WHO DRUG INFORMATION

VOLUME 1 • NUMBER 2 • 1987

PROPOSED INN LIST 57 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 wide audience of health profes­ Annual subscription: Sw.fr. 40.— sionals and policy-makers con­ Price per copy: Sw.fr. 15.—

World Health Organization 1987 Publications of the World Health Organization Authors alone are responsible for views expressed enjoy copyright protection in accordance with in signed contributions. 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 Vol.1, No.2,1987 World Health Organization, Geneva

WHO Drug Information

Contents Pharmacovigilance: a decentralized system 55 Pharmacopoeias, compendia and General Policy Topics texts of GMPs 55 Trademarks versus generic names for Chemical analysis unnecessary pharmaceuticals 39 for most drugs 55 Pharmacists' role in infection control 55 Points of view Research on new drugs involving New trends in drug evaluation in Italy 41 human subjects 56 Bleeding and antibiotic treatment 56 Reports on Individual Drugs Blood disorders associated with pirenzepine 56 Ivermectin in onchocerciasis 43 Intravaginal dinoprostone for induction of labour at term 56 General Information Tardive dyskinesia in antipsychotic therapy 57 Continuous cell lines in the Ibuprofen and aspirin safe in over- production of biologicals 46 the-counter use 57 Focus on interferons 46 "Congesting" nasal decongestants 57 Community pharmaceutical services Electrical stimulation devices to treat in Nigeria: towards self-reliance 47 scoliosis 58 Drugs and alternative medicine 47 Sugar in oral liquid medicines 58 Herbal medicines: safe and effective? 48 Drug interference in thyroid testing 58 Continuous subcutaneous insulin infusion 48 Cardiac pacemaker registry 58 A new focus on pharmaceuticals 49 Oxybutynin prescribing "unusually high" 58 New recommended schedule for active Benzodiazepine dependence 59 immunization of infants and children 49 Amitriptyline in diabetic neuropathy 60 Immunization programmes: inappropriate A review of clinical risks 60 application of contraindications 50 Barbiturate anaesthetics and termination Transmission of hepatitis B with jet gun of pregnancy 60 injections 50 Nicardipine, a new calcium antagonist 60 Screening for non-A, non-B Biotechnology patents for pharmaceuticals 60 hepatitis 50 Standardization of rabies immunoglobulin 61 The evaluation of teratogenicity of World Federation of Associations of chemical substances 51 Clinical Toxicology Centres and Definition of a teratogen 51 Poison Control Centres 61 Fetal abnormalities and use of drugs during pregnancy 52 Update on AIDS Reporting congenital malformations 52 Prospects for vaccines ang antiviral therapy 62 Post-marketing surveillance and Zidovudine 72 medical databases 52 Keeping the AIDS virus out of blood supplies 65 3rd International Conference on AIDS: condoms on prgscription? 65 Pharmacoepidemiology 53 Safety of factor VIIK and IX concentrates 65 Drug abuse in the Americas and the Autologous blood transfusion 65 Caribbean 53 Zidovudine avcilable under AIDS Draft guidelines for the investigation treatment resecrch protocol 66 of bioavailability 54 AIDS, condoms and spermicides 66 Research on healthy volunteers 55 (continued) WHO Drug Information Vol. 1, No. 2 1987

Contents (continued)

Pharmaceutical Products Approved Advisory Notices Benzodiazepine antagonist 67 Pregnancy warnings in data sheets 80 Diagnostic assay for hepatitis delta agent 67 Clinical evaluation of non-steroidal Biotechnology: a new hepatitis B vaccine 67 anti-inflammatory drugs 80 Other products approved 68 Allergen extracts and anaphylaxis 80 Adverse effects of anti-infective drugs 81 Reports from Regulatory Agencies Anabolic steroids and athletic performance 82 Aminophenazone, Anticholinergic drugs, Barbiturates, Bepridil, Bucetin, Essential Drugs Bupivacaine 69 "River blindness" affects 18 million people 83 Captopril, Carbamazepine, Flunitrazepam Diethylcarbamazine 83 Hydrocortisone (topical preparations), Suramin sodium 85 Mefloquine 70 Accelerated stability studies under Mianserin, Metformin, Nifedipine simulated tropical conditions 86 Paracetamol 71 Sensitivity of Plasmodium falciparum to Phenacetin, Spironolactone, Sulpiride, quinine and mefloquine in Thailand 87 Tartrazine, Other decisions 72 Nigeria adopts an essential drugs list 87 Sudan's new drug policy and essential Regulatory Matters drugs list 88 The future of regulatory affairs in Europe 73 Pharmaceuticals in the European Community 73 Recent Publications Controlled studies not essential for Essential malariology 89 "home medicines" 74 Treatment of cardiac tachyarrhythmias 89 Exports of unapproved drugs: Medicinal products for use in self-medication 89 new legislation 74 Drugs in hospitals 90 Carcinogenicity studies 75 Pharmaceutical regulation in Italy 90 Mutual recognition of toxicological data 76 A handbook of pharmaceutical excipients 90 Good Laboratory Practices 76 Drug information for the health care provider 90 Proprietary medicinal products—Nordic Pharmaceutical administration in Japan 90 guidelines for evaluation reports 76 Treatment of sexually transmitted disease 91 Over-the-counter drug (OTC) review 76 Cancer pain relief 91 Good Manufacturing Practices for Human experimentation: legal and ethical medical devices 77 aspects 91 Sterility testing of parenteral drugs 77 Drug consumption in Norway 91 Mutual recognition of inspection certificates 77 Drug information bulletin from Chile 92 Approved veterinary drugs 77 A magazine from the German Labelling and advertising of new Democratic Republic 92 animal drugs 78 An international society of editors of Generic drugs for animals 78 drug bulletins 92 Product liability and its implications for the practice of pharmacy and medicine 78 Proposed International Nonproprietary Drug Regulatory Index 79 Names: List 57 93 WHO Drug Information Vol. 1, No.2,1987

General Policy Topics

Trademarks versus generic aids) such as solvents, preservatives, tablet coat­ ings and capsule shells that determine the stability names for pharmaceuticals of the product and its time-course of action in the patient. A conflict that requires resolution Preparations containing the same drug substance Generic Names are frequently sold under different trademarks in different countries, and even within the same coun­ Generic, nonproprietary or common names are try. The Pharmaceutical Trademark Directory selected by national or international nomenclature shows that in 1985 some 60,000 trademarks for committees to designate pharmacologically active drug products were in use in a total of only 36 coun­ drug substances. As a matter of definition, they tries. cannot be owned by a private party. They are a form of public property which anyone is free to use. Protection of Generic Names

The international nonproprietary names (INNs) The INN nomenclature is based on the use of com­ designated and recommended by WHO offer a mon stems for substances that are chemically or means of identifying each drug substance by a pharmacologically related. Thus each name indi­ unique, globally applicable and accepted generic cates the chemical or pharmacological genus to name (1). This is of critical importance in facilitating which the substance belongs. For example: and rationalizing communication in medical science as well as in the labelling and advertising of medici­ • ß-adrenoreceptor-bbcking agents are identified nal products. Since 1953 some 5,500 INNs have by the suffix -olol (pindolol, propranolol, timolol, been selected. These are first published in the form etc.) of proposals to enable comments and objections to be made during a fixed consultative period. • penicillins end with the suffix -cillin (ampicillin, Proposed names become definitive only in the cloxacillin, etc.) absence of valid objections. A general requirement for both trademarks and Trademarks INNs is that they should be distinctive in sound and spelling, succinct, and readily distinguishable from Trademarks, which are particularly well established other names in common use. However, trademarks, within the pharmaceutical industry, are often unlike INNs, are not required to connote a particular devised by owners to identify their products. They class of products. constitute a form of private property and, once registered in a national trademark office, they may In order to avoid potential conflicts between names be used only with the consent of the owner. the Procedure for the Selection of INNs (2) includes provision for companies to object to proposed Companies adopt trademarks for finished pharma­ names that are either identical or similar to regis­ ceutical products (complete dosage forms such as tered trademarks. INNs are less well protected in tablets, ointments and injections) but not for drug that, formally, trademarks can be refused only if substances. The latter are identifiable only as the they are identical to existing INNs. However, many pharmacologically active ingredients within a companies as well as regulatory authorities now dosage form, which almost invariably contains a accept that a need exists for a broader protective number of other ingredients (or pharmaceutical mandate. General Policy Topics WHO Drug Information Vol. 1, No.2,1987

The potential for conflict rather than product trademarks to establish "brand image". Protection of INNs could be better assured by in­ cluding them in—or associating them with—trade­ A label that identifies a product only by its INN and mark registries. Any proposed trademark would the name of the manufacturer provides an un­ then invariably be checked for potential conflict not ambiguous message to the prescriber. Moreover, in only with other trademarks but also with INNs. clearly distinguishing between products of com­ peting companies, it serves not only a commercial Before the INN system was introduced in the early function but also, on occasion, a therapeutic 1950's stems like -caine and -mycin were com­ purpose. monly incorporated into trademarks. However, perpetuation of this practice now seriously en­ This arises because two apparently interchange­ dangers the systematic selection of new INNs. able products, both of which meet relevant pharma- Great advantage could accrue if manufacturers copoeial specifications, may differ in other charac­ took the initiative to refrain from using INN stems in teristics such as stability and bioavailability. This trademarks. This, and other relevant proposals are can be particularly important in products admin­ contained in a draft Code of Practice for Pharma­ istered for serous conditions and for prolonged ceutical Trademarks that has recently been drawn periods. Some national regulatory authorities, in­ up by the British Pharmacopoeia Secretariat in col­ cluding the Food and Drug Administration of the laboration with the United Kingdom Licensing Au­ United States of America (4), now direct consider­ thority (3). This has now been circulated as a con­ able effort to assuring the therapeutic equival­ sultative document to the Association of the British ence—or interchangeabilrty—of approved generic Pharmaceutical Industry, the Pharmaceutical Soci­ drug products. Unless such guarantees can be ety of Great Britain and other interested parties. offered, consistency of response is better assured The ensuing debate could well stimulate reappraisal in conditions such as diabetes and epilepsy if un­ of the issue in a broader international context. necessary interchange of products from different sources is avoided. "Brand loyalty" can thus some­ New Trends times operate to the advantage of the consumer as well as of the manufacturer. However, its cultivation For many years drug products listed in official is not necessarily dependent upon the generation pharmacopoeias such as quinine tablets, theo­ of a confusing proliferation of registered phylline tablets and epinephrine injections were de­ trademarks. scribed exclusively by their generic names. More recently, however, commercial manufacturers of References generic drugs have sought to distinguish their own 1. Wehrli, A., Pharmaceuticals: Trademarks versus products from those of their competitors by the use generic names, Trademark World, December 1986, of trademarks. In many instances these trade­ pp. 31-33. marks are clearly derived from INNs. This practice 2. Procedure for the selection of recommended inter­ disputes the very principle that INNs are public national nonproprietary names for pharmaceutical property; it can frustrate the rational selection of substances. Text adopted by the Executive Board of further INNs for related substances and, should it WHO in resolution EB 15.R7 (Off. Pec. WldHlth Org., continue, will ultimately compromise the safety of 1955,60:3) and amended by the Board in resolution EB patients by promoting confusion in drug nomencla­ 43.R9 (Off. Rec. Wld. Hlth Org., 1969,173:10). Published with each publication of the proposed INN list. ture and drug prescribing. 3. Pharmaceutical trademarks: a code of practice for pharmaceutical trademarks. Trademark World, December These concerns would be resolved immediately if, 1986, p.34. in competitively promoting products no longer pro­ 4. Approved drug products with therapeutic equivalence tected by patents, generic manufacturers were to evaluations. 7th edition, US Department of Health and rely on the registered name of their company, Human Services, 1987. WHO Drug Information Vol. 1, No.2,1987

Points of View

New trends in drug The Italian Ministry of Health has recently modified its procedures for evaluating a new product in order evaluation in Italy to focus particular attention on any specific therapeutic advantages that it may offer and its by Duilio Poggiolini, Director-General, suitability for the proposed indications. To this end Pharmaceutical Department, each application for marketing a new product is now Ministry of Health, Rome, Italy subjected to a preliminary review in order to deter­ mine whether it meets such requirements. In order The directives of the European Communities (EEC) to facilitate the task of the authorities in evaluating require that an application to market a pharma­ the dossier, and to enable applications to be pro­ ceutical product should include reports by experts cessed more rapidly, it is most important that the on the supporting pharmaceutical, pharmaco¬ protocols should conform, in format, with the rele­ toxicobgical and clinical evidence. vant EEC guidelines.

These reports are intended to provide a brief but To expedite this preliminary review, the applicant is comprehensive description both of the tests per­ required to correlate the chemical structure of each formed to establish the quality of the product and of active substance with that of analogous sub­ the various investigations performed on animals stances in use and to provide details of its route of and human subjects. The experts are also required synthesis. Similarly, the pharmacological, toxi¬ to provide a critical commentary on the characteris­ cological and clinical data must be compared with tics of the product and, in particular, to provide a data on existing products in the same category and clear understanding of the properties of the active any differences in the pharmaceutical, biological or substances, the proposed methods of quality therapeutic properties must be described. Any control, the efficacy and safety of the product, and claimed therapeutic advantages of a new chemical any advantages or shortcomings associated with entity or of a new dosage form must thus be sup­ its use. ported by documented evidence.

The Notice to Applicants published by the EEC in The introduction of these requirements raises the 1986 (1) emphasizes that each request for a mar­ long-standing problem of how the comparator keting authorization must include a justification for "reference drugs" should be chosen. The rules of the use of the product, particularly in the case of the European Communities first introduced the fixed combinations and new pharmaceutical forms. concept of comparative evaluation as long ago as In fact, the main purpose of the clinical documen­ 1975: directive 75/318 includes a provision to relate tation is to compare the therapeutic efficacy of the "the therapeutic effect of a new product with that of new product with that of existing alternative thera­ an established medicinal product of proven pies. The expert thus has a responsibility to state therapeutic value" in the course of clinical trials (2). in his report whether the product is likely to be more Indeed, such comparisons are already contained in or less efficacious and/or to produce more or less many experts' reports. adverse effects than other drugs within the same therapeutic category. If the new product appears to It is important to stress that the new requirements have no advantages over existing products—or to do not mean that a "need clause" has been intro­ involve more risks—it is evident that its use may be duced in Italy. The concept of the "need clause" difficult to justify. has been rejected by the Commission of the Points of View WHO Drug Information Vol. 1, No.2,1987

European Communities (3). Italy has no intention References either to introduce it or to demand evidence that 1. Notice to applicants for marketing authorizations for new products constitute "true innovations". proprietary medicinal products in the Member States of the European Communities on the use of the multistate It is accepted, however, that a critical evaluation of procedure created by the Council Directive 83/570/EEC. the data submitted to support the marketing appli­ Luxembourg, Office for Official Publications of the cation of a new product should securely establish European Communities, 1986. its place in therapy, and that this should be clearly 2. The rules governing medicaments in the European and objectively stated in the approved information Communities. Council Directive of 20 May 1975 sheet (data sheet or package insert). This require­ (75/318/EEC), p.26. Luxembourg, Office for Official Publi­ ment is essential both in order to provide clear in­ cations of the European Communities, 1978. formation to potential users on the product's char­ acteristics and to prevent unsupported or exagger­ 3. Application for criteria of need to pharmaceuticals. Written question No. 170/86 by Mr John Iverson (COM-DK) ated promotional claims. It may also be expected to to the Commission of the European Communities, 21 April discourage applications to market products that 1986. Official Journal of the European Communities, lack any element of innovation. No. C 306/20; 1 December 1986. WHO Drug Information Vol. 1, No.2,1987

Reports on Individual Drugs

Ivermectin in onchocerciasis mycete Streptomyces avermitilis isolated from soil samples in Japan (2), acts by disrupting central neurosynaptic transmission mediated by gamma- For many years diethylcarbamazine and suramin aminobutyric acid (3-5). It is well tolerated in mam­ have been the only drugs that have offered any malian experimental animals, provided it is ex­ possibility of arresting the progress of onchocer­ cluded from penetrating the central nervous system ciasis, or river blindness. However, their toxicity by an effective blood-brain barrier (6), but it is lethal and the need for medical supervision of the in single low-dose exposure to a variety of nema­ required multidose regimens renders them tode and arthropod parasites. However, it has not unsuitable for mass chemotherapy (see p. 83). thus far shown useful activity against trematode or cestode worms. Control of the blackfly has thus far provided the only means of reducing the prevalence of the Its potential in the treatment of human oncho­ disease in the areas of most intense transmission. cerciasis was suggested by its potent micro¬ The World Health Organization, through its filaricidal action in analogous diseases in horses Onchocerciasis Control Programme, has and cattle (7-9). Several studies have since been maintained an extensive spraying campaign within undertaken to demonstrate the efficacy of the com­ the countries of the Volta River Basin in West pound as a microfilaricidal agent in man (10-23). Africa since 1974. It is estimated that this has These include preliminary dose-ranging studies and reduced the attack rate by some 80%. However, subsequent double-blind trials in which ivermectin effective larviciding programmes are impractical in was compared with diethylcarbamazine and other habitats in which the disease is endemic. placebo. Collectively, they have involved the Even in the Volta Basin continual invasion by flies administration of ivermectin to more than 1200 adult from outside the area and the emergence of patients with onchocerciasis of varying severity. insecticide-resistant strains have rendered it The results have been impressively consistent. necessary to extend the treated areas and to They demonstrate that ivermectin in a single oral introduce new insecticides (1). dose of 150 µg/kgrapidl y depresses the dermal microfilarial density to a very low level which is main­ It has thus long been recognized that the existing tained for over 12 months and that this is accom­ benefits can be maintained only if more effective panied by a slow clearing of microfilariae from the drugs can be developed; and three research-based anterior chamber of the eye. Histological studies of pharmaceutical companies which have responded adult female worms suggest that this effect results, to this challenge are currently assessing candidate at least in part, from impairment of the normal compounds. One of these, ivermectin (Merck, intrauterine development of the microfilariae and Sharp & Dohme), has already been submitted to inhibition of their release from the uterus (14,15). extensive clinical evaluation in West Africa within a developmental programme involving the The therapeutic effect is thus more prolonged than collaboration of WHO and the competent that of diethylcarbamazine and, presumably governmental authorities. The results, which are because its microfilaricidal action is less abrupt, its particularly encouraging, raise expectation that a use has thus far not been associated with severe preparation will become available for more systemic or ocular adverse reactions. Fever, pru­ extensive use within the near future. ritus, tenderness of lymph nodes and mild transient hypotension have been reported in some patients, Ivermectin, which is derived from one of several but these have generally been described as mild, macrocyclic lactones produced by an actino- and have rarely required steroid therapy. The Reports on Individual Drugs WHO Drug Information Vol. 1, No.2,1987

totality of the evidence consequently indicates that References a single annual oral dose of ivermectin of the order 1. WHO Independent Commission on the Long- Term of 100 µg/kg will be well tolerated by adult patients Prospects of the Onchocerciasis Control Programme. and will inhibit the symptoms of the disease and Final Report i-xi, 1-77. Geneva, World Health Organization preserve imperilled sight. There is even a possi­ (1981). bility, in view of its effects on the reproductive 2. Campbell, W. C. et al. Ivermectin: a potent new apparatus of the female worm, that multiple dosing antiparasitic agent. Science, 221:823-628 (1983). 3. Campbell, W. C. Ivermectin: An Update. Parasitology may result in a macrofilaricidal action. Hope also Today, 1:10-16(1985). exists that as a result of sustained depression of 4. Wang C. C. & Pon, S. S. Actions of avermectin B1a on the dermal microfilarial density, use of ivermectin GABA nerves. Progress in Clinical and Biological on a community scale will reduce the local intensity Research, 97:373-395 (1982). of transmission of the disease (24,25). 5. Terada, M. et al. Angiostrongylus cantonensis. Paralysis due to avermectin B1a and ivermectin. Experimental Parasitology, 57:149-157 (1984). There is, however, a particular and inevitable need 6. Pulliam, J. D. et al. Investigating ivermectin toxicity in for caution in proposing a new drug for community collies. Veterinary Medicine, 80:33-40 (1985). use. Careful surveillance of many more treated 7. Egarton, J. R. et al. The antiparasitic activity of patients will be required before unanticipated rare ivermectin in horses. Veterinary Parasitology, 8:83-88 reactions can be excluded with adequate confi­ (1981). dence, and plans for extensive post-marketing 8. Wei, T. R. et al. Efficacy of ivermectin (22, 23- surveillance are already in hand. Moreover, iver­ dihydroavermectin B1) against adult Setaria equina and mectin has been shown to be teratogenic on re­ microfilariae of Onchocerca cervicalis in ponies. Journal of Parasitology, 66:859-861 (1980). peated daily administration to mice at a dose some 9. Campbell, W. C. Efficacy of the avermectins against fivefold higher than the proposed single therapeutic filarial parasites: a short review. Veterinary Research dose. It is also toxic to suckling neonatal rats, Communications, 5:251-262 (1982). which unlike human neonates, do not possess a 10. Aziz, M.A. et al. Efficacy and tolerance of ivermectin highly developed blood-brain barrier at birth. Even if in human onchocerciasis. Lancet, 2:171-173 (1982). the potential for such toxicity exists in human 11. Aziz, M.A. et al. Ivermectin in onchocerciasis. beings, the therapeutic dose is likely to be well Lancet, 2:1456-1457(1982). below the threshold for its expression. None the 12. Coulaud, J. P. et al. Ivermectin in onchocerciasis. less, ivermectin should not, in the current state of Lancet, 2:526-527(1984). knowledge, be administered to pregnant or lac¬ 13. Awadzi, K. et al. Ivermectin in onchocerciasis. Lancet, 2:921(1984). tating women or to young children (26). This 14. Awadzi, K. et al. The chemotherapy of imposes an important constraint on the use of a onchocerciasis. An assessment of four single dose drug intended for community treatment and it treatment regimens of MK-933 (ivermectin) in human underscores the need for effective and prolonged onchocerciasis. Annals of Tropical Medicine and post-marketing surveillance. Parasitology, 79:63-78 (1985). 15. Schulz-Key, H. et al. Treatment of human onchocerciasis: the efficacy of ivermectin on the parasite. Despite this important reservation, ivermectin Tropical Medicine Parasitology, 36:20 (1985). remains a compound of outstanding promise. It is 16. Lariviere, M. et al. Double-blind study of ivermectin encouraging that Merck, Sharp & Dohme is and diethylcarbamazine in African onchocerciasis continuing to support investigation of its potential patients with ocular involvement. Lancet, 2:174-177 in other parasitic diseases. This has recently been (1985). rewarded by preliminary clinical findings that, in the 17. Dadzie, K. Y. et al. Ocularfindings i n a double-blind same dosage, it exerts a potent, but less prolonged study of ivermectin vs diethylcarbamazine vs placebo in the treatment of onchocerciasis. British Journal of microfilaricidal effect in bancroftian filariasis (27), a Ophthalmology, 71:78-85 (1987). disease that affects some 80 million people in 18. Greene, B. M. et al. Comparison of ivermectin and tropical and subtropical regions (28). diethylcarbamazine in the treatment of onchocerciasis. WHO Drug Information Vol. 1, No.2,1987 Reports on Individual Drugs

New England Journal of Medicine, 313:133-138(1985). 24. Cupp, E. W. et al. The effects of ivermectin and 19. Awadzi, K. et al. The chemotherapy of oncho­ diethylcarbamazine on the transmission of Onchocerca cerciasis. A double-blind comparative study of ivermectin, volvulus, the causative agent of "river blindness". diethylcarbamazine and placebo in human onchocerciasis Science, 231:740-742 (1986). in Northern Ghana. Annals of Tropical Medicine and 25. Bissan, Y. & Ranque, P. The effect of ivermectin (MK- Parasitology, 80:433-442 (1986). 933) on the transmission of Onchocerca volvulus by 20. Diallo, S. et al. A double-blind comparison of the Simulium sirbanum in the Sudan-Savannah zone of Mali. efficacy and safety of ivermectin and diethylcarbamazine Proceedings of the 10th Meeting of the WHO Scientific in a placebo-controlled study of Senegalese patients with Working Group on Filariasis. Bamako, Mali, November 5-9, onchocerciasis. Transactions of the Royal Society of 1984. Tropical Medicine & Hygiene, 80:927-934 (1986). 26. Aziz, M. A. Chemotherapeutic approach to control of 21. Taylor, H. R. et al. Treatment of onchocerciasis: onchocerciasis. Review of infectious diseases, 8:500-504 Comparison of the ocular effects of ivermectin and (1986).. diethylcarbamazine. Ophthalmology, 104:863-870 27. Diallo, S. et al. Dose-ranging study of ivermectin in (1986). treatment of filariasis due to Wuchereria bancrofti. Lancet, 22. Campbell, W. C. & Benz, G. W. Ivermectin: A review of 1:1030(1987). efficacy and safety. Journal of Veterinary Pharmacology 28. WHO Technical Report Series, No. 702,1984 and Therapeutics, 7:1-16 (1984). (Lymphatic filariasis: fourth report of the Expert 23. White, A. et al. Controlled trial and dose-finding study Committee). of ivermectin for treatment of onchocerciasis. Tropical Medicine and Parasitology, 47:96 (1986). WHO Drug Information Vol. 1, No.2,1987

General Information

Continuous cell lines (CCLs) cell banks that are assured of being in conformity in the production of with WHO requirements. biologicals Reference: Acceptability of cell substrates for pro­ duction of biologicals. Report of a WHO Study Group. Continuous cell lines (CCLs) are populations of WHO Technical Report Series, No. 747 (1987). cells, in some cases derived from tumour tissue, which possess the capacity to divide indefinitely in culture. They have assumed a new significance Focus on interferons with the recent application of recombinant DNA technology and hybridoma technology to the United States of America — A recent issue production of biological products since they of Developments in Oncology (1), which surveys provide the vehicles in which these substances are the current international literature, reviews current synthesized. understanding of the interferons.

There has been speculation that the transfer of Two papers are cited that show interferon alfa components of these abnormal cells may induces regression in AIDS-related Kaposi's constitute a health hazard to the recipients of sarcoma. The greatest effect was obtained with these products. A Study Group on Biologicals was high doses (up to 50 million IU per m2 daily). This thus convened in November 1986 to advise WHO effect is of interest primarily as an academic on: demonstration of antitumour activity rather than as a practical approach to the treatment of Kaposi's • the acceptability of developing generic biological sarcoma. Patients with AIDS rarely succumb to products in new cell systems when the same tumour progression since opportunistic infection is product is already being manufactured by an much more life-threatening. approved technology, and However, experience with interferon alfa in hairy • the degree of risk associated with certain classes cell leukaemia leaves no doubt that this action has of potential contaminants in the product, including impressive therapeutic potential. Response rates heterogeneous DNA, viruses, and transforming have averaged 90% in three large studies, and proteins. interferon alfa-2 has now been approved by the Food and Drug Administration for this single indica­ The Group concluded that, in general, CCLs are tion. The degree to which survival may be prolonged acceptable as substrates for the production of bio­ is not yet evident, but good control has been logical products, but that differences in the nature obtained in patients with progressive disease after of the derived products and the specifics of the splenectomy, the only palliative measure pre­ manufacturing process must always be taken into viously available. account in assessing the safety and acceptability of each product. The interferons no longer represent a mysterious black box labelled "biologic response modifiers". It It also recommended that WHO should establish a is now clear that the interferons are, in fact, cyto­ number of banks of CCL cell seeds to enable Mem­ toxic to tumour cells and, to a lesser extent, to ber States and manufacturers to create derivative normal haematopoietic tissues. It is also evident WHO Drug Information Vol. 1, No.2,1987 General Information

that the flu-like symptoms associated with adminis­ • It is proposed that consideration be given to tration of interferon are not due to impurities amending the Pharmacy Laws in order to reflect present in natural material of low specific contemporary realities, to provide a basis for activity. The same reactions occur when the highly instituting some of these proposals, and to offer an purified recombinant preparations are administered opportunity for integrating into the infrastructure of to patients with respiratory virus infections. They primary health care those aspects of traditional can be minimized, though not eliminated, by dose medicine that can be demonstrated to be reduction (2). efficacious.

References Reference: J. Adelusi-Adeluyi, Towards self-reliance in 1. Developments in Oncology, Volume II, No. 2, Advanced community pharmaceutical services in Nigeria. Pharmacy Therapeutic Communications, Inc, Secaucus, NJ 07094, World, 3:1821 (1986) USA. 2. Medical News and Perspectives. Journal of the American Medical Association, 256:1242 (1986). Drugs and alternative medicine Community pharmaceutical Alternative medicine was the topic of discussion at services in Nigeria: towards a symposium held during the 46th International self-reliance Congress of the International Pharmaceutical Federation, which was convened in Helsinki in Nigeria—A paper recently published in Phar­ September 1986. macy World outlines possible approaches to the development of community pharmaceutical • The Prevalence of Alternative Medicine: Dr Nils services in developing countries and calls on the 6stby (Stockholm) said that some 22% of the support of allied professional groups to enable the Swedish population aged 16-74 years have been community pharmacist to attain self sufficiency. treated by alternative therapies and that 57% of The case is argued that, if national primary health the remainder are positively disposed to such schemes are to attain their objectives, community methods of treatment. pharmacists must be trained and equipped to • Homoeopathy: Dr J.-P. Rhein (Switzerland) become a primary source of counselling and drug defined homoeopathic drugs as substances which, information for patients. when administered to a healthy subject, induce specific symptoms and, when administered to a • Particular emphasis is accorded to the disparities patient, heal the same symptoms. He emphasized created by the inequitable concentration of that, although recent developments in chemistry pharmacies within the large cities, and the need for and physics have allowed new hypotheses to be pharmaceutical services to be provided in the rural developed on the mechanisms of action of and peri-urban areas in support of primary health homoeopathic drugs, their exact role still needs care programmes. verification. • A plea is also made for upgrading the level of education of pharmacists; for ensuring that they • Phytotherapy: Dr Desmond Corrigan (Ireland) have rapid access to needed current information; emphasized that the use of mixtures of substances from more than one plant makes it difficult to for limiting unfair competition from unqualified assess the safety, efficacy and quality of these traders; and for assuring that pharmacies are products for regulatory purposes. Although many reliably supplied with stocks of essential drugs. phytopharmaceuticals have not yet been fully • Community pharmacists themselves, it is tested, scientific studies have shown others to be suggested, could do something to improve the effective. Similarly, although toxicity studies have situation if they were to come together in large units confirmed that a number of plants are innocuous, it for operative purposes. cannot be assumed, in the absence of adequate General Information WHO Drug Information Vol. 1, No.2,1987

evidence, that all plant medicines are harmless. Continuous subcutaneous Assurance must be provided that inherently toxic substances and components that might interact insulin infusion adversely with orthodox medicines have been excluded. He concluded that, whereas proponents Australia— Mechanical insulin delivery systems of phytotherapy can sometimes over-estimate the are discussed in the editorial columns of a recent medicinal properties of plants, sceptics can readily issue of the Australian Prescribes under-estimate them. Insulin Pumps—Devices that measure and res­ • Traditional Chinese Medicine:Prof. Ding Guang- pond to minute-by-minute fluctuations of the blood Sheng (Shanghai, China) described how a scientific glucose level have been developed for research approach to herbal pharmacology already has purposes. A commercial version (the Biostator, provided a wide variety of new therapeutic leads Miles Laboratories, U.S.A.) is now available for including: hospitalized patients but, because it is complex to • artemisinin for the treatment of malaria, use, it has only limited application outside research • indirubin for chronic granulocytic leukaemia, units. • biphenyl dimethyl dicarboxylate and for hepatitis, Systems for outpatient use— Continuous sub­ • gossypol as a male contraceptive agent, cutaneous infusions can be delivered by miniatur­ • trichosanthin and yuanhuacine as ized pumps connected by a catheter to a small abortifacients, needle inserted in the abdominal subcutaneous tis­ • changrolin as an anti-arrhythmic agent, sue. This system requires frequent self-monitoring • 10-hydroxycamptothecin as a antineoplastic of blood glucose. The pump is programmed to satis­ agent, and fy mean basal requirements (about 55% of the total • tetrandrine as a calcium channel blocking agent. daily supply) and boluses are given before meals. If the basal delivery rate is altered, a new plateau Reference: Fédération Internationale Pharmaceutique (F.I.P.), Newsletter, July 1986. blood insulin level is attained in 7-8 hours. Newer devices are smaller (down to a cigarette packet size) but more expensive.

Patient selection—Continuous subcutaneous Herbal medicines: insulin infusion is only recommended for patients safe and effective? who:

United Kingdom — The Drug and Therapeutics • have unsatisfactory control despite multiple con­ Bulletin of the Consumers' Association has ventional injections; published a commentary on the safety and efficacy • are reliable and motivated; of herbal medicines. It is estimated that in the • undertake regular and frequent self blood glucose United Kingdom about 1000 products derived from monitoring; a total of some 550 herbs are currently marketed • have participated in a formal diabetes education and therefore subject to review by the Committee programme; on the Review of Medicines. Many other herbal • will have access to expert advice at all times. remedies which are sold without claims of efficacy or therapeutic activity do not require product While these delivery systems offer important licences.It is stressed that naturally-occurring benefits, they also have disadvantages: herbal substances cannot be assumed to be safe in the absence of the appropriate scientific • needle site infection may occur if the needle evidence and a list of herbs with potentially toxic position is not changed daily; properties is presented. • needles may be dislodged from the skin; • batteries may run down; Reference: Herbal medicines - Safe and effective? Drug • if the infusion is inadvertently interrupted for more and Therapeutics Bulletin, 24:97-100 (1986). than 2 hours, ketosis may develop rapidly; WHO Drug Information Vol. 1, No.2,1987 General Information

• confused hypoglycaemic patients could make essential drugs but also an infrastructure capable inappropriate adjustments to the rate of infusion. of ensuring that the drugs are reliably delivered and safely administered to the patient. Whereas the if the use of insulin infusion devices is to become large majority of the drugs included in WHO's model widespread, they will need to become smaller, more list are out of patent and supplies are thus reliable and less expensive. The editorial empha­ frequently available from a number of competitive sizes that while the quality, safety and efficacy of sources, it is recognized that several drugs of new drugs imported to Australia are subjected to crucial importance in the treatment of infections review by the Commonwealth Department of Health, and vector-borne diseases such as rifampicin and no similar review is currently conducted on praziquantel remain prohibitively expensive for devices. most Third World purchasers.

Reference: Editorial. Continuous subcutaneous insulin The report recognizes that opportunities and infusion. Australian Prescriber,9:50-5 1 (1986). frustrations are inherent in collaborative ventures between developed and developing countries. Many of the difficulties are conceded to be beyond the control of the pharmaceutical industry, but the need for solutions is regarded as imperative. A new focus on Maintenance of a constructive dialogue between pharmaceuticals industry and the national and international bodies directly concerned is proposed as the most United Kingdom — A report issued by the effective way of defining and assessing the Pharmaceutical Economic Development Committee options. of the National Economic Development Office reviews the contribution of the pharmaceutical Reference: A New Focus on Pharmaceuticals, Pharma­ industry to the UK economy. An earlier report was ceuticals EDC, Her Majesty's Stationery Office, London, published in 1972. Information and data are November 1986. provided on the relationship between the industry and the State-supported health services, current concerns in research and development, and future perspectives. New recommended schedule A chapter on Medicines and the Third World for active immunization of reviews the size and the expected growth of the pharmaceutical market in developing countries as infants and children well as the potential contribution of new drugs in resolving health problems in these countries. In United States of America — Until recently, considering research relevant to Third World the recommended schedule for active immunization needs, the report emphasizes that many medicines of normal infants and children involved adminis­ needed for tropical diseases fall into the category tration of combined measles-mumps-rubella (MMR) of "orphan drugs" because the industry is not in a vaccine at 15 months and the subsequent adminis­ position to recoup research and development tration of both the fourth dose of diphtheria, tetanus costs. The WHO Special Programme for Tropical toxoid and pertussis vaccine (DTP) and the third Disease Research is identified as offering dose of oral poliovirus vaccine (OPV) at 18 months. challenging opportunities for joint ventures and disappointment is expressed that the programme is A large, randomized, double-blind trial has recently not supported by governments to the extent it been completed, and sufficient data are now avail­ deserves. able to establish the safety and efficacy of the simultaneous administration of MMR, DTP, and In its conclusions, the report points out that Third OPV to all children aged 15 months or older who are World countries require not only access to low-cost eligible to receive these vaccines. It is anticipated General Information WHO Drug Information Vol. 1, No.2,1987

that implementation of this new schedule will result Transmission of hepatitis B in: with jet-gun injections • a decrease in the number of visits required for immunization during the second year of life, United States of America — In March 1985, during the course of routine investigation of • an accompanying decrease in costs, and reported cases of hepatitis B, an epidemiologist at • an increase in the percentage of children who will Long Beach (California) Department of Public be fully or partially immunized by 24 months of age. Health noted that 3 of the patients had received jet- gun injections at the same weight-reduction clinic The complete recommended vaccination schedule shortly before the onset of disease; 31 additional for normal infants and children is now as follows: cases were subsequently found among individuals attending the clinic who had received similar injections.

2 months first DTP and OPV Reference: Weekly Epidemiological Record, 61:309 4 months second DTP and OPV (1986). 6 months third DTP 15 months MMR, fourth DTP and third OPV 24 months Polysaccharide vaccine for Haemophilus influenzaetype b 4-6 years fifth DTP and fourth OPV. Screening for non-A, non-B hepatitis Reference: Morbidity and Mortality Weekly Report, 35: 577-579(1986). United States of America—The American Association of Blood Banks has announced that its member organizations will be screening all donated blood for evidence of non-A, non-B hepatitis, which is now considered to represent a more serious health hazard than previously thought. Two Immunization programmes: different blood tests will be used to obtain an inappropriate application of indirect indication of the potential for a donor to contraindications? transmit this disease. One measures the level of alanine amino-transferase (ALT), commonly used In a WHO-sponsored review of national immuniza­ as an indicator of liver dysfunction. The other tion programmes, inappropriate application of con­ detects the presence of antibodies to hepatitis-B traindications was identified as a significant con­ core antigen (anti-HBc). High levels of donor ALT tributory factor to suboptimal immunization cover­ and the presence of anti-HBc both correlate with age. subsequent development of non-A, non-B hepatitis. The American Red Cross is also implementing ALT A comparison of the risks of adverse reactions testing at its blood banks. consequent upon immunization with the risks of complications following natural disease demon­ A major concern for blood centres will be the toss of strated that the decision to withhold the benefits of donors from false positives from the ALT and anti- immunization from an eligible child should never be HBc tests, and it is estimated that the tests will taken lightly. In particular, low-grade fever, mild increase the cost of a unit of blood by US$ 3. This respiratory infection, or diarrhoea should not be comes at a time when screening for antibodies to considered a contraindication to immunization. HIV has already had a marked negative impact on the blood supply. Reference: Weekly Epidemiological Record, 62:17 (1987). Reference: Nature, 323:7(1986). WHO Drug Information Vol. 1, No.2,1987 General Information

The evaluation of the Definition of a teratogen teratogenicity of chemical In a signed editorial published in Teratology Robert substances L Brent presents the case for claiming that terato¬ genesis, in contrast to carcinogenicity, is in most The Netherlands—A committee of the Health instances a threshold phenomenon. He points out Council has issued a comprehensive report on the that a "no effect" dose can be demonstrated even teratogenic potential of substances present in with thalidomide and that both the incidence and foods, the environment, the work place and in severity of malformations increase with the dose. medicines. Graduation of response is even more evident in the response to less-potent teratogens including It describes the established methods of investigat­ vitamin D, aspirin, insulin, vitamin A and meclozine. ing teratogenicity and discusses the relevance of data generated in animals for defining acceptable It is argued, therefore, that the classification of sub­ levels for human beings. The necessity for com­ stances into definite, probable, questionable and plementing these studies with subsequent unlikely teratogens must be made with reference to epidemiological studies is emphasized. anticipated exposure. As long as this remains below a critical threshold level, the risk of Although relatively few substances have been teratogenesis is not increased. The relative safety unequivocally demonstrated to be teratogenic in of a particular drug or chemical thus depends on the man, the report concludes that the totality of magnitude of the difference between the evidence derived from animal experiments, clinical teratogenic dose and the recommended therapeutic observations and epidemiological investigations dose or permitted chemical exposure. places a much larger number of substances under suspicion. These include some medicines, and a variety of occupational and environmental Teratogenic Carcinogenic and chemicals. changes mutagenic changes Threshold phenomena Stochastic phenomena The difficulty of establishing causal correlations is compounded because certain effects, including Caused by multicellular Caused by damage to one functional disturbances of the central nervous injury or more cells system, may only become apparent long after birth. Affect discrete cellular Affect cellular DNA or organ specific It is suggested that more consideration should be processes given to developing methods capable of detecting Result in malformations, Result in neoplasia damage occurring during gametogenesis and the growth retardation, death, Mutation pre-implantation stages and of demonstrating chemical toxicity, etc. impairment in functional behaviour. Risk disappears com­ Risk exists at all exposures, pletely below the although at low exposure, A chapter dealing with the predictive value of threshold dose the excess risk is less than experimental methods concludes that further the spontaneous risk fundamental research should be undertaken into Both the severity and Incidence of disease the apparent differences between man and other incidence of disease increases with exposure, species in their sensitivity to teratogenic increase with high but severity and nature of substances. exposure disease remain unchanged

Reference: Evaluation of the Teratogenicity of Chemical Substances, Health Council of the Netherlands Reference: Brent, R. L, Definition of a teratogen and (Gezondheidsraad) Report No. 1985/6, The Hague, The the relationship of teratogenicity and carcinogenicity. Netherlands. Teratology, 34:359-360 (1986). General Information WHO Drug Information Vol. 1, No.2,1987

Fetal abnormalities Reporting congenital and use of drugs malformations during pregnancy United States of America — Several improve­ United Kingdom—The extent to which drugs ments introduced in 1981 in the system of recording are responsible for fetal abnormalities remains congenital malformations on the birth certificates of uncertain, if only because some apparently newborns used by the Utah Valley Regional Medical unexplained anomalies may be the result of a Centre have now been demonstrated to be effec­ forgotten exposure. A recent prospective study in tive. They include: the UK indicates that about 10% of pregnant women are exposed to one or more drugs during the • transfer of responsibility for reporting congenital first trimester. Similarly, a survey in the United malformations from the mother's physician to the States of America has shown that about 45% of paediatrician; women use at least one prescription drug during pregnancy, and many more use over-the-counter • inclusion of a reporting sheet for congenital mal­ products. formations in each infant's file;

Defects are recorded in about 2% to 5% of babies • according responsibility for reviewing hospital at birth. Of these about 25% are regarded as medical records and for completing birth certifi­ genetic in origin and 65% have no known cause. cates to a specified person. Only 2% to 3% are suspected of being associated with drug treatment. None the less, it is recom­ Both the rate and accuracy of reporting have im­ mended that routine consideration be given to the proved since these measures were introduced and following points in the management of pregnant a scheme for classifying birth defects is now being women who have taken, or who are currently taking developed that is expected further to increase the drugs: utility of the system.

Reference: Minton, S. D. & Scegmiller, R.E. An • the precise time of exposure. The period of improved system for reporting congenital malformations. maximum teratogenic sensitivity, which occurs Journal of the American Medical Association, 256:2976- during the stage of embryonic development, 2979(1986). extends from 18 to 55 days after conception. During the fetal phase, from 56 days to term, the effects of drugs are usually limited to defects of growth and functional impairment rather than gross Post-marketing surveillance structural abnormalities; and medical databases • the exact nature of the drug, in order that the teratogenic risk can be assessed; United States of America — Post-marketing drug surveillance frequently requires collection of • the possibility of establishing a prenatal diagno­ data on unusually large sample sizes. In an article sis of a particular teratogenic event. The most in Trends in Pharmacological Sciences B. L. Strom effective method is high-resolution ultrasound of the University of Pennsylvania Medical School scanning. In optimal conditions this provides good reviews the types of medical database now being images of the fetal brain and spine, the heart, the established. arms, legs and hands, and the face. Traditionally, post-marketing surveillance has been Reference: Whittle, M. J. & Hanretty, K. P. Prescribing performed by physicians voluntarily reporting in pregnancy. Identifying abnormalities. British Medical cases of suspected adverse drug reactions either Journal, 293:1485-1486 (1986). to their national regulatory bodies, to pharmaceu- WHO Drug Information Vol. 1, No.2,1987 General Information

tical companies, or to medical journals. Although medical practitioners, health care administrators, this approach has undoubted value for generating the pharmaceutical industry and regulatory "signals"of possible adverse effects, it does not agencies on pharmacoepidemiological approaches provide information on the size of the total popula­ to studying the efficacy and safety of pharmaceu­ tion using the drug (the denominator). Furthermore, ticals. reporting can vary considerably, even of events associated with drugs of the same therapeutic Information on the conference is available from the class, sometimes as a function of how recently the Division of Epidemiology, School of Public Health, drug was marketed or how assiduous the manufac­ University of Minnesota, 611 Beacon St St. SE, turer has been in soliciting reports. Minneapolis, MN 55455, USA.

Large-scale "cohort" studies are conducted by some pharmaceutical companies. Typically, a com­ pany's sales force is asked to recruit 2,000 co­ Drug abuse in the Americas operative physicians, each of whom is then asked and the Caribbean to report on the experience of five patients who have received the drug. This approach, despite its Cocaine cost which may be well over a million dollars, is subject to bias both in the mechanism of recruit­ Coca leaf chewing has traditionally been accepted ment and because it provides no control group for incultures of the Andean highlands of South comparison. America, very much like the use of alcohol or tobacco elsewhere. Recently, however, this In an attempt to address some of the deficiencies traditional custom has given rise to serous cocaine of existing systems in a cost-effective way, inves­ abuse in urban settings elsewhere. The leaves of tigators have begun to use existing medical data­ the coca bush (Erythroxylon coca), which is grown bases compiled for other purposes. Among these mainly in Peru and Bolivia, are processed to yield are a number of computerized collections of cocaine hydrochloride which is largely smuggled to medical billing data used by private health care North America and Europe. organizations. However, whereas these databases provide some relevant information on large num­ A different variety of coca grown in Colombia is bers of subjects quickly and inexpensively they commonly prepared as a sulfate salt in the form of cannot be expected to provide all the data ideally basuco. its greater rate of absorption when sniffed required within the context of the planned study. (90-95%) makes this a more dangerous substance than the hydrochloride. Reference: Strom, B. L. Medical databases in post­ marketing drug surveillance. Trends in Pharmacological Several recent reports indicate that simply chewing Sciences, 7:377-380 (1986). the coca leaf can cause permanent functional brain damage resulting in a cognitive deficit. In Bolivia and Peru epidemiological research has distin­ guished between the direct toxic effects of coca 3rd International paste and the secondary effects of malnutrition. A Conference on clear-cut anorectic effect produces an extreme de­ Pharmacoepidemiology gree of malnutrition in chronic users of cocaine sul­ fate which is often exacerbated by abuse of alcohol United States of America — An International and other drugs. Conference "Contributions of Pharmaco­ epidemiology to Public Heatth"will be held from 9 to ft is frequently reported from South America that 11 September 1987 in Minneapolis. The purpose of abuse of coca and its derivatives is increasing, but the conference is to provide a forum for an there are no general population surveys to confirm exchange of views between academic researchers, this impression. General Information WHO Drug Information Vol. 1, No.2,1987

Cannabis people, and by women rather than by men. In most Latin American countries benzodiazepines are The drug now most commonly abused in the among the leading compounds produced by phar­ Americas is cannabis which is usually smoked as maceutical companies. marihuana. This practice was uncommon until the 1950s, but it reached epidemic proportions in the Solvent inhalation United States by the 1960s, when it was adopted as a symbol of rebellion against the establishment In the last decade, the sniffing of glue and other by the hippie counterculture. Rates of increase in volatile solvents has increased throughout large Latin America and the Caribbean are not as high as cities, especially among younger children within the those in Canada and the United States, but they lower socioeconomic strata. are important enough to be of concern in almost all countries throughout the region. References 1. Weekly Epidemiological Record. 62:366-367 (1986). It is now evident that chronic heavy use induces 2. Weekly Epidemiological Record. 62:373-375 (1986). both psychological dependence and tolerance, but these disturbances rapidly regress when the drug is withdrawn. However, there have been reports of brain damage, and particularly of residual cognitive Draft guidelines for the deficit. Cannabis can also trigger different kinds of psychiatric disorders. The totality of the evidence investigation of now available establishes marihuana as a bioavailability dangerous substance. It is certainly not as innocuous as it was assumed in the heyday of its The scientific principles underlying the study of bio­ popularity. availability were first published by WHO in 1974 (1). More recently these principles have been Although Colombia still seems to be the main reformulated by many national and international supplier in the region, Jamaica has also become an bodies including the Commision of the European important production centre of high-potency Communities (2). cannabis which is illicitly cultivated on a com­ mercial basis. There is no firm epidemiological To complement this information, the WHO Regional evidence on the extent and trend of marihuana use Office for Europe is preparing guidelines for the in Latin America and the Caribbean. Nevertheless, investigation of bioavailability intended for clinical many countries have launched primary prevention and pharmacological investigators carrying out campaigns, some of which, as in Mexico and biopharmaceutical studies (3). The draft will be Venezuela, are nationally directed. submitted for consultation to experts, institutions and governments and the definitive text will be Tranquillizers settled by a working group. References The nonmedical use of psychotropic substances is 1. Bioavailability of drugs: Principles and problems. Report less widely publicized than that of illicit narcotics of a WHO Scientific Group. WHO Technical Report Series, and other drugs, but this does not reduce its impor­ No. 536 (1974). tance. Clinical experience and anecdotal data 2. Official Journal of the European Communities 1984; 27. indicate that the patterns of abuse of tranquillizers 3. Guidelines for the Investigation of Bioavailability, Draft and other psychotropic compounds differ from 15 August 1986, World Health Organization, Regional those of other drugs. They seem to be predomi­ Office for Europe, Copenhagen, Denmark. nantly abused by adults rather than by young WHO Drug Information Vol. 1, No.2,1987 General Information

Research on healthy Dangoumau in his introduction to a book that is the volunteers first to explain the structure and the objectives of the system in detail. United Kingdom—The Royal College of Physicians has published a report at the request of Reference: Royer, R. J. & Lagier, G. La Pharmaco­ the Medicines Commission on the testing of new vigilance, Editions Médicales Specia, 1986. drugs in healthy volunteers. Early drug development studies on healthy volunteers have increased both in number and in scale over recent years. In part this seems to have arisen as a result Pharmacopoeias, of a belief that the Licensing Authority will look compendia and texts of more favourably on applications for new drugs if GMPs studies are presented involving large numbers of healthy subjects, rather than small precisely An updated catalogue of national and international focused and carefully designed studies intended to Pharmacopoeias, Compendia and texts of Good produce specific and essential information for Manufacturing Practices (GMPs) can be obtained regulatory purposes. from the World Health Organization.

The College considers that the Licensing Authority References: Documents WHO/PHARM/86.39 and should clearly state its policy regarding the role and 86.53, World Health Organization, 1211 Geneva 27, the scope of such studies in drug development Switzerland. programmes.

The report provides a useful working definition of a Chemical analysis healthy volunteer and it proposes guidelines that unnecessary for most drugs are addressed not only to investigators, sponsors, Research and Ethics Committees and institutions United Kingdom—The Department of Health where such research is undertaken, but also to the and Social Services proposes to change the basic volunteers themselves. Suggestions are also made drug testing scheme for controlling dispensing regarding provision of compensation for injury. practices by pharmacists which it recommends to family practitioner committees. Under the new Reference: Research on Healthy Volunteers. Journal of proposals, unit dose medicines (tablets, capsules, the Royal College of Physicians of London, Vol. 20, No. 4, ampoules, etc.), which can be identified with October 1986. reasonable certainty by appearance, size and weight, will not normally be chemically analysed. Instead, a sample will be subjected only to visual examination unless there is reason to suspect it Pharmacovigilance: does not conform to the prescribed medicine. a decentralized system Reference: The Pharmaceutical Journal, 237:351 (1986). France—The system of drug monitoring in France is unique insofar as it brings health professionals and the public into close contact at regional level and that it directly involves represen­ Pharmacists' role in tatives from the pharmaceutical industry. At the infection control heart of the system are the regional centres which play a key role in integrating the system on the one United States of America—The American hand with the health care services and on the other Society of Hospital Pharmacists has issued a hand with the companies responsible for the statement enumerating the responsibilities of the development of new drugs. This point is made by J. pharmacist in the control of nosocomial infections. General Information WHO Drug Information Vol. 1, No.2,1987

They include: • Carboxypenicillins (carbenicillin, ticarcillin), the • advising the hospital authorities on the selection ureidopenicillins (piperacillin) and some and use of appropriate antiseptics, disinfectants cephalosporins (latamoxef, ceftriaxone) present a and sterilants; particular risk to patients with kidney damage when they are administered at full dosage. At high plasma • collaborating in the establishment of policies concentrations platelet receptors are blocked by determining the prophylactic use of antibiotics and the drug or its metabolites. This results in platelet imposing restrictions on the use of specific aggregation and prolonged bleeding time. antibiotics; • Latamoxef can cause bleeding as a result of • conducting in-service training programmes in hypoprothrombinaemia. It is important to remember aseptic technique, antimicrobial therapy, and that the administration of this substance and some sterilization methods; other oral antibiotics is particularly dangerous after abdominal surgery. • participating in public health education campaigns on the control and spread of infectious diseases. Bleeding may also result from interactions between certain antibiotics and oral anticoagulants. Reference: The Pharmaceutical Journal 237:390 (1986). Reference: Saignements imputables aux antibiotiques. Folia Pharmacotherapeutica, 13:37 (1986). Ministère de la Santé Publique et de la Famille, Bruxelles, Belgium. Research on new drugs involving human subjects

France—The report of a Study Group on Medical Blood disorders associated Ethics which met in Paris in October 1985 has with pirenzepine recently been published. It presents a detailed discussion of the legal and ethical responsibilities Two cases of agranulocytosis and thrombopenia of the medical investigator, of the pharmaceutical associated with the use of pirenzepine (Gastro- company and of the competent national authority in zepin® Boots) have been reported. The temporal the study of a new drug in man. relationship between the intake of pirenzepine and the onset of the blood disorders in both patients Reference: Experimentation chez I'homme du nouveau suggests that a causal relationship exists. medicament, Collection de Médecine Legale et de Toxi­ cologic Medical, No. 122 Masson, Paris 1986. Reference: Strieker, B. H. Ch. et al. Blood disorders associated with pirenzepine. British Medical Journal, 293: 1074(1986). Bleeding and antibiotic treatment

Belgium—The May 1986 issue of Folia Phar¬ Intravaginal dinoprostone macotherapeutica, a publication sponsored by the for induction of labour at Ministry of Public Health and Family Affairs, includes a note on the increasing frequency of term reports of bleeding associated with the adminis­ tration of certain antibiotics. A variety of Ireland — Like other inducing agents, dino­ mechanisms is involved: prostone can induce uterine hypertonus which, on occasion, may force the fetal head against the • Chloramphenicol and trimethoprim inhibit the bone bony margin of the unprepared cervical canal and marrow and bleeding results from thrombocyto­ vagina. An instance in which this led not only to penia. fetal loss but also to death of the mother from WHO Drug Information Vol. 1, No.2,1987 General Information

intravascular coagulation and cerebral haemor­ renal toxicity. The incidence of potentially serious rhage is reported. This is a rare occurrence, but it drug-related elevations of BUN and serum illustrates the need for monitoring uterine activity creatinine was studied within a group of 1468 and fetal well-being until the time of delivery, once patients with rheumatoid arthritis or osteoarthritis these products have been administered. who took daily therapeutic doses of aspirin and ibuprofen equal to or higher than those used for Reference: Annual Report 1985 of the National Drugs over-the-counter indications. Slight increases in Advisory Board, Dublin, Ireland (1986). these indicators occurred in about 5% of the patients. However, these were considered to be clinically significant in only three (<1%) patients, each of whom was receiving concomitant diuretic Tardive dyskinesia in therapy. None of the changes led to adverse antipsychotic therapy clinical consequences.

Ireland — The National Drugs Advisory Board Reference: Bonney, S. L et al. Renal safety of two analgesics used over the counter: ibuprofen and aspirin. requires that the following warning be included in Clinical Pharmacology and Therapeutics, 40:373-377 the prescribing information for antipsychotic drugs (1986). and major tranquillizers:

Tardive dyskinesia, a syndrome characterized by involuntary dyskinetic movements, may develop in patients on antipsychotic therapy and occasionally "Congesting" nasal even in those who have discontinued such treat­ ment. Those at particular risk include the elderly, decongestants females, and patients who have received high dosages or prolonged treatment. Fine vermicular United Kingdom — Writing in the British Medical movements of the tongue are an early sign and, Journal, L. H. Capel and A. R. Swanston issue a provided treatment is promptly discontinued, the reminder regarding the long-recognized damage to syndrome may not progress. In some cases, the nasal mucosa caused by long-term use of however, it is irreversible or slow to resolve. topical "decongestants" (vasoconstrictors) which remain widely prescribed, are prominently displayed There is no effective treatment for the syndrome, in chemists' shops, and are extensively advertised which may be masked by antipsychotic drugs or on posters and television. This contrasts with anticholinergic agents. The latter do not predispose advice offered in the British National Formulary to tardive dyskinesia but they should not be used which says that if decongestants are needed, routinely to reduce the parkinsonian effects of ephedrine is the drug of choice and it should be antipsychotic drugs because of the danger that used for short periods only. they will also obscure the early signs of tardive dyskinesia. The vasoconstrictors are mostly sympathomimetic amines. The α-adrenergic agonists constrict Reference: Annual Report1 985 of the National Drugs subepithelial precapillary sphincters, arterioles and Advisory Board, Dublin, Ireland (1986). venous sinuses, and the 3-agonists mediate vasodilatation.

Out of 460 new patients seen in the rhinitis clinic of Ibuprofen and aspirin safe in the Royal National Throat, Nose and Ear Hospital in over-the-counter use London in 1985, 60 (13%) had used vasoconstrictor nose drops for more than two months to relieve United States of America — The widespread persistent nasal obstruction. However, in reality, use of nonsteroidal anti-inflammatory drugs their symptoms were aggravated and sustained by (NSAIDs) has produced concern over their possible such treatment. General Information WHO Drug Information Vol. 1, No.2,1987

The authors suggest that nasal decongestant Drug interference in thyroid sprays and drops should not be advertised to the public and that a warning, "Use of these drops for testing more than five days becomes increasingly harmful", should be printed prominently on the United Kingdom — Because an increasing containers. number of drugs has been shown to interfere with the standard tests of thyroid function both in vivo Reference: Capel, L. H. & Swanston, A. R. Beware and in vitro the assessment of thyroid status is congesting nasal decongestants, British Medical Journal, becoming more complex. The following drugs are 293:1258-1259(1986). among those that cause serious interference:

• Amiodarone induces antithyroid antibodies. Electrical stimulation • Fenclofenac, by displacing thyroxine from binding sites, causes an apparent reduction in the total devices to treat scoliosis thyroxine concentration.

United States of America—The Food and • Fenoprofen increases the free triiodothyronine Drug Administration has approved an electrical concentration. device consisting of a two-channel stimulator and dual sets of electrodes which conduct electrical Reference: D'Arcy, D. F. Thyroid tests: interference by impulses to selected muscles, causing contrac­ fenoprofen and flurbiprofen. Pharmacy International, tions that gradually correct abnormal curvatures of 7:221(1986). the spine in children. Electrical stimulation must be used until the child's spine is mature. The devices are not approved for use in infants or adults or for patients with structural spinal deformities. Cardiac pacemaker registry

Reference: FDA Consumer, Vol. 20, No. 7, p. 4, United States of America — The Food and September 1986. Drug Administration and the Health Care Financing Administration have published a regulatory proposal providing for the establishment of a national cardiac pacemaker registry (Federal Register of 15 May 1986). The proposed registry is Sugar in oral liquid designed to provide information that will assist the medicines Secretary of Health and Human Resources in determining when Medicare payments for pace­ United Kingdom — The British Pharmacopoeia maker devices may properly be made, in studying Commission is hoping to discourage the use of the use of the devices, and in monitoring their per­ sugar in medicines by allowing "BP" preparations to formance. be formulated using alternative substances when this is considered desirable. Rather than making Reference: From the Food and Drug Administration. specific recommendations for replacements, the Journal of the American Medical Association, 256:817 relevant monograph will specify the use of a (1986). "suitable vehicle".

Certain of the current sugar-based formulae will be retained for extemporaneous preparations since Oxybutynin prescribing these are rarely supplied for long-term use. "unusually high" Reference: Medicines Act Information Letter, Mail 47, July 1986. United Kingdom — "Pilots Laboratories, which is WHO Drug Information Vol. 1, No.2,1987 General Information

one of the two companies developing oxybutynin Benzodiazepine for the UK market under the name Cystrin®, has alerted doctors that the prescribing of the drug has dependence reached an "unusually high" level under the named- patient exemption and is creating administrative David Nutt, writing in the November 1986 issue of problems both for pharmacists and for the Trends in Pharmacological Sciences, examines the company. The product is not yet licensed in the UK basis of the public concern that has arisen within and it is supplied only on a named-patient basis. It the past decade over possible "addiction" or is expected that it will become generally available "dependence" to the widely prescribed benzo­ within the next two years and, in the meantime, the diazepines. prescriber must assume full responsibility for the use of the drug. Smith & Nephew is also developing Benzodiazepines were introduced in the early oxybutynin, as Ditropan®. 1960s and were quickly shown to be effective anxiolytics and hypnotics. In the mid-1970s it Oxybutynin is not a new drug. It has been marketed became clear that tolerance develops extremely for several years in many countries, including the rapidly to their anticonvulsant and sedative effects. United States of America. It has anticholinergic Indeed, it was shown that patients taking over­ properties and a direct antispasmodic effect on the doses of benzodiazepines would commonly leave smooth muscle of the bladder. hospital with plasma (and therefore most certainly brain) levels of the drug greater than those at the Reference: The Pharmaceutical Journal, 237:548 time they were comatose. (1986). Dependence upon benzodiazepines may be evident from clinical observation of withdrawal symptoms or United Kingdom —The efficacy and safety of dose escalation. A plethora of symptoms has been oxybutynin have been reviewed in the Drug attributed to curtailment of benzodiazepine Newsletter of the Northern Regional Health therapy. However, the mechanisms of Authority. In incontinent children with spina bifida, benzodiazepine tolerance, dependence and with­ continence was achieved in 70-80%, although drawal remain ill understood. intermittent catheterization remained necessary. However, these studies were not controlled and the The symptoms of withdrawal are highly variable and contribution of the drug to the outcome is regarded many patients do not experience any disturbance. as difficult to assess. Among the important determinants are the rate of withdrawal (both fast and slow discontinuation may Two placebo-controlled studies of the use of present problems), and the pharmacokinetics of the oxybutynin to reduce bladder contraction following drug being withdrawn (diazepam and other long- transurethral surgery were contradictory in their acting drugs tend to be easier to stop). Intrinsic findings and inadequately documented. The characteristics of the patient are probably of great reviewer concludes that oxybutynin seems importance: individuals who are markedly de­ effective in some patients but that it is associated pendent and inadequate in their personalities do with a high incidence of adverse effects, including badly. Previous or co-existent depression may also dry mouth, impaired vision, tachycardia and prejudice the prognosis. nausea. There are at least 250,000 chronic users of benzo­ The relevant published studies are considered to diazepines in the UK. Opinion varies on the extent be of poor quality and those which compare to which they should be encouraged to stop. oxybutynin with propantheline are dismissed as of little value. In all, it is felt that the merits of Reference: Nutt, D. Benzodiazepine dependence in the oxybutynin therapy have yet to be established. clinic: reasons tor anxiety. Trends in Pharmacological Sciences, 7:457-460 (1986). Reference: Drug Newsletter of the Northern Regional Health Authority, No. 38, June 1986. General Information WHO Drug Information Vol. 1, No.2,1987

tration of an ultrashort-acting barbiturate Amitriptyline in anaesthetic (Brevital®) prior to termination of pregnancy. In all seven cases cardiorespiratory diabetic neuropathy arrest occurred either during induction, during the surgical intervention, or in the recovery room. United States of America — In a randomized, double-blind cross-over clinical trial conducted by Short-acting barbiturates are the intravenous the National Institute of Dental Research ami­ anaesthetics of choice for most anaesthesiolo¬ triptyline was shown to provide effective relief of gists. They are commonly used to induce general the pain of diabetic neuropathy, without any anaesthesia and sometimes for maintenance during evidence of elevation in mood. Patients received a procedures lasting no more than 15-20 minutes. single nightly dose ranging from 25 mg to 150 mg These deaths underscore the need for care in cal­ (mean dose 90 mg) for six weeks. culating dosage on a weight basis, supervision of Reference: From the National Institutes of Health. administration by a qualified anaesthesiologist and Journal of the American Medical Association, 257:14 adequate recovery room monitoring. (1987). Reference: Morbidity and Mortality Weekly Report, Vol. 35, No. 37, p.579-587,1986. A review of clinical risks United Kingdom — Clinical practice, in virtually Nicardipine, every speciality, involves the acceptance of calculated risks. Bernie O'Brien of the Health a new calcium antagonist Economics Research Group at Brunei University United Kingdom — The Drugs Newsletter of the considers the nature of these risks and how they Northern Regional Health Authority has recently are perceived both by doctors and patients. As reviewed published comparative trials of the new pointed out in an introductory message by George calcium antagonist nicardipine (Cardene®, Syntex) Teeling Smith, the health professions, the with nifedipine. These indicate that nicardipine is consumerist organizations and the media need to usefully effective in the treatment of both hyper­ develop a more sophisticated awareness of the tension and angina, although trials in hypertension ways in which patients can be helped to appreciate have been of relatively short duration. No adequate the relative risks of illness and treatment. This comparisons with verapamil or diltiazem have yet booklet should help to promote this all-important been published. As is the case with other calcium awareness. antagonists, nicardipine can be combined with beta- Reference: Bernie O'Brien, "What are my chances blockers to obtain a more potent hypotensive doctor?", A review of clinical risks, Office of Health effect. The adverse effects of nicardipine are Economics, London, November 1986. similar to those of nifedipine, and include dizziness, headache and oedema of the feet.

Reference: Drug Newsletter, Northern Regional Health Barbiturate anaesthetics Authority, No. 40, October 1986. and termination of pregnancy Biotechnology patents United States of America—The New York for pharmaceuticals City Bureau of Maternity Services and Family Planning has reported that, since 1980, seven United States of America—Of 1,232 US deaths have been associated with the adminis­ patents issued in the field of biotechnology last WHO Drug Information Vol. 1, No.2,1987 General Information

year, 673, or 54.6%, were directly related to World Federation of pharmaceuticals and other healthcare products. Associations of Clinical The greatest number was accorded to Syntex (15), followed by Merck (13), Miles Laboratories and Eli Toxicology Centres and Lilly (12 each). Poison Control Centres Reference: Newsletter of the Pharmaceutical Manufacturers Association, Vol. 29, No. 3,26 January At its General Assembly in October 1985 the 1987, Washington DC, United States of America. Federation focused its attention on industrial toxicology, particularly on packaging and labelling of pesticides, and on the training of nurses and others in clinical toxicology and veterinary Standardization of rabies toxicology. immunoglobulin Reference: Journal de Toxicologie clinique et experimental, No. 4, Juillet-Aout 1986, Masson, Paris, WHO is initiating a collaborative study to resolve France. problems that have arisen in the potency testing of rabies immunoglobulin and anti-rabies sera. Until further notice, the International Standard of rabies immunoglobulin should be considered only as a reference reagent of unknown potency.

Reference: Weekly Epidemiological Record, 61:373 (1986). WHO Drug Information Vol. 1, No.2,1987

Update on AIDS

Prospects for vaccines whether this results in an augmented immune response associated with neutralizing antibodies and antiviral therapy against different strains of HIV. This vaccine, however, contains live vaccinia virus as the carrier In the six years since AIDS was first described, the which, it has been suggested, could trigger AIDS in causative retrovirus (human immunodeficiency a previously infected person by placing an virus, HIV) has been isolated, identified and additional stress on an already compromised cultured. (1). Methods have been devised for immune system (15). detecting antibodies raised against the organism (2,3) which can virtually eliminate the risk of There is, however, a general consensus among the contracting AIDS through blood transfusion, and experts involved — and expressed during the Third the task of developing a vaccine has begun. Many International Conference on AIDS in Washington in genetic variants of the virus exist that form a June 1987—that, even if the development of an continuum of related strains (4-6). Moreover, since effective vaccine proves to be feasible, it is the disease attacks the immunological defence unrealistic to expect a marketable product to system responsible for cellular immunity become available within the next five years. In the (particularly T cells and macrophages) and invokes interim, fundamental knowledge already acquired only a weak humoral antibody response, a on the mechanism of replication of the virus has successful vaccine will need to boost both identified approaches to the treatment, as opposed reactions immediately and vigorously if it is to offer to the prevention of the disease, that could exert a an effective defence against subsequent infection. significant influence on its management within a much shorter time-frame. Already, zidovudine Nonetheless, an impressive amount of fundamental (azidothymidine, Retrovir® Wellcome), the first research has already been accomplished that has compound to have been shown in a controlled direct bearing upon the development of a vaccine. setting to attenuate the progress of the disease, Specific glycoprotein components of the virus has been approved for marketing in seven envelope have been identified as having biological countries in Europe and North America, and the significance both as major antigens (2,8-11) and United States Food and Drug Administration has as foci that react with specific receptors on target announced that 16 other products are under cells of the immune system (12, 13). The United consideration for clinical testing (see table p. 64). States Food and Drug Administration anticipates that at least two applications will be made this year Zidovudine to test candidate vaccines in human subjects. Meanwhile, preliminary results have already been Zidovudine (azidothymidine) is a synthetic published of a study undertaken in Zaire in which thymidine analogue that is metabolized in volunteers were immunized with a recombinant mammalian cells but which frustrates the vaccinia virus expressing envelope glycoprotein construction of nucleic acid chains because it does derived from a defined strain of HIV (14). Whereas not provide for the formation of the necessary the primary immune response resulted in phosphodiester linkages. It is presumed to act by neutralizing antibodies that exhibited specificity for preventing production of viral DNA during the the strain from which the vaccine was derived, the process of reverse transcription on which its investigators claim that selected cell-mediated replication within the cells depends (16). The responses were stimulated, in different degree, by clinical basis of this claim resides in the findings of an antigenically distinct strain of virus. Some of a preliminary open study (17) and of a single unpub­ these volunteers have now received second, lished double-blind placebo-controlled study which boosting doses of the vaccine to determine WHO Drug Information Vol. 1, No.2,1987 Update on AIDS

started in February 1986 involving 282 patients who vomiting, and sporadic cases of more serious had either recovered from a recent episode of Pneu­ central nervous system toxicity have been reported mocystis carinii pneumonia or who had advanced (25, 26). AIDS-related complex and were at risk of developing opportunistic infections (18). These problems underscore the fact that clinical experience with zidovudine is still limited. Optimal In the initial study, which involved 19 patients, dosage regimens have yet to be defined. The long- zidovudine was first administered intravenously for term sequelae of treatment remain uncertain, yet two weeks and then orally for one month during demonstration of the rapid return of circulating HIV which time the compound was shown to be antigen following reduction or cessation of efficiently absorbed. Most patients gained weight treatment (27) suggests it may be needed for life. and improved both clinically and in their immune The results of ongoing trials must be awaited before status. Similar improvements soon became evident any assessment can be made of the potential within the controlled study and the placebo control toxicity of the compound in less severely infected was discontinued after eight months when an individuals. It has even been suggested that the interim analysis revealed that 19 deaths had myelotoxic effects of treatment in these groups occurred among the 137 control patients but only might exacerbate the disease process by imposing one among the 145 patients who has received an additional stress on the immune system (23). zidovudine. More recently, a preliminary review has been undertaken of the progress of 3247 patients in the United States of America who had received Much attention is inevitably being devoted to the zidovudine prior to mid-January 1987 on a compas­ possibility of attenuating the adverse effects of sionate use basis. Thus far, 97 deaths have been treatment by concomitant use of other agents. A recorded in this group, only 21 of which occurred in case has been made for the physiological patients who had received the drug for more than stimulation of formed blood elements by three weeks (18). Some of these patients have haematopoietins (28) as well as for the synergistic received zidovudine continuously for more than 18 use of other immuno-modulating agents, such as months and reports of their progress suggest not acyclovir which has been claimed to potentiate the only that their life-expectancy is increased but that action of zidovudine in vitro (21). However, an associated neurological signs, ranging from apparent case of neurotoxicity, confirmed by peripheral neuropathy to profound dementia — and rechallenge, in a patient that received the latter which are now recognized to constitute an combination (29) underscores the need for caution important complication of the disease — may in multiple drug therapy. partially regress (16,19). The advent of zidovudine has created optimism, Although, in vitro, the reverse transcriptase of HIV where none existed before, that an effective and is much more susceptible to the inhibitory effects safe means may eventually be developed for of zidovudine than the analogous mammalian holding the disease in check indefinitely. However, enzyme (20,21), this specificity is reduced in vivo it cannot be regarded as an end in itself: in those (17,22). This has important implications for the countries where the drug has been registered it is toxicity of the compound. Overall, 25% of the as yet available only to subgroups of infected patients who took zidovudine in the controlled patients, not primarily on grounds of cost which at study developed severe anaemia due to bone current prices has recently been estimated at about marrow suppression which was considered, in US$ 7000 a year, but on considerations of safety. some degree, to be drug-induced (23,24). Other agents, including a related pyrimidine Treatment had to be interrupted in about one-fifth of analogue, dideoxycytidine, are already being these and many others required repeated trans­ subjected to clinical evaluation and it is reasonable fusions even after reduction of the initial dosage. — even in the current state of knowledge —to Approximately half of the patients complained of anticipate significant, if not spectacular, progress headache, sometimes associated with nausea and in discovering less toxic alternatives. Update on AIDS WHO Drug Information Vol. 1, No.2,1987

Products under consideration for clinical 10. Allen, J. S. Major glycoprotein antigens that induce testing antibodies in AIDS patients are encoded by HTVL-III. Science, 229:1091-1094 (1985). 11. Montagnier, L et al. Identification and antigenicity of Immuno-modulating agents the major envelope glycoprotein of lymphadenopathy- Thymopentin (Ortho Pharmaceutical Corp.) associated virus. Virology, 144:283-289 (1985). Thymostimulin (Serono Laboratories Inc.) 12. Dalgleish, A. G. et al. The CD4 (T4) antigen is an Inosine pranobex (Newport Pharmaceuticals) essential component of the receptor for the AIDS retrovirus. Nature, 312:763-767 (1984). Anti-viral agents 13. Klatzmann, D. et al. T- lymphocyte T4 molecule Ansymycin (Adria Laboratories) behaves as the receptor for the human retrovirus LAV. Ribavirin (Viratek/ICN Pharmaceuticals) Nature, 312:767-768 (1984). Dideoxycytidine or DDC (National Cancer Institute) 14. Zagury, D. et al. Immunization against AIDS in Antimoniotungstate HPA-23 (Rhône-Poulenc) humans. Nature, 326:249-250 (1987). AL 721 (Matrix Laboratories) 15. Anonymous. Candidate AIDS vaccine. Science, Foscarnet sodium (National Institute of Allergy & 235:1575(1987). Infectious Diseases) 16. Yarchoan, R. & Broder, S. Development of antiretroviral therapy for the acquired immunodeficiency Biological products syndrome and related disorders. New England Journal of Interferon alfa (Hoffmann-La Roche, Inc.) Medicine, 316:557-564 (1987). Interferon gamma (Genetech, Inc.) 17. Yarchoan, R. et al. Administration of 3'-azido-3'- Imreg-I (IMREG, Inc.) deoxythymidine, an inhibitor of HTVL-III/LAV replication, to patients with AIDS or AIDS-related complex. Lancet, 1: lnterleukin-2 (Hoffmann La Roche, Inc.) 575-586(1986). Poly IC12U (HEM Research) 18. Marwick, C. AZT (Zidovudine). Journal of the American Immune globulin IG-IV (Sandoz Pharmaceuticals Corp. Medical Association, 257:1281-1282 (1987). and Alpha Therapeutics). 19. Yarchoan, R. et al. Response of human- immunodeficiency-virus-associated neurological disease to 3'-azido-3'-deoxythymidine. Lancet, 1:132-135 (1987). References 20. Wagar, M. A. et al. Effects of 2', 3'-dideoxynu- 1. Gallo, R. C. & Montagnier, L The Chronology of AIDS cleosides on mammalian cells and viruses. Journal of research. Nature, 326:435-436 (1987). Cellular Physiology, 121:402-408 (1984). 2. Samgadharan, M. G. et al. Antibodies reactive with 21. Mitsuya, H. et al. Rapid in vitro systems for assessing human T-lymphotopic retroviruses (HTLV-III) in the serum activity of agents against HTLV-III/LAV. In: Broder, S. ed. of patients with AIDS. Science, 224:506-508 (1984). AIDS: Modem concepts and therapeutic challenges. New 3. Brun-Vezinet, F. et al. Detection of IgG antibodies to York, Marcel Dekker. pp. 303-333 (1987). lymphadenopathy-associated virus in patients with AIDS 22. Furmann, P. A. et al. Phosphorylation of 3'-azido-3'- or lymphadenopathy syndrome. Lancet, 1: 1253-1256 deoxythymidine and selective interaction of the 5'- (1984). triphosphate with human immunodeficiency virus reverse 4. Wong-Staal, F. et al. Genomic diversity of human T- transcriptase. Proceedings of the National Academy of lymphotropic virus type III (HTLV-III). Science, 227:759- Sciences, USA, 83:8333-37 (1986). 762(1985). 23. Anonymous. Zidovudine. Lancet, 1:876 (1987). 5. Hahn, B. H. et al. Genetic Variation in HTVL-III/LAV 24. Anonymous. Zidovudine. Medical Letter, 28:107-109 over time in patients with AIDS or at risk for AIDS. (1986). Science, 232:1452-1453 (1986). 25. Haglar, D. N. & Frame, P. T. Azidothymidine 6. Starcich, B. R. et al. Identification and character­ neurotoxicity. Lancet, 2:1392-1393 (1986). isation of conserved and variable regions in the envelope 26. Davtyan, D. & Vinters, H. Wernicke's encephalopathy gene of HTLV-III/LAV, the retrovirus of AIDS. Cell, 45:637- in AIDS patient treated with zidovudine. Lancet, 1:919- 648(1986). 920(1987). 7. Gallo, R. C. The AIDS virus. Scientific American, 27. Chaisson, R. E. et al. Significant changes in HIV 256(1): 39-48 (1987). antigen level in the serum of patients treated with 8. Kitchen, L W. et al. Aetiology of AIDS-antibodies to azidothymidine. New England Journal of Medicine, 315: human T-cell leukaemia virus (type III) in haemophiliacs. 1610-1611(1986). Nature, 312:367-369 (1984). 28. Donahue, R. E. et al. Suppression of in vitro 9. Veronese, F. et al. Characterization of gp41 as the heamatopoiesis following human immunodeficiency virus transmembrane protein coded by the HTLV-III/LAV infection. Nature, 326:200-203 (1987). envelope gene. Science, 229:1402-1405 (1985). 29. Bach, M. C. Possible drug interaction during therapy WHO Drug Information Vol. 1, No.2,1987 Update on AIDS

with azidothymidine and acyclovir tor AIDS. New England contraceptives for exemption from prescription Journal of Medicine, 316:547 (1987). charges.

Reference: The Pharmaceutical Journal, 237:624 (1986). Keeping the AIDS virus out of blood supplies Safety of factor VIII and IX United States of America — Participants in a concentrates Consensus Conference organized by the National Institutes of Health concluded that autologous United States of America — The effects of blood transfusion offers the safest option for blood exposure to blood factor concentrates containing replacement for a person facing elective surgery. It donations from identified AIDS patients have been was recommended that blood banks and blood reviewed in a recent paper by Janine Jason and centres should provide this facility whenever others. The authors compared recipients of eight possible; the donation process should be simplified lots of factors VIII and IX subsequently withdrawn to the fullest possible extent, and physicians and from distribution because of suspected contami­ patients should be informed about the advantages nation with AIDS virus with a nonexposed cohort and mechanics of this approach. matched by age, sex, and factor use. By 14 July 1986, 422 people in the United States had developed AIDS as a consequence of None of these cohorts differed in HIV antibody receiving infected blood or blood products. This prevalence or in any other tests of immune number, which does not include haemophiliacs, function, but both the exposed and non-exposed represents less than 2% of all the people who have cohorts had high rates of HIV seroprevalence developed AIDS, and this proportion is expected to (>70%). It is concluded that this type of regulatory fall as a result of the introduction of routine blood control offers insufficient means of limiting the screening in 1985. spread of the AIDS virus in the haemophiliac population. It was emphasized that the currently used ELISA tests for antibodies to the AIDS virus occasionally Wet or dry heat treatment which appears to be yield a 'false negative" result, particularly in the effective in inactivating HIV and related viruses is case of recently infected individuals who have very recommended as a mandatory precaution in the low blood levels of antibodies. An effective solution manufacture of all blood-factor concentrates. to this problem demands the development of more sensitive antibody tests, or tests that measure the Reference: Jason, J. et al. Effects of exposure to factor virus or its proteins directly. concentrates containing donations from identified AIDS patients. Journal of the American Medical Association, Reference: Barnes, D. B. Keeping the AIDS virus out of 256:1758(1986). blood supply. Science, 233:514-515 (1986). Autologous blood AIDS: condoms on transfusion prescription? United States of America —The Council on Scientific Affairs of the American Medical Associa­ United Kingdom—To encourage their use in tion has endorsed guidelines on the use of combating the transmission of AIDS, the Council of "autologous blood" (blood collected for retransfu¬ the Pharmaceutical Society has urged that sion at a later time into the same individual). It condoms be made available on prescription and provides assurance that safe matched blood is that they should qualify in the same way as oral readily available, and it eliminates the risk of AIDS related Matters WHO Drug Information Vol. 1, No.2,1987

alloimmunization or transmission of infectious The physician must also provide periodic patient disease from transfusion. progress reports to the company which will provide supplies, initially free of charge, to patients with Several hospitals have already developed AIDS who have recovered from one or more successful transfusion programmes on this basis, episodes of Pneumocystis carinii pneumonia and and the Council believes autologous blood trans­ who do not have AIDS-associated conditions that fusions to be the safest form of transfusion require chemotherapy (such as Kaposi's sarcoma). therapy. Reference: Council on Scientific Affairs. Autologous Patients must have a total granulocyte count blood transfusions. Journal of the American Medical > 1000/mm3, haemoglobin > 9.0 g/dl, platelet Association, 256:2378-2380 (1986). count > 50,000, SGOT < 3 times the upper limit of normal value, serum creatinine < 1,5 mg/dl and Australia—Autologous blood transfusion in one positive antibody for HIV confirmed by any federally of its three major forms — preoperative collection licensed ELISA test kit. They must also have a and storage, and acute perioperative collection Karnofsky performance status of at least 60 with haemodilution — has been advocated for many (defined as requiring occasional assistance but years as a safe and appropriate means for pro­ able to care for most of their needs). Patients viding blood for selective surgical procedures. should not be younger than 12 years of age. Preg­ nant women, nursing mothers, fertile women not using barrier contraception and patients receiving Although there is little, if any, risk for the recipient, any myebsuppressive, nephrotoxic or cytotoxic there are potential risks to surgeons, anaesthetists drug are also excluded from the controlled trial. and ancillary staff members if the donor happens to be hepatitis B surface antigen (HBsAg) positive. This risk can be avoided if autologous donations Reference: From the Food and Drug Administration. Journal of the American Medical Association, 256:2657 are grouped as a routine and screened appropri­ (1986). ately for potential infections in exactly the same way as isologous donations.

Reference: Beal, R. Blood banking public and private, isologous or autologous. The Medical Journal of Australia, AIDS, condoms 144:393-394(1986). and spermicides

United Kingdom — Evidence is emerging not only to demonstrate that the HIV retrovirus cannot Zidovudine available under permeate the condom membrane but that it is AIDS treatment research inactivated by commercially available spermicides. A recent study showed that HIV is inactivated in protocol vitro in 60 seconds by 0.05% nonoxylol-9, an ingredient present at concentrations of 5-12.5% in United States of America — The Food and several spermicides widely used in Britain. There Drug Administration has allowed extended use of is, however, no proof that spermicides offer zidovudine (AZT®) under a special protocol as a effective protection in practice, nor can many result of its promising performance in a controlled available brands of condoms be relied upon to trial and a subsequent open study. provide the degree of mechanical protection re­ quired particularly during anal sex. Manufacturers To prescribe zidovudine for appropriate patients, a are only now beginning to produce condoms physician experienced in diagnosing and treating specifically designed for prophylactic use. patients with AIDS must file a patient registration form and an informed consent form with Burroughs Reference: Wellings, K. AIDS and the condom. British Wellcome, the developer of the drug. Medical Journal, 293:1259 (1986). WHO Drug Information Vol. 1, No.2,1987

Pharmaceutical Products Approved

Benzodiazepine antagonist hepatitis is endemic; and others who are exposed to high risk of contracting hepatitis B infections. The first benzodiazepine antagonist, flumazenil Reference: From the Food and Drug Administration. (Anexate® Roche), a competitive receptor- Journal of the American Medical Association, 256:1657 blocking agent, may shortly become commercially (1986). available. Its potential clinical applications include rapid reversal of benzodiazepine-induced anaesthesia and diagnosis and treatment of benzodiazepine overdosage. It may also assist in the differential diagnosis of drug overdosage where Biotechnology: a new an unknown mixture of substances has been hepatitis B vaccine taken. A new recombinant DNA vaccine against hepatitis B In a double-blind trial in 40 patients premedicated has been approved for marketing in Belgium with diazepam for outpatient gastroscopy it has (Engerix-B®, SmithKline Biologicals). This vaccine been reported that patients given flumazenil were will compete directly with a similar recombinant DNA fully alert 30 minutes after the procedure. vaccine produced by Merck (Recombivax H-B®) and already approved by the Food and Drug Ad­ Reference: The Pharmaceutical Journal, 237:548 ministration in the United States of America. Both (1986). companies are synthesizing the vaccines in yeast cells. Small double-stranded rings of Escherichia coli DNA are used to transfer the portion of the gene which codes for the surface protein of the hepatitis Diagnostic assay for B virus into the genetic code of yeast cells. hepatitis delta agent The new vaccine has now been tested on 6,000 volunteers. It effectively boosts immunity con­ United States of America — The Food and ferred by the plasma-derived vaccine with which it Drug Administration has approved an in vitro radio­ appears to be equi-effective. Four doses may be immunoassay for antibody to hepatitis D antigen in necessary to produce a protective degree of immu­ human serum or plasma (Anti-Delta®, Abbott)). The nity which, it is anticipated, will persist for about ten hepatitis D virus, or delta agent, is an incomplete years (1). RNA virus that requires coinfection with the hepati­ tis B virus for survival and replication. Chronic hep­ The price for both the new genetically engineered atitis D infection is associated with chronic active vaccines and the plasma-derived vaccines will hepatitis, cirrhosis, and fulminant hepatitis. The initially be similar, but the cost of the newer test is indicated as an aid in the diagnosis of hep­ vaccines is expected to fall as production capacity atitis D virus infection in patients who have severe increases (2). hepatitis B virus infections; patients with non-A, non-B hepatitis; persons who are hepatitis B References 1. Ward, R. New hepatitis-B vaccine launched. Nature, surface-antigen positive; chronic carriers of 324:506(1986). hepatitis B virus; intravenous drug users; patients 2. The Pharmaceutical Journal, 237:752 (1986). undergoing haemodialysis; individuals from the Mediterranean region and other areas where Pharmaceutical Products Approved WHO Drug Information Vol. 1, No.2,1987

Other products approved insufficiency (i. e., serum creatinine 3.0 mg/dl). Reference: Letter to WHO dated 16 January 1987 from Australia—The following products have been the Food and Drug Administration of the United States of approved for marketing: America. Misoprostol (Cytotec®, Searle) 200 µg tablets. A synthetic prostaglandin E 1 analogue and the first of a new class of antisecretory, cytoprotective United States of America — The Food and agents to be approved for the treatment of acute Drug Administration has approved a transdermal duodenal and gastric ulcer. preparation of the antihypertensive agent clonidine (Catapres-TTS®, Boehringer Ingelheim) 2 Leuprorelin (Lucrin® Injection, Abbott). available in sizes of 3.5,7.0, or 10.5 cm to deliver A synthetic analogue of naturally-occurring luteiniz­ in vivo 0.1, 0.2 or 0.3 mg clonidine per day for 7 ing hormone releasing hormone (LHRH) approved days. for the palliative treatment of advanced prostatic cancer. Its role in the long-term management of the Reference: Food and Drug Administration, New Drug disease has yet to be established. Application No. 18-891.

Terfenadine (Teldane® Merrel Dow). The first of a number of long-acting antihistamines to be approved for the management of seasonal United States of America — The Food and allergic rhinitis. Terfenadine is claimed to have little Drug Administration has approved for marketing or no effect on the central nervous system. buspirone hydrochloride (Buspar®, Mead Whether this claim can be sustained will depend on Johnson & Co.), an antianxiety agent chemically more extensive experience of its use. and pharmacologically unrelated to benzo­ diazepines or barbiturates. Reference: Australian Prescriber, 9:69 (1986). The mechanism of action is unknown. It differs from benzodiazepines because it is devoid of anticonvulsant and muscle relaxant activity. United States of America—The Food and Indications include management of anxiety disor­ Drug Administration has approved a 250 mg tablet ders and short-term relief of the symptoms of formulation of acetohydroxamic acid anxiety. Buspirone is contraindicated in patients (Lithostat®, Uro-Research) for use as palliative with severe hepatic or renal impairment. Adverse adjunctive therapy in patients with chronic urinary effects include dizziness, nausea, headache, infections due to urea-splitting organisms. The drug nervousness, light-headedness, and excitement. should not be used in lieu of curative treatment. There is no evidence of tolerance or physical or The recommended starting dose is 12 mg/kg/day, psychological dependence. administered in divided doses at 6-8 hour intervals Reference: From the Food and Drug Administration. between meals. This dose should be reduced in Journalof the American Medical Association, 256:1657 patients with impaired renal function and the drug is (1986). contraindicated in patients with advanced renal WHO Drug Information Vol. 1, No.2,1987

Reports from Regulatory Agencies

Aminophenazone Bepridil

Brazil — The Division of Medicines decided to France — The Minister of Health has reminded withdraw aminophenazone from medicinal products physicians that the vasodilator agent bepridil may as from 23 May 1986. Manufacturers were granted induce burst dysrhythmia (torsades de pointe or a period of 90 days to remove products from the clusters of brief episodes of ventricular tachycar­ market. dia), particularly in elderly patients receiving other drugs that predispose to dysrhythmias. The prod­ Reference: Portaria No. 09 of 23 May 1986 sent to WHO uct information has been amended to recommend a under cover of a letter from the Division of Medicines of reduced dose of 200 mg daily for patients over 70 the National Health Secretariat of Brazil, dated 24 July years of age. Concurrent treatment with quinidine- 1986. like dysrhythmic agents, sotalol, amiodarone, fenoxedil, lidoflazine, prenylamine and vincamine must be avoided. Monitoring of the electrocardio­ Anticholinergic drugs gram is recommended, particularly with respect to the length of the Q-T segment. Hypokalemia United States of America — The Food and should be corrected before treatment is instituted Drug Administration has decided in the course of its and serum potassium levels monitored during ongoing review of "over-the-counter" products, that treatment. anticholinergic drugs used for the symptomatic treatment of hay fever, rhinitis and the common Reference: Decision of the French Minister of Health, cold may continue to be marketed after 10 Novem­ 21 February 1986, Revue Prescrire, 5:3(1986). ber 1986 only if a full application for registration has been approved by the Agency.

Reference: Letter from the US Food and Drug Bucetin Administration, dated 19 May 1986. Federal Republic of Germany—Further to its decision to withdraw products containing phen¬ Barbiturates acetin from the market, the Federal Office of Health has now also withdrawn products containing the New Zealand — The Division of Clinical Services phenacetin analogue, bucetin. of the Ministry of Health has proposed that the use of barbiturates be further restricted, having regard Reference: Letter to WHO from the Federal Health to continued reports of fatal overdosage (five in Office dated 2 September 1986. 1985). The approval of the Ministry of Health is likely to be required for each individual prescription and supplies will be available from hospital phar­ Bupivacaine macies only. Practitioners are asked to review the possibility of transferring patients to alternative Egypt — The Drug Organization of the Ministry of sedatives. Phenobarbital, which is used primarily Health has restricted the approved indications of as an anticonvulsant, is exempted from these the local anaesthetic bupivacaine. Its use is now measures. contraindicated in regional intravenous anaesthe­ sia and paracervical block, and it is indicated for Reference: Clinical Services Letter No. 243,11 July use in obstetric practice only in concentrations of 1986. 0.25% and 0.5%. Doctors are also warned that use Reports from Regulatory Agencies WHO Drug Information Vol. 1, No.2,1987

of higher concentrations in epidural anaesthesia Reference: Letter to WHO from the Permanent Mission has resulted in cardiac arrest. of Turkey in Geneva, dated 4 November 1986.

Reference: Letter from the Egyptian Drug Organization, Ministry of Health, dated 19 April 1986. Hydrocortisone (topical preparations) Captopril Canada — The Health Protection Branch of the Federal Republic of Germany — The Federal Ministry of Health and Welfare has amended the Health Office has revised the product information Food and Drug Regulations to permit non­ for preparations containing the angiotensin- prescription pharmacy-only sale of monocom¬ converting enzyme blocking-agent, captopril. A ponent products for external use containing warning is added that treatment of patients with hydrocortisone or hydrocortisone acetate at a cardiac insufficiency should start under close concentration of no more than 0.5%. Indications medical supervision with 2-3 daily dosages of 6.25 must be limited to temporary relief of minor skin mg. Blood pressure must be monitored for 60 irritation associated with symptoms of redness, minutes after the first dose. Patients with severe itching, dryness and scaling. Products intended for renal impairment must be carefully assessed ophthalmic, otic or buccal use remain under before treatment is started and renal function prescription control. The package size must be should be monitored throughout treatment. The limited to 15 g for ointments, creams and gels and maintenance requirement should be reached by 30 ml for lotions. cautiously increasing the dose and should not exceed the minimum effective amount. The package insert must include the following warnings: Reference: Letterto WHO from the Federal Health Office dated 3 September 1986. • For external use only. • Do not use in children aged 2 years or younger, unless directed by a physician. Carbamazepine • Do not use in or around eyes. • Do not apply to large areas of the body. France—The Directorate of Pharmacy and Drugs • Do not use to treat vulvar itching associated with has informed WHO that products containing the a vaginal discharge. anticonvulsant carbamazepine (Tegretol®, Ciba- • Do not use for more than 7 days. If symptoms Geigy) are now additionally indicated for the treat­ persist after this time, or return after discontinuing ment of manic or hypomanic excitation and for the use of the product, consult a physician. prevention of recurrent episodes of manic de­ • Do not apply to the affected area more than 3 or 4 pression, particularly in patients resistant to or intol­ times daily. erant of lithium. Reference: Information Letter No. 714,10 September Reference: Decision of the Minister of Social Affairs and 1986. Health Protection Branch, Health and Welfare, Employment dated 17 July 1986. Canada.

Flu nitrazepam Mefloquine Turkey — In view of its frequent abuse by drug addicts, the Ministry of Health and Social Assis­ Brazil — In order to prevent, as far as is possible, tance has subjected flunitrazepam to controls the development of mefloquine-resistant strains of equivalent to those applied to drugs in Schedule II Plasmodium falciparum, the Division of Medicine of of the 1971 Convention on Psychotropic Sub­ the National Health Secretariat has decided, in stances. conformity with the recommendations of the WHO WHO Drug Information Vol. 1, No.2,1987 Reports from Regulatory Agencies

Working Group on Chemotherapy of Malaria, to Metformin restrict the use of mefloquine as follows: France — The Minister of Health has decided that • purchase, distribution and use of medicinal pro­ data sheets for products containing the oral ducts containing mefloquine have been placed antihyperglycaemic agent metformin should include under the direct control of the Ministry of Health; a warning that their use is associated with severe lactic acidosis, and that the risk is of the order of 1 • the indication for these products should state that case in 40,000 treatment years. use should be restricted to radical treatment of infections caused by multi-resistant Plasmodium Reference: Decision of the Minister of Health, falciparum; 21 February 1985.

• having regard to the lack of conclusive evidence on the safety and efficacy of mefloquine-containing products in pregnant women and in children, they Nifedipine are contraindicated during pregnancy (unless their use is regarded as imperative) and in children of Japan — Having regard to reports of cases of less than two years of age. gingival hyperplasia associated with the use of the antihypertensive calcium-channel blocking-agent Reference: Portaria No. 5 of 24 April 1986, sent under nifedipine, the Pharmaceutical Affairs Bureau of the cover of letter to WHO fromthe Divisio n of Medicines of Ministry of Health and Welfare has recommended the National Health Secretariat of Brazil dated 24 July that the precautions contained in the product 1986. information be extended to include the following statement: Mianserin "Oral cavity: gingival hyperplasia may occur in patients receiving long-term treatment with nifedipine. In this event the drug should be dis­ United Kingdom — The Licensing Authority has continued." requested that the product information for pharma­ ceuticals containing the antidepressant mianserin Reference: Information on Adverse Reactions to Drugs, (Bolvidon® Organon; Norval® Beecham) should No. 75, October 1985, Pharmaceutical Affairs Bureau, include reference to the risk of bone marrow de­ Ministry of Health and Welfare, Japan. pression as follows:

"Bone marrow depression, usually presenting as granulocytopenia or agranulocytosis, has been Paracetamol reported. These reactions have occurred most commonly after 4-6 weeks of treatment. A full Chile — The Institute of Public Health has decided blood count is recommended every four weeks that product information for pharmaceutical during the first three months of treatment. In preparations containing paracetamol should addition, monitoring of the patient's clinical include: condition should continue and if fever, sore • advice that the dosage for children must be throat, stomatitis or other signs of infection adapted to their age and that a doctor should be develop, treatment should be stopped and a full consulted if fever persists for more than two days blood count obtained. These adverse reactions when paracetamol is used in the treatment of febrile have been observed in all age groups but appear children; to be more common in the elderly." • warnings that allergic reactions and hepatic damage are important adverse effects; Reference: Letter to WHO from the Department of • a statement that these products are contra- Health and Social Security of the United Kingdom, dated indicated in persons with hepatic or renal disease, 24 July 1986. and Reports from Regulatory Agencies WHO Drug Information Vol. 1, No.2,1987

• a caution that the duration of use should not • the maximum daily dose in schizophrenia should exceed 10 days. not exceed 100 mg.

Reference: Boletin Informative sobre Medicamentos, Reference: Deutsche Apotheker Zeitung, 126: VII Institute of Public Health of Chile, Vol. 3, No. 1, March (1986). 1986. Phenacetin Tartrazine Egypt—The Drug Organization of the Ministry of Oman—The Ministry of Health has prohibited the Health has decided that products containing import and marketing of products containing tartrazine as a colouring agent should bear a phenacetin as from 1 January 1987 having regard warning on the package insert that ingestion may to their potential to cause hepatic and renal evoke allergic reactions. damage. Reference: Letter from the Egyptian Drug Organization, Reference: Letterto WH O from the Ministry of Health Ministry of Health, dated 19 April 1986. dated 20 September 1986. Spironolactone United Kingdom — Because of concern regard­ Other decisions ing the possible carcinogenic risk associated with long-term use of spironolactone, the Committee on Egypt - The Egyptian Technical Committee for Safety of Medicines has decided that the Drug Control has announced the following regu­ indications for all spironolactone-containing pro­ latory decisions: ducts should be limited to: • Domperidone (anti-emetic) - Injectable prep­ • cirrhosis with ascites and oedema, arations containing domperidone have been with­ • malignant ascites, drawn from the market following reports of • nephrotic syndrome, cardbtoxicity, sometimes fatal. Other dosage • diagnosis and treatment of primary hyperaldoster¬ forms will remain available. onism, and • congestive cardiac failure. • Buprenorphine (analgesic) - Preparations con­ taining this substance will no longer be considered Reference: Telex from the Medicines Division, Depart­ for registration to avoid the possibility of abuse. ment of Health and Social Security, 9 October 1986. • Etretinate- Preparations containing this sub­ Sulpiride stance will be available only for the treatment of hospitalized patients with acute psoriasis causing Federal Republic of Germany—The Federal psychological disturbances. The approved product Health Office proposes to restrict the approved labelling must indicate that cardiac function should indications for products containing sulpiride to be monitored carefully before and during treatment neurotic and exogenous depression that fails to and that blood lipids and blood coagulation indices respond to other antidepressants, and to acute and should be estimated periodically, as the drug has chronic schizophrenia in adults. It also proposes to occasionally been associated with myocardial amend the product information by deleting ischaemia and infarction. recommendations for paediatric use and by emphasizing that: Reference: Drug Information, published by the Egyptian Pharmacopoeial Information Centre, Vol. 5, No.2, May • the product is contraindicated in children and 1986. patients with prolactin-dependent tumours and mammary tumours; WHO Drug Information Vol. 1, No.2,1987

Regulatory Matters

The future of regulatory Pharmaceuticals in the affairs in Europe European Community

The first meeting of the Council for European The results of twenty years of working towards Regulatory Affairs (CERA) was organized in Brus­ harmonization of pharmaceutical regulation in sels on 14 and 15 October 1986 by the British Insti­ Europe have been reviewed by Fernand Sauer, tute of Regulatory Affairs to promote commu­ Principal Administrator, Commission of the nication between regulatory affairs personnel European Communities, Brussels, in Industrie throughout Europe. Santé. The rules governing pharmaceuticals now comprise seven basic directives, one Council Professor P. Juul, Chairman of the Danish Recommendation and various other texts which Regulatory Registration Committee, discussed the apply to most newly-registered medicinal products, occasional difficulties faced by Denmark in trying excluding immunological, blood and radioactive pro­ to comply with approaches to harmonization both ducts, and homoeopathic medicines. By 1990 it is with the European Economic Community (EEC) and intended that each of these provisions will be the Nordic Council. Differences of principle be­ applied to longer-established medicines. tween the two groups of countries exist in several particulars, including attitudes towards fixed com­ In discussing the EEC Multistate Procedure for bination products, and the need for placebo-con­ Drug Registration in Europe, the author concedes trolled clinical studies. that only if a single body is created with powers to act for the Community as a whole, will discrepan­ Professor D. Poggiolini, Director General, Pharma­ cies which still arise between national decisions be ceutical Department, Italian Ministry of Health, said eliminated. However, support for a decentralized that compliance with EEC directives had resulted in system remains strong within most Member States, a substantial reduction in the number of pharma­ among Members of the European Parliament and ceutical manufacturers in Italy as well as in the among representatives of the pharmaceutical number of registered products. industry.

Dr P. Klein, Head of the Registration Department Several initiatives taken by the Community are within the Swiss Intercantonal Office for the Control presented as having operated to the benefit of the of Medicines explained that the "Scheme for the biotechnology industry in Europe. These include Mutual Recognition of Evaluation Reports on Phar­ the development of a four-year programme costing maceutical Products" (PER Scheme) had been 55 million ECU (European Currency Unit, 1 ECU = revised in June 1986 to provide for the use of an approx. US$ 1.2) that embraces training, promotion alternative reporting format developed within the of fundamental research, protection of biotechno¬ European Economic Community (EEC). The PER logical innovation, access to the necessary agri­ Scheme, which is administered by the European cultural raw materials at world prices (particularly Free Trade Association (EFTA) Secretariat in sugar and starch), and creation of a stable regula­ Geneva, continues to gain adherents, the latest tory environment as a prerequisite to a large and country to join being the Federal Republic of unified European market. Germany. Proposals for a variety of legislative measures Reference: International Drug & Device Regulatory have been submitted to the Council, including Monitor, No. 162, November 1986. provision for prior consultation at Community level, Regulatory Matters WHO Drug Information Vol. 1, No.2,1987

on applications relating to products derived from manufacturers claim for the treatment of major bioengineering and other high-technology process­ conditions the claims must be capable of substan­ es. If adopted, these proposals would also require tiation by the results of clinical trials in the same each Member State to notify the Commission of any way as would claims for new medicines. If, draft national regulations affecting the manufac­ however, claims are restricted to the symptomatic ture, marketing or use of such products before their relief of self-limiting conditions, the Committee has adoption in an attempt to obviate further frag­ advised the licensing authority that it maybe mentation of domestic markets. unreasonable to demand controlled trials. Other planned initiatives include: "Nevertheless, the Committee does expect a • extension of the harmonization programme to pharmacological rationale and bibliographical evi­ include immunological products and substitutes for dence of efficacy. Many old products contain illogi­ blood products by 1987; cal combinations, and considerable modifications, • proposals on the transparency measures govern­ often including the omission of unjustified ingredi­ ing pricing and reimbursements of medicinal ents, may be necessary before the Committee and products; and the licensing authority will be satisfied. Herbal • harmonization of rules governing the information medicines are being dealt with the same way as or­ supplied by manufacturers to doctors and patients, thodox medicines. Provided the claims are restrict­ and on the controls applied to the supply of ed to the relief of minor self-limiting conditions, prescription medicines to patients. bibliographical evidence may be acceptable. For herbal preparations, as for all products, concern Reference: Industrie Santa, No. 117, p. 23-27, over quality or safety may override otherwise December 1986. acceptable indications for use and prevent the grant of a full licence.

"Self-medication plays a vital and growing role in Controlled studies not health care as members of the public become better essential for "home informed about their ailments and increasingly conscious of the need not to take up their doctor's medicines" time with self-limiting conditions."

United Kingdom — The Committee on the Reference: Annual Report for 1985 of the Medicines Review of Medicines, which is evaluating all Commission, HM Stationery Office, London, 1986. products marketed before the implementation of the 1968 Medicines Act, says in its annual report: "The products awaiting review under the Medicines Exports of unapproved Act have been available for at least 15 years and many of them for much longer. Any major safety drugs: problems arising from their use would probably new legislation (though not definitely) have come to light by now. As to quality, the licensing authority and the United States of America — Pharmaceutical Committee consider the ingredients and the and biological products may now be exported in manufacturing process very carefully to ensure precisely defined circumstances without that they comply with modern standards. necessarily having been approved for domestic use by the US Food and Drug Administration. Stringent "The main problem with these medicines is to criteria for the exportation of such pharmaceutical establish satisfactory criteria for judging efficacy. products are defined in the recently passed Drug The distinction between claims for treating major Export Amendment Act of 1986. After applying to and for treating minor conditions is central to our the federal government for permission, a manu­ approach. The Committee has advised that when facturer of an unapproved "new drug" or an WHO Drug Information Vol. 1, No.2,1987 Regulatory Matters

unlicensed biological product intended for human or provided the Secretary finds that the scientific animal use may export the product to another evidence, including the clinical investigations, country recognized to possess a sophisticated establish that the drug is safe and effective for use health care regulatory system provided: in the country to which it is to be exported.

• the manufacturer is actively pursuing approval of Reference: Letter from the Food and Drug Admin­ the product in the United States; istration of the United States of America to WHO dated 29 December 1986. • the receiving country has approved the import­ ation of the product;

• the product was manufactured in the United Carcinogenicity studies States in accordance with officially approved standards of good manufacturing practices and is Ireland—The National Drugs Advisory Board labelled for export, and requires the results of carcinogenicity studies to be included in marketing applications for new drugs in • the Secretary of Health and Human Services has the following circumstances: determined that the manufacture of the drug for export is not contrary to the public health and • If the drug substance bears a close chemical safety of the United States. analogy to substances known to have carcinogenic or cocarcinogenic activity, or if it is a hormone or The Secretary may revoke an application for export has hormonal effects. if either the manufacturer of the product no longer meets the criteria for approval or if the product is • If the drug substance is likely to be used over being trans-shipped to a country not on the long periods of time in man, either by continuous approved list. dosing or frequent intermittent use, particularly if it is likely to be administered regularly to infants, The Act lists 21 countries recognized as having a children, or pregnant women. sophisticated drug regulatory system: • If standard studies suggest that the drug Australia Italy substance is mutagenic, or affects the immune Austria Japan mechanisms. Belgium Luxembourg Canada The Netherlands • If evidence has emerged from other studies to Denmark New Zealand suggest a potential carcinogenic effect. Federal Republic Norway of Germany Portugal • If evidence from other tests indicates that the Finland Spain drug or its metabolites are retained or sequestered France Sweden for long periods in the body. Iceland Switzerland Ireland United Kingdom The Board acknowledges that many cortico­ steroids, in particular, were introduced long before The Secretary may add other countries to the list the above requirements were formulated. To some provided that their drug regulatory systems meet extent their widespread use over this period has certain stringent criteria, as specified in the Act, to provided an epidemiological indication of freedom ensure that drugs used in their countries are safe from carcinogenic potential. None the less many and effective. corticosteroids are known to interfere with immune responsiveness and to disturb endocrine The Act also includes special provisions for the equilibrium. The Board consequently requires export of unapproved drugs (and biologicals) for carcinogenicity studies in all applications to market the treatment or prevention of tropical diseases, new products containing corticosteroids and it is Regulatory Matters WHO Drug Information Vol. 1, No.2,1987

encouraging similar testing of all marketed cortico­ reports are used in national registration procedures steroid substances. in all Nordic countries. The guidelines were thus prepared to conform to the requirements of each of Reference: Annual Report 1985 of the National Drugs the national authorities within the region and, in Advisory Board, Dublin, Ireland (1986). particular, to provide a check-list to assist each national authority on whether a product should be approved — or not. The report should not exceed Mutual recognition of 15 pages and should provide: toxicological data •a summary of the product documentation, France and the United States of America have • a commentary on the documentation prepared by agreed to accept toxicological data generated in the regulatory authority; and each other's countries and submitted in support of • conclusions and recommended regulatory action. applications for pharmaceutical products, provided the tests have been conducted in accordance with Reference: Evaluation Reports on Proprietary Medicinal nationally-prescribed Good Laboratory Practices Products, Nordic Guidelines, 1986, NLN Publication No. (GLP). This agreement will eliminate the need for 17, Nordiska Läkemedelsavdelning, Box 607, S-751 25 costly, time-consuming repetition of toxicological Uppsala, Sweden. tests and the number of laboratory animals required for these purposes. Over-the-counter drug Reference: Federal Register, Vol 51, No. 132, pp. 25104- 25105,10 July 1986. (OTC) review A difficult and time-consuming process Good Laboratory Practices United States of America — The OTC drug Italy—A Ministerial Decree issued on 26 June review process was initiated by the Food and Drug 1986 provides the regulatory basis for establishing Administration in 1972. The aim was to complete a Good Laboratory Practices in accordance with the comprehensive review of the safety, efficacy and recommendations of the Organization for Economic labelling of marketed OTC drug products in order to and Commercial Development (OECD). In order to establish general conditions for the marketing of assure the quality of the data included in marketing products in each therapeutic class that would applications for pharmaceutical products, whether provide assurance that they are safe, effective and they are submitted to the Italian Ministry of Health "not misbranded". or to foreign regulatory bodies, all toxicological tests performed in Italy are now required to conform Originally estimated to be completed in three to five to these regulations. years, it is now apparent that the programme will not be fully completed until the mid-1990s. Although Reference: Gazzetta Ufficiale No. 76, Supplements proposed monographs have been published for all Ordinario, 27 August 1986, Rome, Italy. 26 therapeutic categories, only one substantive final OTC monograph (for antacid products) has been issued to date. As each stage provides for an Proprietary medicinal opportunity to submit additional data and products comments, development of final monographs has proved to be a very difficult and time-consuming Nordic guidelines for evaluation process. reports Reference: Hamer, R. A. Importation of drugs and The Nordic Council on Medicines has issued medical devices in the US: an overview of FDA pre-market guidelines on the compilation of Evaluation Reports approval requirements. Pharmacy International, 7:214- on Proprietary Medicinal Products. Evaluation 218(1986). WHO Drug Information Vol. 1, No.2,1987 Regulatory Matters

Good Manufacturing for the exchange of certificates of inspection of pharmaceutical manufacturing premises. The certifi­ Practices for medical cates will be written in English and endorsed by the devices competent regulatory authority. Circumstances are specified in which either side may request The Food and Drug Administration of the United additional information. States of America and the Department of Health and Social Security of the United Kingdom have All such inspections must conform to mutually signed an agreement to accept each other's acceptable standards and, in every case, the inspection reports as providing formal evidence criteria established by the World Health that manufacturers of medical devices have Organization for Good Practices in the Manufacture complied with Good Manufacturing Practices. and Quality Control of Pharmaceutical Products will apply. Reference: FDA Consumer, 20:32 (1986). A similar agreement has already been signed by the two countries concerning Good Laboratory Practice. Sterility testing of Reference: Bundesanzeiger, No. 236, p. 17076, 19 parenteral drugs December 1986.

Canada — The Health Protection Branch of the Ministry of Health and Welfare has recently issued new regulations for assuring the sterility of Approved veterinary drugs parenteral drugs. A representative sample of each lot of the drug taken from the final container must United States of America be found to be sterile when tested by an acceptable • A List of Approved Veterinary Drugs will shortly be method, except: published by the Food and Drug Administration providing, as a minimum, the following information: • in the case of living vaccines, and - Chemical name of primary active ingredient(s) • where the manufacturer has submitted evidence - Trade name to prove that processing controls ensure the - Sponsor's name sterility of the drug in its final container. - New Drug Application (NDA) number Reference: Information Letter, No. 175,10 September - Availability (Rx or OTC) 1986. Health Protection Branch, Health and Welfare - Approval date Canada. - Species in which the product is approved for use. • The Veterinary Drug Adverse Reaction Reporting Center is currently developing a computerized data file containing details of all notified adverse Mutual recognition of reaction reports. The Center solicits these reports inspection certificates within the context of its surveillance of animal drug performance under field conditions. All information between Japan and the that could be used to identify the source of these Federal Republic of reports is held in strict confidence. Germany Reference: FDA Veterinarian, Vol. I, No. 2, November/December 1986. A bilateral agreement has been signed by Japan and the Federal Republic of Germany that provides Regulatory Matters WHO Drug information Vol. 1, No.2,1987

Labelling and advertising of Product liability and its new animal drugs implications for the practice of pharmacy and medicine United States of America —The Federal Food, Drug and Cosmetic Act specifically prohibits United Kingdom — The recent Directive of the a manufacturer of a drug intended for human use European Economic Community (EEC) on Strict from using approval of the Food and Drug Adminis­ Product Liability states that if a product is defec­ tration (FDA) for promotional purposes. No similar tive, the producer shall be liable, except when: prohibition applies to new animal drugs. • its provenance is unknown, An FDA policy guide regarding the use of FDA • the retailer has attached his own name or trade­ approval statements in labelling and advertising of mark or other distinguishing feature to the product, new animal drugs is now available which provides or guidance to drug sponsors interested in voluntarily • it has been imported from outside into the placing FDA approval information on labels or European Community. package inserts or in advertising and promotional material for approved drugs. In these instances it is emphasized that the retailer or the importer will be liable without proof of Reference: FDA Veterinarian, Vol. 1, No 1, p. 5, October 1986. negligence (2). Thus, whenever a product is dispensed in a container other than the original pack, the retailer might well be strictly liable for a defect rather than the manufacturer.

Generic drugs for animals Under the Directive, the test of liability will be based upon "reasonable expectation" of the safety of the United States of America—The Drug Price product when it was put into circulation. However, Competition and Patent Term Restoration Act of any evidence of negligence by the claimant will also 1984 authorized abbreviated premarketing be taken into account. approvals for generic versions of innovative drugs for human use approved after 1982, and restored a The principal defences to an action arising from a portion of the patent protection time lost due to claim that a product is defective are as follows: premarketing requirements. Animal drugs were not included in this legislation. • Assumption of risk —A patient, having been given all relevant information, assumes the risk of Legislation referring to generic drugs for animal use taking the product. For instance, a patient who has now been introduced in both the Senate and assumes the risk of baldness following chemo­ the House of Representatives. Both versions of the therapy for cancer would not be able to claim legislation would eliminate the necessity for full damages for a defect in this regard. safety and effectiveness testing for generic versions of most post-1982 animal drugs. As with • Tampering — If the retailer, e.g. the pharmacist, human drugs, the Food and Drug Administration tampered with the original product by covering or would provide a list of products for which abbrevi­ obliterating manufacturers' labels or warnings, or by ated new animal drug applications may be removing the patient information leaflet, the liability submitted. of the retail supplier would be considerably increased. Reference: FDA Veterinarian, Vol. 1, No 1, p. 1, October 1986. If an individual is to assume the risk of using a medicinal product, he must be given the necessary information leaflets and warnings. Failure of the WHO Drug Information Vol. 1, No.2,1987 Regulatory Matters

pharmacist to provide these could create a legal Drug Regulatory Index liability.

In a commentary in the British Medical Journal (3) The WHO Collaborating Centre for Drug Information it is pointed out that many doctors could be and Quality Assurance in Budapest, Hungary, affected by a Consumer Protection Bill now being periodically issues the "Drug Regulatory Index". introduced in the UK, in that: This title has acquired a broad connotation since • a doctor could become a producer if he mixes a many different types of documents are covered, preparation of his own or dilutes a liquid preparation ranging from laws to explanatory leaflets that or cream; provide information on drug policy, drug registration • a general practitioner is called upon from time to or the drug control practices of individual countries. time to supply his patients with drugs, particularly in emergencies. As a supplier he will need to keep The first issue of the Index (No. 1, 1984, as revised detailed records of the sources of supply of every in 1985) dealt with clinical guidelines irrespective of drug he dispenses for at least 10 years. Drugs their origin. The second issue (No.2) was devoted used in premarketing clinical trials are likely to be to documents relating to drug regulation exempted from these requirements. promulgated by international organizations.

References Index No. 3, which is now published, lists 1. Council Directive No. 85/374/EEC of 25 July 1985 on documents issued by individual European the approximation of the laws, regulations and administra­ countries. tive provisions of the Member States concerning liability for defective products. Official Journal of the European Reference: Drug Regulation Index No. 3- Documents Communities, No. L 210, 7 August 1985, pp. 29-33. issued by national agencies, 1986 - WHO Regional Office 2. Smith, A. J. Impact of new legislation upon the practice for Europe, Scherfigsvej 8, 2100 Copenhagen 0, of pharmacy. The Pharmaceutical Journal, 237:393(1986). Denmark. 3. Dyer, C. Product liability comes closer. British Medical Journal, 293:1489-1490 (1986). WHO Drug Information Vol. 1, No.2,1987

Advisory Notices

Pregnancy warnings Clinical evaluation of in data sheets non-steroidal anti-inflammatory drugs United Kingdom — All officially-required drug data sheets must now include a statement about United States of America—The Food and the safety of the product in pregnancy. Ideally the Drug Administration has issued a revised draft statement should summarize evidence from animal Guideline for the Clinical Evaluation of Nonsteroidal studies and experience in man. In practice, how­ Anti-inflammatory Drugs. The first edition, ever, only the former is generally available since published in 1977, was concerned exclusively with very few drugs have been proven to be human nonsteroidal anti-inflammatory drugs (NSAIDs). In teratogens. These include thalidomide; cytotoxic this edition additional guidelines are presented for drugs, particularly alkylating drugs and methotrex­ disease modifying anti-rheumatic drugs (DMARDs) ate; and retinoids (etretinate, isotretinoin). in adults and children. The Committee on Safety of Medicines and the Committee on Review of Medicines consider that Responsibility for updating this information lies with data sheets providing the following elements of the FDA Arthritis Advisory Committee which information should enable a doctor to make a approved the revised guidelines in May 1986. balanced assessment between the potential risks to the fetus and the benefits to the mother: In a separate statement it also discussed the use of dimethyl sulfoxide (DMSO) in scleroderma and it • Animal data — Any positive evidence of animal concluded that the available information did not teratogenicity, embryotoxicity, or other adverse provide adequate evidence of efficacy. effects on reproductive behaviour, including the nature of the abnormality or risk, the animal Reference: Draft Guideline for the Clinical Evaluation of species, and the timing and dose-relationships. Nonsteroidal Anti-inflammatory Drugs. Food and Drug Administration, Rockville, MD 20857, United States of • Human experience — Factual statements on any America. human population studies and any anecdotal reports.

• Interpretation —While it is always appropriate to advise against the use of drugs in pregnancy Allergen extracts and unless there is an overriding clinical need, more specific advice should be given, both for use during anaphylaxis pregnancy and in women of childbearing potential. Three categories of products are specified: United Kingdom — The Committee on Safety of Medicines issued a letter to all doctors on 8 October 1986 informing them that severe anaphy­ • use during pregnancy is acceptable, lactic reactions have occurred following treatment • use during pregnancy is advisable only if with desensitizing vaccines (allergen extracts). the disease itself carries significant risks for the mother or child, Since 1957, in the UK alone, 26 patients are known • use is contraindicated during pregnancy. to have died from anaphylaxis caused by these Reference: Committee on Safety of Medicines. British products. 11 of these patients, most of whom were Medical Journal, 293:1495 (1986). young, have died within the past six years, 5 in the WHO Drug Information Vol. 1, No.2,1987 Advisory Notices

last 18 months. In most of these cases adequate cytosis, and haemolytic anaemia) are also repre­ facilities for cardio-respiratory resuscitation were sented and these have been the subject of several not available. The frequency of anaphylaxis, both warnings by the Committee. fatal and non-fatal, may vary from 1 in 500 to 1 in 28,000 courses of treatment, according to the • The penicillins account for the greatest single nature of the extract. Patients with asthma appear number of cases — 2,502, of which 54 were fatal. to be particularly susceptible. The majority of these reactions were rashes, associated principally with ampicillin and amoxy­ It is important that doctors always carefully cillin. Nearly 200 cases of diarrhoea were reported: balance the known risks of desensitizing vaccines 42 were diagnosed as pseudomembranous colitis against their potential benefits. They should only (13 of them fatal) and 26 as colitis (4 fatal). be administered where facilities for full cardio­ respiratory resuscitation are immediately available, • Sulfonamides—The fact that only 322 adverse and patients should be kept under medical obser­ reactions were reported (11 fatal) is interpreted as vation for at least 2 hours after treatment. offering evidence of substantial under-reporting.

Reference: Committee on Safety of Medicines, United • Cefalosporins —Thirteen different cefalosporins Kingdom, letter to WHO dated 8 October 1986. accounted for 788 cases (28 fatal), the most serious being 46 cases of pseudomembranous colitis, 12 of which were fatal. 65 reports (7 deaths) of haemorrhage and coagulation defects were Sweden — The National Board of Health and Wel­ attributed to latamoxef. fare has requested producers of all marketed aller­ gen extracts to file registration applications. • Antituberculosis drugs prompted 799 reports (52 Extracts currently available may remain on the fatal cases). Blood dyscrasias accounted for 59 of market until a final decision has been taken. How­ these (6 fatal) and jaundice or hepatitis 161 (22 ever, having regard to recently reported adverse fatal). The latter were associated mainly with reactions, preparations derived from mites rifampicin and isoniazid. There were 58 reports of (Dermatophagoides pteronyssinus or D. farinae), optic neuritis, most of them associated with etham- moulds (Alternaria or Cladosporium) and certain butol, and 42 of renal impairment or failure, usually animals (horse, dog, cat) may no longer be used following treatment with rifampicin (4 fatal). except on special licence or within the framework of a clinical trial. • Aminoglycosides — Of the 299 reported reac­ tions, 30 were associated with deafness, 16 with Reference: Information från Socialstyrelsens renal impairment (2 fatal), and 7 with pseudo­ läkemedelsavdelning 1986:2, 7 April 1986 and 1986:3, membranous colitis (2 fatal). 26 May 1986. • Metronidazole was implicated in 589 reports, 7 of them fatal (one case of anaphylaxis and two of blood dyscrasias). There were also 20 reports of Adverse effects of neuropathy and 13 of paraesthesia. anti-infective drugs • Antimalarial prophylaxis — Several reports United Kingdom — The Committee on Safety of received in the period 1984-1986 cited Maloprim®, Medicines (CSM) has reviewed all reported Fansidar® and amodiaquine. Each of these drugs adverse effects of anti-infective drugs notified has been associated with agranulocytosis, and between 1964 and 1985. These constitute about some cases have been fatal. Amodiaquine is no 19% of the 150,000 "yellow card" reports received longer recommended for prophylaxis because of during this period. The highest proportion (20%) the frequency of this reaction. Fansidar® has also relate to skin reactions. However blood dyscrasias been associated with Stevens-Johnson syndrome of all types (including aplastic anaemia, agranulo­ and renal failure. Advisory Notices WHO Drug Information Vol. 1, No.2,1987

• Co-trimoxazole (trimethoprim and sulfadoxine) has been responsible for fatal aplastic anaemia more frequently in patients aged over 65 than in those under 40.

Reference: Committee on Safety of Medicines. British Medical Journal, 293:1163 (1986).

Anabolic steroids and athletic performance

United States of America — ft has been estimated that athletes spend nearly $100 million annually to obtain anabolic steroids in an endeavour to enhance their athletic performance.

Numerous approved and unapproved drug products have been used for this purpose, most of which are obtained through illicit channels. They include ethylestrenol, fluoxymesterone, metandienone, various testosterone esters, oxandrolone and nandrolone esters. Such treatment carries sub­ stantial health risks and the Food and Drug Adminis­ tration has asked manufacturers and distributors to assist in curbing unlawful diversion of supplies. It has also appealed to health professionals to report suspected improper use of these drugs.

Reference: From the Food and Drug Administration. Journal of the American Medical Association, 256:1851 (1986). WHO Drug Information Vol. 1, No.2,1987

Essential Drugs

"River blindness" affects mation on breeding habits of other Simulium vectors is needed before effective control measures can be 18 million people devised in other parts of the Americas. Control of the vectors by the specific microbial larvicide, Onchocerciasis or "river blindness", which affects Bacillus thuringiensis H-14 holds promise if more almost 18 million people, is most prevalent in tropi­ effective formulations can be developed. cal Africa, particularly along the rivers of the sa­ vanna south of the Sahara. The endemic area ex­ Essential drugs tends into the south-west Arabian peninsula and foci also exist in Central and South America. The drugs now generally used to treat the disease, and which are currently featured in WHO'S Model The disease is caused by a filarial nematode, On­ List of Essential Drugs, are unsuited for mass chocerca volvulus. Larval forms are transmitted chemotherapy. when man is bitten by an infected blackfly (Simulium damnosum and related species). These Diethylcarbamazine is more active on the microfi­ mature into adult worms or "macrofilariae" over a lariae while suramin destroys the macrofilariae, an period of one to two years, usually in subcutaneous action which is essential to the radical cure of the tissue, where they form nodules. disease. The manifest deficiencies of these drugs are evident from model prescribing sheets recently The major symptoms of the disease, intense itching prepared by WHO which are set out on the following and progressive visual impairment, are caused by pages. large numbers of migratory microfilariae shed by female worms. These lodge preferentially in the However, new hope of a more effective and less dermis where they may be picked up by the blackfly toxic approach to the treatment of this disease has vectors and in the eye where they subsequently resulted from the development of new filaricidal com­ degenerate causing local inflammation and scar­ pounds by Ciba Geigy in Switzerland and Merck, ring. Sharp & Dohme in the United States of America. Prospects are now bright that a suitable preparation Prevention of the MSD compound, ivermectin (see p. 43), can be made available, at least for limited use , before Control is primarily dependent upon the use of in­ the end of 1987. secticides to reduce the vector population at their breeding sites and teaching the communities at risk how to avoid contact with the blackfly. Diethylcarbamazine tablet 50 mg (citrate) Aerial spraying with larvicidal compounds, including temephos, chlorphoxim and permethrin has been A filaricidal piperazine derivative which is readily effective in the savanna regions of the Volta River absorbed following oral administration and is widely Basin and the campaign is being extended to other distributed in non-fatty tissues. It is excreted, areas of West Africa. However, spraying is difficult largely as urinary metabolites, within 48 hours. in forested areas, and too costly to use in lesser In onchocerciasis, it is effective only against micro­ endemic foci. In Guatemala, effective larvicidal con­ filariae. However, in lymphatic filariasis and loiasis, trol of S. ochraceum is possible but more infor­ Essential Drugs WHO Drug Information Vol. 1, No.2,1987

it kills both the microfilariae and adult worms. Contraindications and precautions Uses The drug should always be given under medical As a microfilaricide in onchocerciasis, diethyl- supervision and systemic corticosteroids should carbamazine is used: only be administered in a hospital or a special treatment centre. • in curative treatment at low initial doses under steroid cover before and after the macrofilaricide, • Pregnant women should not be treated until after suramin, initially to reduce the microfilarial load delivery. and, subsequently, to kill residual microfilariae; and • Patients with malaria should first receive a course • in suppressive treatment at intermittent low of antimalarial therapy since diethylcarbamazine dosage, to preserve sight and relieve pruritus by may provoke a severe attack. reducing the microfilarial bad. • Pulmonary tuberculosis and other contraindica­ tions to steroid therapy must be excluded or treated Dosage before dexamethasone or other corticosteroids are Curative treatment administered. Prior to suramin therapy in heavily infected patients: Adverse effects • 25 mg initially, doubled on successive days to 100 mg twice daily on day 4. Then 200 mg (4-5 mg/kg) in The Mazzotti reaction, which most patients experi­ two divided doses for 5-7 days until the microfilarial ence following their first dose of diethylcarba­ load in the skin approaches zero; mazine, results from the death of microfilariae. Its intensity depends upon the dose and the microfi­ • a course of dexamethasone 80 µg/kg daily is larial load. Less severe reactions are confined to started two days before the first dose of diethylcar¬ the skin, but severe ophthalmic and systemic bamazine to prevent a severe reaction resulting effects can occur. from the death of microfilariae (Mazzotti reaction). This dosage should be maintained for 5 days before Cutaneous component: gradual withdrawal is attempted. • An intensely irritant urtico-papular rash develops After suramin therapy: 1 -24 hours after administration.

• 200 mg daily for three days, repeated monthly, un­ • Depending on the distribution of microfilariae this til no Mazzotti reaction occurs. Steroid cover and may be confined to one limb or cover the whole low initial dosage are rarely necessary in patients body. pretreated with diethylcarbamazine. • Regional lymph nodes become swollen and tender. Suppressive treatment Ophthalmic complications: • 50-200 mg given each month in a single dose fol­ lowing a full course of treatment may keep skin and • If microfilariae are present in the conjunctiva, eyes virtually clear of microfilariae despite the cornea or anterior chamber of the eye, lachryma¬ presence of many fertile female worms. Periodic tion, photophobia, conjunctivitis and acute iridocy­ ophthalmic examinations are essential. clitis occur. WHO Drug Information Vol. 1, No.2,1987 Essential Drugs

• Symptomatic treatment may be necessary to pre­ Because it forms stable complexes with protein, vent formation of synechiae. suramin must be administered intravenously. It en­ ters the extracellular space but does not penetrate • Prolonged administration of diethylcarbamazine into the CSF. may result in inflammatory and subsequent degen­ erative changes in the optic disc and retina, which It dissociates slowly from plasma proteins and is classically cause peripheral field loss, tunnel vision detectable unchanged in the urine for up to three and night-blindness. months after the last dose. Systemic component: Uses • Postural hypotension, collapse, respiratory dis­ tress, vertigo, fever, joint pains, muscular aches As a macrofilaricide in the curative reatmentoi se­ and headache may occur. vere onchocerciasis. In heavily infected patients suramin is better tolerated if it is preceded by an • These effects can be severe and may persist for oral course of diethylcarbamazine to reduce the several days. microfilarial load. Subsequently, further short courses of diethylcarbamazine may be needed to kill residual microfilariae. Overdosage Dosage Adverse dose-related effects, including nausea, vomiting, headache, dizziness and drowsiness, Suramin is administered by slow intravenous injec­ occur only when the daily dose exceeds 30 mg/kg. tion of a 10% aqueous solution.

A total of 66.7 mg/kg is administered in six succes­ Storage sive increasing weekly doses apportioned as follows: Store in tightly closed containers.

Week 1 2 3 4 5 6 Note on other microfilaricides: Other drugs with microfilaricidal activity include metrifonate, mebendazole, and levamisole. All are less effective than Mg/kg 33 6.7 10.0 133 16.7 16.7 diethylcarbamazine. However, evidence from ongoing clinical studies indicates that a single dose of ivermectin (see p. 43) kills microfilariae gradually without evoking a Precautions for the first injection (0.2 g in 2 ml water severe Mazzotti reaction and that a low microfilarial for a 60 kg adult): because collapse has occasion­ density is maintained for at least 12 months. ally occurred, this should be administered with par­ ticular caution:

• Wait at least one minute after injecting the first Suramin sodium few µl powder for injection 1 g vial • Inject the next 0.5 ml over 30 seconds and wait one minute. Suramin in adequate doses kills the adult worms re­ • Inject the remainder over several minutes. sponsible for onchocerciasis. Microfilariae are somewhat more resistant. Essential Drugs WHO Drug Information Vol. 1, No.2,1987

Contraindications and precautions Indirect reactions attributable to the death of Suramin is an extremely toxic drug. It should al­ the parasites include: ways be given under medical supervision. To avoid unacceptable toxicity in heavily infected patients • urticaria, swelling, tenderness and abscess for­ at risk of reinfection, it is often preferable to reduce mation around adult worms; the parasite load with diethylcarbamazine rather than to attempt a radical cure. • painful immobilization of the hip resulting from an inflammatory reaction around worm bundles against The general condition of the patient should first be the joint capsule; improved as far as possible and a satisfactory food and fluid intake maintained throughout treatment. • an intensely irritant urtico-papular rash associated Treatment should be discontinued immediately in with death of microfilariae; patients who develop serious adverse effects in­ cluding heavy albuminuria with casts. • inflammatory and subsequent degenerative changes in the optic nerve and retina resulting from Suramin should not be administered to: the death of intraocular microfilariae; and

• old or infirm individuals or patients with severe • swollen painful joints, particularly in the hands and hepatic or renal disease who may not be strong feet, possibly due to the formation of immune com­ enough to withstand its effects; plexes.

• totally blind patients, unless they require relief Storage from intensely irritant skin lesions; Store in well-closed containers protected from light. • lightly to moderately-infected subjects who have no symptoms and whose eyes are not at risk; and

• pregnant women who should be treated after Note on other macrofilaricides: Suramin is the delivery. only drug in routine use. Another compound, CGP 6140, is now at an early stage of clinical evaluation.

Adverse effects Adverse effects result either from the innate toxic Accelerated stability studies ity of the drug or its filaricidal action. under simulated tropical Direct toxic effects conditions • Toxic effects that call for immediate withdrawal of treatment include rare cases of potentially fatal Many pharmaceutical substances are known to collapse during the first injection, heavy albumin­ deteriorate during distribution and storage, uria, stomal ulceration, exfoliative dermatitis, se­ particularly in the hot, humid climates that prevail in vere diarrhoea, prolonged high fever and prostra­ many developing countries. The World Health tion. Organization has commissioned a systematic • Less severe symptoms, which are common, in­ survey of the stability of many widely used clude tiredness, anorexia, malaise, polyuria, in­ substances contained within its Model List of creased thirst and tenderness of the palms and Essential Drugs and has developed simplified tests soles. to detect or exclude gross degradation of the least WHO Drug Information Vol. 1, No.2,1987 Essential Drugs

stable substances. As well as providing information held in Lagos in December 1986 that the country on stability this report provides detailed information has adopted an Essential Drugs List (EDL). The list, on which substances are degradable and which are which is adapted from the WHO model list, resistant to degradation. comprises 205 essential drugs. Only listed drugs will be used in government hospitals and other Reference: Accelerated Stability Studies of Widely institutions and it is anticipated that this will both Used Pharmaceutical Substances under Simulated rationalize prescribing and at the same time Tropical Conditions, document WHO/PHARW86.529, eliminate ineffective, overpriced, unsafe medicines World Health Organization, 1211 Geneva 27, Switzerland. and irrational combinations.

The editor of the Pharmacy World, If eanyi Atueyi, Sensitivity of Plasmodium says that since these drugs will be identified only by their generic names, some resentment will be falciparum to quinine and evoked in drug manufacturers who are implicitly mefloquine in Thailand required to "trail the simple and common path towards primary health care goals". He anticipates Thailand — Between 1982 and 1984 a regimen of that the change to generic prescribing will lower quinine and tetracycline was routinely used in drug costs because investment in brand name Thailand to treat outpatients with microscopically promotion will be reduced and because prices of confirmed falciparum malaria. Due in part to inad­ products sold under the same generic name will be equate compliance with the 7-day multiple-dose more responsive to market forces. regimen, the recrudescence rate was as high as 30%. The author also acknowledges that experience in other countries has shown that manufacturers Epidemiologically-based studies undertaken in four invariably resist the introduction of essential drugs areas of Thailand also indicated that the sensitivity lists and that, in some instances, they have of P. falciparum to quinine was decreasing attempted to undermine governmental efforts significantly with time. A less marked reduction in through litigation. He expresses confidence, how­ sensitivity to the structurally-related drug ever, that any adverse financial effect this decision mefloquine was also detected. These findings may have on private industry will be more than emphasize the urgent need for an effective, compensated by the advantages of the Essential acceptable, single-dose treatment for falciparum Drugs List to the nation. malaria. Lastly, he expresses the hope that manufacturers Reference: Suebsaeng, L. et al. Sensitivity to quinine will demonstrate social conscience by voluntarily and mefloquine of Plasmodium falciparum in Thailand. withdrawing any hazardous and irrational drugs Bulletin of the World Health Organization, from the market and by directing their efforts to 64:759-765(1986). respond to health needs.

The introduction of the Essential Drugs List calls for understanding and committed cooperation from the Nigeria adopts an pharmaceutical industry and, not least, strong essential drugs list political will on the part of the government. Reference: Editorial by Ifeanyi Atueyi, The debut of Nigeria — The Federal Minister of Health, Prof. essential drugs list. Pharmacy World, 3:2 (1986). Olikoye Ransome-Kuty, announced at a meeting Essential Drugs WHO Drug Information Vol. 1, No.2,1987

Sudan's new drug policy and essential drugs list

Sudan—The national health authorities, with the assistance of the World Health Organization and the United Nations Industrial Development Organization, have formulated both a national drug policy and a list of essential drugs. The list, which was first published in 1983, and is currently being revised, contains about 400 active substances and 600 dosage forms.

It is claimed that since the list came into use shortages of essential drugs have been fewer and less severe and that the selection, procurement, management, distribution, registration and control of drugs has become more efficient. Another less predictable consequence of the policy is that the contribution of the indigenous drug industry to total sales has increased from 5% to about 20%. The list has apparently left the country's manufacturers in no doubt about the types and quantities of drugs that are principally needed.

Reference: Ali, H. M. et al. Sudan's new drug policy proves its worth. World Health Forum, 7:256-258 (1986). WHO Drug Information Vol. 1, No.2,1987

Recent Publications

Essential malariology tricular tachycardia, vagal stimulation should be tried first; if the tachycardia continues, verapamil in United Kingdom — The second edition of this doses of 5 mg to a total of 50 mg should be book by Leonard Jan Bruce-Chwatt is more broadly- administered intravenously under close ECG- and based than the first. The world's malaria situation blood surveillance. In atrial flutter and fibrillation, has deteriorated in recent years. Because of electroconversion should be considered in cases of adverse social and economic conditions many fibrillation/flutter of no more than a few days' developing countries have been unable to standing. Digitalis remains the treatment of first implement an effective strategy for malaria control choice to normalize ventricular rates in patients (which is now accepted as a more realistic with chronic atrial fibrillation/flutter. Prophylactic objective than malaria eradication). treatment with quinidine may be used to maintain rhythm following electroconversion. In ventricular tachycardia and fibrillation that has persisted for Some 1600 million people throughout the world more than 30 seconds, immediate defibrillation is remain exposed to considerable risk of infection. indicated. Failing this, lidocaine is the drug of The message is emphasized that any country that choice. institutes a malaria control campaign must organize it as a component of its primary health care system, keeping in mind the need for a nucleus of Reference: Workshop on Pharmacological Treatment of Cardiac Tachyarrhythmias, National Board of Health and specialized professional expertise. Welfare, Drug Information Committee, Uppsala, Sweden (1986). in addition to providing a scientific account of recent advances in the parasitology, entomology, epidemiology and immunology of malaria, the new edition contains a detailed description of Medicinal products for use in prevention, diagnosis, treatment and control of malaria in both developing and developed self-medication countries. The WHO Regional Office for Europe has issued guidelines for the assessment of medicinal The text and illustrations are so clearly presented products used in self-medication. The term "assess­ that the book serves not only as a standard work for malariologists but also as an effective primer in ment" is used rather than "clinical evaluation" since the subject for all health personnel. the guidelines are concerned with the review of existing data and experience rather than the Reference: L. J. Bruce-Chwatt, Essential Malariology, generation of new data through clinical Heinemann, London, 1985. investigation, though the latter may on occasion be necessary. The document is not intended as a basis for regulation, nor is it intended to set an administrative or legal standard. It is hoped that it will promote research, constructive discussion and Treatment of cardiac the development of a more rational approach to the tachyarrhythmias principle of self-medication.

The Swedish Drug Information Committee has Reference: Guidelines for the Assessment of Medicinal recently reviewed the treatment of tachyarrhyth­ Products for Use in Self-Medication, World Health mias. It advises that in paroxysmal supraven­ Organization Regional Office for Europe, Copenhagen, Denmark. Recent Publications WHO Drug Information Vol. 1, No.2,1987

Drugs in hospitals cal and physical, and to ensure appropriate selec­ tion of excipients. The WHO Regional Office for Europe has issued the report of the 14th European Symposium on The handbook, which has taken 11 years to pro­ Clinical Pharmacological Evaluation in Drug Control duce, involves 200 contributors and contains 148 held in November 1985. The introduction discusses monographs on the most commonly used general aspects of drug use in hospitals and the excipients in pharmaceutical formulations. body of the report describes the objectives of hospital drug and formulary committees, reviews Reference: Handbook of Pharmaceutical Excipients. the problems of drug supply in hospitals and American Pharmaceutical Association, Washington, United States of America, and Pharmaceutical Society of analyses the relationship of hospital drug therapy Great Britain, London, United Kingdom. to general practice.

Reference: Drugs in Hospitals, Provisional edition, 1986, World Health Organization Regional Office for Drug information for Europe, Copenhagen, Denmark. the health care provider

United States of America— The 6th edition Pharmaceutical regulation of this two-volume series has recently been published by the United States Pharmacopeial in Italy Convention.

Italy—A book in English entitled "Pharmaceutical Volume I provides drug information for doctors, Regulatory Activities in Italy" and edited by Duilio pharmacists, nurses and other health care person­ Poggiolini, Director-General of the Pharmaceutical nel. Each drug or drug combination is presented as Department of the Ministry of Health, provides a a monograph which includes concise sections on comprehensive overview of the drug regulatory pharmacological properties, clinical indications, process. Information is included on economic chemistry, pharmacokinetics, precautions, ad­ aspects of pharmaceutical production in Italy as verse effects as well as information on dosage and well as details of current requirements for drug dosage forms. It is supplemented regularly as part registration. Space is also devoted to international of a continuing subscription service. activities, particularly within the EEC. Volume II contains a parallel series of monographs Reference: Pharmaceutical Regulatory Activities in which are intended to provide answers to patients' Italy, E. I. S., Reginharstrasse 34, 5060 Bergisch- concerns about the medicines they are receiving. Gladbach, Federal Republic of Germany. Reference: Drug Information for the Health Care Provider. United States Pharmacopeial Convention, Inc., Rockville, MD 20852, United States of America. A handbook of pharmaceutical excipients Pharmaceutical The Pharmaceutical Society of Great Britain and the American Pharmaceutical Association have administration in Japan issued a joint publication on pharmaceutical excipi­ ents. It is widely assumed that excipients are inert The 3rd Edition of Pharmaceutical Administration in substances, but they can, on occasion, interfere Japan has just been published under the aegis of with active ingredients in drug dosage forms. the Pharmaceutical Affairs Bureau, Ministry of Preformulation studies always need to be under­ Health and Welfare. In particular, it provides, both taken to identify potential interactions, both chemi­ in English and Japanese, information on the whole WHO Drug Information Vol. 1, No.2,1987 Recent Publications

range of governmental pharmaceutical services. In comprehensive management of cancer pain, edu­ particular it describes the mechanisms of pharma­ cation and training of health personnel, legal con­ ceutical administration, the Pharmaceutical Affairs siderations and the abuse potential of analgesics. Law, the procedure for approval of drugs and related products, and other activities aimed at Reference: Cancer Pain Relief, World Health Organiza­ ensuring drug safety and for providing compen­ tion, 1986,1211 Geneva 27, Switzerland. sation to drug-induced injury. Many tables and charts are included in the book.

Reference: Pharmaceutical Administration in Japan. Human experimentation: Pharmaceutical Affairs Bureau, Ministry of Health and legal and ethical aspects Welfare, Japan. United States of America — Alexander M. Capron of the Law Center, University of Southern California, has undertaken a comprehensive review Treatment of sexually of the legal and ethical aspects of human exper­ transmitted diseases imentation. His book begins with an examination of terminology and presents a justification for Sweden —The Drug Information Committee of the research using human subjects. It provides an National Board of Health and Welfare publishes, historical survey of major developments and from time to time, comprehensive "state-of-the-art" concludes with a description of the system now in reviews on the therapeutic management of specific use in the United States. The final section explores diseases. The latest booklet in this series reviews a number of currently relevant ethical and social the treatment of sexually transmitted diseases and issues including specific problems in surgical exper­ particularly of infections caused by the gono¬ imentation; the degree to which commercial coccus, Chlamydia trachomatis, herpes simplex pressures contribute to the demand for virus and human papilloma viruses as well as non­ comparative drug testing; problems in social and specific bacterial genital infections. psychological studies; difficulties in performing potentially valuable but intrinsically risky Reference: Workshop on Treatment of Sexually experiments; and the barriers to conducting Tansmitted Dseases, National Board of Health and research on vulnerable subjects, including children Welfare, Drug Information Committee, Uppsala, Sweden, and the unborn. 1986. Reference: A. M. Capron, Human experimentation, BioLaw, A Legal and Ethical Reporter on Medicine, Health Care, and Bioengineering, University Publications of Cancer pain relief America, 1986.

A "three-step ladder" approach to treatment of cancer pain has been proposed in a booklet published by the World Health Organization. It is Drug consumption in Norway based upon the sequential use of increasingly Norway—The Norwegian Medicinal Depot has potent oral analgesics ranging from non-opioids published its sixth yearbook which provides (paracetamol and acetylsalicylic acid) to mild information on drug consumption in Norway from (codeine) and then strong (morphine) opioids with 1981 to 1985. An original feature of this publication the aim of keeping the patient free from pain. is the inclusion of commentaries on the statistical material which focus on issues of current It is emphasized that analgesics need to be given therapeutic importance. every four to six hours, and not "as required". The practicability of this approach has been Reference: The Drug Consumption in Norway 1981- demonstrated in studies carried out in both Japan 1985, Norwegian Medicinal Depot, P. O. Box 100, and Italy. The booklet includes sections on the Veitvet,0518 Oslo 5, Norway. Recent Publications WHO Drug Information Vol. 1, No.2,1987

Drug information bulletin Spanish and Russian is distributed free of charge. No. 77,1986, contains reviews on new non- from Chile glycoside cardiotonic substances, hormonal contraception, the efficacy of carbamazepine and a Chile — The Drug Control Department of the listing of new drugs developed within the National Institute of Public Health publishes a drug pharmaceutical industry of the GDR. information bulletin on a regular basis that includes updates on approved information sheets for Reference: Medicamentum, Glienicker Weg 125/127, selected drugs. The July 1986 issue features 1199 Berlin-Adlershof, German Democratic Republic. amiodarone, domperidone and interferon. Another section, which is intended to maintain doctors' awareness of drug-related risks and to engage their collaboration in reporting them, deals with the An international society monitoring of adverse reactions to drugs. of editors of drug bulletins

Reference: BoletinInformativ osobre Medicamentos, India — In the latest issue of its Drugs Bulletin the Departamento Control Nacional, Ministerio de Salud Department of Pharmacology of the Postgraduate Pública de Chile, Avda. Marathon N° 1000, Santiago, Institute of Medical Education and Research in Chile. Chandigarh provides a commentary on the first meeting of Editors of Drug Bulletins held in Madrid in May, 1985 at which the International Society of Drug Bulletins was inaugurated. The establishment A magazine for physicians of the Society is regarded as an important milestone in the dissemination of independent and pharmacists from the information on drugs especially in developing German Democratic countries — which are in greatest need of such Republic services — and in the promotion of rational and economic use of drugs. German Democratic Republic— A quarterly magazine entitled Medicamentum and published by Reference: Drugs Bulletin, Vol. 9, No. 4, Department of Pharmacology, Postgraduate Institute of Medical the national health authority in English, French, Education and Research, Chandigarh, India. WHO Drug Information, 1987 Vol 1, No.' 2 International Nonproprietary Names for Pharmaceutical Substances

In accordance with article 3 of Comments on, or formal ob­ The inclusion of a name in the lists the Procedure for the Selection jections to, the proposed names of proposed international nonpro­ of Recommended International may be forwarded by any person prietary names does not imply any Nonproprietary Names for Phar­ to the Pharmaceuticals unit of recommendation for the use of the maceutical Substances,1 notice is the World Health Organization substance in medicine or pharmacy. hereby given that the following within four months of the date of names are under consideration their publication in WHO Drug by the World Health Organiza­ Information, e.g., for List 57 tion as Proposed International Prop. INN not later than 31 Oc­ Nonproprietary Names. tober 1987.

Proposed International Nonproprietary Names (Prop. INN): List 572 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number

adibendanum 5,7-dihydro-7.7-dimethyl-2-(4-pyridyl)pyrrolo[2,3-f]benzimidazol-6(3H)-one adibendan C16H14N4O 100510-33-6

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. 6, 1982, World Health Organization, Geneva (ISBN 92 4 056013 0) (price: Sw. fr. 55.-). 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 April 1982. The printout also indicates in which of the 47 individual lists of proposed names and 21 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 See Annex 1. 2 Other lists of proposed and recommended international nonproprietary names can be found in Cumulatire List No. 6, 1982. Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number

aloxistatinum ethyl (+ )-(2S,3S)-2,3-epoxy-N-[(S)-1-(isopentylcarbamoyl)-3- aloxistatin methylbutyl]succinamate C17H30N2O5 88321-09-9

anaritidum L-arginyl-L-seryl-L-seryl-t-cysteinyl-L-phenylalanylglycylglycyl-L-arginyl-L-methyl anaritide ionyl-L-aspartyl-L-arginyl-L-isoleucylglycyl-L-alanyl-L-glutaminyl-L-serylglycyl- L-leucylglycyl-L-cysteinyl-L-asparaginyl-L-seryl-L-phenylalanyl-L-arginyl- L-tyrosine cyclic (4-20)-disulfide C112H175N39035S3 95896-08-5

argatrobanum (2R,4R)-4-methyl-1-[(S)-N2-[[(RS)-1,2,3,4-tetrahydro-3-methyl-8-quinolyl]- argatroban sultonyl]arginyl]pipecolic acid C23H36N605S 74863-84-6

bemarinonum 5,6-dimethoxy-4-methyl-2(1H)-quinazolinone bemarinone C11H12N2O3 92210-43-0 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name {Latin, English) Chemical Abstracts Service (CAS) registry number

benexatum benzyl salicylate, trans-4-(guanidinomethyl)cyclohexanecarboxylate benexate C23H27N3O4 78718-52-2

beperidii iodidum cis-1-ethyl-4-hydroxy-1-methylpiperidinium iodide ( + )-a-(hexahydro-1H- beperidium iodide azepin-1-yl)-,1,2-benzisoxazole-3-acetate, mixture with frans-1-ethyl-4- hydroxy-1-methylpiperidinium iodide (±)-a-(hexahydro-1H-azepin-1-yl)-1,2- benzisoxaxole-3-acetate (1:1) C23H34IN3O3 86434-57-3

bermoprofenum (± )-10,11-dihydro-fi,8-dimethyl-11-oxodibenz[b,r]oxepin-2-acetic acid bermoprofen C18H16O4 72619-34-2

bifeprofenum ( + )-2'-chloro-α-methyl-4-biphenylacetic acid, ester with 1-glycoloyl-4- bifeprofen methylpiperazine C22H25CIN2O3 108210-73-7

bisfentidinum N-isopropyl-N'-[p-(2-methylimidazol-4-yl)phenyl]formamidine bisfentidine C14H18N4 96153-56-9 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number

cefepimum 1-[[(6R,7R)-7-[2-(2-amino-4-thiazolyl)glyoxylamido]-2-carboxy-8-oxo-5-thia-1- cefepime azabicyclo[4.2.0]oct-2-en-3-yl]methyl-1-methylpyrrolidinium hydroxide, inner salt, 72-(Z)-(0-methyloxime) C19H24N6O5S2 88040-23-7

cefmepidii chloridum 4-[[[(6R,7R)-7-[2-(2-amino-4-thiazolyl)glyoxylamido]-2-carboxy-8-oxo-5-thia-1- cefmepidium chloride azabicyclo[4.2.0]oct-2-en-3-yl]methyl]thio]-1-methylpyridinium chloride 72-(Z)-[O-(1-carboxy-1-methylethyl)oxime] S-oxide C23H25CIN6O8S3 107452-79-9

cefpodoximum (±)-1-hydroxyethyi ( + )-(6R,7R)-7-[2-(2-amirto-4-thiazoiyl)glyoxylamido]-3- cefpodoxime (methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, 72- (Z)-(O-methyloxime), isopropyl carbonate (ester) C21H27N5O9S2 87239-81-4

clopidogrelum methyl (+ )-α-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4W)-acetate clopidogrel C16H16CINO2S 94188-84-8

daltrobanum [p-[2-(p-chlorobenzenesulfonamido)ethyl]phenyl]acetic acid daltroban C16H16CINO4S 79094-20-5 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number

datelliptii chloridum 2-[2-(diethylamino)ethyl]-9-hydroxy-5,11-dimethyl-6H-pyrido[4,3-6]- datelliptium chloride carbazolium' chloride C23H28CIN3O 105118-14-7

dexamethasoni acefuras 9-fluoro-11ß,17,21-trihydroxy-16a-methylpregna-1,4-diene-3,20-dione 21- dexamethasone acefurate acetate 17-(2-fuorate) C29H33FO8 83880-70-0

dobupridum 4-amino-2-butoxy-5-chloro-N-[1-(1,3-dioxolan-2-ylmethyl)-4-piperidyl]benz- dobupride amide C20H30CIN3O4 106707-51-1

dramedilolum acetone (± )-[6-[3-[(3,4-dimethoxyphenethyl)amino]-2-hydroxypropoxy]-3- dramedilol pyridazinyl]hydrazone C20H29N5O4 76953-65-6

droxidopa (- )-threo-3-(3,4-dihydroxyphenyl)-L-serine droxidopa C9H11NO5 23651-95-8 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number

ebrotidinum p-bromo-N-[[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]- ebrotidine thio]ethyl]amino]rnethylene]benzenesulfonamide C14H17BrN6O2S3 100981-43-9

eltoprazinum 1-(1,4-benzodioxan-5-yl)piperazine eltoprazine C12H16N2O2 98224-03-4

elziverinum 6,7-dimethoxy-4-[[4-(o-methoxyphenyl)-1-piperazinyl]methyl]-1-veratryliso- elziverine quinoline C32H37N3O5 95520-81-3

eprovafenum 5-(3-phenylpropyl)-2-thiophenevaleric acid eprovafen C18H22O2S 101335-99-3

epsiprantelum (±)-2-(cyclohexylcarbonyl)-2,3,6,7,8,12b-hexahydropyrazino[2,1-a][2]benz- epsiprantel azepin-4(1H)-one C20H26N2O2 98123-83-2 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number

etanidazolum N-(2-hydroxyethyl)-2-nitroimidazole-1-acetamide etanidazole C7H10N4O4 22668-01-5

etofenproxum α-[(p-ethoxy-ß,ß-dimethylphenethyl)oxy)-/77-phenoxytoluene etofenprox C25H28O3 80844-07-1

exametazimum (±)-(3RS, 3'RS)-3,3'-[(2,2-dimethyltrimethylene)diimino]di-2-butanone exametazime dioxime C13H28N4O2 105613-48-7

fotemustinum (+ )-diethyl [1-[3-(2-chloroethyl)-3-nitrosoureido]ethyl]phosphonate fotemustine C9H19CIN3O5P 92118-27-9

guaisteinum thioacetic acid, S-ester with ( + )-3-(mercaptoacetyl)-2-[(o- guaisteine methoxyphenoxy)methyl]thiazolidine C15H19NO4S2 103181-72-2 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number

ibacitabinum 2'-deoxy-5-iodocytidine ibacitabine C9H12IN3O4 611-53-0

indolidanum 3,3-dimethyl-5-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)-2-indolinone indolidan C14H15N3O2 100643-96-7

iobenguanum (131l) (m-iodo-131/-benzyl)guanidine 131 131 iobenguane ( l) C8H10 IN3 77679-27-7

lacidipinum 4-[o-[(E)-2-carboxyvinyl]phenyl]-1,4-dihydro-2,6-dimethyl-3,5-pyridine- lacidipine dicarboxylic acid, 4-terf-butyl diethyl ester C26H33N06 103980-78-4

levocarnitinum (L-3-carboxy-2-hydroxypropyl)trimethylammonium hydroxide, inner salt levocarnitine C7H15NO3 541-15-1 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number

levofenfluraminum (- )-(R)--ethyl-a-methyl-m-(trifluoromethyl)phenethylamine levofenfluramine C12H16F3N 37577-24-5

lixazinonum N-cyclohexyl-N-methyl-4-[ (1,2,3,5-tetrahydro-2-oxoimidazo[2,1-5]quinazolin-7- lixazinone yl)oxy]butyramide C21H28N4O3 94192-59-3

lodaxaprinum 1-[6-(o-chlorophenyl)-3-pyridazinyl]-4-piperidinol lodaxaprine C15H16CIN3O 93181-81-8

loperamidum oxidum (rans-4-(p-chlorophenyl)-4-hydroxy-A/,W-dimethyl-«,«-diphenyl-1-piper- loperamide oxide idinebutyramide 1-oxide C29H33CIN2O3 106900-12-3 Proposed Internationa! Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number

lorcinadolum (E)-3-chloro-6-(4-cinnamyl-1-piperazinyl)pyridazine lorcinadol C17H19CIN4 104719-71-3

lovastatinum (S)-2-methylbutyric acid, 8-ester with (4R,6R)-6-[2-[(1S,2S,6fl,8S,8afi)- lovastatin 1,2,6,7,8,8a-hexahydro-8-hydroxy-2,6-dimethyl-1-naphthyl]ethyl]tetrahydro-4- hydroxy-2H-pyran-2-one C24H36O5 75330-75-5

loxiglumidum (±)-4-(3,4-dichlorobenzamido)-N-(3-methoxypropyl)-W-pentylglutaramic acid loxiglumide C21H30CI2N2O5 107097-80-3

mafoprazinum 4'-[3-[4-(o-fluorophenyl)-1-piperazinyl]propoxy]-m-acetanisidide mafoprazine C22H28FN3O3 80428-29-1

midaglizolum (± )-2-[α-(2-imidazolin-2-ylmethyl)benzyl]pyridine midaglizole C16H17N3 66529-17-7 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number

molfarnatum 3,7,11-trimethyl-2,6,10-dodecatrienyl 4,8,12-trimethyl-3,7,11-tridecatrienoate molfarnate C31H50O2 83689-23-0

niguldipinum ( + )-3-(4,4-diphenylpiperidino)propyl methyl 1,4-dihydro-2, niguldipine 6-dirnethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate C36H39N3O6 102993-22-6

nuclomedonum (±)-6-(p-chlorobenzyl)-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-5,7(6H)-dione nuclomedone C13H11CIN2O2S 75963-52-9

orbutoprilum (2S,3aS,7aS)-1-[(S)-N-[(S)-1-carboxypentyl]alanyl]hexahydro-2-indoline- orbutopril carboxylic acid, 1-ethyl ester C20H34N2O5 108391-88-4

parodilolum (±)-1-[(2-indol-3-yl-1,1-dimethylethyl)amino]-3-(indol-4-yloxy)-2-propanol parodilol C23H27N3O2 103238-56-8 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number

pelanserinum 3-[3-{4-phenyl-1-piperazinyl)propyl]-2,4(1H,3H)-quinazolinedione pelanserin C21H24N4O2 2208-51-7

pimonidazolum (+ )-α-[(2-nitroirnidazol-1-yl)rnethyl]-1-piperidineethanol pimonidazole C11H18N4O3 70132-50-2

pirtenidinum 1,4-dihydro-1-octyl-4-(octyIimino) pyridine pirtenidine C21H38N2 103923-27-9

pravastatinum ( + )-(PR,8R,1S,2S,6S,8S,8afl)-1,2,6,7,8,8a-hexahydro-P,8,6,8-tetrahydroxy-2 pravastatin methyl-1-naphthaleneheptanoic acid, 8-[(2S)-2-methylbutyrate] C23H36O7 81093-37-0

ramoplaninum factor A2 of the antibiotic complex A/16686 produced by Actinoplanes sp. ramoplanin ATCC 33076 empirical molecular formula C119H154CIN21O40

ranolazinum ( + )-4-[2-hydroxy-3-(o-methoxyphenoxy)propyl]-1-piperazineaceto-2',6'- ranolazine xylidide C24H33N3O4 95635-55-5 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number

retelliptinum 1-[[3-(diethylamino)propyl]amino]-9-methoxy-5,11-dimethyl-6H-pyrido[4,3-i)]- retelliptine carbazole C25H32N4O 72238-02-9

rilmenidinum 2-[{dicyclopropylmethyl) amino]-2-oxazoline rilmenidine C10H16N2O 54187-04-1

risperidonum 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino]ethyl]-6J,8,9-tetrahydro-2- risperidone methyl-4H-pyrido[1,2-a]pyrimidin-4-one C23H27FN4O2 106266-06-2

rocastinum (+ )-2-[2-(dimethylamino)ethyl]-3,4-dihydro-4-methylpyrido[3,2-f]-1,4-ox- rocastine azepine-5(2H)-thione Cl3H19N3OS 91833-77-1

ronactololum (+ )-4'-[2-hydroxy-3-(isopropylamino)propoxy]-p-anisanilide ronactolol C20H26N2O4 90895-85-5 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number

rotraxatum p-[[trans-4-(aminomethyl)cyclohexyl]carbonyl]hydrocinnamic acid rotraxate C17H23NO3 92071-51-7

rufloxacinum 9-fluoro-2,3-dihydro-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4- rufloxacin benzothiazine-6-carboxylic acid C17H18FN3O3S 101363-10-4

seglitidum cyclo(N-methyl-L-alanyl-L-tyrosyl-D-tryptophyl-L-lysyl-L-valyl-L-phenyl- seglitide alanyl) C44H56N8O7 81377-02-8

sibutraminum (±)-1-(p-chlorophenyl)-a-isobutyl-A/,A/-dimethylcyclobutan§methylamine sibutramine C17H26CIN 106650-56-0 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number

sizofiranum Schizophyllan or Poly[3-(0-p-D-glucopyranosyi-(1->3)-0-[f3-D- sizofiran glucopyranosyl-(1-*6)]-0-p-D-glucopyranosyl-(1->3)-0-(3-D-glucopyr- anosyl)-1] (C24H40O20)n 9050-67-3

somatorelinum growth hormone-releasing factor (human) somatorelin C215H358N72O66S 83930-13-6

tameridonum 7-[2-(4-indol-3-ylpiperidino)ethyl]theophylline tameridone C22H26N6O2 102144-78-5

tifuracum 7-[p-(methylthio)benzoyl]-5-benzofuranacetic acid tifurac C18H14O4S 97483-17-5

tigemonamum [[[(Z)-(2-amino-4-thiazolyl)[[(3S)-1-hydroxy-2,2-dimethyl-4-oxo- tigemonam 3-azetidinyl]carbamoyl]rnethylene]amino]oxy]acetic acid hydrogen sulfate (ester) C12H15N5O9S2 102507-71-1 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number

tilisololum ( + )-4-[3-(tert-butylamino)-2-hydroxypropoxy]-2-methylisocarbostyril tilisolol C17H24N2O3 85136-71-6

tilmicosinum 4A-O-de(2,6-dideoxy-3-C-methyl-a-L-r/t)O-hexopyranosyl)-20-deoxo-20-(c/s-3,5- tilmicosin dimethylpiperidino)tylosin C46H80N2O13 108050-54-0

tiospironum N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-1,1-cyclopentanediacet- tiospirone imide C24H32N4O2S 87691-91-6

tiprotimodum 2-[(3-carboxypropyl)thio]-4-methyl-5-thiazoleacetic acid tiprotimod C10H13NO4S2 105523-37-3

topiramatum 2,3:4,5-di-0-isopropylidene-)3-D-1ructopyranose sulfamate topiramate C12H21NO8S 97240-79-4 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number

urofollitropinum a preparation of menopausal gonadotropin extracted from human urine, urofollitropin but possessing negligible luteinising hormone (LH) activity

vadocainum (+ )-6'-methoxy-2-methyl-1-piperidinepropiono-2',4'-xylidide vadocaine C18H28N2O2 72005-58-4

vesnarinonum 1-(1,2,3,4-tetrahydro-2-oxo-6-quinolyl)-4-veratroylpiperazine vesnarinone C22H25N3O4 81840-15-5

vinorelbinum 3',4'-didehydro-4'-deoxy-8'-norvincaleukoblastine vinorelbine C45H54N4O8 71486-22-1 AMENDMENTS TO PREVIOUS LISTS

Supplement to Vol. 32, No. 9, 1978 Proposed International Nonproprietary Names (Prop. INN): List 40 p. 7 cinoquidoxum replace graphic formula by: cinoquidox

Supplement to Vol. 34, No. 9, 1980 Proposed International Nonproprietary Names (Prop. INN): List 44

p. 8 ciadoxum replace graphic formula by: ciadox

Supplement to Vol. 38, No. 2, 1984 Proposed International Nonproprietary Names (Prop. INN): List 51 p. 2 ademetioninum replace chemical name, graphic formula and CAS reg. no. by the following: ademetionine (+)-5'-[(R*)-[(R*)-3-amino-3-carboxypropyl]methylsulfonio]-5'-deoxy- adenosine hydroxide, inner salt 17176-17-9 Supplement to Vol. 40, No. 1, 1986 Proposed International Nonproprietary Names (Prop. INN): List 55

p. 2 ardacinum add the following graphic formula: ardacin

p. 17 tetronasinum replace molecular formula by: C35H54O8 tetronasin p. 20 omoconazolum delete 4991 rev. and insert the following CAS reg. no.: 105102-19-0 omoconazole 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 which a name is being consid­ 1. Proposals for recommended inter­ not be selected by the World Health ered; national nonproprietary names shall Organization as a recommended in­ be submitted to the World Health Or­ (iv) set forth the time within which ternational nonproprietary name while ganization on the form provided comments and objections will there exists a formal objection thereto therefor. be received and the person and 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 as nated for this purpose, for considera­ C. In forwarding the notice, the Di­ cordance with subsection A of artio tion in accordance with the "General rector-General of the World Health 3 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 commended international nonpro­ appended to this procedure. The necessary to prevent the acquisition prietary name. name used by the person discovering of proprietary rights in the proposed 8. In forwarding a recommended in­ or first developing and marketing a name during the period it is under ternational nonproprietary name to pharmaceutical substance shall be consideration by the World Health Or­ Member States under article 7, the accepted, unless there are compelling ganization. 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 1 ganization. name is being considered. take such steps as are necessary to prevent the acquisition of proprietary 5. A formal objection to a proposed A. Such notice shall be given by 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. letter to Member States and to na­ of publication, under article 3, of the name in the Chronicle of the World tional pharmacopoeia commissions or 1 * Text adopted by the Executive Board of WHO other bodies designated by Member Health Organization. in resolution EB15.R7 {Off. Rec Wld Hlth Org.. States. A. Such objection shall: 1955, 60, 3) and amended by the Board in resolu­ 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 changed to (iii) set forth the reasons for his ob­ WHO Chronicle in January 1959. From 1987 cerned with a name under con­ 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 conveniently long and should not be These primary principles are to be the acid name, e.g. "oxacillin" and liable to confusion with names in implemented by using the following "oxacillin sodium", "ibufenac" and common use. secondary principles "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 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 particularly for new groups. There 8. Provided that the names suggested 1 stance and not in the amine-salt style. are in accordance with these princi­ are many other stems in active use. 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- -astum -ast anti-asthmatic, anti-allergic substances not acting primarily as antihistaminics -astinum -astine antihistaminics -azepamum -azepam substances of the diazepam group -bactamum -bactam ß-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 ß-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 -relinum -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- vinca type alkaloids -vin- -vin-

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. 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 genera! 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 reasons for, and the implications of, {Nonproprietary Names for Pharmaceutical Sub­ The official texts relating to the stances. Twentieth Report of the WHO Expert the change are fully discussed. Also procedures for selecting, and general Committee), ISBN 92 4 120581 4. Price: Sw. fr. 6

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