WHO Drug Information Vol. 03, No. 4, 1989

WHO DRUG

INFORMATION

VOLUME 3 • NUMBER 4 • 1989

PROPOSED INN LIST 62 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 (INN). Its contents reflect, but do stimulating discussion not only not present, WHO policies and ac­ in these columns but wherever tivities and they embrace socio­ relevant decisions on this subject economic as well as technical mat­ have to be taken. ters. WHO Drug Information is pub­ The objective is to bring issues that lished 4 times a year in English and are of primary concern to drug French. regulators and pharmaceutical manufacturers to the attention of a Annual subscription: Sw.fr. 50.— wide audience of health profes­ Airmail rate: Sw.fr. 60.— sionals and policy-makers con­ Price per copy: Sw.fr. 15.—

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

ISSN 1010-9609 WHO Drug Information Vol. 3, No. 4, 1989 World Health Organization, Geneva

WHO Drug Information

Contents

General Policy Topics Ethylene oxide: a potential carcinogen? 183 Hair restorers on prescription only 184 Reserve antibiotics 165 Mefloquine: restrictive labelling 184 Metamizole: withdrawal of combination Personal Perspectives products 184 Counterfeit medicines: a problem Sulfonamides: suppository formulations of today 167 withdrawn 185 L-Tryptophan supplements Reports on Individual Drugs and eosinophilia-myalgia syndrome 185 Vasodilator therapy following myocardial infarction 169 Advisory Notices Praziquantel: are there brand differences? 169 Delayed shock and low osmolar Progestational contraceptives: radiocontrast media 186 also a risk factor for breast cancer? 170 Counterfeit dermatological products 186 Plasma substitutes and renal failure 171 Counterfeit Fansidar® 186 Haemopoietic growth factors as Flunarizine and extrapyramidal symptoms 186 adjuvants in cancer chemotherapy 171 Minoxidil and contact dermatitis 186 Haemophilia: the therapeutic dilemma 172 Retinoids and necrotizing vasculitis 187 Calcium channel blockers: a need Steroid aerosols and cataract 187 for reassessment? 173 Oral contraceptives and older women 188 Antimalarials and pruritus 174 Xamoterol: inappropriate for severe heart failure 188 General Information Zidovudine: carcinogenic potential 188 Should antimalarials be given to all Zidovudine-induced neutropenia 188 pregnant women at risk? 175 Cost-effective health care delivery 176 Cost-conscious prescribing 176 Essential Drugs Hazards of herbal medicines 177 WHO Model List: Sixth Revision 191 Generic drug products: is interchangeability still an issue? 178 204 Drugs in donated blood 179 Newly Registered Products Adverse reaction reporting: engaging commitment 179 DNA probes: a new generation Recent Publications of diagnostic tools 180 The role and function of the pharmacist How often are drugs really taken? 181 in Europe 205 Asthma: inadequacies in concepts Clandestinely produced drugs, and management 181 analogues and precursors 205 Naming organic compounds 205 Regulatory Matters The business of pharmaceutical inspection 206 Aminoglycoside antibiotics: restrictive measures 183 Aphrodisiac activity: no more claims 183 Proposed International Non­ Cosmetics: disclosure of ingredients 183 proprietary Names: List 62 207

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WHO Drug Information Vol. 3, No. 4, 1989

General Policy Topics

Reserve antibiotics with the emergence of multiresistant staphylococci Few would contest that antibiotics have contributed (many of which are now sensitive only to vanco­ more to the advancement of medical care over the mycin), has shown that the evolution of resistance past half-century than virtually any other class of constantly threatens to outstrip innovative capacity. therapeutic substances. Where they are readily available and effectively used, bacterial disease Great harm has similarly resulted, to quote but one has long ceded its former dominance as a primary further example, from widespread incursions of cause of mortality. But there are no grounds for resistant beta-lactamase-producing strains of complacency because pathogenic bacteria are Haemophilus influenzae (7) and gonococci (8). Now constantly posing new therapeutic challenges. fears are being expressed that multiresistant strains Earlier editions of institutional and national formu­ of such major and ubiquitous pathogens as laries provide a salutory reminder that, twenty years Streptococcus pyogenes (9) and Streptococcus ago, all but the most exceptional needs were pneumoniae (10) threaten to become more widely satisfied by 20 to 30 substances. Today, the same distributed. As yet, there is no means of determin­ handbooks list at least three times as many. Costs ing the likely extent of such trends since they follow are also escalating: it is claimed that, in many no established pattern. health-care settings, antibiotics now account for 15 to 30 per cent of the total drug budget (1). What is certain is that these and many other manifestations of resistance are genetically In some measure, these developments are forced determined and that the diverse cytoplasmic by the degree to which the effectiveness of long- transposons and plasmids that carry many of the established, relatively cheap antibiotics has been responsible genes sometimes migrate to other eroded by resistant strains of pathogenic bacteria strains and species of bacteria (3). The potential for (2, 3). It is inevitable that any use of antibiotics will transfer of one, or even of several genes encoding tend to generate selection pressure favouring the for specific mechanisms of resistance is conse­ emergence of resistant strains. However, this quently limitless and largely unpredictable. Inevita­ pressure has been intensified, gratuitously and bly, the outcome is that the resulting emergence of sometimes recklessly, firstly, by the prodigious resistance often makes the cheaper, long-estab­ scale on which these substances are now used — lished antibiotics unreliable for use in serious not only within medicine but in livestock farming (4) infections. — and, secondly, by irrational prescribing practices often inspired by the promotion of broad spectrum This reality has led a WHO Expert Committee, antibiotics as panaceas which dispose of the need meeting in Geneva in December 1989, to consider for diagnostic precision (5, 6). how the situation might best be reflected in the latest biennial revision of the Model List of Essential Too often in the past such complacency has been Drugs (set out on page 191 of this issue). It has fuelled by expectation that the pharmaceutical decided that the concept and purpose of the List industry can be confidently relied upon to produce would be unacceptably compromised simply by yet another generation of effective and safe incorporating into it a range of relatively new and substances to replace those compromised by resis­ expensive antibiotics. Instead, it proposed the con­ tance, and that the prevalence of resistant strains cept of "reserve antibiotics" — substances which can, in any case, be reduced simply by adjusting are useful for a wide range of infections, but which prevailing prescribing policies to relieve the are inappropriate for unrestricted use because of selection pressure. Neither of these assumptions is the need to reduce the risk of development of resis­ warranted. The performance of the research-based tance to them and because of their relatively high pharmaceutical industry in the innovation of cost. It identified the third generation cefalosporins, antibiotics has, indeed, been spectacular. However, the quinolones, and vancomycin as being illustra­ experience over the past two decades, particularly tive of such products in the following situations:

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"Several third generation cefalosporins are suitable ment and use of antibiotics everywhere and that, for the treatment of bacterial meningitis or severe without them, the health and lives of seriously ill pneumonia, particularly in children, where some patients can be jeopardized. strains of Haemophilus influenzae type B are re­ sistant to chloramphenicol. Some will also cure References gonorrhoea and chancroid. However, they should be used for the former only where strains resistant 1. Col, N.F., O'Connor, R.W. Estimating worldwide to penicillin and spectinomycin are prevalent and, current antibiotic usage: Report of Task Force 1. Reviews of Infectious Diseases, 9: S232-S243 (1987). for the latter, only where there is a high preva­ lence of Haemophilus ducreyi strains resistant to 2. McGoean, J.E. Antimicrobial resistance in hospital tetracyclines and trimethoprim/sulfamethoxazole. organisms and its relation to antibiotic use. Reviews of Infectious Diseases, 5: 1033-1048 (1983). "An extensively-used, broad-spectrum quinolone, such as ciprofloxacin, is of value in a variety of 3. O'Brian, T.F. et al. Resistance of bacteria to antibac­ circumstances including the treatment of: terial agents: Report of Task Force 2. Reviews of Infec­ tious Diseases, 9: S244-S260 (1987). • typhoid fever and other systemic salmonella infections where there are strains resistant to 4. Lowe, D.A. Manufacture of penicillin. In: Queener, S., Queener, S.W., Webber, J.A., ed. Beta-lactam antibiotics chloramphenicol, amoxicillin and trimethoprim/ for clinical use. New York, Marcel Dekker, pp. 117-161, sulfamethoxazole; 1986. • severe shigellosis where there are strains resistant to the above three antibacterials and to 5. Kunin, CM., Chambers, ST. Responsibility of the tetracyclines; infectious disease community for optimal use of antibiot­ • gonorrhoea and chancroid, as an alternative to ics: views of the membership of the Infectious Diseases cefalosporins, when an orally-administered drug is Society of America. Reviews of Infectious Diseases, 7: appropriate; 547-549 (1985). • hospital-acquired infections due to Gram-negative 6. Marr, J.J., Moffet, H.L., Kunin, CM. Guidelines for bacilli, including Escherichia coli, Klebsiella spp. improving the use of antimicrobial agents in hospitals: a and Pseudomonas aeruginosa, that are resistant statement by the Infectious Diseases Society of America. to essential drugs such as amoxicillin, tetracy­ Journal of Infectious Diseases, 157: 869-875 (1988). clines, piperacillin, chloramphenicol and gentami¬ cin. 7. Walterspeil, J.N., Kaplan, S.L., Kessler, M.J., Reid, L.F. Ampicillin and chloramphenicol resistance in "Meticillin-resistant Staphylococcus aureus strains systemic Haemophilus influenzae disease. Journal of the are resistant to all beta-lactam antibiotics and American Medical Association, 251: 884-885 (1984). usually also to unrelated drugs such as erythro­ 8. Brunton, J.L, Clare, D., Meier, M.A. Molecular epide­ mycin, clindamycin, chloramphenicol, tetracyclines miology of antibiotic resistance plasmids of Haemophilus and the aminoglycosides. The only effective species and Neisseria gonorrhoeae. Reviews of reserve drug for infections due to these multi- Infectious Diseases, 8: 713-724 (1986). resistant organisms is vancomycin, which is expensive and must be administered intrave­ 9. Stingemore, N., Graham, R.J.F., Toohey, M., nously." McGechie, D.B. The emergence of erythromycin resistance in Streptococcus pyogenes in Freemantle, These examples reveal that the concept of reserve Western Australia. Medical Journal of Australia, 150: 626- 631 (1989). antibiotics has practical meaning only when locally- relevant information on the prevailing sensitivities of 10. Klugman, KP., Koornhof, H.J. Worldwide increase in important bacterial pathogens is available both to pneumococcal antibiotic resistance. Lancet, 2: 444 health planners and to clinicians with direct (1989). reponsibility for patient care. The Expert Committee recalled that WHO has twice previously pointed to 11. Surveillance of Antimicrobial Resistance, Report of a the urgent need for governments to set up refer­ WHO Consultation. Unpublished WHO document BVI/ ence laboratories for this purpose in developing as PHA/ANT/82.2 (1982). well as developed countries (11, 12). Its report will underscore the message that the data generated by 12. Antimicrobial Resistance. Report of a WHO Working such laboratories are vital to the rational procure­ Group. Bulletin of the World Health Organization, 61: 383-394 (1983).

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Personal Perspectives

Counterfeit medicines: The major incentive to such trade is the high demand for goods in a market which is faced with a problem of today severe shortages, usually because of import controls or other government constraints imposed in the light of perceived economic difficulties. It Dr Richard Arnold goes without saying that the level of professional Executive Vice-President control and supervision in such markets, as well as International Federation of Pharmaceutical available legislation and means of enforcement, is Manufacturers Associations inadequate. Close imitations of well-known brands, on the other So-called counterfeit medicines present a threat to hand, require sophisticated plant as well as health in many countries of the world. Several pharmaceutical and other skills of a high order. This delegates at recent World Health Assemblies have presupposes a substantial level of organization and spoken of the problem and media stories of serious scale of production. It would appear to be very incidents become more frequent. What is the nature much a manifestation of professional crime. Not of the problem, how widespread is it, and what can suprisingly, high-grade forgeries are only found of be done to eliminate it? the newer, more costly products and they are distributed through legitimate channels by taking Strictly speaking, a counterfeit product is one which advantage of weaknesses in the distribution chain. is got up to look and behave like an original. A Legitimation of parallel importation in Europe counterfeit drug will be packaged like the original, represents one such weakness and appears to will be presented in a similar-looking dosage form explain how samples of counterfeit Zantac®, and contain the same active ingredient, but it does originating from Greece, were found in the United not necessarily follow that it is of acceptable quality, Kingdom. High-grade forgeries do not necessarily contains the right amount of active substance and contain the correct ingredient and there have been has the correct bioavailability characteristics. plenty of examples of products which have obvi­ ously been made in modern pharmaceutical plants, But this is too narrow a definition to describe the but which have been very difficult to recognize as problem which exists today and which might better forgeries until they have been analysed. be referred to as one of "deceitful products". A more realistic, broader definition must include It is impossible to assess the real scale of the products packaged and labelled to look like the problem. In many countries in Africa and South- original but containing none of the active ingredient East Asia, the widespread existence of fake or even a different active principle. It should also products is only too evident. Most can be readily embrace products "got up" in packages which, identified by knowledgeable people on superficial superficially, look like the originals but on closer in­ inspection. Nigeria appears to be particularly badly spection are seen to have a different brand name, affected; some estimates put the incidence of different ingredients and often different indications. spurious products in that country as high as 50 per cent. The level in other developing countries, where The cruder types of deceitful products may take the purchasing power of the population is lower, advantage of the use of more than one written may be less but it may still represent a significant language in a country, coupled with literacy proportion of medicines sold. shortcomings, as well as a lack of knowledge and access to advice about medicines on the part of the population concerned. Such products require little It is much more difficult to assess the incidence of in the way of pharmaceutical skills for their manu­ sophisticated counterfeiting, if only because it is facture, more demand perhaps for printing skills, much harder to spot the fakes. These are less likely and are often — but by no means always — locally to attract attention because of unexpected adverse made in small "back room" factories. reactions or lack of efficacy although some counter-

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feits which may bear a close resemblance to the collaboration, it requires determination on the part original may be ineffective and a hazard to health. of all the parties concerned to take effective action, Examples of skilful counterfeits have come to light and this applies particularly to governments, some in several European countries but accepting the of whom appear to have been somewhat compla­ honesty of the overwhelming majority of the cent about the problem even though aware of its professionals involved in the distribution and sale of existence. prescription medicines, as well as the degree of inspection and control in the countries concerned, It is true that some major companies have been the level of counterfeits that get to patients must be reluctant to discuss the issue of counterfeiting. In fairly low. This, in turn, implies a relatively small many developing countries they have been number of factories involved in their production but powerless to take any action to defend their with a very highly-developed marketing and products. The laws have been inadequate, espe­ distribution capability. Nevertheless, those ex­ cially for dealing with products having only a amples of forgeries which have been seen in superficial resemblance to their own. Those advanced markets must be the tip of an iceberg — responsible have been difficult to identify, and it is but an iceberg of indeterminate size. often impossible to find witnesses prepared to testify against them. Companies have also had to Counterfeiting is an economic crime providing weigh carefully the consequences of creating lack illegal benefits for the perpetrators at the expense of confidence among patients about the existence of both the patient and the company whose of counterfeit versions of their products. products have been pirated. It also damages, or risks damaging, the health of the individual. Counterfeiting is a criminal activity, and as such Ineffective copies of antibiotics, which have resulted must be dealt with through law enforcement in the death of the patient, spurious injectabtes agencies and the courts. As with other types of which, through contamination and lack of sterility, crime it is undesirable for the aggrieved company to have caused horrendous abscesses or death in try to take the matter into its own hands but that children in West Africa are familiar stories. Many company should collaborate fully with the authori­ cases have been reported but many more, by far, ties, both by notifying cases of which it is aware and must have gone unreported or unrecognized for by providing information, evidence and witnesses to what they were. assist the due processes of the law.

What should be done about deceitful products and There have been encouraging signs recently of a who should be doing it? In every country there must greater determination to deal with the problem by be a clear legal base for treating the dissemination both governments and companies. At the instiga­ of deceitful products as a criminal offence. Those tion of the Minister of Health, the Nigerian Govern­ responsible for making, importing, distributing and ment has taken measures to deal severely with selling products which are false imitations of those involved in the illicit trade and recently many authentic products or otherwise designed to raids and seizures have been carried out through­ mislead the user that they are the same as authen­ out the country, sometimes in the face of strong tic products, should be liable to conviction. But the resistance from the dealers. Such determination is mere existence of a law does not guarantee that it commendable and it is to be hoped that other will be effectively administered, and governments governments will follow suit. must ensure that offending products are identified and those responsible brought to justice. Among other things, this implies an effective system for Evidence of government commitment to take action licensing and inspecting manufacturers, distributors will find a ready response from the reputable and vendors. pharmaceutical industry. Several leading compa­ nies have recently been very forthcoming about Effective control of counterfeiting requires close col­ problems they have experienced with several of laboration between the law enforcement agency, their products, and IFPMA has encouraged its the justice department and the health ministry of constituents to be more forthcoming and active in each country, and between these government fighting the menace. Like many of today's prob­ departments on one hand and professional bodies lems, solutions will only be found by open dialogue and reputable companies and their representative and collaboration between interested parties. organizations on the other. In addition to this Perhaps the process is effectively under way.

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Reports on Individual Drugs

Vasodilator therapy following conventional vasodilators for this purpose — a point that is still being put to the test in ongoing myocardial infarction collaborative studies.

It is estimated that myocardial infarction is followed, References in up to 50 per cent of cases, by functional impair­ ment sufficient to cause demonstrable ventricular 1. Warren, S.E., Royal, H.D., Markis, J.E. et al. Time course of left ventricular dilation after myocardial enlargement (1, 2). This stimulates a measure of infarction: influence of infarct related artery and success adaptive hypertrophy in the residual myocardium of coronary thrombolysis. Journal of the American but, in more severe cases, this is insufficient to College of Cardiologists, 11: 12-19 (1988). restore adequate contractile force. Further cardiac dilatation then ensues (3) culminating, sooner or 2 Jeremy, R.W., Allman, K.C., Bautovitch, G., Harris, later, in ventricular failure (4). P.J. Patterns of left ventricular dilation during the six months after myocardial infarction. Journal of the A significant improvement in long-term survival American College of Cardiologists, 13: 304-310 (1989). could reasonably be expected if left ventricular 3 Lamas, G.A., Pfeffer, MA. Increased left ventricular dilatation could be attenuated or arrested by volume following myocardial infarction in man. American reducing diastolic filling pressure. Preliminary Heart Journal, 111: 30 (1986). animal studies with the angiotensin converting enzyme (ACE) inhibitor, captopril, have indicated 4 White, H.D., Norris, R.M., Brown, M.A. et al. Left that this might be achieved by vasodilatation (5) ventricular end systolic volume as the major determinant and, more recently, small-scale clinical trials in of survival after recovery from myocardial infarction. which captopril was also used have been deemed Circulation, 76: 44-51 (1987). sufficiently encouraging to warrant large-scale investigation (6, 7). According to a commentary 5. Pfeffer, J.M., Pfeffer, M.A., Braunwald, E. Influence of recently published in the Lancet (8), a multicentre chronic captopril therapy on the infarcted ventricle of the study involving patients shown to have a consid­ rat. Circulatory Research, 57: 84-85 (1985). erably reduced ejection fraction following recent cardiac infarction is already planned. More than 6. Sharpe, N., Murphy, J., Smith, H., Hannon, S. Treatment of patients with symptomless left ventricular 2000 patients are to be followed, after randomiza­ dysfunction after myocardial infarction. Lancet, 1: 255- tion for treatment with either placebo or captopril, 259 (1988). for a median of several years. 7. Pfeffer, M.A., Lamas, G.A., Vaughan, D.E. et al. Effect Such an undertaking will require considerable of captopril on progressive ventricular dilatation after anterior myocardial infarction. New England Journal of financial investment and will doubtless make a Medicine, 319: 80-86 (1988). large commitment on the research resources of many of the participating centres for extended 8. Editorial. ACE inhibitors after myocardial infarction. periods of time. The Lancet therefore queries Lancet, 2: 1133-1134 (1989). whether sufficient preliminary investigation has yet been completed to enable a critical phase 4 trial to be planned. It highlights two points, in particular. Firstly, treatment will not be started until at least 3 Praziquantel: days — and, in extreme instances, up to 16 days — are there brand differences? after infarction, but it remains possible that captopril will perform to best effect if it is first administered as Sudan — Praziquantel has transformed the primary therapy in the post-infarction period before treatment of schistosomiasis. Severe adverse the initial ventricular enlargement is well advanced. effects have yet to be reported and one oral dose Secondly, it has yet to be confirmed, in practice, offers a potential cure for all forms of the disease. that captopril will have practical advantage over The excellent response to treatment has recently

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been confirmed in a comparative trial of tablets previously been used by 110 patients with newly-di­ prepared by two different manufacturers in a village agnosed breast cancer and 252 randomly-selected population of some 4200 individuals in the Gezira controls. In this group as a whole, no association region of Sudan. Stool samples taken six months between use of DMPA and risk of breast cancer after treatment indicated that both preparations had was evident. More than nine out of ten cancers cured more than 90 per cent of cases. Unexpect­ recorded in the study were diagnosed in women edly, however, the reported incidence of unwanted over 35 and, among these, there was no evidence reactions associated with the two products was that DMPA is a risk factor, no matter how long it is markedly different. On direct questioning, 60 per used. There was also an apparent (although non­ cent of patients receiving one preparation, but only significant) reduction in risk among women who had 40 per cent of those receiving the other, claimed to used it many years earlier. This was offset, how­ have experienced one or more adverse effects ever, by an increase in risk among recent users. within a week of taking the drug. The difference Further analyses indicated that the increase was was judged to be highly significant. greatest among the very few long-term users who started using DMPA before the age of 25, but it was Of itself, this finding is without importance since also evident to a lesser degree among users who none of the presumed reactions was in any sense developed breast cancer before they were 35 serious. The authors suggest the discrepancy may (relative risk 2.0; confidence interval 1.0 to 3.8). reflect differences in the absorption of the two formulations and they plan to study their specific If these results are truly representative — and it has pharmacokinetics further. If their prediction is to be emphasized that the positive associations are correct, it may well be that the dosage of one of the based on very few cases — it appears that DMPA brands can be lowered substantially without may have an initially harmful influence followed by impairing efficacy. This could result in material a protective effect. It is pointed out that a biphasic savings to those countries where schistosomiasis is action of this nature is comparable to the influence hyperendemic and where cost is the greatest of pregnancy, which is associated with a short-term constraint on effective therapy. If they are wrong, increase in risk of breast cancer followed, after they have a rare opportunity to investigate possible some years, by the protective effect of parity (2, 3). sources of recall or reporting bias in their study, and Such an action would also imply that DMPA acts to to make an important contribution to the assess­ promote breast cancer during the later stages of ment of symptomatic illness. carcinogenicity but not to induce it. The same ex­ planation has been proposed by an expert panel of Reference: Homeida, M.M.A., Eltom, I.A., Sulaiman, the US Food and Drug Administration to account for S.M. et al. Tolerance of two brands of praziquantel. similar postulated associations noted in analogous Lancet, 2: 391 (1989). studies on combined oral contraceptives (4).

This study has also been reviewed by an advisory Progestational contraceptives: committee to WHO, which has concluded that the also a risk factor for breast cancer? data currently available are neither sufficient nor consistent enough to warrant any recommendation for change in clinical practice (5). It is manifestly New Zealand — The debate as to whether early urgent in these circumstances to generate further use of steroidal contraceptives may be associated relevant information and it is hoped that the final with an increased risk of breast cancer now report of a similar case-control study coordinated by embraces the injectable progestational preparation, the World Health Organization in centres in depot medroxyprogesterone acetate (DMPA), as Thailand, Kenya and Mexico will be published well as oral preparations containing estrogens and toward the end of 1990. progestogens in combination. References This latest signal derives from a small population- based case-control study undertaken in New 1. Paul, C, Skegg, D.C.G., Spears, G.F.S. Depot Zealand, where DMPA has been used over the past medroxyprogesterone (Depo-Provera) and the risk of 20 years more extensively than in any other breast cancer. British Medical Journal, 299: 759-762 developed country (1). Within the study, DMPA had (1989).

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2. Bruzzi, P., Negri, E., La Vecchia, C. et al. Short term properties are remarked upon in a case report increase in breast cancer risk following a full term published in the British Medical Journal which pregnancy. British Medical Journal, 297: 1096-1098 implicates them in the development of permanent (1988). renal failure in a patient undergoing extensive vascular surgery (5). In this case, the slow admini­ 3. Millar, A.B., Bulbrook, R.D. UICC multidisciplinary project on breast cancer: the epidemiology, aetiology and stration of an infusion containing 2 litres of gelatins prevention of breast cancer. International Journal of is unlikely to have been more than a contributory Cancer, 37. 173-177(1986). cause of the renal damage, since it was admini­ stered only after a fall in urine output had become 4. Ezzell, C. FDA sceptical about link between breast apparent. None the less, the authors present cancer and the pill. Nature, 337: 108 (1989). indirect evidence based on changes in serial estimations of albumin concentration that the 5. Statement on DMPA and breast cancer. Steering gelatins accumulated throughout the infusion. They Committee of the WHO Task Force on Safety and consequently consider that gelatins should not be Efficacy of Fertility Regulating Methods. 29 September 1989. administered in large amounts whenever there is a possibility that either urine flow or renal perfusion pressure is reduced.

Plasma substitutes References and renal failure 1. Chinitz, J.L., Kim, K.E., Onesti, G., Swartz, C. Pathophysiology and prevention of dextran-40-induced United Kingdom — Transfused blood has long anuria. Journal of Laboratory and Clinical Medicine, 77: been known to be an important vehicle for the 76-87 (1971). transmission of the hepatitis viruses, and more recently of HIV and other distantly-related retro­ 2. Mailloux, L, Swartz, CD., Capizzi, R. et al. Acute renal viruses responsible for insidious damage to failure after administration of low molecular weight immune cells. Direct screening tests for most of dextran. New England Journal of Medicine, 277: 1113- these agents, with the notable exception of non-A, 1118 (1967). non-B hepatitis virus, are now available, but all 3. Moran, M., Kapsner, C. Acute renal failure associated tests have failure rates and they are too costly for with elevated plasma oncotic pressure. New England routine use in all but the most affluent settings. Journal of Medicine, 317: 150-153 (1987).

Because they obviate risk of viral infection, plasma 4. Michie, A.J., Koop, C.E., Walker, J.M. et al. Renal substitutes are used on an ever-increasing scale for haemodynamics following intravenous administration of restoring circulatory volume and oncotic pressure gelatin. Journal of Applied Physiology, 4: 677-681 (1952). after blood loss. However, since they lack oxygen- carrying capacity, they cannot be used to replace 5 Hussain, S.F., Drew, P.J.T. Acute renal failure after more than about 15 per cent of the total blood infusion of gelatins. British Medical Journal, 299: 1137- 1138(1989). volume. Moreover, in large amounts, the dextrans are a well-recognized cause of acute renal failure (1). This is presumed to occur because they are hyperoncotic in comparison with plasma and, when Haemopoietic growth factors as water is resorbed to an unusually high degree from adjuvants in cancer chemotherapy the proximal tubules, the smaller molecules that enter into the filtrate tend to precipitate and form casts (2, 3). United States of America — No less than nine haemopoietic growth factors (hormone-like proteins that control the development and differentiation of Gelatin solutions are also used widely as plasma blood cells) have now been identified and produced substitutes and they have been claimed, on the in quantity by recombinant DNA technology. basis of toxicological studies, to involve no risk of Several of them are already being assessed renal failure (4). However, the preparations used clinically and their therapeutic promise is such that are similarly hyperoncotic and, like the dextrans, the Food and Drug Administration has sponsored a they contain molecules of varying sizes, many of workshop to review and exchange information on which are filtered by the kidneys and which their properties and potential (1). Interest was precipitate from concentrated solutions. These

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granulocyte colony-stimulating factor and granulo­ Not until 1983 was a method developed for heating cyte/macrophage colony-stimulating factor — as lyophilized concentrates to a degree that would adjuvants in cancer chemotherapy, in supporting inactivate most of the contaminating viruses without the survival of bone-marrow grafts, in sustaining denaturing the clotting factor (7-9). Unfortunately, patients with congenital neutropenia and, more cost and limited supply compromised the extent to controversially, in potentiating zidovudine as an which heat-treated preparations could be used for inhibitor of HIV replication (2). There is already some years. Earlier products manufactured in this much evidence that both are highly effective in way provided incomplete protection, particularly ameliorating leukopenias of varied etiology. It was against non-A, non-B hepatitis virus (10), and also emphasized, however, that it will be essential to sometimes against HIV (11). Newer products show that this is accompanied by functional benefit, treated by heating to 80°C, by vapour heating, or by and particularly by increased resistance to intercur­ processing in a solvent and detergent, promise to rent infection, before tangible therapeutic benefit be safer, but the manufacturing processes are can be claimed. complicated and, as yet, none is in routine use (11). Fortunately, it now seems that pasteurization may References offer a relatively simple means of producing a comparably safe product: a pilot production unit is 1. From the Food and Drug Administration. Journal of the claimed to have inactivated both the hepatitis American Medical Association, 262: 1295 and 1296 viruses (12) and HIV-I and HIV-2 (13), even in (1989). concentrates prepared from unscreened plasma. 2. Perno, C.F., Yarchoan, R., Cooney, D. et al. Replica­ These efforts, while encouraging, do not dispose of tion of human immunodeficiency virus in monocytes. Granulocyte/macrophage colony-stimulating factor (GM- the need for ultra-pure preparations, as manufac­ CSF) potentiates viral production yet enhances the tured either by monoclonal antibody techniques or antiviral effect mediated by 3'-azido-2'3-dideoxythymidine by recombinant DNA technology (14) which offer (AZT) and other dideoxynucleoside congeners of the prospect of completely supplanting plasma thymidine. Journal of Experimental Medicine, 169: 933- concentrates and of replacing them with prepara­ 952 (1989). tions reliable enough to be used prophylactically. Until this aim is realized, concern can never be totally allayed that sporadic cases of transmission Haemophilia: will continue to occur, and — it has been argued — the possibility will be ever present that haemo­ the therapeutic dilemma philiacs will sooner or later fall victim to further tragedy from equally dangerous viral pathogens as Twenty-five years ago the discovery of a cryo¬ yet unidentified (15). precipitate rich in clotting factor VIII promised near- normal life to haemophiliac patients by simplifying References the management of acute bleeding episodes (1). It amply fulfilled this expectation. However, the 1. Pool, J.G., Shannon, A.E. Production of high potency administration of concentrates prepared from the concentrates of antihemophilic globulin in a closed bag pooled plasma of as many as 20 000 donors system: assay in vitro and in vivo. New England Journal of Medicine, 273: 1443-1447(1965). involved a high risk of transmission of viral disease and throughout the 1970s most of the recipients 2. Levine, P.H., McVerry, B.A., Attock, B., Dormany, K.M. developed abnormalities of liver function (2) which, Health of the intensively treated hemophiliac, with special in a few, progressed to active hepatitis, cirrhosis reference to abnormal liver chemistries and spleno­ and end-stage liver disease (3). Virtually everyone megaly. Blood, 50: 1-9 (1977). treated at that time subsequently developed serological evidence of hepatitis B, non-A, non-B 3. Hay, C.R.M, Preston, F.E., Triger, D.R., Underwood, or, less commonly, delta agent infection (4). Not­ J.C.E. Progressive liver disease in haemophilia: an withstanding the gravity of this situation, it is now understated problem? Lancet, 1: 1495-1498 (1985). overshadowed by realization that most of these patients have additionally become HIV positive (5). 4. Rizzetto, M., Morello, C., Mannucci, P.M. et al. Delta Indeed, since 1985, the leading cause of death infection and liver disease in hemophilic carriers of the hepatitis B surface antigen. Journal of Infectious among treated haemophiliacs in the USA is no Diseases, 145: 18-22 (1982). longer bleeding, but AIDS (6).

172 WHO Drug Information Vol. 3, No. 4, 1989 Reports on Individual Drugs

5. Goedert, J.J., Kessler, C.M., Aledort, L.M. et al. A pro­ Calcium channel blockers: spective study of human immunodeficiency virus type 1 infection and the development of AIDS in subjects with a need for reassessment? hemophilia. New England Journal of Medicine, 321: 1141-1148(1989). Calcium channel blocking agents are now among 6. Johnson, R.E., Lawrence, D.N., Evatt, B.L et al. the most frequently prescribed drugs for patients Acquired immunodeficiency syndrome among patients with cardiovascular disease. Worldwide, annual attending hemophilia treatment centers and mortality sales have been estimated to exceed US$10 000 experience of hemophiliacs in the United States. million (1). However, the justifiability of a substantial American Journal of Epidemiology, 121: 797-810 (1985). proportion of the use that this represents is cast in doubt by a recent overview derived from a meta¬ 7. Rouzioux, C, Chamaret, S., Montagnier, L. et al. analysis of randomized controlled clinical trials Absence of antibodies to AIDS virus in haemophiliacs directed to assessing their use in acute myocardial treated with heat-treated factor VIII concentrate. Lancet, infarction or unstable angina (1). 1:271-272(1985).

8. Centers for Disease Control. Safety of therapeutic Overall, data obtained in 22 trials involving about products used for hemophiliac patients. Morbidity and 18 000 patients were examined. Of these, 17 Mortality Weekly Record, 37: 441-450 (1988). evaluated the response to short-term treatment instituted within a few hours of onset of symptoms. 9. Brettler, D.B., Levine, P.H. Factor concentrates for The remaining five examined the value of long-term treatment of hemophilia: which one to choose? Blood, 73: use started either shortly after or within a few 2067-2073 (1989). weeks of an infarction. Most of the studies de­ scribed experience with one of three drugs: 10. Colombo, M., Mannucci, P.M., Carnelli, V. et al. Transmission of non-A, non-B hepatitis by heat-treated verapamil, nifedipine and diltiazem. Data from factor VIII concentrate. Lancet, 2: 1-4 (1985). these individual trials were combined using non- parametric methods with a view to reassessing the 11. Pierce, G.F., Lusher, J.M., Brownstein, A.P. et al. The influence of treatment both on mortality and on the use of purified clotting factor concentrates in hemophilia: risk and extent of infarction or reinfarction within the influence of viral safety, cost, and supply on therapy. pooled sample of patients. The analysis conformed Journal of the American Medical Association, 261: 3434- to principles established in previous approaches to 3438(1989). meta analysis, and direct comparisons were made only between different treatment groups within the 12. Schimpf, K., Mannucci, P.M., Kreutz, W. et al. same trial. Absence of hepatitis after treatment with a pasteurized factor VIII concentrate in patients with hemophilia and no previous transfusion. New England Journal of Medicine, Treated in this way, the consolidated results 316:918-922(1987). provided no indication that calcium channel blocking agents can either limit the size of recently- 13. Schimpf, K., Brackmann, H.H., Kreutz, W. et al. sustained infarcts or reduce the risk of recurrence: Absence of anti-human immunodeficiency virus types 1 873 of 8870 patients receiving these drugs died as and 2 seroconversion after treatment of hemophilia A or compared with 825 of 8889 receiving placebo. The von Willibrand's disease with pasteurized factor VIII slight excess of deaths observed among treated concentrate. New England Journal of Medicine, 321: 1148-1152(1989). patients has no statistical significance, but it was evident in each category of trial. Comparably 14. White, G.C., McMillan, C.W., Kingdon, H.S., negative results were obtained from an analogous Shoemaker, C.B. Use of recombinant antihemophilic assessment of the studies on unstable angina. factor in the treatment of two patients with classic Calcium channel blocking agents are also used to hemophilia. New England Journal of Medicine, 320: 166- improve exercise tolerance in patients with stable 170(1989). angina induced by effort. The results of the meta analysis do not bear upon this indication, which is 15. Roberts, H.R. The treatment of hemophilia: past founded on physiological evidence that they either tragedy and future promise. New England Journal of decrease oxygen requirements or improve oxygen Medicine, 321: 1188-1190 (1989). supply within the myocardium (2). It has recently been claimed that they are clinically as effective as

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propranolol in this context (3). It would clearly now Antimalarials and pruritus be unwarranted to assume that any symptomatic benefit they may offer in the short term is associ­ Nigeria — Chloroquine continues to be the most ated with a longer term protective effect. Indeed, effective treatment for acute falciparum malaria taken at face value, the results of the meta analysis wherever the parasite remains fully sensitive. deny the possibility that calcium channel blocking However, in Africa in particular, intolerance to the agents offer effective protection against myocardial drug has always posed a major problem since infarction under any circumstances. between 8 and 20 per cent of patients develop persistent pruritus within a few hours of taking the There is an inevitable danger here that a tangible first dose which is effectively relieved only by benefit to a defined subgroup of patients will be suspending treatment (1). obscured in an attempt to define composite norms. There may thus well be a case for further examin­ Having regard to the increasing prevalence of ing specific claims that drugs of this class may chloroquine-resistant strains of P. falciparum reduce both mortality and risk of reinfarction in throughout the countries of the region, all other patients with 'non-Q wave' myocardial lesions (4-6). candidate antimalarial compounds have recently In the interim, however, the authors of the current been evaluated for efficacy, safety and tolerability in review consider themselves fully justified in an area of Nigeria where the current prevalence of advocating that "calcium channel blocking agents chloroquine-resistant strains remains under 10 per cannot be recommended prophylactically in cent (2). Pruritus proved to constitute an important patients during or after acute myocardial infarction potential constraint on treatment with several of the or in those with unstable angina". drugs. Within samples of between 50 to 60 patients it occurred in 14 per cent of those receiving References chloroquine, 27 per cent of those on amodiaquine and 13 per cent on halofantrine. It was entirely 1. Held, P.H., Yusuf, S., Furberg, C.D. Calcium channel absent among patients treated with quinine and blockers in acute myocardial infarction and unstable angina: an overview. British Medical Journal, 299: 1187- mefloquine. 1192(1989). The effect may have a genetic basis since it is 2. Braunwald, E. Mechanism of action of calcium channel known to occur mainly in Africans and because all blocking agents. New England Journal of Medicine, 307: patients who itched when given halofantrine were 1618-1627(1982). known also to be intolerant of chloroquine. How­ ever, the converse did not always apply. Although 3. Picca, M., Azzollini, F., Cereda, A., Pelosi, G. the mechanism of the effect remains unknown, the Comparison of the antianginal efficacy of four calcium information has immediate relevance to the antagonists and propranolol in stable angina pectoris. selection of alternatives to chloroquine in Africa, European Journal of Clinical Pharmacology, 37: 325-331 (1989). both for individual patients and for national malaria control programmes. 4. Gibson, R.S., Boden, W.E., Theroux. P. et al. Diltiazem and reinfarction in patients with non-Q wave myocardial References infarction. New England Journal of Medicine, 315: 423- 429 (1986). 1. Salako, LA. Toxicity and side-effects of antimalarials in Africa: a critical review. Bulletin of the World Health 5. Eisenburg, P.R., Lee, R.G., Biello, D.R. et al. Chest Organization, 62 (suppl): 63-68 (1984). pain after non transmural infarction: the absence of remediable coronary vasospasm. American Heart 2. Sowunmi, A., Walker, O., Salako, LA. Pruritus and Journal, 110: 515-521 (1985). antimalarial drugs in Africans. Lancet, 2: 213 (1989).

6. Multicenter Diltiazem Postinfarction Trial Research Group. The effect of diltiazem on mortality and reinfarc­ tion after myocardial infarction. New England Journal of Medicine, 319: 385-392 (1988).

174 WHO Drug Information Vol. 3, No. 4, 1989

General Information

Should antimalarials be given to ail The authors conclude that in the Gambia, and perhaps in other areas of Africa where the pattern pregnant women at risk? of malaria is similar, it is, indeed, important to offer chemoprophylaxis to primigravidae. Whereas Gambia— Pregnant women living in endemic protection seemed to confer less benefit on areas commonly receive malaria chemoprophylaxis multigravidae, they warn that it would be premature as a matter of policy since their susceptibility to the to offer antimalarials selectively to primigravidae disease is believed to be increased, particularly without being sure that their use during any one among primigravidae (1, 2). Moreover, should pregnancy does not increase susceptibility to infection occur, the mother may become seriously malaria in the next. In a wider context, they point anaemic (2, 3) and the growth rate of the fetus may out that regular administration of chemoprophylaxis be depressed as a result of placental insufficiency by traditional birth attendants encourages them to (1, 2, 4). However, there have been few direct establish a personal relationship with their patients demonstrations of the benefit of chemoprophylaxis before delivery, and the most decisive result of the (5-7) since ethical constraints preclude any possibil­ study was to show that the outcome of pregnancy ity of assessing its value in a controlled setting was least favourable among women who failed to where it is already provided routinely as a compo­ seek advice prenatally. nent of antenatal care. References Because of this difficulty, a randomized, placebo- controlled study recently reported from the Faraf¬ 1. Brabin, B.J. An analysis of malaria in pregnancy in enni region of the Gambia holds particular interest Africa. Bulletin of the World Health Organization, 61: (8). It was undertaken within the national primary 1005-1016 (1983). health care programme in parallel with the training 2. McGregor, I.A. Epidemiology, malaria and pregnancy of traditional birth attendants who were instructed, American Journal of Tropical Medicine and Hygiene, 33: in accordance with a predetermined plan, to give 517-525 (1984). each pregnant woman either a tablet containing dapsone 100 mg and pyrimethamine 25 mg or a 3. Gilles, H.M., Lawson, J.B., Sibelas, M. et al. Malaria, placebo at fortnightly intervals until delivery. The anaemia and pregnancy. Annals of Tropical Medicine and accuracy of their record-keeping and drug admini­ Parasitology, 63: 245-263 (1969). stration was checked by submitting random urine samples to enzyme-linked immunosorbant assays. 4. Watkinson, M., Rushton, D.I. Plasmodial pigmentation Over the course of three years 1208 pregnancies of placenta and outcome of pregnancy in West African were monitored. Among primigravidae, those who mothers. British Medical Journal, 287: 251-254 (1983). did not receive chemoprophylaxis had almost twice 5. Morley, D., Woodland, M., Cuthbertson, W.F.J. the incidence of demonstrable parasitaemia, their Controlled trial of pyrimethamine in pregnant women in packed cell volume was on average some 12 per an African village. British Medical Journal, 1: 667-668 cent lower, and low birthweight babies were three (1964). to four times more common. These differences were decidedly less marked among multigravidae, 6. Fleming, A.F., Ghatoura, G.B.S., Harrison, K.A. et al. in whom chemoprophylaxis had no apparent effect The prevention of anaemia in pregnancy in primigravidae on haematological parameters and relatively little in the Guinea savanna of Nigeria. Annals of Tropical effect on birth weight except among women who Medicine and Parasitology, 80: 211-233 (1986). were in their sixth or subsequent pregnancy. Overall, both stillbirths and neonatal deaths were 7. Spencer, H.C., Kaseje, D.C.O., Sempebwa, E.K.N. et fewer among women receiving prophylaxis and no al. Malaria chemoprophylaxis to pregnant women adverse effects were observed that might have provided by community health workers in Saradidi, Kenya. Annals of Tropical Medicine and Parasitology, 81 been attributed to the drugs. (suppl.1): 83-89 (1987).

175 General Information WHO Drug Information Vol. 3, No. 4, 1989

8. Greenwood, B.M., Greenwood, A.M., Snow, R.W. et al. limited availability of funds, someone must ulti­ The effects of malaria chemoprophylaxis given by mately bear responsibility for translating them into traditional birth attendants on the course and outcome of statements of policy. pregnancy. Transactions of the Royal Society of Tropical Medicine and Hygiene, 83: 589-594 (1989). References

1. Leaf, A. Cost effectiveness as a criterion for Medicare Cost-effective health care delivery coverage. New England Journal of Medicine, 321: 898- 900 (1989).

United States of America — Doctors in many 2. Committee for Evaluating Medical Technologies in countries are finding themselves increasingly Clinical Use. Assessing Medical Technologies. National accountable for their expenditure of public funds. In Academy Press, Washington, D.C. (1985). the USA this is currently apparent in a proposal that cost-effectiveness be included as a criterion for 3. Detsky, AS. Are clinical trials a cost-effective recognizing specific techniques or procedures for investment? Journal of the American Medical reimbursement purposes in federal insurance Association, 262: 1795-1800 (1989). schemes. In commenting on the proposal the New 4. Fletcher, R.H. The costs of clinical trials. Journal of the England Journal of Medicine contends that accu­ American Medical Association, 262: 1842 (1989). rate estimates of benefits to patients or of costs to society can be elusive and imprecise, and that neither will ever diminish the need for sound clinical judgement (1). On balance, none the less, it Cost-conscious prescribing supports the proposal on the grounds that much of what is done in diagnosis and treatment is a United States of America — in the last analysis, consequence of training rather than objective reductions in prescribing costs can be achieved analysis and because custom and even tradition in only by changing the attitudes and habits of medicine offer no guarantee of effectiveness. practising physicians. As a result of the ever burgeoning costs of health care delivery within the The support offered by the journal is qualified, public sector, health authorities have approached however, in two respects. Firstly, it argues that the problem in a variety of ways (1-6). Rarely, substantial funding will need to be allocated to however, has the impact of different approaches open-ended evaluation of current practices and, for been compared in a controlled setting. this to be undertaken on a broad front, new methods of assessment will have to be devised to One such study, recently reported from a public complement the classical double-blind, placebo- service hospital in Nashville, Tennessee, compares controlled studies that are so demanding of time the responses of 31 doctors each attached to the and resources. Secondly, it considers that the same general medical clinic, to two different objectives of the health care system will need to be persuasive influences (7). Those in one randomly- more clearly defined, preferably with more weight selected group were visited individually at weekly being accorded to the quality of life rather than life- intervals for several months by a clinical pharmacist expectancy alone. who reviewed their prescribing of expensive targeted products. Another group received weekly Critics will doubtless claim that enough is already computerized reports to indicate how their individ­ spent on clinical trials in more affluent countries. It ual prescribing costs compared with those of their has been estimated that over $1 billion is invested colleagues. The remainder served as controls. Only annually to this end in the USA alone (2). However, among those who were interviewed was a cost- this represents less than 0.3 per cent of the national effective result achieved. The savings were not health expenditure and it has been claimed — large, amounting to less than $500 per capita over using established methods of cost-effectiveness the period of the study after all costs had been analysis — that these costs are small in compari­ offset. Feedback of computerized information had son with the costs of applying the interventions in no measurable effect. practice (3). The central question, then, is not the cost of obtaining the information but how much These results offer support to the conclusions of society is prepared to pay in using it to extend a life others that personal rather than impersonal inter­ or improve its quality (4). Value judgements ventions are more likely to influence doctors in their inevitably weigh heavily in such decisions but, with professional judgement (1, 8). They offer no insight,

176 WHO Drug Information Vol. 3, No. 4, 1989 General Information

however, into either the clinical implications of the cines in patients with unusual or unexplained economies achieved or the period of time for which symptoms or signs. At issue in these particular they were sustained. The likelihood is that, for busy examples are photosensitivity reactions (1) and doctors, cost consciousness, once inculcated, acute, unexplained liver damage (2). needs to be boosted through constant reinforce­ ment and that the most efficient way to achieve this In the first instance, causality was definitively for those in hospital practice is through the introduc­ established without difficulty. Typical signs of tion of institutional formularies. photosensitivity developed and recurred on challenge in a patient who was taking a herbal References remedy containing high concentrations of psoralens for vitiligo. The cases of liver damage presented 1. Avorn, J., Soumerai, S.B. Improving drug therapy greater difficulty. The possibility that natural plant decisions through educational outreach: a randomized remedies were responsible for jaundice that controlled trial of academically-based "detailing". New developed in each of four women who had recently England Journal of Medicine, 308: 1457-1463 (1983). started to take "natural plant remedies" bought in 2. Gehlback, S.H., Wilkinson, W.E., Hammond, W.E. et health shops to relieve stress was established al. Improving drug prescribing in a primary care practice. essentially by inference, but the authors were able Medical Care, 22: 193-201 (1984). to identify two components of the products, skullcap (Scutellaria sp.) and valerian (Valeriana sp.), as 3. Winickoff, R.N., Coltin, K.L., Morgan, M.M. et al. possible hepatotoxins. They emphasize that their Improving physician performance through peer compari­ suspicions are no more than tentative, however, son feedback. Medical Care, 22: 527-534 (1984). because these and many similar products contain many ingredients, some of which may not be 4. Manning, P.R., Lee, P.V., Clintworth, W.A. et al. Changing prescribing practices through continuing labelled and few of which are pure substances. medical education. Journal of the American Medical Even when ingredients are clearly stated, assur­ Association, 256: 230-232 (1986). ance is far from absolute that the same species of plant is always used as the source material (3). 5. Hershey, CO., Porter, D.K., Breslau, B.A., Cohen, D.I. Influence of simple computerized feedback on prescrip­ Other plant components, and particularly the tion charges in an ambulatory clinic. Medical Care, 24: pyrrolizidines, have long been associated with 472-481 (1986). veno-occlusive disease of the liver and cirrhosis in countries where there is high exposure (4). Valerian 6. Avorn, J.A., Soumerai, S.B., Taylor, W. et al. Reduc­ has also recently been shown to contain potent tion of incorrect antibiotic dosing through a structured educational order form. Archives of internal Medicine, alkylating agents (5). The authors point to other 148: 1720-1724 (1988). cases of putative drug-induced liver damage reported in the United Kingdom that have been 7. Steele, M.A., Bess, D.T., Franse, V.L., Graber, S.E. attributed, variously, to herbal teas (6), herbal Cost effectiveness of two interventions for reducing medicines containing mistletoe (7, 8) and to outpatient prescribing costs. Annals of Pharmacotherapy, comfrey (9). Many similar cases, they assume, 23:497-500(1989). remain unrecognized. They join with pharmacists (3) in challenging the practice of advertising such 8. Schaffner, W., Ray, W.A., Federspiel, C.F. et al. products as free from undesirable effects and, Improving antibiotic prescribing in office practice: a having regard to the acknowledged toxicity of some controlled trial of three educational methods. Journal of the American Medical Association, 250: 1728-1732 ingredients, they question whether more could be (1983). done to restrict the availability of products that contain them.

Hazards of herbal medicines References 1. Maurice, P.D.L., Cream, J.J. The dangers of United Kingdom — Illustrative case histories are herbalism. British Medical Journal, 299: 1204 (1989). used in two recent reports to the British Medical Journal to underscore the need to inquire about 2. MacGregor, F.B., Abernethy, V.E., Dahabra, S. et al. recent use of herbal as well as prescribed medi­ Hepatotoxicity of herbal remedies. British Medical Journal, 299: 1156-1157 (1989).

177 General Information WHO Drug Information Vol. 3, No. 4, 1989

3. Phillipson, J.D., Anderson, L.A. Herbal remedies used •inspecting the production facilities of 31 manufacturers, in sedative and antirheumatic preparations: parts 1 and 2. including some brand-name manufacturers that also Pharmaceutical Journal, 233: 80-82 and 111-114 (1984). make generic products; and

4. World Health Organization. Pyrrolizidine alkaloids. • inspecting contract laboratories that undertake Geneva, World Health Organization, 1988 (Environ­ premarket testing to ensure that product approvals mental Health Criteria, No. 80). are based on valid data. 5. Braun, von R., Dittmar, W., Machut, M. et al. Valepotri¬ ate mit epoxidstruktur-beachtlichen Alkylantien. Deutsche Since 1985 the Food and Drug Administration has Apotheker Zeitung, 122: 1109-1113(1982). no longer required direct evidence of safety and efficacy in applications for marketing generic 6. Kumana, C.R., Ng, M., Lin, H.J. et al. Hepatic veno- products. Instead, reliance has been vested in occlusive disease due to toxic alkaloid in herbal tea. documentary demonstration of bioequivalence (2). Lancet, 2: 1360-1361 (1983). Thus far, the tests have been undertaken by, or on behalf of, the manufacturer but the regulations may 7. Harvey, J., Colin-Jones, D.G. Mistletoe hepatitis. now be changed to enable the FDA itself to analyse British Medical Journal, 282: 186-187 (1981). samples of products in order to establish the 8. Stirpe, F. Mistletoe toxicity. Lancet, 1: 295 (1983). authenticity of the materials used. 9. Weston, C.F., Cooper, B.T., Davies, J.D., Levine, D.F. In 1985, the American Society of Hospital Pharma­ Veno-occlusive disease of the liver secondary to cists issued guidelines (3) to assist their members ingestion of comfrey. British Medical Journal, 295: 183 in purchasing multisource pharmaceutical products. (1987). These emphasize the need to take into considera­ tion factors relating to quality as well as price, including, in particular: Generic drug products: is • procedures instituted by the manufacturer or interchangeability still an issue? distributor for analytical control and sterility testing; United States of America — The Food and Drug Administration has responded promptly and • the need to review bioavailability data and de­ forcefully to recently publicized improprieties in the scriptions of testing procedures for both raw generic drug approval process. It has withdrawn the materials and finished products; marketing approval of 30 generic products made by four manufacturers because of uncertainties about • the company's history of recalls of defective their submitted data and ft is committed to imple­ products; menting a series of controls that will indicate what additional measures may still be needed. Mean­ • its compliance with official compendial standards; while, the American Journal of Hospital Pharmacy (1) has emphasized that generic products are • the identity of the manufacturer of the final dosage dispensed against one-third of all prescriptions form; and issued in the USA, and that the experience of physicians, pharmacists, and patients indicates that • the availability of therapeutic, biopharmaceutic, the overwhelming majority of these products are and toxicological information. safe and effective. Recent events, the Society considers, vindicate its The supplementary measures to which the Food long-established belief that "selecting multisource and Drug Administration is now committed to drug products is one of the most important respon­ assure complete confidence in the system include: sibilities of pharmacists".

• sampling and analysing the 30 most prescribed References generic drug products for potency, dissolution, composition and other specifications; 1. Zellmer, W.A. Generic drug products. American Journal of Hospital Pharmacy, 46: 2005 (1989). • analysing product samples submitted by manufac­ turers to ensure their validity;

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2. Hogan, G.F. Repercussions of the "Drug Price 3. Michel, J., Sharon, R. Detection of penicillins in the Competition and Patent Term Restoration Act" of 1984. sera of "healthy" blood donors. Vox Sanguinis, 38: 19-21 American Journal of Hospital Pharmacy, 42: 849-851 (1980). (1985). 4. Okuno, T. Anti-penicillin antibodies in transfused blood. 3. ASHP guidelines for selecting pharmaceutical Journal of the American Medical Association, 218: 95 manufacturers and distributors. American Journal of (1971). Hospital Pharmacy, 41: 331-332 (1984). 5. Ferner, R.E., Dunstan, J.E., Chaplin, S. Drugs in donated blood. Lancet, 2: 93-94 (1989).

Drugs in donated blood 6. Dunstan, J.E., Chaplin, S., Ferner, RE. Donors on Medication. Newcastle upon Tyne, Northern Regional United Kingdom — Adverse reactions are rarely Blood Transfusion Service, 1988. attributed to drug residues in transfused blood (1, 2), but such events may occur more frequently than is generally appreciated. Detectable concentrations Adverse reaction reporting: of penicillin were reported some years ago, for example, in 30 of some 10 000 samples of serum engaging commitment from healthy individuals (3), and it has been estimated that passive transfer of anti-penicillin United Kingdom — The spontaneous notification antibodies may occur in some 3 per cent of of suspected adverse drug reactions by practising transfusions (4). This has raised speculation that clinicians to a national agency is a vital component some cases of "non-specific" transfusion reactions of any system of post-marketing surveillance (1). are, in fact, manifestations of drug-induced ana­ The system notionally involves all prescribers, all phylaxis in susceptible recipients (5). Basing its patients and all drugs. Indeed, in those countries calculations on known pharmacodynamic properties that register large numbers of newly-developed of over 500 widely-used drugs, the Northern drugs, it can be regarded as a "fine tuning" mecha­ Regional Blood Transfusion Service in the United nism for the regulatory process. In practice, Kingdom has prepared guidelines on the time that however, the system is compromised by a ubiqui­ should be allowed to elapse between the admini­ tous and apparently intractable apathy among stration of the last dose of each of these drugs and doctors (2). Reporting rates are low everywhere, blood donation. This ranges from zero for drugs particularly in hospitals, where serious reactions are with a large volume of distribution that are not most commonly found. known to induce anaphylaxis to two years for etretinate, a proven human teratogen with an To promote better and more frequent reporting, extremely prolonged half-life (5, 6). pharmacists and nurses as well as doctors have been encouraged to document relevant incidents In the absence of such information, medical officers over the past five years in a busy regional hospital responsible for blood donation services are at in north-east England (3). These are reviewed and increased risk, both of accepting blood that is screened at weekly intervals by a staff pharmacist potentially harmful to the recipient and, more and a clinical pharmacologist, and reports consid­ frequently, of needlessly turning away donors who ered to merit notification are then forwarded to the could have safely contributed blood. In the latter national monitoring centre. The impact of the case, the authors suggest, this will often result in system was immediately apparent. During the first the loss of far more than one unit of blood since year the number of notifications increased five fold, first-time donors, once rejected, are most unlikely to and this rate has since been consistently main­ return. tained. In this particular hospital commitment was manifestly high; one of the members of the organiz­ References ing group is also a member of the UK Committee on Safety of Medicines. However, the results 1. Michel, J., Sharon, R. Nonhaemolytic adverse reaction suggest that, with little organizational commitment, after transfer of a blood unit containing penicillin. British similar schemes — which can be operated at Medical Journal, 280: 152-153 (1980). relatively little cost and which also have important educational value — could be successfully intro­ 2. Branch, D.R., Houghton, G. Allergic reaction to duced elsewhere. transfused cephalothin antibody. Journal of the American Medical Association, 241: 495-496 (1979).

179 General Information WHO Drug Information Vol. 3, No. 4, 1989

References Mycobacterium tuberculosis in clinical specimens (including sputum, gastric aspirate, abscess 1. Rawlins, M.D. Spontaneous reporting of adverse drug aspirate, and biopsy samples) without recourse to reactions. I: the data; II: uses. British Journal of Clinical culture (7). Pharmacology, 26: 1-11 (1988).

2. Bennett, R.S., Lipman, A.G. Comparative study of Even though many of these tests will require further prospective surveillance and voluntary reporting in refinement before they are sufficiently reliable and determining the incidence of adverse drug reactions. cost-effective for routine use, their potential is American Journal of Hospital Pharmacy, 34: 931-936 already firmly established. None the less, as the (1977). Lancet emphasizes, the benefits of rapid identifica­ tion of pathogens will remain limited for as long as 3. Winstanley, P.A., Irvin, L.E., Smith, J.C., Orme, M.L'E., their sensitivity to candidate drugs has to be Breckenridge, A.M. Adverse drug reactions: a hospital determined by traditional microbiological methods. pharmacy-based reporting scheme. British Journal of The ultimate objective must be to devise probes Clinical Pharmacology, 28: 113-116 (1989). that will reveal not only the identity, but the antibi­ otic sensitivity of common pathogens. There is no doubt that this is possible. Indeed, a test for DNA probes: a new generation detecting genes coding for beta-lactamase produc­ of diagnostic tools tion in Neisseria gonorrhoeae (8) has already been developed. The task of generating information about the distribution of genes coding for antibiotic Not least among the challenges of managing resistance in most of the common pathogens is infectious disease is the identification of the formidable, but given the current status of the causative agent. With traditional microbiological technology and contemporary concerns regarding methods, several weeks are often required to confirm the identity of viruses, mycobacteria and drug resistance, it is not only feasible: it is urgent. parasites in clinical specimens. An ability to make prompt, precise diagnoses directly from these References specimens would not only represent a considerable saving in health care costs but, by accelerating 1. Editorial. DNA technology and rapid diagnosis of therapeutic management, it would also decrease infection. Lancet, 2: 897-898 (1989). the case-fatality of severe infections. 2. Pao, C.C., Lin. S.S., Wu, S.Y. et al. The detection of mycobacterial DNA sequences in uncultured clinical The possibility that DNA probes may soon be used specimens with cloned Mycobacterium tuberculosis DNA routinely in this way in hospital laboratories to as probes. Tubercle, 69: 27-36 (1988). identify a wide range of pathogenic organisms is discussed in a recent issue of the Lancet (1). Kits 3. Saiki, R.K., Gelfand, D.H., Stoffel, S. et al. Primer- for routine use are already available to detect directed enzymatic amplification of DNA with a thermo­ gonococci, tubercle bacilli and other mycobacteria, stable DNA polymerase. Science, 239: 487-491 (1988). legionella and herpes simplex virus, and many others have been developed for research purposes. 4. Lench, N., Stainer, P., Williamson, R. Simple non­ invasive method to obtain DNA for gene analysis. Lancet, 1: 1356-1358(1988). At present, most of these perform reliably only when isolates cultured on solid media are tested 5. Laure, F., Courgnaud, V., Rouzioux, C. et al. Detection (2). Solution hybridization — potentially the most of HIV I DNA in infants and children by means of the suitable technique for testing clinical specimens — polymerase chain reaction. Lancet, 2: 538-541 (1988). was too insensitive until recently to detect low levels of target DNA. However, through use of the 6. Griffais, R., Thibon, M. Detection of Chlamydia polymerase chain reaction, small amounts of DNA trachomatis by the polymerase chain reaction. Research can be replicated, or amplified, in the presence of in Microbiology, 140: 139-141 (1989). DNA polymerase and a specific primer (3). Several 7. Brisson-Noël. A., Gicquel, B., Lecossier, D. et al. Rapid tests dependent upon DNA amplification and diagnosis of tuberculosis by amplification of myco­ subsequent hybridization are currently under trial bacterial DNA in clinical samples. Lancet, 2: 1069-1071 (4-6), among them a probe capable of detecting (1989).

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8. Perine, P.L., Totten, P.A., Holmes, K.K. et al. Evalu­ monitor will also prove its worth in routine clinical ation of a DNA hybridization method for detection of practice. They may well be right. When a patient African and Asian strains of Neisseria gonorrhoeae in fails to respond to treatment, the need to assess men with urethritis. Journal of Infectious Diseases, 152: pill-taking habits before embarking upon costly 59-63 (1985). clinical investigations or altering prescribed drug regimens is self-evident and the methods currently available are manifestly inadequate. How often are drugs really taken? References United States of America — All doctors are aware that, for one reason or another, many patients are 1. Stewart, R.B., Cluff, L.E. A review of medication errors less than assiduous in following their advice (1). and compliance in ambulant patients. Clinical Pharma­ cology and Therapeutics, 13: 463-468 (1972). They may be ambivalent, forgetful, careless, or simply unable to accept their illness. Surprisingly, it 2. Cramer, J.A., Collins, J.F., Mattson, R.H. Can has been claimed that these attitudes are inde­ categorization of patient background problems be used to pendent of the severity of the illness, the patient's determine early termination in a clinical trial? Controlled understanding of the disease process and the Clinical Trials, 9: 47-63 (1988). objectives of treatment (2). Despite the ubiquity of the problem and its crucial importance to patient 3. Cramer, J.A., Mattson, R.H., Prevey, M.L. et al. How care, it has attracted relatively little investigation. often is medication taken as prescribed? A novel assessment technique. Journal of the American Medical Association, 261: 3273-3277 (1989). In routine settings, checks on whether patients are complying with prescribed treatment schedules have been limited to occasional pill counts and spot estimates of plasma drug concentrations. Since Asthma: inadequacies in wayward patients anxious to avoid a breach of trust concepts and management with their doctor will be more strongly disposed to take their prescribed medicines before a scheduled Asthma is the most prevalent chronic disease of visit to the clinic and may even remove pills that adults and children in the developed world. Within a should have been used from boxes that might be general practice of 2000 patients as many as 150 inspected, both methods have obvious shortcom­ may have asthma. However, a recent leading ings. article in the Lancer (1) claims that only one in four adults and one in ten children with the disease are A novel and more informative method of identifying identified by their family doctors (2) and that these these patients may now be at hand since micro­ are not necessarily the individuals with the most processors can be fitted into the caps of standard severe symptoms (3). Even among the patients pill bottles which record each opening as a pre­ who are treated, control of symptoms is often less sumptive dose. Their use in assessing compliance than satisfactory. It is estimated that each week two among newly-treated and long-term patients with in three patients are awakened by acute exacerba­ epilepsy has shown that more complex dosage tions on at least 3 nights (4). Moreover, although regimens are a severe test of most patients' asthma is not a frequent cause of death, most of memories and sense of purpose. Whereas 87 per those that do occur may be preventable (5). cent of patients were able to adhere to a once-daily dosing regimen, only 39 per cent were able to cope effectively with six-hour dosing schedules (3). No Whereas a few patients are acknowledged to be significant correlation was demonstrated between resistant to treatment, this unsatisfactory situation is these findings and drug concentrations in blood attributed primarily to suboptimal therapy. Some of samples drawn in the clinic, and pill counts over­ this is due to inadequate understanding on the part estimated consumption most decisively in the least of the patients. Many, it seems, have no concept of compliant patients. how their drugs work and they cannot provide a precise account of how to cope with an acute attack (6). But also at issue, the Lancet contends, is a More reliable means of assessing compliance will need for many clinicians to change their approach be welcomed, particularly in a research context, to the treatment of the disease. To define the when need arises to assess dose-related properties condition as reversible airflow obstruction, it of drugs. In the opinion of the authors, the pill suggests, is unhelpful in a therapeutic context since

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this is the result, not the cause, of the underlying 2. Speight, A.N.P., Lee, D.A., Hey, E.N. Underdiagnosis bronchial inflammation. Bronchospasm is most and undertreatment of asthma in childhood. British effectively prevented not by use of bronchodilators, Medical Journal, 286: 1253-1258 (1983). but by inhaled topical steroids and cromoglicic acid (2, 7). If management is to improve, regular inhaled 3. Mortagy, A.K., Howell J.B.L., Waters, W.E. Respiratory symptoms in bronchial reactivity: identification of a prophylaxis must be favoured rather than bron­ syndrome and its relation to asthma. British Medical chodilators as the first-line treatment for patients Journal, 293: 525-529 (1986). with recurrent symptoms. Corticosteriods are advocated as the drugs of choice for adults, and for 4. Turner-Warwick, M. Nocturnal asthma: a study in those children who do not respond to cromoglicic general practice. Journal of the Royal College of General acid. But in order to titrate treatment effectively, it Practitioners, 39: 239-243 (1989). emphasizes the need to meter peak expiratory air flow. Fluctuations of 20 per cent indicate that the 5. British Thoracic Association. Death from asthma in two dose of topical steroids should be increased, while regions of England. British Medical Journal, 285: 1251- 1255(1982). variations of more than 50 per cent offer warning of an impending severe attack and of a temporary 6. Bucknall, C.E., Robertson, C, Moran, F., Stevenson, need for supplementary oral corticosteroids (8). R.D. Management of asthma in hospital: a prospective study. British Medical Journal, 296: 1637-1639 (1988). In this context, effective prophylaxis is not simply good medicine, it is also sound economics. Several 7. Stead, R.J., Cooke, N.J. Adverse effects of inhaled studies have shown that prevention of acute corticosteroids. British Medical Journal, 298: 403-404 exacerbations is more cost-effective than treatment (1989). (9-11). Particularly dramatic reductions in the use of emergency services, hospital facilities and medical 8. Hetzel, MR, Clarke, T.J.M., Braithwaite, M.A. Asthma: consultations are claimed to have followed the analysis of sudden death and ventilatory arrests in hospital. British Medical Journal, 1: 808-811 (1977). introduction of cromoglicic acid into a standardized maintenance programme in New Zealand (12). If 9. O'Brien, S., Hein, E.W., Sly, R.M. Treatment of acute such experiences have general applicability, a rare asthmatic attacks in a holding unit of a paediatric opportunity exists for effecting important economies emergency room. Annals of Allergy, 45: 159-162 (1980). that will at the same time enhance patient care. The sums at issue are not small: the direct annual cost 10. Willert, C., Davis, AT., Herman, J.J. et al. Short term of treating the asthmatic population in the USA has holding room treatment of asthmatic children. Journal of been estimated to be as high as $8.7 billion (11). Paediatrics, 106: 707-711 (1985).

11. Ross, R.N., Berman, B.A. Asthma costs. New Zealand Medical Journal, 102: 450 (1989). References 12. Ross, R.N., Morris, M., Berman, B.A. Cost-effective­ 1. Editorial comment. Management of asthma in the ness of including cromolyn sodium in the treatment community. Lancet, 2: 199-200 (1989). programme for asthma: a retrospective record based study. Clinical Therapeutics, 10: 188-203 (1988).

182 WHO Drug Information Vol. 3, No. 4, 1989

Regulatory Matters

Aminoglycoside antibiotics: Cosmetics: disclosure of restrictive measures ingredients

Spain — In the light of a review it has undertaken Canada — Since 1978, manufacturers of cosmetics on the efficacy and safety of a number of amino­ have been required by regulation to provide the glycoside antibiotics, the Ministry of Health has Health Protection Branch with a qualitative and decided, having regard to their narrow therapeutic quantitative listing of all ingredients of cosmetic index and their toxic potential, to withdraw paren­ products as a condition of marketing. However, this teral dosage forms of paromomycin and to restrict information has not been available to the consumer. the use of dibekacin, kanamycin and ribostamycin The Branch is now proposing that these regulations to hospitals with microbiological laboratory facilities be amended to require all ingredients to be for antibiotic sensitivity testing. declared on product labelling by common names most familiar to consumers and in descending order Reference: Instituto Nacional de la Salud. Información of concentration. The objective is to enable Terapéutica de la Seguridad Social, 13:7 (1989). purchasers to identify products containing ingredi­ ents to which they are sensitive. Comments are being requested from interested parties on whether, Aphrodisiac activity: as an additional requirement, a centralized data base providing information on the composition of no more claims cosmetic products should also be created.

United States of America — The sale of Reference: Health Protection Branch, Health and nonprescription drugs promoted as aphrodisiacs Welfare, Canada, Information Letter, No. 768 (1989). will be banned from 8 January 1990. Among the ingredients contained in many of the products are: anise, cantharides (or "Spanish fly", a chemical Ethylene oxide: derived from the dried bodies of beetles), estro­ gens, fennel, ginseng, golden seal, tou kila, Korean a potential carcinogen? ginseng, licorice, mandrake, methyltestosterone, minerals, nux vomica, Pego Palo, sarsaparilla, United Kingdom — The Licensing Authority has strychnine, testosterone, vitamins and yohimbine. requested information from pharmaceutical The Food and Drug Administration has no evi­ manufacturers on the use of ethylene oxide both as dence to show that any of the materials traditionally a disinfecting and sterilizing agent, and in chemical used as aphrodisiacs are either effective or safe. syntheses. Experimental evidence to show that it Only the male sex hormones, which are potent may act as a genotoxic carcinogen has raised compounds associated with potentially serious concerns that significant residues — both of side-effects, are known to influence libido. It ethylene oxide itself and its breakdown products, advises patients with sexual problems to consult including ethylene halohydrin and ethylene glycol their doctor and not to indulge in self-medication. — may exist in some medicinal products.

References Manufacturers are asked to supply data on any product, ingredient or component which includes or 1. Federal Register, 54: 28780-28786 (1989). has been exposed to ethylene oxide or its degrada­ tion products. Non-ionic surfactants, herbs/spices, 2. FDA Talk Paper, T89-42 (1989).

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starches, capsule shells, bulk laxatives, pre¬ Mefloquine: restrictive labelling sterilized containers and delivery systems are specifically mentioned. Federal Republic of Germany — In the light of recent reports of adverse neurological reactions Information has also been requested on any associated with the antimalarial agent, mefloquine changes in production processes that have been sulfate, the Federal Health Office has reminded introduced to eliminate exposure to ethylene oxide. doctors that this preparation is indicated only for the Reference: Letter from the Department of Health and treatment of infections due to multiresistant strains Social Security, London, June 1989. of Plasmodium falciparum and for prophylaxis in short-term visitors to countries where such strains are endemic. It is now specifically contraindicated in patients with a history of epilepsy and, for prophy­ Hair restorers on prescription only laxis, in aircraft pilots. The labelling must also include a warning that anyone taking the drug United States of America — The Food and Drug should be particularly careful when driving or Administration has announced that sale of any non­ operating machinery, and an indication that adverse prescription hair cream, lotion or other external neurological effects, including depression, confu­ product claiming to grow hair or prevent baldness, sion, anxiety, hallucinations, paranoia and convul­ will be banned as from 8 January 1990. sions, have been associated with use of the drug, even at the lowest dosage schedules. Products currently promoted for this purpose include amino acids, amino-benzoic acid, ascorbic Reference: Mefloquin: Ergänzungen in der acid, benzoic acid, biotin and all other B-vitamins, Packungsbeilage zu den Abschnitten Nebenwirkungen dexpanthenol, estradiol and other topical und Kontraindikationen. Bundesgesundheitsblatt, 10: hormones, jojoba oil, lanolin, nucleic acids, polysor¬ 469-470 (1989). bate 20, polysorbate 60, sulfanilamide, sulfur 1% on carbon in a fraction of paraffinic hydrocarbons, tetracaine hydrochloride, urea, and wheat germ oil. Metamizole: withdrawal of The agency has received no data to establish the safety and effectiveness of these or any other combination products ingredients. Spain — The Ministry of Health has announced The ban is directed specifically at products for that all fixed combination products containing meta­ external use. The Food and Drug Administration mizole sodium — with the exception of those con­ has warned, however, that it will be extended on a taining a spasmolytic — will be withdrawn from the case-by-case basis to other products for which market. This will affect a large range of products in such claims continue to be made, including oral which metamizole is variously combined with other formulations of vitamins and food supplements. analgesics, antibiotics, barbiturates, corticosteroids and vitamins. In announcing this decision, the At present, a 2% topical solution of minoxidil, which National Institute of Health has commented that is subject to prescription control, is the only product such combination products result in much unneces­ approved by the Food and Drug Administration for sary use of metamizole, which is known to be stimulating hair growth in individuals with male- associated with cases of agranulocytosis. Restric­ pattern baldness. tions have also been imposed on the labelling of single ingredient preparations of metamizole which References may now be indicated only for short-term sympto­ matic relief of post-traumatic and post-operative 1. HHS News, P89-32 (1989). pain, abdominal colic, and high fever unresponsive to other antipyretics. 2. Federal Register, 54: 28772-28777 (1989). Reference: Instituto Nacional de la Salud. Información Terapéutica de la Seguridad Social, 13: 6-7 (1989).

184 WHO Drug Information Vol. 3, No. 4, 1989 Regulatory Matters

Sulfonamides: suppository products containing "supplements" of L-tryptophan were earlier recalled when it was established that formulations withdrawn they were associated with eosinophilia-myalgia syndrome. This is a condition which is character­ Spain —The Ministry of Health has announced the ized by severe muscle and joint pain, swelling of withdrawal of a suppository formulation of the the arms and legs, skin rash and, sometimes, by antibiotic combination, trimethoprim and sulfa­ fever. Over 700 cases have been notified thus far methoxazole. The action has been taken in the light and a suspected association with several deaths is of evidence that absorption of sulfonamides by this being investigated. Evidence of possible chemical route is unacceptably erratic. It is planned to or microbial contamination is being sought but, as subject other suppositories that contain sulfon­ yet, no cause for the illness has been established. amides to review very shortly. Many of these patients were taking the substance in daily quantities of 1 to 2 grams. Reference: Institute Nacional de la Salud. Information Terapéutica de la Seguridad Social, 123: 4 (1989). Foods containing L-tryptophan as a natural ingredient and multi-ingredient food products containing the amino acid as a minor ingredient are L-Tryptophan supplements and excluded from recall. At issue are several hundred unapproved products that have been used in eosinophilia-myalgia syndrome attempts to treat a variety of problems including sleeping difficulties, premenstrual syndrome, stress United States of America — The Food and Drug and depression. Administration has informed WHO that it is im­ pounding all finished dosage forms of preparations containing the amino acid L-tryptophan, as well as Reference: Update on L-tryptophan, FDA Talk Paper, shipments of the bulk substance intended for T89-76 (1989). importation into the USA. All non-prescription

185 WHO Drug Information Vol. 3, No. 4, 1989

Advisory Notices

This is not the first time that such products — which Delayed shock and low can so readily bring about the death of seriously ill osmolar radiocontrast media patients — have entered the distribution chain.

Japan —The Pharmaceutical Affairs Bureau has The World Health Organization, which is becoming received notifications of cases of shock occurring increasingly concerned about the extent and several hours after administration of iodine- consequences of counterfeiting, applauds the containing radiocontrast media at a time when transparency with which the company has treated patients may no longer remain under close super­ this episode, and its willingness to share informa­ vision. It has requested doctors to submit details of tion on other counterfeited products. It appeals to all cases that come to their attention in order to anyone who is aware of, or who suspects, the obtain an estimate of their frequency. existence of counterfeited drugs anywhere in the world to immediately inform the competent health Reference: Pharmaceutical Affairs Bureau. Information authorities, the manufacturer (or local representa­ on Adverse Reactions to Drugs, No. 96 (1989). tive) of the original product and the Pharmaceuti­ cals Programme, WHO, 1211 Geneva 27, Switzer­ land. Counterfeit Reference: Communication from Hoffmann-La Roche, dermatological products Basle, dated 28 August 1989.

United Kingdom — The Medicines Control Agency has informed WHO that it has identified various Flunarizine and counterfeit proprietary dermatological products — among them copies of widely-used topical steroid extrapyramidal symptoms preparations — most of which contain little or no active ingredient. Some of the products contain Japan — The Pharmaceutical Affairs Bureau has package inserts in Arabic and some are labelled to informed doctors that it has received several give the impression that they have been manufac­ reports of extrapyramidal symptoms and depres­ tured in France or Italy. They were being sold sion occurring in patients under treatment with the outside the legitimate pharmaceutical distribution peripheral vasodilator, flunarizine. Similar cases chain and there is no evidence at present that any notified to other national authorities have most of them have been introduced into these channels. frequently involved women and older patients. Pharmacists have been alerted as a precautionary Doctors have been specifically requested to report measure and enquiries are continuing. all such cases in order that their incidence and any predisposing factors may be better assessed. Reference: Communication from the Medicines Control Agency, 21 November 1989. Reference: Pharmaceutical Affairs Bureau. Information on Adverse Reactions to Drugs, No. 96 (1989). Counterfeit Fansidar® Minoxidil and contact dermatitis Nigeria — Hoffmann-La Roche has informed WHO that counterfeit Fansidar® tablets that contain about Denmark — The Adverse Drug Reactions Centre 5 mg of chloramphenicol instead of sulfadoxine and has received reports of 27 cases of contact pyrimethamine, have been discovered in Nigeria. dermatitis associated with topical application of They are readily distinguished from the authentic minoxidil since it was registered to treat male- product by their darker colour and single (rather pattern baldness in October 1987. The duration of than a cross) break marks. use before signs were noticed ranged from 7 to 420 days and, in 11 patients who applied the product

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again subsequently, rechallenge was positive. It is Steroid aerosols and cataract estimated from these reports that the risk of dermatitis is at least 0.2 to 0.5 per cent and, since other cases may well have occurred, the true United Kingdom — A report published in the incidence may be substantially higher. British Medical Journal describes three patients, aged between 47 and 52 years, who developed Reference: Ugeskrift for Laeger, 151:1834 (1989). posterior subcapsular cataracts after having taken beclometasone by inhaler supplemented by intermittent short courses of oral corticosteroids over several years for bronchial asthma (1). None Retinoids and necrotizing vasculitis was found to have any other sign of steroid-induced toxicity, but neither was any other condition Selective clinical details are provided in a communi­ predisposing to cataract formation detected. cation to the Lancet (1) concerning 19 patients who developed clinical and pathological signs of The authors emphasize that a causal relationship immune complex vasculitis following or during cannot be established on these data, particularly treatment with the retinoids, isotretinoin and since one survey — now over 20 years old — etretinate. The case reports, which had been indicated that cataracts of this type may be present notified from several countries to the manufacturer, in more than 0.5 per cent of the adult population Hoffmann-La Roche, were subsequently submitted (2). However, within the past decade — and some to panel review. The patients had presented with a years after inhaled steroids became widely avail­ variety of toxic cutaneous and visceral changes able — their prevalence within the asthmatic popu­ resulting from necrotizing vasculitis that resolved lation in Australia was estimated to be about 9 per after withdrawal of therapy and over a variable time cent (3), while independent estimates conducted course, in some cases following short-term steroid among asthmatic children place the corresponding therapy. figure as much as three-fold higher (4). The immune mechanisms underlying these effects In the authors' opinion it seems possible that remain uncertain but, in several instances, evi­ inhaled steroids alone may have been sufficient to dence of vasculitis developed in patients receiving have caused the cataracts detected in their patients etretinate within a matter of days after first expo­ and they call for planned prospective studies to be sure, thereby suggesting a direct toxic effect of the compound. In other instances, however, the onset undertaken to explore this possibility further. of symptoms was long delayed and in some of these cases it may have been triggered by inciden­ References tal use of antibiotics. The authors cite previous reports associating the use of retinoids with severe 1. Allen, MB., Ray, S.G., Leitch, A.G. et al. Steroid vasculitis (2) and an erythema nodosum syndrome aerosols and cataract formation. British Medical Journal, (3) and they emphasize the need for clinicians to be 299: 432-433(1989). aware of these effects. 2. Spaeth, G.L., Smallman, von L. Corticosteroids and cataracts. International Ophthalmology Clinics, 6: 915- References 929 (1966).

1. Dwyer, J.M., Kenicer, K., Thompson, B.T. et al. 3. Kewley, G.D. Possible association between beclo­ Vasculitis and retinoids. Lancet, 2: 494-496 (1989). metasone dipropionate aerosol and cataracts. Australian Paediatric Journal, 16: 117-118 (1980). 2. Epstein, E.H., McNutt, N.S., Beallo, R. et al. Severe vasculitis during isotretinoin therapy. Archives of 4. Rooklin, A.R., Lampert, S.I., Jaeger, E. et al. Posterior Dermatology, 123: 1123-1125 (1987). subcapsular cateracts in steroid-requiring asthmatic children. Journal of Allergy and Clinical Immunology, 63: 3. Kellett, J.K., Beck, M.H., Chalmers, R.J.G. Erythema 383-386 (1979). nodosum and circulating immune complexes in acne fulminans after treatment with isotretinoin. British Medical Journal, 290:820 (1985).

187 Advisory Notices WHO Drug Information Vol. 3, No. 4, 1989

Oral contraceptives Zidovudine: carcinogenic potential and older women United States of America — The Burroughs Wellcome Company has recently completed United States of America — The Fertility and standard lifetime carcinogenicity studies on Maternal Health Drugs Advisory Committee of the zidovudine in both rats and mice. In both species a Food and Drug Administration has recommended number of vaginal squamous cell carcinomas were that the labelling of oral contraceptive products detected toward the end of the studies in high- should be amended to set no age limit for their use dosed females (1). Whereas these are accepted to by women who do not smoke. The statement in the be drug related, they have tenuous relevance to the current labelling warns that use of oral contracep­ clinical use of zidovudine. Moreover, since the tives is associated with an increase in mortality tumours were specific in nature, sex-linked in their among smokers aged over 35 and non-smokers distribution, of late onset, and associated only with aged over 40. extremely high and prolonged doses, the com­ pound cannot be regarded as a potent carcinogen. The increased mortality among non-smokers was presumed to be related to the higher doses of The manufacturer has advised that these results do estrogen used in these products when the warning not preclude the clinical use of zidovudine if, in the was introduced in the early 1970s. These products judgement of the doctor and the patient, the were subsequently withdrawn at the recommenda­ benefits of the drug outweigh any potential risk. tion of the Committee in 1988 when they were This view is supported by the US Food and Drug shown to be no more effective than lower dose Administration, which has commented that products. Those commonly prescribed today "Zidovudine is the only therapeutic agent approved contain only 30 or 35 micrograms of estrogen and, by the FDA that is known to act against the HIV whereas the Committee cannot exclude the virus, although other agents are under study. possibility that these, too, might constitute a risk Therefore, in spite of the new animal findings, factor for cardiovascular disease, it considers such patients with [AIDS] appear to be at far greater risk risks to be outweighed by the benefits of oral from not receiving zidovudine treatment than from contraception. any potential risk of cancer associated with its use" Reference: Advisory Committee on Use of Oral Contra­ (2). ceptives in Older Women. FDA Talk Paper, T89-70 (1989). References 1. Burroughs Wellcome Company, USA. Circular letter to doctors dated 5 December 1989. Xamoterol: inappropriate 2. US Department of Health and Human Services. for severe heart failure Statement on AZT rodent lifetime carcinogenicity studies communicated to WHO on 7 December 1989. United Kingdom — The manufacturer of the beta adrenoreceptor blocking agent, xamoterol, has urged doctors never to prescribe the product for patients with severe degrees of heart failure since it Zidovudine-induced neutropenia has been approved specifically for the management of mild to moderate degrees of decompensation United States of America — It has been shown in resulting in no more than increased breathlessness a prospective study involving 30 patients with AIDS and fatigue on exertion. Paradoxically, it has been or AIDS-related complex, that the incidence of shown to exacerbate more severe degrees of infections did not increase significantly during failure. treatment with zidovudine until the polymorpho­ nuclear cell count fell below 500 per microlitre (1). Under this level, the risk of bacterial infection — but Reference: The Pharmaceutical Journal, 242: 194 (1989). not of the opportunistic infections, which remained predominant — rose sharply. Overall, bacterial

188 WHO Drug Information Vol. 3, No. 4, 1989 Advisory Notices

infection was six times more likely at these times that their now established practice of withdrawing than when the count was above 1000 per microlitre. therapy temporarily only when the count drops Most frequent was skin cellulitis due to Staphylo­ below 500 per microlitre is both safe and advanta­ coccus aureus or Pseudomonas aeruginosa. In geous. It enables patients to benefit from continu­ addition, three cases of pneumonia occurred due, ous treatment with zidovudine and to avoid the respectively, to Legionella pneumophila, Haemo­ problems associated with frequent interruptions of philus influenzae, and Streptococcus pneumoniae. therapy (4). Bacteraemia, in this instance due to Enterobacter aerogenes, occurred on one occasion only and it References responded satisfactorily to antibiotic therapy. 1. Shaunak, S., Bartlett, J.A. Zidovudine-induced Several factors are likely to have contributed to the neutropenia: are we too cautious? Lancet, 2: 91-92 relatively low incidence of bacterial infection. None (1989). of the patients continued to use intravenous drugs; 2. Pinching, A.J., Helbert. M., Peddel, B. et al. Clinical none was on chemotherapy; and all were main­ experience with zidovudine for patients with AIDS and tained as outpatients to reduce the risk of noso­ ARC. Journal of Infection, 18 (S1): 33-40 (1989). comial infection. The results, none the less, hold importance because neutropenia — defined as less 3. Williams, I., Gabriel, G., Cohen, H. et al. Zidovudine — than 1000 cells per microlitre — has been esti­ the first year of experience. Journal of Infection, 18 (S1): mated to occur in more than one-third of patients 23-31 (1989). receiving zidovudine and it has been taken as a sign by many doctors to reduce the dose or to 4. Dournon, E., Matheron, S., Rozenbaum, W. et al. Effects of zidovudine in 365 consecutive patients with discontinue treatment (2, 3). The authors consider AIDS and ARC. Lancet, 2: 1297-1302 (1988).

189 WHO Drug Information 1990 Subscription

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Essential Drugs

WHO Model List: Sixth Revision injection for spinal anaesthesia. 5% (hydrochloride) in 2-ml ampoule Section 1: to be mixed with 7.5% glucose solution Anaesthetics topical forms, 2 - 4% (hydrochloride) dental cartridge, 2% (hydrochloride) GENERAL ANAESTHETICS AND OXYGEN + epinephrine 1.80 000 ether, anaesthetic (2) inhalation diazepam (1b, 2) injection, 5 mg/ml PREOPERATIVE MEDICATION in 2-ml ampoule atropine injection, 1 mg (sulfate) in 1 ml ampoule halothane (2) inhalation chloral hydrate syrup, 200 mg/5 ml ketamine (2) injection, 50 mg/ml in 10-ml vial *diazepam (1b) injection, 5 mg/ml nitrous oxide (2) inhalation in 2-ml ampoule oxygen inhalation (medicinal gas) *morphine (1a) injection, 10 mg (sulfate or *thiopental (2) powder for injection, 0.5 g, 1.0 g hydrochloride) in 1-ml ampoule (sodium salt) in ampoule *promethazine elixir or syrup, 5 mg (hydrochloride)/5 ml LOCAL ANAESTHETICS *bupivacaine (2, 9) injection, 0.25%, 0.5% (hydrochloride) in vial Section 2: injection for spinal anaesthesia, Analgesics, antipyretics, non­ 0.5% (hydrochloride) in 4-ml ampoule steroidal anti-inflammatory drugs to be mixed with 8% glucose and drugs used to treat gout *lidocaine injection, 1%, 2% (hydrochloride) in vial NON-OPIOIDS injection, 1%, 2% (hydrochloride) acetylsalicylic acid tablet, 100 - 500 mg + epinephrine 1:200 000 in vial suppository, 50 - 150 mg

* Example of a therapeutic group. Various drugs can serve as alternatives.

(4) In renal insufficiency, contraindicated or dosage Explanatory Notes adjustments necessary; When the strength of the drug is specified in terms of a (5) To improve compliance; selected salt or ester, this is mentioned in brackets; (6) Special pharmacokinetic properties for purpose; when it refers to the active moiety, the name of the salt or (7) Adverse effects limit benefit/risk ratio; ester in brackets is preceded by the word "as". (8) Limited indications or narrow spectrum of activity; Numbers in parentheses following the drug names (9) For epidural anaesthesia. indicate: Letters in parentheses following the drug names indicate (1a) Drugs subject to international control under the the reasons for the inclusion of complementary drugs: Single Convention on Narcotic Drugs (1961); (A) When drugs in the main list cannot be made (1b) Drugs subject to international control under the available; Convention on Psychotropic Substances (1971); (8) When drugs in the main list are known to be ineffec­ (2) Specific expertise, diagnostic precision, or special tive or inappropriate for a given individual; equipment required for proper use; (C) For use in rare disorders or in exceptional circum­ (3) Greater potency or efficacy; stances.

191 Essential Drugs WHO Drug Information Vol. 3, No.4, 1989

allopurinol (4) tablet, 100 mg ipecacuanha syrup, containing 0.14% ipecacuanha alkaloids colchicine (7) tablet, 500 µg calculated as emetine *ibuprofen tablet, 200 mg SPECIFIC *indometacin capsule or tablet, 25 mg atropine injection, 1 mg (sulfate) paracetamol tablet, 100 - 500 mg in 1-ml ampoule suppository, 100 mg deferoxamine powder for injection, 500 mg (mesilate) in vial syrup, 125 mg/5 ml dimercaprol (2) injection in oil, 50 mg/ml OPIOID ANALGESICS in 2-ml ampoule *codeine (1a) tablet, 30 mg (phosphate) *methionine tablet, 250 mg (DL) *morphine (1a) injection, 10 mg (sulfate or methylthioninium chloride injection, 10 mg/ml hydrochloride) in 1-ml ampoule (methylene blue) in 10-ml ampoule oral solution, 10 mg/5 ml naloxone injection, 400 µg (hydrochloride) tablet, 10 mg (sulfate) in 1-ml ampoule penicillamine (2) capsule or tablet, 250 mg Complementary drug *pethidine (A) (1a, 4) injection, 50 mg sodium calcium edetate (2) injection, 200 mg/ml (hydrochloride) in 1 -ml ampoule in 5-ml ampoule tablet, 50 mg, 100 mg (hydrochloride) sodium nitrite injection, 30 mg/ml in 10-ml ampoule sodium thiosulfate injection, 250 mg/ml Section 3: in 50-ml ampoule Antiallergics and drugs potassium ferric hexa¬ powder for oral cyanoferrate (ll)*2H20 administration used in anaphylaxis (Prussian blue)

*chlorphenamine tablet, 4 mg (hydrogen maleate) injection, 10 mg (hydrogen Section 5: maleate) in 1-ml ampoule Antiepileptics *dexamethasone tablet, 500 µg, 4 mg injection, 4 mg (as sodium carbamazepine scored tablet, 100 mg, 200 mg phosphate) in 1-ml ampoule *diazepam (1b) injection, 5 mg/ml in 2-ml epinephrine injection, 1 mg (as hydro­ ampoule (intravenous or rectal) chloride) in 1-ml ampoule ethosuximide capsule or tablet, 250 mg hydrocortisone powder for injection, 100 mg syrup, 250 mg/5 ml (as sodium succinate) in vial phenobarbital (1b) tablet, 15- 100 mg *prednisolone tablet, 5 mg elixir, 15 mg/5 ml phenytoin capsule or tablet, 25 mg, 100 mg (sodium salt) Section 4: injection, 50 mg Antidotes and other (sodium salt)/ml in 5-ml vial substances used in poisonings valproic acid (7) enteric coated tablet, 200 mg, 500 mg (sodium salt) GENERAL *charcoal, activated powder

* Example of a therapeutic group. Various drugs can serve as alternatives.

192 WHO Drug Information Vol. 3, No. 4, 1989 Essential Drugs

Section 6: benzylpenicillin powder for injection, Anti-infective drugs 600 mg (= 1 million IU), 3 g (= 5 million IU) ANTHELMINTHICS (as sodium or potassium salt) in vial *cloxacillin capsule, 500 mg (as sodium salt) INTESTINAL ANTIHELMINTHICS powder for oral solution, 125 mg albendazole tablet, 200 mg (as sodium salt)/5 ml levamisole (8) tablet, 50 mg, 150 mg powder for injection, 500 mg *mebendazole chewable tablet, 100 mg (as sodium salt) in vial niclosamide chewable tablet, 500 mg phenoxymethylpenicillin tablet, 250 mg (as potassium salt) piperazine tablet, 500 mg hydrate (as adipate or citrate) powder for oral suspension, 250 mg (as potassium salt)/5 ml elixir or syrup (as citrate) equivalent to 500 mg hydrate/5 ml *piperacillin powder for injection, 1 g, 2 g (as sodium salt) in vial praziquantel tablet, 150 mg, 600 mg procaine benzylpenicillin powder for injection, pyrantel chewable tablet, 250 mg 1 g (= 1 million IU), (as embonate) 3 g (= 3 million IU) oral suspension, 50 mg (as embonate)/ml OTHER ANTIBACTERIALS *chloramphenicol (7) capsule, 250 mg tiabendazole chewable tablet, 500 mg oral suspension, 150 mg/5 ml lotion, 500 mg/5 ml (as palmitate salt) ANTIFILARIALS powder for injection, 1 g diethylcarbamazine tablet, 50 mg (as sodium succinate) in vial (dihydrogen citrate) *erythromycin capsule or tablet, 250 mg ivermectin scored tablet, 6 mg (as stearate or ethyl succinate) suramin sodium (2, 7) powder for injection, powder for oral suspension, 125 mg 1 g in vial (as stearate or ethyl succinate) ANTISCHISTOSOMALS powder for injection, 500 mg metrifonate tablet, 100 mg (as lactobionate) in vial oxamniquine capsule, 250 mg *gentamicin (2, 4, 7) injection, 10 mg, 40 mg (as sulfate)/ml in 2-ml vial syrup, 250 mg/5 ml *metronidazole tablet, 200 - 500 mg praziquantel tablet, 600 mg injection, 500 mg in 100-ml vial ANTIBACTERIALS suppository, 500 mg, 1 g

PENICILLINS oral suspension, 200 mg (as benzoate)/5 ml *amoxicillin capsule or tablet, 250 mg, 500 mg (anhydrous) spectinomycin (8) powder for injection, 2 g powder for oral suspension, (as hydrochloride) in vial 125 mg (anhydrous)/5 ml *sulfadimidine (4) tablet, 500 mg ampicillin powder for injection, 500 mg oral suspension, 500 mg/5 ml (as sodium salt) in vial injection, 1 g (sodium salt) benzathine powder for injection, in 3-ml ampoule benzylpenicillin (5) 1.44 g benzylpenicillin (= 2.4 million IU) in 5-ml vial

Example of a therapeutic group. Various drugs can serve as alternatives.

193 Essential Drugs WHO Drug Information Vol. 3, No.4, 1989

*sulfamethoxazole tablet, 100 mg + 20 mg, ANTIPROTOZOAL DRUGS trimethoprim (4) 400 mg + 80 mg ANTIAMOEBIC AND oral suspension, ANTIGIARDIASIS DRUGS 200 mg + 40 mg/5 ml *tetracycline capsule or tablet, 250 mg *diloxanide tablet, 500 mg (furoate) (hydrochloride) *metronidazole tablet, 200 - 500 mg Complementary drugs doxycycline (B) (5, 6) capsule or tablet, injection, 500 mg in 100-ml vial 100 mg (as hyclate) oral suspension, 200 mg (as benzoate)/5 ml injection, 100 mg (as hyclate)/5 ml in ampoule Complementary drug chloroquine (B) tablet, 150 mg nitrofurantoin (B) (4, 7) tablet, 100 mg (as phosphate or sulfate) trimethoprim (B) tablet, 100 mg, 200 mg

ANTILEISHMANIASIS DRUGS ANTILEPROSY DRUGS *meglumine antimoniate injection, clofazimine capsule, 50 mg, 100 mg 30%, equivalent to approx. 8.5% antimony in 5-ml ampoule dapsone tablet, 50 mg, 100 mg pentamidine (5) powder for injection, 200 mg rifampicin capsule or tablet, 150 mg, 300 mg (as isetionate) in vial

ANTITUBERCULOSIS DRUGS ANTIMALARIAL DRUGS ethambutol (4) tablet, 100 - 400 mg (hydrochloride) (a) FOR CURATIVE TREATMENT isoniazid tablet, 100 - 300 mg *chloroquine tablet, 150 mg (as phosphate or sulfate) pyrazinamide tablet, 500 mg syrup, 50 mg rifampicin capsule or tablet, 150 mg, 300 mg (as phosphate or sulfate)/5 ml streptomycin (4) powder for injection, primaquine tablet, 7.5 mg, 15 mg 1 g (as sulfate) in vial (as diphosphate) thioacetazone + tablet, 50 mg + 100 mg, quinine tablet, 300 mg (as bisulfate or sulfate) isoniazid 150 mg + 300 mg injection, 300 mg (as dihydrochloride)/ml rifampicin + tablet, 150 mg + 100 mg, in 2-ml ampoule isoniazid 300 mg + 150 mg Complementary drugs ANTIFUNGAL DRUGS mefloquine (B) tablet, 250 mg (as hydrochloride) amphotericin B (4) powder for injection, 50 mg in vial *sulfadoxine + tablet, 500 mg + 25 mg pyrimethamine (B) griseofulvin capsule or tablet, 125 mg, 250 mg *tetracycline (B) capsule or tablet, 250 mg *ketoconazole (2) tablet, 200 mg (hydrochloride) oral suspension, 100 mg/5 ml (b) FOR PROPHYLAXIS nystatin tablet, 500 000 IU chloroquine tablet, 150 mg (as phosphate or sulfate) pessary, 100 000 IU syrup, 50 mg (as phosphate Complementary drug or sulfate)/5 mi flucytosine (B) (4, 8) capsule, 250 mg proguanil tablet, 100 mg (hydrochloride) infusion, 2.5 g in 250 ml

* Example of a therapeutic group. Various drugs can serve as alternatives.

194 WHO Drug Information Vol. 3, No. 4, 1989 Essential Drugs

ANTITRYPANOSOMAL DRUGS cisplatin (2) powder for injection, 10 mg, 50 mg in vial (a) AFRICAN TRYPANOSOMIASIS cyclophosphamide (2) tablet, 25 mg melarsoprol (5) injection, 3.6% solution powder for injection, pentamidine (5) powder for injection, 200 mg 500 mg in vial (as isetionate) in vial cytarabine (2) powder for injection, suramin sodium powder for injection, 1 g in vial 100 mg in vial (b) AMERICAN TRYPANOSOMIASIS dacarbazine (2) powder for injection, 100 mg in vial benznidazole (7) tablet, 100 mg dactinomycin (2) powder for injection, 500 µg in vial nifurtimox (2, 8) tablet, 30 mg, 120 mg, 250 mg *doxorubicin (2) powder for injection, 10 mg, INSECT REPELLANTS 50 mg (hydrochloride) in vial etoposide (2) capsule, 100 mg diethyltoluamide, generic name solution, 50%, 75% for N,N-diethyl-m-toluamide injection, 20 mg/ml in 5-ml ampoule (DEET) fluorouracil (2) injection, 50 mg/ml Section 7: in 5-ml ampoule Antimigraine drugs mercaptopurine (2) tablet, 50 mg methotrexate (2) tablet, 2.5 mg (as sodium salt) FOR TREATMENT OF ACUTE ATTACK injection, 50 mg acetylsalicylic acid tablet, 300 - 500 mg (as sodium salt) in vial ergotamine (7) tablet, 2 mg (tartrate) procarbazine capsule, 50 mg (as hydrochloride) paracetamol tablet, 300 - 500 mg vinblastine (2) powder for injection, 10 mg (sulfate) in vial FOR PROPHYLAXIS vincristine (2) powder for injection, 1 mg, 5 mg (sulfate) in vial *propranolol tablet, 10 mg, 20 mg (hydrochloride) Complementary drug calcium folinate (C) (2)1 tablet, 15 mg injection, 3 mg/ml Section 8: in 10-ml ampoule Antineoplastic and HORMONES AND ANTIHORMONES immunosuppressive drugs *dexamethasone tablet, 500 µg, 4 mg injection, 4 mg (as sodium IMMUNOSUPPRESSIVE DRUGS phosphate) in 1-ml ampoule *azathioprine (2) tablet, 50 mg *ethinylestradiol tablet, 50 µg powder for injection, 100 mg (as sodium salt) in vial *prednisolone tablet, 5 mg injection, 20 mg, 25 mg CYTOTOXIC DRUGS (as sodium phosphate or bleomycin (2) powder for injection, 15 mg (as sulfate) in vial sodium succinate) in vial tamoxifen tablet, 10 mg, 20 mg (as citrate)

* Example of a therapeutic group. Various drugs can serve as alternatives. 1 Drug for "rescue therapy" with methotrexate.

195 Essential Drugs WHO Drug Information Vol. 3, No.4, 1989

Section 9: PLASMA FRACTIONS FOR SPECIFIC USE3 albumin, human (2, 8) injectable solution, 5% Antiparkinsonism drugs Complementary drugs *biperiden tablet, 2 mg (hydrochloride) *factor VIII concentrate (C) (2, 8) (dried) injection, 5 mg (lactate) *factor IX complex (coagulation in 1-ml ampoule factors II, VII, IX, X) concentrate (C) (2, 8) (dried) levodopa + tablet, 100 mg + 10 mg, *carbidopa (5, 6) 250 mg + 25 mg Section 12: Cardiovascular drugs Section 10: Drugs affecting the blood ANTIANGINAL DRUGS glyceryl trinitrate tablet (sublingual), 500 µg ANTIANAEMIA DRUGS *isosorbide dinitrate tablet (sublingual), 5 mg ferrous salt tablet, equivalent to 60 mg iron *propranolol tablet, 10 mg, 40 mg (hydrochloride) oral solution, equivalent to injection, 1 mg (hydrochloride) 25 mg iron (as sulfate) in 1 ml in 1-ml ampoule ferrous salt + folic acid 2 tablet, 60 mg + 250 µg *nifedipine capsule or tablet, 10 mg folic acid (2) tablet, 1 mg ANTIDYSRHYTHMIC DRUGS injection, 1 mg (as sodium salt) lidocaine injection, 20 mg in 1 -ml ampoule (hydrochloride)/ml in 5-ml ampoule hydroxocobalamin (2) injection, 1 mg *propranolol tablet, 10 mg, 40 mg (hydrochloride) in 1-ml ampoule Complementary drug injection, 1 mg (hydrochloride) *iron dextran (B) (5) injection, equivalent in 1 -ml ampoule to 50 mg iron/ml in 2-ml ampoule verapamil (8) tablet, 40 mg, 80 mg (hydrochloride) ANTICOAGULANTS AND ANTAGONISTS injection, 2.5 mg (hydrochloride)/ml heparin injection, 1000 lU/ml, in 2-ml ampoule 5000 IU/ml, 20 000 lU/ml in 1-ml ampoule Complementary drugs phytomenadione injection, 10 mg/ml *procainamide (B) tablet, 250 mg, in 5-ml ampoule 500 mg (hydrochloride) protamine sulfate injection, 10 mg/ml injection, 100 mg (hydrochloride)/ml in 5-ml ampoule in 10-ml ampoule *warfarin (2, 6) tablet, 1, 2 and 5 mg (sodium salt) *quinidine (A) tablet, 200 mg (sulfate) Section 11: Blood products and ANTIHYPERTENSIVE DRUGS *hydralazine tablet, 25 mg, 50 mg (hydrochloride) blood substitutes powder for injection, 20 mg (hydrochloride) in ampoule PLASMA SUBSTITUTES *dextran 70 injectable solution, 6% *hydrochlorothiazide tablet, 25 mg, 50 mg *nifedipine capsule or tablet, 10 mg *polygeline injectable solution, 3.5%

* Example of a therapeutic group. Various drugs can serve as alternatives. 2 Nutritional supplement for use during pregnancy. 3 All plasma fractions should comply with the WHO Requirements for the Collection, Processing and Quality Control of Blood, Blood Components, and Plasma Derivatives (Revised 1988). WHO Technical Report Series, No. 786, 1989.

196 WHO Drug Information Vol. 3, No. 4, 1989 Essential Drugs

*propranolol tablet, 40 mg, 80 mg silver sulfadiazine cream, 1%, in 500-g container (hydrochloride) mupirocin cream, 2% Complementary drugs ANTI-INFLAMMATORY AND methyldopa (B) (7) tablet, 250 mg ANTIPRURITIC DRUGS *reserpine (A) tablet, 100 µg, 250 µg *betamethasone (3) ointment or cream, injection, 1 mg in 1-ml ampoule 0.1% (as valerate) *calamine lotion lotion *sodium nitroprusside powder for preparing (C) (2, 8) infusion, 50 mg in ampoule *hydrocortisone ointment or cream, 1% (acetate) *captopril (B) scored tablets, 25 mg ASTRINGENT DRUGS aluminium diacetate solution, 13% for dilution CARDIAC GLYCOSIDES digoxin (4) tablet, 62.5 µg, 250 µg KERATOPLASTIC AND KERATOLYTIC AGENTS oral solution, 50 µg/ml benzoyl peroxide lotion or cream, 5% injection, 250 µg/ml in 2-ml ampoule coal tar solution, topical 5% dithranol ointment, 0.1 - 2% Complementary drug digitoxin (B) (6) tablet, 50 µg, 100 µg fluorouracil ointment, 5% oral solution, 1 mg/ml *podophyllum resin (7) solution, 10 - 25% injection, 200 µg in 1-ml ampoule salicylic acid solution, topical 5%

DRUGS USED IN VASCULAR SHOCK SCABICIDES AND PEDICULICIDES dopamine injection, 40 mg benzyl benzoate lotion, 25% (hydrochloride)/ml in 5-ml vial lindane (7) cream, lotion or powder, 1% ANTITHROMBOTIC DRUGS permethrin lotion acetylsalicylic acid tablet, 100 mg SUNBLOCKERS 15 Section 13: para-aminobenzoic acid, SPF cream, lotion or gel Dermatological drugs *benzophenones cream, lotion or gel Section 14: ANTIFUNGAL DRUGS (TOPICAL) benzoic acid + salicylic acid ointment or Diagnostic agents cream, 6% + 3% *miconazole ointment or cream, 2% (nitrate) OPHTHALMIC DRUGS fluorescein eye drops, 1% (sodium salt) nystatin ointment or cream, 100 000 lU/g *tropicamide eye drops, 0.5% Complementary Drug selenium sulfide (C) shampoo, 2% RADIOCONTRAST MEDIA ANTI-INFECTIVE DRUGS *amidotrizoate injection, 140 - 420 mg iodine *methylrosanilinium chloride (as sodium or meglumine (gentian violet) aqueous solution, 1% salts)/ml in 20-ml ampoule tincture, 1% barium sulfate powder suspended in water *neomycin + *bacitracin ointment, *iopanoic acid tablet, 500 mg 5 mg neomycin sulfate + 500 IU bacitracin zinc/g

Example of a therapeutic group. Various drugs can serve as alternatives.

197 Essential Drugs WHO Drug Information Vol. 3, No.4, 1989

ANTIEMETIC DRUGS *propyliodone oily suspension, 500-600 mg/ml in 20-ml ampoule4 metoclopramide tablet, 10 mg (as hydrochloride) injection, 5 mg (as hydrochloride)/ml Complementary drug in 2-ml ampoule *iotroxate (C) solution, 5 - 8 g iodine (as meglumine) in 100-250 ml *promethazine tablet, 10 mg, 25 mg (hydrochloride) elixir or syrup, 5 mg Section 15: (hydrochloride)/5 ml Disinfectants injection, 25 mg (hydrochloride)/ml in 2-ml ampoule *chlorhexidine solution, 5% (digluconate) ANTIHAEMORRHOIDAL DRUGS for dilution *local anaesthetic, astringent ointment hydrogen peroxide solution, 1.5% and anti-inflammatory drug or suppository

*iodine solution, 2.5% ANTI-INFLAMMATORY DRUGS hydrocortisone suppositories, 25 mg (acetate) Section 16: sulfasalazine (2) tablet, 500 mg Diuretics ANTISPASMODIC DRUGS *atropine tablet, 1 mg (sulfate) *amiloride (4, 7, 8) tablet, 5 mg (hydrochloride) injection, 1 mg (sulfate) *furosemide tablet, 40 mg in 1 -ml ampoule injection, 10 mg/ml in 2-ml ampoule CATHARTIC DRUGS *senna tablet, 7.5 mg (sennosides) *hydrochlorothiazide tablet, 25 mg, 50 mg (or traditional dosage forms)

Complementary drugs DRUGS USED IN DIARRHOEA mannitol (C) injectable solution, 10%, 20% spironolactone (C) tablet, 25 mg ORAL REHYDRATION SALTS

powder for reconstitution to prepare Section 17: glucose-electrolyte solution powder, 27.9 g/l Gastrointestinal drugs G lucose-electrolyte solution g/l ANTACIDS AND OTHER ANTIULCER DRUGS sodium chloride 3.5 aluminium hydroxide tablet, 500 mg trisodium citrate dihydrate5 2.9 oral suspension, 320 mg/5 ml potassium chloride 1.5 glucose 20.0 *cimetidine tablet, 200 mg injection, 200 mg in 2-ml ampoule magnesium hydroxide oral suspension, equivalent to 550 mg ANTIDIARRHOEAL (SYMPTOMATIC) DRUGS magnesium oxide/10 ml *codeine (1a) tablet, 30 mg (phosphate) sodium citrate oral solution, 8.82% (0.3 mol/l)

* Example of a therapeutic group. Various drugs can serve as alternatives. * This suspension is for administration only into the bronchial tree. 5 Trisodium citrate dihydrate may be replaced by sodium bicarbonate (sodium hydrogen carbonate) 2.5g/L. However, as the stability of this latter formulation is very poor under tropical conditions, it is only recommended when manufac­ tured for immediate use.

198 WHO Drug Information Vol. 3, No. 4, 1989 Essential Drugs

Section 18 ESTROGENS Hormones, other endocrine drugs *ethinylestradiol tablet, 50 µg and contraceptives INSULINS AND OTHER ANTIDIABETIC AGENTS insulin injection (soluble) injection, 40IU/ml in 10-ml vial, ADRENAL HORMONES AND 80IU/mlin 10-ml vial, SYNTHETIC SUBSTITUTES 100 IU/ml in 10-ml vial *dexamethasone tablet, 500 µg, 4 mg intermediate-acting insulin injection, injection, 4 mg (as sodium 40 lU/ml in 10-ml vial, phosphate) in 1-ml ampoule 80 Ill/ml in 10-ml vial, 100 IU/ml in 10-ml vial hydrocortisone powder for injection, 100 mg (as compound insulin zinc suspension (as sodium succinate) in vial or isophane insulin) *prednisolone tablet, 1 mg, 5 mg tablet, 500 mg a *tolbutamide Complementary drug OVULATION INDUCERS fludrocortisone (C) tablet, 100 µg (acetate) Complementary drug ANDROGENS *clomifene (C) (2, 8) tablet, 50 mg (citrate) Complementary drug PROGESTOGENS testosterone (C) (2) injection, 200 mg norethisterone tablet, 5 mg (enantate) in 1-ml ampoule THYROID HORMONES AND CONTRACEPTIVES ANTITHYROID DRUGS tablet, 50 µg, 100 µg HORMONAL CONTRACEPTIVES levothyroxine (sodium salt) *ethinylestradiol + tablet, 30 µg + 150 µg, *levonorgestrel 50 µg + 250 µg potassium iodide tablet, 60 mg

*ethinylestradiol + tablet, 50 µg + 1.0 mg *propylthiouracil tablet, 50 mg *norethisterone

Complementary drugs Section 19: depot medroxypro­ injection, 150 mg/ml gesterone acetate (B) (7, 8) in 1-ml, 3-ml vials Immunologicals *norethisterone (B) tablet, 350 µg DIAGNOSTIC AGENTS norethisterone tuberculin,6 injection enantate (B) (7, 8) purified protein derivative (PPD) injection, 200 mg in vial INTRAUTERINE DEVICES SERA AND IMMUNOGLOBULINS7 copper-containing device anti-D immunoglobulin (human) injection, BARRIER METHODS 250 µg/ml condoms with or without spermicide (nonoxinol) antirabies hyperimmune injection, 1000 IU serum in 5-ml ampoule diaphragms with spermicide (nonoxinol) antitetanus immunoglobulin injection, 500 IU (human) in vial

* Example of a therapeutic group. Various drugs can serve as alternatives. 6 All tuberculins should comply with the WHO Requirements for Tuberculins (Revised 1985). WHO Technical Report Series, No. 745, 1987. 7AII plasma fractions should comply with the WHO Requirements for the Collection, Processing and Quality Control of Blood, Blood Components and Plasma Derivatives (Revised 1988). WHO Technical Report Series, No. 786, 1989.

199 Essential Drugs WHO Drug Information Vol. 3, No.4, 1989

antivenom sera injection suxamethonium (2) injection, 50 mg (chloride)/ml in 2-ml ampoule antiscorpion sera injection powder for injection (chloride) diphtheria antitoxin injection, 10 000 IU, 20 000 IU in vial Complementary drug immunoglobulin, pyridostigmine (B) (2, 8) tablet, 60 mg (bromide) injection human normal (2) injection, 1 mg (bromide) in 1-ml ampoule tetanus antitoxin injection, 50 000 IU in vial VACCINES8 Section 21: FOR UNIVERSAL IMMUNIZATION Ophthalmological preparations BCG vaccine (dried) injection ANTI-INFECTIVE AGENTS diphtheria-pertussis-tetanus injection vaccine *idoxuridine solution (eye drops), 0.1% diphtheria-tetanus vaccine injection eye ointment, 0.2% measles vaccine injection gentamicin solution (eye drops), 0.3% measles-mumps-rubella vaccine injection silver nitrate solution (eye drops), 1% poliomyelitis vaccine (inactivated) injection *tetracycline eye ointment, 1% (hydrochloride) poliomyelitis vaccine oral solution ANTI-INFLAMMATORY AGENTS (live attenuated) prednisolone eye drops, 0.5% tetanus vaccine injection LOCAL ANAESTHETICS *tetracaine solution (eye drops), 0.5% FOR SPECIFIC GROUPS OF INDIVIDUALS (hydrochloride) hepatitis B vaccine injection influenza vaccine injection MIOTICS AND ANTIGLAUCOMA DRUGS acetazolamide tablet, 250 mg meningococcal vaccine injection *pilocarpine solution (eye drops), 2%, 4% rabies vaccine injection (hydrochloride or nitrate) rubella vaccine injection *timolol solution (eye drops), 0.25%, 0.5% typhoid vaccine injection (maleate) yellow fever vaccine injection MYDRIATICS atropine solution (eye drops), 0.1%, 0.5%, 1%

Section 20: Complementary drug Muscle relaxants epinephrine (A) solution (eye drops), 2% (as hydrochloride) (peripherally acting) and cholinesterase inhibitors Section 22: Oxytocics and antioxytocics *gallamine (2) injection, 40 mg (triethiodide)/ml in 2-ml ampoule OXYTOCICS *neostigmine tablet, 15 mg (bromide) *ergometrine tablet, 200 µg (maleate) injection, 500 µg, 2.5 mg injection, 200 µg (maleate) (metilsulfate) in 1-ml ampoule in 1-ml ampoule

* Example of a therapeutic group. Various drugs can serve as alternatives. 8 All vaccines should comply with the WHO Requirements for Biological Substances.

200 WHO Drug Information Vol. 3, No. 4, 1989 Essential Drugs

oxytocin injection, 10 IU in 1-ml ampoule *salbutamol tablet, 2 mg, 4 mg (as sulfate)

ANTIOXYTOCICS inhalation (aerosol), 100 µg *salbutamol (2) tablet, 4 mg (as sulfate) (sulfate) per dose injection, 50 µg (as sulfate)/ml syrup, 2 mg (as sulfate)/5 ml in 5-ml ampoule injection, 50 µg (as sulfate)/ml in 5-ml ampoule Section 23: Complementary drugs Peritoneal dialysis solution *cromoglicic acid (B) inhalation (cartridge), 20 mg (sodium salt) per dose intraperitoneal dialysis solution parenteral solution (of appropriate composition) ephedrine (A) tablet, 30 mg (hydrochloride) elixir, 15 mg (hydrochloride)/5 ml Section 24: injection, 50 mg (sulfate) in 1-ml ampoule Psychotherapeutic drugs ANTITUSSIVES *amitriptyline tablet, 25 mg (hydrochloride) *codeine (1a) tablet, 10 mg (phosphate) *chlorpromazine tablet, 100 mg (hydrochloride) syrup, 25 mg (hydrochloride)/5 ml Section 26: injection, 25 mg (hydrochloride)/ml Solutions correcting water, in 2-ml ampoule electrolyte and *diazepam (1b) scored tablet, 2 mg, 5 mg acid-base disturbances *fluphenazine (5) injection, 25 mg (decanoate or enantate) in 1-ml ampoule ORAL REHYDRATION oral rehydration salts see section 17 *haloperidol tablet, 2 mg, 5 mg potassium chloride oral solution injection, 5 mg in 1-ml ampoule lithium carbonate (2, 4) capsule or tablet, 300 mg PARENTERAL *compound solution injectable solution of sodium lactate Section 25: glucose injectable solution, Drugs acting on the 5% isotonic, 50% hypertonic glucose with injectable solution, respiratory tract sodium chloride 4% glucose, 0.18% sodium chloride (Na+ 30 mmol/L, CI - 30 mmol/l) ANTIASTHMATIC DRUGS potassium chloride injectable solution *aminophylline (2) tablet, 100 mg, 200 mg sodium bicarbonate injectable solution, 1.4% injection, 25 mg/ml in 10-ml ampoule isotonic (Na+ 167 mmol/l, HC03- 167 mmol/l); beclometasone inhalation (aerosol), 50 µg 8.4% solution in 10-ml ampoule (dipropionate) per dose epinephrine injection, 1 mg (as hydrochloride) sodium chloride injectable solution, 0.9% + in 1-ml ampoule isotonic (Na 154 mmol/l, CI-154 mmol/l)

* Example of a therapeutic group. Various drugs can serve as alternatives.

201 Essential Drugs WHO Drug Information Vol. 3, No.4, 1989

MISCELLANEOUS *nicotinamide tablet, 50 mg water for injection in 2-ml, 5-ml, 10-ml ampoules pyridoxine tablet, 25 mg (hydrochloride) *retinol sugar-coated tablet, 10 000 IU (as palmitate) (5.5 mg) Section 27: capsule, 200 000 IU (as Vitamins and minerals palmitate) (110 mg) oral oily solution, *ergocalciferol capsule or tablet, 1.25 mg 100 000 lU/ml in multidose dispenser (50 000 IU) (as palmitate) oral solution, water-miscible injection, 250µg/ml(10 000 IU/ml) 100 000 IU (as palmitate) (55 mg) in 2-ml ampoule iodine (8) injection, iodinated oil, 1 ml (480 mg iodine), riboflavin tablet, 5 mg 0.5 ml (240 mg iodine) in sodium fluoride (8) tablet, 500 µg 5-ml and 10-ml ampoules thiamine tablet, 50 mg (hydrochloride) oral iodinated oil, 1 ml (480 mg iodine), 0.5 ml (240 mg iodine) in Complementary drugs 5-ml and 10-ml ampoules ascorbic acid (C) tablet, 50 mg capsule, 200 mg calcium gluconate (C), (2, 8) injection, 100 mg/ml in 10-ml ampoule

* Example of a therapeutic group. Various drugs can

202 WHO Drug Information Vol. 3, No. 4, 1989

WHO Expert Committee on the Use of Essential Drugs

The WHO Expert Committee on the Use of Essential Drugs met in Geneva from 27 November to 2 December 1989. The full report of this meeting, containing the sixth revision of the model list in final form, will appear shortly in the WHO Technical Report Series.

Members Other organizations represented by observers:

Dr E.A. Babajan, Board for the Approval of New United Nations Children's Fund (UNICEF). Drugs and Medical Equipment, Ministry of Health, Commonwealth Pharmaceutical Association (CPA). Moscow, USSR. International Pharmaceutical Federation (FIP). International Federation of Pharmaceutical Manu­ Professor M. Duran, Javeriana University, Bogota, facturers Associations (IFPMA). Colombia. International Union of Pharmacology (IUPHAR). World Federation of Proprietary Medicines Manu­ Dr A. Kucers, Director of Medical Services, Fairfield facturers (WFPMM). Hospital, Fairfield, Victoria, Australia. In revising the model list of essential drugs the Professor Li Jia Tai, Director, Institute of Clinical Committee made the following changes: Pharmacology, Beijing, China. Deletions: probenecid, dehydroemetine, sodium Professor M.M. Reidenberg, Head, Division of stibogluconate, sulfacetamide, hydrocortisone, Clinical Pharmacology, The New York Hospital, nomatropine, iohexol, oral ampicillin. New York, USA (Rapporteur). Additions: potassium ferric hexacyanoferrate (II)• Dr Chiravat Sadavongvivad, Department of 2H2O (Prussian blue), albendazole, amoxicillin, Pharmacology, Mahidol University, Bangkok, rifampicin + isoniazid, diethyltoluamide, dacarba¬ Thailand. zine, polygeline, captopril, selenium sulfide, mupirocin, benzoyl peroxide, permethrin, para¬ Professor L.A. Salako, Department of Pharma­ aminobenzoic acid, SPF15, benzophenones, cology and Therapeutics, University of Ibadan, iohexol, hydrogen peroxide, measles-mumps- Nigeria (Chairman). rubella vaccine, iodinated oil.

203 WHO Drug Information Vol. 3, No.4, 1989

Newly Registered Products anistreplase Contraindications: Hypersensitivity. Caution in patients with liver dysfunction. Precautions: Safety in pregnancy, lactation, and in recombinant human tissue plasminogen- children has not been established. streptokinase activator (TPSA) Eminase®: Beecham Laboratories, Ireland Adverse effects: Skin rashes, diarrhoea, abdominal pain, gastric discomfort and impairment of hepatic solution for injection 30 lU/ampoule Indications: Acute myocardial infarction. and renal function have been reported Contraindications: Risk of haemorrhage. Precautions: Safety of use during pregnancy and ramipril lactation not established. Adverse reactions: Bleeding, flushing, bradycardia, hypotension, fever, nausea, vomiting and allergic angiotensin-converting enzyme (ACE) inhibitor reactions, including rashes, occasional broncho- Triatec®: Hoechst, France. constriction, and anaphylaxis have been reported. Trilace®: Hoechst, Ireland. capsules 1.25, 1.5, 5, 10 (Ireland only) mg Indications: Mild to moderate hypertension. Contraindications: Known hypersensitivity. batroxobin Precautions: Safety has not been established during pregnancy and lactation, or in children. fibrinolytic enzyme, derived from snake venom Ability to drive or operate machines may be Defibrase®: Tobishi, Japan impaired. solution for IV infusion: 10 units/ampoule Caution required in hepatic or renal impairment. Indications: Exacerbation of peripheral arterio­ Adverse effects: Nausea, vertigo, headache, gas­ sclerotic vascular disease. Sudden nerve deafness trointestinal pain have been reported. attributed to intra-arterial thrombosis. Contraindications: Risk of haemorrhage. Severe hepatic or renal impairment. Hypersensitivity. Caution is required in the elderly and patients on rilmazafone anticoagulants or antithrombotic drugs. Precautions: Monitoring of hepatic enzymes, renal hypnotic sedative function and of signs of spontaneous haemorrhage Rhythmy®: Shionogi, Japan required. Safety of use in pregnancy, lactation and tablet 1, 2 mg in children has not been established. Indications: Insomnia, preanaesthetic medication. Adverse effects: Gastrointestinal symptoms, rash, Contraindications: Acute narrow-angle glaucoma, urticaria, dizziness, headache, haemorrhagic myasthenia gravis. Children, women of child- episodes, chest pain and shock have been re­ bearing potential, and during lactation. Caution is ported. required in patients with pulmonary insufficiency or cerebrovascular accidents. Caution in patients with cardiac, hepatic or renal impairment or with organic brain disorders, and in pravastatin the elderly. Precautions: Patients should not drive or operate antihyperlipidaemic machinery. Hepatic and renal function should be Mevalotin®: Sankyo, Japan monitored. tablet 5 mg; granules 0.5% Adverse effects: Skin rashes, disorders of the Indications: Hyperlipidaemia, hyper­ central nervous system, diarrhoea, abdominal pain cholesterolemia. and gastric discomfort have been reported.

204 WHO Drug Information Vol. 3, No. 4, 1989

Recent Publications

The role and function of the measures, either nationally or internationally. First detected within the illicit supply channels were pharmacist in Europe variants of fentanyl, pethidine and the hallucino­ genic amphetamine compounds but, more recently, Towards the end of 1988 the World Health Organi­ highly potent synthetic narcotic substances have zation's Regional Office for Europe convened two also been seized. meetings to review how contemporary changes in the structure of health care services are impinging This report provides a detailed overview of the upon the work of the pharmacist. The report of evolution of the situation, its public health implica­ these meetings, which focuses primarily on the tions, and the legal, legislative and law enforcement responsibilities of community and hospital pharma­ problems. Among its recommendations for address­ cists, emphasizes that the long-established task of ing the latter, the meeting placed strong emphasis the profession — to ensure that the patient is on the need for: supplied with products of good quality — remains basic and essential. Complementary to this duty, • national governments to amend existing legisla­ the report perceives the pharmacist as command­ tion to provide for the scheduling of analogues of ing an increasingly important role in the provision of those psychoactive substances and narcotic drugs information and advice about these products and that are already controlled; other aspects of health care. Not only do pharma­ cists possess the technical knowledge to assume • an effective international early warning system, this charge but — as the report points out — their coordinated by the United Nations, to signal the ready availability to all concerned, including the emergence of new analogues; general public, patients, doctors, nurses and other health professionals, places them in an ideal • an emergency international scheduling procedure; position to act effectively, and more extensively and than hitherto, as advisors and counsellors. • an international data base to provide information, Reference: The Role and Function of the Pharmacist in not only on chemical and toxicological data, but on Europe Lunde, I., Dukes, G., ed. WHO Collaborating national programmes intended to identify and Centre for Clinical Pharmacology and Drug Policy contain the problem. Science, University of Groningen, Groningen, Nether­ lands, Styx Publications, 1989. ISBN 90 72371 06 2. Reference: Klein, M., Saplenza, F., McClain, H., Khan, I. ed. Clandestinely produced drugs, analogues and precur­ sors: problems and solutions. Washington, D.C., United Clandestinely produced drugs, States Department of Justice, Drug Enforcement analogues and precursors Administration, 1989.

The proceedings have recently been published of an international conference held in Morocco in 1987 Naming organic compounds which was co-sponsored by the United States Drug Enforcement Administration and the World Health All newly developed compounds, including pharma­ Organization, on the abuse of controlled drug ceutical substances under development, need to be analogues, more widely known as "designer drugs". precisely identified in accordance with existing These substances, produced in clandestine internationally observed principles set out in the laboratories, are variants of controlled drug Chemical Abstracts Index Guide and the IUPAC substances that possess — and are intended to (International Union of Pure and Applied Chemistry) possess — the same abuse potential. However, Organic Rule Book. This book claims to break no because they are chemically distinctive, they do not new ground, but to provide "a programme or recipe fall de facto within the ambit of established control for devising an acceptable name for a chemical

205 Recent Publications WHO Drug Information Vol. 3, No.4, 1989

under the existing rules in the form of a set of ment arm of the regulatory apparatus and they are procedures not requiring the skills of a nomencla­ the guardians of all the activities that embody ture specialist". This underplays what has been quality assurance. Their task is onerous, and there achieved. In fact, the experience on which the book are all too few of them in virtually every country. is based is derived from a task accomplished within the Laboratory of the Government Chemist in the The Pharmaceutical Inspection Convention United Kingdom, which has been largely instrumen­ represents a collaborative international effort, tal in producing a catalogue of over 16 000 trade initiated by the countries of the European Free chemicals for the European Commission's Com­ Trade Association, that is directed to harmonization mon Customs Tariff. In doing this, it was found to of standards of inspection and mutual acceptance be necessary in the interests of consistency, to of inspection reports. It has the primary aim of supplement the existing principles with a number of reducing the number — and the associated costs in-house sub-rules and rationales. These are now — of overseas factory inspections among the shared with a wider public. The instructions are participating countries. Harmonization has been intended to yield names consistent with those of the achieved largely through inculcating confidence and European Customs Inventory but, because their reaching reciprocal understandings. Much of this application would foster harmonization of working has been accomplished by convening technical procedures, they may deserve wider international seminars on different aspects of the work. The consideration. seminar held in September 1987 in the United Kingdom — with the support of the Department of Reference: Godly, E.W. Naming organic compounds: a Health — addressed a particularly broad agenda systematic instruction manual. Chichester, United touching upon every aspect of the work of a Kingdom, Ellis Horwood. 1989. ISBN 0 7458 0359 8 national inspectorate. The report, which has recently been published, has relevance to every government anxious to assure the quality of The business of pharmaceutical pharmaceutical products on which its health inspection services depend. Reference: The business of pharmaceutical inspection: Pharmaceutical inspectors form a bridge between proceedings of a seminar held in Cambridge from 21 to the centralized bureaucracy of the national drug 24 September 1989 Convention for the mutual recogni­ regulatory authority and the pharmaceutical tion of inspectors in respect of the manufacture of manufacturing and distribution system that operates pharmaceutical products. Available from EFTA Secretar­ under its jurisdiction. They represent the enforce­ iat. 9-11 rue de Varembé, 1211 Geneva 20. Switzerland.

206 WHO Drug Information Vol. 3, No. 4, 1989

International Nonproprietary Names for Pharmaceutical Substances

In accordance with article 3 of the Procedure for The inclusion of a name in the lists of proposed the Selection of Recommended International international nonproprietary names does not Nonproprietary Names for Pharmaceutical imply any recommendation for the use of the Substances,1 notice is hereby given that the substance in medicine or pharmacy. following names are under consideration by the World Health Organization as Proposed Action and Use International Nonproprietary Names. The statements in italics indicating the action and use are based largely on information sup­ plied by the manufacturer. The information is meant to provide an indication of the potential Comments on, or formal objections to, the pro­ use of new substances at the time they are ac­ posed names may be forwarded by any corded proposed INN. WHO is not in a position person to the Pharmaceuticals unit of the World either to uphold these statements or to comment Health Organization within four months of the on the efficacy of the action claimed. Because of date of their publication in WHO Drug Informa­ their provisional nature these descriptors will be tion, e.g., for List 62 Prop. INN not later than neither revised nor included in the Cumulative 31 May 1990. Lists of INN.

Proposed International Nonproprietary Names (Prop. INN): List 622

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. AH names from Lists 1-58 of Proposed international Nonproprietary Names, together with a molecular formula index, will be found in: International Nonproprietary Names (INN) for Pharmaceutical Substances. Cumulative List No. 7, 1988, World Health Organization, Geneva (ISBN 92 4 0560149} (price: Sw. fr. 65.-). This publication consists, in the main, of a computer printout which groups together all the proposed and recommended international nonproprietary names (INN)—in Latin, English, French, Russian, and Spanish-—published up to March 1988. The printout also indicates in which of the 58 individual lists of proposed names and 27 lists of recommended names each INN was originally published, and gives references to national nonproprietary names, pharmacopoeia monographs, and other sources. In addition, the list contains molecular formulae and Chemical Abstracts Service registry numbers. For easy reference, national nonproprietary names that differ from INN, molecular formulae, and Chemical Abstracts Service registry numbers are indexed in a series of annexes. A final annex describes the procedure for selecting recommended INN and outlines the general principles to be followed in devising these names. All the textual material published in this volume appears in both English and French. These publications may be obtained, direct or through booksellers, from the sales agents listed on the back cover of WHO Drug Information. Orders from countries where sales agents have not yet been appointed may be addressed to: World Health Organization, Distribution and Sales Service, 1211 Geneva 27, Switzerland.

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

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

acidum risedronicum [1-hydroxy-2-(3-pyridyl)ethylidene]diphosphonic acid risedronic acid C7H11]NO7P2 105462-24-6 calcium regulator

actaritum (p-acetamidophenyl)acetic acid actarit C10H11NO3 18699-02-0 immunomodulator

aloracetamum N-[2-(3-formyl-2,5-dimethytpyrrol-1-yl)ethyl]acetamide aloracetam C11H16N2O2 119610-26-3 nootropic agent

H3C — C —NH — CH2 — CH2

alprafenonum ( ± )-3-[3-[2-hydroxy-3-(tert-pentylamino)propoxy]-4-methoxyphenyl]- alprafenone 4'-methylpropiophenone C25H35NO4 124316-02-5 antidysrhythmic

ataprostum (+ )-(2E,3aS,4R,5R,6aS)-4-[(1 E,3S)-3-cyclopentyl-3-hydroxypropenyl]- ataprost 3,3a,4,5,6,6a-hexahydro-5-hydroxy-Δ2(1H) 6-pentalenevaleric acid 6552 C21H32O4 83997-19-7 platelet aggregation inhibitor

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

batoprazinum 8-(1-piperazinyl)coumarin batoprazine C13H1aN2O2 105685-11- psychotropic

brifentanilum cis-N-[1-[2-(4-ethyl-5-oxo-2-tetrazolin-1-yl)ethyl]-3-methyl-4-piperidyl]-2'- brifentanil fluoro-2-methoxyacetanilide C20H29FN6O3 101345-71-5 narcotic analgesic

butenafinum N-(p-tert-bulylbenzyl)-N-methyl-1-naphthalenemethylamine butenafine C23H27N 101828-21-1 antifungal

candoxatrilatum (αS)-1-[(cis-4-carboxycyclohexyl)carbamoyl]-α-[(2-methoxyethoxy)methyl]- candoxatrilat cyclopentanepropionic acid C20H33NO7 123122-54-3 antihypertensive

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

candoxatrilum (αS)-1-[(cis-4-carboxycyclohexyl)carbamoyl]-α-[(2- candoxatril methoxyethoxy)methyl]cyclopentanepropionic acid, α-5-indanyl ester C29H41NO7 123122-55-4 antihypertensive

cenciaminum ( ± )-3-(3,4-dichlorophenyl)-2-(dimethylarnino)-2-methyl-1-propanol cericlamine C12H17CI2NO 112922-56-1 antidepressant

ciclesonidum 11ß,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dione, cyclic 16,17-acetal ciclesonide with cyclohexanecarboxaldehyde, 21-isobutyrate C32H44O7 glucocorticosteroid

daniquidonum 8-aminoisoindolo[1,2-b]quinazolin-12(10H)-one daniquidone C15H11N3O 67199-66-0 antineoplastic

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

dapropterinum (- )-(6R)-2-amino-6-[(1 R,2S)-1,2-dihydroxypropyl]-5,6,7,8-tetrahydro-4(3H)- dapropterin pteridinone C9H15N5O3 62989-33-7 antihyperphenylalaninaemic

desfluranum (±)-difluoromethyl 1,2,2,2-tetrafluoroethyl ether desflurane C3H2F6O 57041-67-5 general anaesthetic

devazepidum (S)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)indole- devazepide 2-carboxamide C25H20N4O2 103420-77-5 cholecystokinin receptor antagonist

dexrazoxanum (+ )-(S)-4,4'-propylenedi-2,6-piperazinedione dexrazoxane C11H16N4O4 24584-09-6 antineoplastic

ditekirenum tert-butyl (2S)-2-[[(αS)-α-[[(1S)-1-[[(1S,2S,4S)-2-hydroxy-1-isobutyl-5-methyl- ditekiren 4-[[(1S,2S)-2-methyl-1-[(2-pyridylmethyl)carbamoyl]butyl]carbamoyl]- hexyl]carbamoyl]-2-imidazol-4-ylethyl]methylcarbamoyl]phenetyl]- carbamoyl]-1-pyrrolidinecarboxylate C50H75N9O8 103336-05-6 renin inhibitor

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

dosmalfatum [µ8-[[diosmin octasulfato](8-)]]tetracontahydroxyhexadecaaluminum dosmalfate C28H64Al16O79S8 122312-55-4 antacid

-SO3Al8(OH)5

duteplasum 245-L-methionineplasminogen activator (human tissue-type 2-chain form duteplase protein moiety) C2736H4174N914O824S46 120608-46-0 thrombolytic

ecogramostimum N-L-methionylcolony-stimulating factor 2 (human U937 cell protein moiety ecogramostim reduced) 123120-99-0 immunostimulant

elsamitrucinum 10-[[2-O(2-amino-2,6-dideoxy-3-O-methyl-α-D-galactopyranosyl)-6-deoxy-3-C- elsamitrucin methyl-ß-D-galactopyranosyl]oxy]-6-hydroxy-1-methylbenzo[h][1]- benzopyrano[5,4,3-cde][1]benzopyran-5,12-dione C33H35NO13 97068-30-9 antineoplastic

epoetinum alfa 1-165-erythropoietin (human clone AHEPOFL13 protein moiety) epoetin alfa C809H1301N229O240S5 113427-24-0 antianaemic

epoetinum beta 1-165-erythropoietin (human clone λHEPOFL13 protein moiety), glycoform β epoetin beta C809H1301N229O240S5 122312-54-3 antianaemic

212 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number Action and use eptastigminum N-demethyl-N-heptylphysostigmine or (3aS,8aR)-1,2,3,3a,8,8a-hexahydro- eptastigmine 1,3a,8-trimethylpyrrolo[2,3-b]indol-5-yl heptylcarbamate C21H33N3O2 101246-68-8 acetylcholinesterase inhibitor

fedotozinum ( + )-(R)-α-ethyl-N,N-dimethyl-α-[[(3,4,5-trimethoxybenzyl)oxy]methyl]benzyl- fedotozine amine C22H31NO4 123618-00-8 gastrointestinal agent

finasteridum N-tert-butyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide finasteride C23H36N2O2 98319-26-7 antineoplastic

fluvastatinum (±)-(3R*,5S*,6E)-7-[3-(p-fluorophenyl)-1-isopropylindol-2-yl]-3,5-dihydroxy-6- fluvastatin heptenoic acid C24H26FNO4 93957-54-1 antihyperlipidaemic

213 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number Action and use fosinoprilatum (4S)-4-cyclohexyl-1-[[hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-proline fosinoprilat C23H34NO5P 95399-71-6 angiotensin converting enzyme inhibitor

fosphenytoinum 3-(hydroxymethyl)-5,5-diphenylhydantoin, dihydrogen phosphate (ester) fosphenytoin C16H15N2O6P 93390-81-9 antiepileptic

fosquidonum benzyl 5,8,13,14-tetrahydro-14-methyl 1-8,13-dioxobenz[5,6]isoindolo- fosquidone [2,1-b]isoquinolin-9-yl hydrogen phosphate C28H22NO6P 114517-02-1 antineoplastic

gemcitabinum 2'-deoxy-2', 2'-difluorocytidine gemcitabine C9H11F2N3O4 95058-81-4 antineoplastic

214 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number Action and use girisopamum 1-(m-chlorophenyl)-7,8-dimethoxy-4-methyl-5H-2,3-benzodiazepine girisopam C18H17CIN2O2 82230-53-3 anxiolytic

glipalamidum (±)-5-methyl-N-(p-tolylsulfonyl)-2-pyrazoline-1-carboxamide glipalamide C12H15N3O3S 37598-94-0 antidiabetic

ipazilidum N-[3-(diethylamino)propyl]-4,5-diphenylpyrazole-1-acetamide ipazilide C24H30N4O 115436-73-2 antidysrhythmic

isbufyllinum 7-isobutyltheophylline isbufylline C11H16N4O2 90162-60-0 antiasthmatic

itrocinonidum 6α,9-difluoro-11β,16α,17-trihydroxy-3-oxoandrosta-1,4-diene-17β-carboxylic itrocinonide acid, ester with ethyl (S)-1-hydroxyethyl carbonate, cyclic (R)-16,17-acetal with butyraldehyde C29H38F2O9 106033-96-9 glucocorticosteroid

215 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number Action and use levemopamilum (-)-(S)-2-isopropyl-5-(methylphenethylamino)-2-phenylvaleronitrile levemopamil C23H30N2 101238-51-1 calcium antagonist

levetiracetamum (S)-α-ethyl-2-oxo-1-pyrrolidineacetamide levetiracetam C8H14N2O2 102767-28-2 nootropic agent

lidanserinum ( ± )-4-[3-[3-[4-(p-tluorobenzoyl)piperidino]propoxy]-4-methoxyphenyl]- lidanserin 2-pyrrolidinone C26H31FN2O4 73725-85-6 serotonin antagonist

lifibrolum ( ± )-p-[4-(p-terf-butylphenyl)-2-hydroxybutoxy]benzoic acid lifibrol C21H26O4 96609-16-4 antihyperlipidaemic

melquinastum ethyl 6-ethyl-5,6-dihydro-9-methyl-5-oxo-s-triazolo[1,5-c]quinazoline- melquinast 2-carboxylate C15H16N4O3 87611-28-7 antiallergic

216 Proposed International Chemical Name or Description. Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number Action and use meribendanum 4,5-dihydro-5-methyl-6-(2-pyrazol-3-yl-5-benzinnidazolyl)-3(2H)-pyridazinone meribendan C15H14N6O 119322-27-9 positive inotropic agent

nardeterolum (±)-α-[[[3-(1-benzimidazolyl)-1,1-dimethylpropyl]arnino]methyl]-2-fluoro-4- nardeterol hydroxybenzyl alcohol C20H24FN3O2 73865-18-6 β2-adrenoreceptor agonist

N

neltenexinum 4',6'-dibromo-α-[(trans-4-hydroxycyclohexyl)amino]-2-thiophene- neltenexine carboxy-o-toluidide C18H20Br2N2O2S 99453-84-6 mucolytic

nepinalonum ( ± )-3,4-dihydro-1-methyl-1-(2-piperidinoethyl)-2(1H)-naphthalenone nepinalone C18H25NO 22443-11-4 antitussive

nitecaponum 3-(3,4-dihydroxy-5-nitrobenzylidene)-2,4-pentanedione nitecapone C12H11NO6 116313-94-1 antiparkinson

217 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number Action and use oxilofrinum erythro-p-hydroxy-α-[1-(methylamino)ethyl]benzyl alcohol oxilofrine C10H15NO2 365-26-4 sympathomimetic

pancopridum ( ± )-4-amino-5-chloro-α-cyclopropyl-N-3-quinuclidinyl-o-anisamide pancopride C18H24CIN3O2 121650-80-4 antiemetic, anxiolytic

pantoprazolum 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]- pantoprazole benzimidazole C16H15F2N3O4S 102625-70-7 antiulcer

pibaxizinum [2-[2-[4-(diphenylmethylene)piperidino]ethoxy]ethoxy]acetic acid pibaxizine C24H29NO4 82227-39-2 antispasmodic, antihistaminic

pilsicainidum tetrahydro-1 H-pyrrolizine-7a(5H)-aceto-2',6'-xylidide pilsicainide C17H24N2O 88069-67-4 antidysrhythmic

218 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number Action and use quinagolidum ( ± )- N, N-diethyl-N'-[(3R*,4aR*,10aS*)-1,2,3,4,4a, 5,10,10a-octahydro-6-hydroxy- quinagolide 1-propylbenzo[g]quinolin-3-yl]sulfamide C20H33N3O3S 87056-78-8 D2-dopamine receptor agonist

risotilidum 4 -[isopropyl[2-(isopropylamino)ethyl]sulfamoyl]methanesulfonanilide risotilide C15H27N3O4S2 120688-08-6 antidysrhythmic

rociclovirum 2-amino-9-[[2-isopropoxy-1-(isopropoxymethyl)ethoxy]methyl]purine rociclovir C15H25N5O3 108436-80-2 antiviral

sampirtinum 2,6-diamino-3-(p-fluorobenzyl)pyridine sampirtine C12H12FN3 115911-28-9 anti-inflammatory

sarafloxacinum 6-fluoro-1-(p-fluorophenyl)-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline- sarafloxacin carboxyalic acid C20H17F2N3O3 98105-99-8 antibacterial (vet)

219 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number Action and use saviprazolum 2-[[[4-(2,2,3,3,4,4,4-heptafluorobutoxy)-2-pyridyl]methyl]sulfinyl]-1H- saviprazole thieno[3,4-d]imidazole C15H10F7N3O2S2 121617-11-6 antiulcer

secalciferolum (5Z,7E,24R)-9,10-secocholesta-5,7,10(19)-triene-3β,24,25-triol secalciferol C27H44O3 55721-11-4 calcium regulator

sezolamidum ( + )-(S)-5,6-dihydro-4-(isobutylamino)-4H-thieno[2,3-b]thiopyran- sezolamide 2-sulfonamide 7,7-dioxide C11H18N2O4S3 123308-22-5 carbonic anhydrase inhibitor

sobuzoxanum 4,4'-ethylenebis[1-(hydroxymethyl)-2,6-piperazinedione] bis(isobutyl sobuzoxane carbonate) (ester) C22H34N4O10 98631-95-9 antineoplastic

220 Proposed International Chemical Name or Description, Molecular and Graphic Formulae Nonproprietary Name (Latin, English) Chemical Abstracts Service (CAS) registry number Action and use somalaporum N-L-alanylgrowth hormone (pig clone pPGH-1 reduced) somalapor C977H1527N265O287S7 106282-98-8 growth hormone

somenoporum N-L-alanyl-32-de-L-glutamic acid-33-de-L-arginine-34-de-L-alanine-35-de-L- somenopor tyrosine-36-de-L-isoleucine-37-de-L-proline-38-de-L-glutamic acidgrowth hormone (pig clone pPGH-1 reduced) C938H1469N255O275S7 119693-74-2 growth hormone

timirdinum 3-(2-amino-4-chlorophenyl)-2-iminothiazolidine timirdine C9H10CIN3S 100417-09-2 antidepressant

tiracizmum ethyl 5-(N,N-dimethylglycyl)-10,11-dihydro-5H-dibenz[b,f]azepine-3-carbamate tiracizine C21H25N3O3 83275-56-3 antidysrhythmic

trelnarizinum (E)-1-[bis(p-fluorophenyl)methyl]-4-(3,4-dirnethoxycinnamyl)piperazine trelnarizine C28H30F2N2O2 123205-52-7 vasodilator

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

tropisetronum 1αH,5αH-tropan-3α-yl indole-3-carboxylate tropisetron C17H20N2O2 89565-68-4 serotonin antagonist

vapreotidum D-phenylalanyl-L-cysteiryl-L-tyrosyl-D-tryptophyl-L-lysyl-L-valyl-L-cysteinyl-L- vapreotide tryptophanamide cyclic (2 7)-disulfide C57H70N12O9S2 103222-11-3 antineoplastic

zatebradinum 3-[3-[(3,4-dimethoxyphenethyl)methylamino]propyl]-1,3,4,5-tetrahydro-7,8- zatebradine dimethoxy-2H-3-benzazepin-2-one C26H36N2O5 85175-67-3 bradycardic agent

222 Names for Radicals and Groups

Some substances for which may be of complex composi­ and groups have been de­ a proposed international non­ tion and it is then inconvenient vised or selected, and they are proprietary name has been to refer to them in systematic suggested for use with the established may be used in chemical nomenclature. Con­ proposed international non­ the form of salts or esters. The sequently, shorter nonpropri­ proprietary names. radicals or groups involved etary names for some radicals bezomilum (benzoyloxy)methyl bezomil C8H7O2

erbuminum tert-butylamine erbumine C4H11N

hyclas monohydrochloride hemiethanolate hemihydrate hyclate ½(C2H10CI2O2)

½ (2HCI.C2H5OH.H2O)

223 AMENDMENTS TO PREVIOUS LISTS

Chronicle of the World Health Organization, Vol. 12, No. 3, 1958 Proposed International Nonproprietary Names (Prop. INN): List 6 p. 105 lauralkonii chloridum replace the chemical name by the following: lauralkonium chloride benzyl[2-[p-(lauroyl)phenoxy]ethyl]dimethylammonium chloride

WHO Chronicle, Vol. 18, No. 11, 1964 Proposed International Nonproprietary Names (Prop. INN): List 14 p. 434 benzetimidum replace the CAS registry number by the following: benzetimide 119391-55-8

Supplement to WHO Chronicle, Vol. 38, No. 4, 1984 Proposed International Nonproprietary Names (Prop. INN): List 52 p. 10 etomoxirum replace the chemical name by the following: etomoxir ( + )-ethyl 2-[6-(p-chlorophenoxy)hexyl]glycidate

WHO Drug Information, Vol. 1, No. 3, 1987 Proposed International Nonproprietary Names (Prop. INN): List 58 p. 182 isamoltanum replace the CAS registry number by the following: isamoltan 116861-00-8

WHO Drug Information, Vol. 2, No. 2, 1988 Proposed International Nonproprietary Names (Prop. INN): List 59 p. 9 manidipinum replace the CAS number by the following: manidipine 120092-68-4 p. 9 muroderminum replace the graphic formula by the following: murodermin

p. 10 nebracetamum replace the CAS number by the following: nebracetam 116041-13-5

p. 10 ondansetronum replace the Chemical Abstracts Number by the following: ondansetron 116002-70-1

224 WHO Drug Information, Vol. 3, No. 2, 1989 Proposed International Nonproprietary Names (Prop. INN): List 61 p. 88 bakeprofenum replace the CAS registry number by the following: bakeprofen 117819-25-7 p. 89 carmoxirolum replace the action and use statement by the following:

carmoxirole D2-dopamine receptor agonist p. 95 gevotrolinum replace the chemical name by the following: evotroline 8-fluoro-2,3,4,5-tetrahydro-2-[3-(3-pyridyl)propyl]-1H-pyrido[4,3-b]indole p. 98 natrii borocaptate (10B) replace the molecular formula by the following: sodium borocaptate (10B) B12H12Na2S p. 105 cefprozilum replace the graphic formula by the following: cefprozil

Procedure and Guiding Principles

The text of the Procedures for the Selection of Recommended International Nonproprietary Names for Pharmaceutical Substances and General Principles for Guidance in Devising International Nonproprietary Names for Pharmaceutical Substances will from now on be reproduced in uneven numbers of proposed INN lists only.

225

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