn, the International Pharmacopoeia and rules of procedure. Director-General of the World Health Pharmaceutical Preparations desig­ Organization shall give notice in ac­ nated for this purpose, for considera­ C. In forwarding the notice, the Di­ cordance with subsection A of article 3 tion in accordance with the "General rector-General of the World Health that the name has been selected by principles for guidance in devising In­ Organization shall request that Mem­ the World Health Organization as a re­ ternational Nonproprietary Names", ber States take such steps as are ne­ commended international nonpro­ appended to this procedure. The cessary to prevent the acquisition of prietary name. name used by the person discovering proprietary rights in the proposed name during the period it is under 8. In forwarding a recommended in­ or first developing and marketing a ternational nonproprietary name to pharmaceutical substance shall be consideration by the World Health Or­ ganization. Member States under article 7, the accepted, unless there are compelling Director-General of the World Health reasons to the contrary. 4. Comments on the proposed name Organization shall: may be forwarded by any person to 3. Subsequent to the examination the World Health Organization within A. request that it be recognized as provided for in article 2, the Director- four months of the date of publica­ the nonproprietary name for the sub­ General of the World Health Organ­ tion, under article 3, of the name in stance; and ization shall give notice that a pro­ the Chronicle of the World Health Or­ B. request that Member States posed international nonproprietary ganization. 1 take such steps as are necessary to name is being considered. prevent the acquisition of proprietary A. Such notice shall be given by 5. A formal objection to a proposed rights in the name, including prohibit­ publication in the Chronicle of the name may be filed by any interested ing registration of the name as a World Health Organization1 and by person within four months of the date trade-mark or trade-name. of publication, under article 3, of the letter to Member States and to na­ name in the Chronicle of the World tional pharmacopoeia commissions or Health Organization.1 * Text adopted by the Executive Board of WHO other bodies designated by Member in resolution EB15.R7 (Off. Rec. Wld Hlth Org., 1955, 60, 3) and amended by the Board in resolu­ States. A. Such objection shall: tion EB43.R9 (Off. Rec. Wld Hlth Org., 1969. 173. (i) Notice may also be sent to spe­ (i) identify the person objecting; 10). cific persons known to be con­ (ii) state his interest in the name; 1 The title of this publication was change WHO Chronicle in January 1959. From 1987 cerned with a name under con­ (iii) set forth the reasons for his ob­ wards lists of INNs are published in WHO Drug sideration. jection to the name proposed. Information.

GENERAL PRINCIPLES FOR GUIDANCE IN DEVISING INTERNATIONAL NONPROPRIETARY NAMES FOR PHARMACEUTICAL SUBSTANCES 1. International Nonproprietary Names pathological or therapeutic sugges­ 4. In devising INN for acids, one-word (INN) should be distinctive in sound tion should be avoided. names are preferred; their salts and spelling. They should not be in­ should be named without modifying These primary principles are to be conveniently long and should not be the acid name, e.g. "oxacillin" and implemented by using the following liable to confusion with names in "oxacillin sodium", "ibufenac" and secondary principles common use. "ibufenac sodium". 2. The INN for a substance belonging 3. In devising the INN of the first sub­ to a group of pharmacologically re­ stance in a new pharmacological 5. INN for substances which are used lated substances should, where ap­ group, consideration should be given as salts should in general apply to the propriate, show this relationship. to the possibility of devising suitable active base or the active acid. Names Names that are likely to convey to a INN for related substances, belonging for different salts or esters of the patient an anatomical, physiological, to the new group. same active substance should differ

106 only in respect of the name of the in­ used instead of "ph", "t" instead of 9. Group relationship in INN (see active acid or the inactive base. "th", "e" instead of "ae" or "oe", and Guiding Principle 2) should if possible For quaternary ammonium sub­ "i" instead of "y"; the use of the let­ be shown by using a common stem. stances, the cation and anion should ters "h" and "k" should be avoided. The following list contains examples be named appropriately as separate of stems for groups of substances, components of a quaternary sub­ 8. Provided that the names suggested particularly for new groups. There stance and not in the amine-salt style. are in accordance with these princi­ are many other stems in active use.1 ples, names proposed by the person Where a stem is shown without any 6. The use of an isolated letter or discovering or first developing and hyphens it may be used anywhere in number should be avoided; hyphen­ marketing a pharmaceutical prepara­ the name. ated construction is also undesirable. tion, or names already officially in use 7. To facilitate the translation and in any country, should receive prefer­ pronunciation of INN, "f" should be ential consideration.

Latin English -acum -ac anti-inflammatory agents of the ibufenac group -actidum -actide synthetic polypeptides with a corticotrophin-like action -adolum -adol analgesics -adol- -adol- stum -ast anti-asthmatic, anti-allergic substances not acting primarily as antihistaminics astinum -astine antihistaminics -azepamum -azepam substances of the diazepam group -bactamum -bactam β-lactamase inhibitors bol bol steroids, anabolic -buzonum -buzone anti-inflammatory analgesics of the phenylbutazone group -cain- -cain- antifibrillant substances with local anaesthetic activity -cainum -caine local anaesthetics cef- cef- antibiotics, derivatives of cefalosporanic acid -cillinum -cillin antibiotics, derivatives of 6-aminopenicillanic acid -conazolum -conazole systematic antifungal agents of the miconazole group cort cort corticosteroids, except those of the prednisolone group -dipinum -dipine calcium antagonists of the nifedipine group -fibratum -fibrate substances of the clofibrate group gest gest steroids, progestogens gli- gli- sulfonamide hypoglycemics io- io- iodine-containing contrast media -ium -ium quaternary ammonium compounds -metacinum -metacin anti-inflammatory substances of the indometacin group -mycinum -mycin antibiotics, produced by Streptomyces strains -nidazolum -nidazole antiprotozoal substances of the metronidazole group -ololum -olol β-adrenergic blocking agents -oxacinum -oxacin antibacterial agents of the nalidix acid group -pridum -pride sulpiride derivatives -pril(at)um pril(at) angiotensin-converting enzyme inhibitors -profenum -profen anti-inflammatory substances of the ibuprofen group prost prost prostaglandins elinum -relin hypophyseal hormone release-stimulating peptides terolum -terol bronchodilators, phenethylamine derivates -tidinum -tidine H2-receptor antagonists -trexatum -trexate folic acid antagonists -verinum -verine spasmolytics with a papaverine-like action vin- vin- -vin- -vin- vinca type alkaloids

1 A more extensive listing of stems is contained in the working document Pharm S/Nom 15 which is regularly updated and can be requested from Pharmaceuti­ cals, WHO, Geneva.

107 Annex 2 NONPROPRIETARY NAMES FOR PHARMACEUTICAL SUBSTANCES: TWENTIETH REPORT OF THE WHO EXPERT COMMITTEE

In its twentieth report1 the WHO Ex­ reported is the intention to change guidance for devising, international pert Committee on Nonproprietary the practice with regard to the no­ nonproprietary names are reproduced Names for Pharmaceutical Sub­ menclature of individual members of in two annexes to the report. Other stances reviewed the general princi­ polymeric series. annexes give examples of interna­ ples for devising, and the procedures Other sections of the report con­ tional nonproprietary names that in­ for selecting, international nonpro­ cern instructions to be followed by corporate selected stems, the most prietary names (INN) in the light of bodies making application for inter­ frequently used initial groups of let­ developments in pharmaceutical national nonproprietary names, the ters in international nonproprietary compounds in recent years. The most availability of computer-printed cu­ names, a historical review of the pro­ significant recent change has been mulative lists of international nonpro­ gramme of selecting international the extension to the naming of syn­ prietary names, information supplied nonproprietary names, some useful thetic chemical substances of the by WHO Member States concerning literature references, and a model of practice previously used for sub­ their official use of national or inter­ the form to be used in all applica­ stances originating in or derived from national names for pharmaceutical tions for international nonproprietary natural products. This practice in­ products, and proposals relative to names. volves employing a characteristic the withdrawal of international non­ "stem" indicative of a common prop­ proprietary names allocated to sub­ erty of the members of a group. The stances that are no longer in use. 1 WHO Technical Report Series, No. 581, 1975 (Nonproprietary Names for Pharmaceutical Sub­ reasons for, and the implications of, The official texts relating to the pro­ stances. Twentieth Report of the WHO Expe the change are fully discussed. Also cedures for selecting, and general Committee), ISBN 92 4 120581 4. Price: Sw. fr. 6.

108