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WHO DRUG

INFORMATION V O L U M E 11 • N U M B E R 1 • 1 9 9 7

R E C O M M E N D E D I N N L I S T 3 7 I N T E R N A T I O N A L N O N P R O P R I E T A R Y N A M E S F O R P H A R M A C E U T I C A L S U B S T A N C E S

W O R L D H E A L T H O R G A N I Z A T I O N • G E N E V A

Volume 11, Number 1, 1997 World Health Organization, Geneva

WHO Drug Information

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Withdrawal of blood products 19Benzodiazepines, drug dependence and

rebound effects 19Carteolol and bronchial asthma 19Mucocutaneous reactions and carbamazepine 20Mebendazole deregulated to over-the-

counter (OTC) status 20Donepezil: new treatment for Alzheimers

disease 20Whole-oat foods and heart disease 20Nifedipine: restricted use 20Emergence of multidrug-resistant salmonella 21Tolrestat: hepatic necrosis 21Somatropin for wasting syndrome in AIDS 22Ivermectin approved for human use 22Naproxen available over-the-counter (OTC) 22Influenza virus vaccines for 1997–1998 22

Essential Drugs:WHO Model FormularyAnticonvulsants/antiepileptics 23

Carbamazepine 24Clonazepam 25Diazepam 25Ethosuximide 26Phenobarbital 26Phenytoin 27Valproic acid 27

Recent PublicationsNordic statistics on medicines: 1993–1995 29Pharmacological action and therapeutic

use of drugs — list of terms 29

Recommended InternationalNonproprietary Names: List 37 31

Contents

General Policy TopicsAdverse drug reaction monitoring: new

issues 1

Reports on Individual DrugsRotavirus vaccine nearing registration 5Hearing loss from ototoxics 7International study of hormone replacement

therapy (HRT) announced 10Betacarotene, vitamin A and E may not prevent

cancer or cardiovascular diseases 10Driving ability in cancer patients treated with

morphine 11

General InformationThe implications of the TRIPS Agreement

for the protection of pharmaceuticalinventions 12

Regulatory MattersProposed withdrawal of terfenadine 17Restrictions on use of sotalol 18Fluoroquinolones and tendon rupture 18Fatal adverse drug reaction trends 18Aspartame: no apparent link with brain tumours 18Anthranoids, herbal medicines and

carcinogenic potential 19Adrenal cortex extract associated with

infections 19Herbal medicines adulterated with

antirheumatics 19Herbal hay-fever remedy and conventional

drugs 19

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WHO Drug Information Vol. 11, No. 1, 1997

General Policy Topics

Adverse drug reactionmonitoring: new issuesWhen a new drug reaches the market, patientsexpect it to be safe and effective. During develop-ment, preclinical and clinical studies usually providesufficient evidence of the product's effectiveness,but this is not the case for its safety. Normally, nomore than 3000 patients have been treated with thedrug during the clinical trial phase, making it likelythat adverse drug reactions with an incidence ofless than one in 10 000 will remain undetected.Indeed, several examples serve to prove that pre-marketing clinical trials may fail to detect sideeffects that later manifest themselves as adversedrug reactions.

Adverse drug reactions can cause severe suffering,and are probably more frequent than many peoplethink. They are estimated to cause 3–5% of allhospital admissions (1), and a survey carried out in1971 (2) found that they may be responsible for160 000 deaths each year in US hospitals alone. Amore recent study has concluded that adverse drugreactions significantly prolong the length of hospita-lization — which may double the cost — and areassociated with an almost twofold risk of death (3).

Reporting of adverse drug reactions is thereforeessential to obtain the necessary information on thesafety of products. In addition, many subpopula-tions, such as young children, the old, pregnantwomen, and patients using other medicines con-comitantly, or with complicated disease conditions,are not normally exposed to the drug in clinicaltrials during the development phase.

The origin of adverse drug reaction monitoring liesin the often-quoted thalidomide catastrophe (4),which created a new perception of drug control,accelerating the enforcement of already estab-lished, but sometimes dormant, regulatory systemsin many countries. In 1967, the World HealthOrganization reacted to these events by setting upa project on the international monitoring of adversereactions to drugs (5). Within a few years, thisproject was extended and developed into the WHOProgramme on International Drug Monitoring.

Originally established by ten highly developedcountries, the WHO Programme currently numbersfifty members. All of these countries possess anational centre for adverse drug reaction monitoringand a national programme. These national centrescollect reports from health professionals and passthem on for entry into the international data basehoused at the WHO Collaborating Centre forInternational Drug Monitoring in Uppsala, Sweden.

Over the last five years, some twenty new countrieshave joined the programme, and almost all of themare from the developing world. Several othercountries have expressed the wish to join, and arecurrently in contact with the WHO CollaboratingCentre, which offers the guidance necessary forsetting up a national monitoring programme.

Development of a national programme requiresspecial approaches, since these new centres oftendo not have an infrastructure that allows them tocollect and follow-up large numbers of reports. Indeveloped countries, however, people can build onthe experience of others and the importance ofadverse drug reaction monitoring can be empha-sized in professional education. Specific training indrug safety can be more easily organized.

Reports of adverse drug reactions are traditionallycollected from health professionals, mainly physi-cians — at the national level. Many countries,however, are now in the process of decentralizingtheir reporting systems, with the consequentestablishment of regional centres for adverse drugreaction monitoring (6, 7). A regionalized systempermits closer contact with the reporter, and isparticularly suitable when pharmacists are alsoincluded in the monitoring process.

The WHO Collaborating Centre plays an essentialrole in the WHO Programme since it is responsiblefor maintaining the data base of reports receivedfrom those countries participating. At the presenttime, there are some 1 600 000 reports on file, andeach year almost 200 000 new reports are added.The data base can, under certain conditions, beinterrogated by third parties (8). It may alsogenerate signals of potentially severe drug toxicityand provide confirmation of signals generated in

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WHO Drug Information Vol. 11, No. 1, 1997General Policy Topics

specific countries or regions. The Centre also actsas the guardian of the standardized terminology ofadverse drug reactions in computerized systems(WHOART).

The terminology currently in use within the contextof the programme was developed at an early stage,and has been continuously updated. It is used bynational centres and by many pharmaceutical com-panies. None the less, it has become evident thatthe terminology no longer covers all areas of drugmonitoring such as premarketing, clinical trial, orsocial history data. As a result, terminology thataddresses the needs of the majority of drugregulatory authorities is now under development.The ultimate goal of this activity is to develop a trulyglobal terminology with relevance for all countries.This would lead to considerable savings in terms ofstaff and resources, both within industry andregulatory authorities.

National and regional differences in medical cultureand tradition, and availability of resources, result indifferent diagnostic and, consequently, pharmaco-therapeutic practices (9). Because of the sub-stantially different conditions in developing coun-tries in terms of endemic diseases, overcrowding,poverty, malnutrition, and health services, thebenefit-risk ratio for drugs determined in developedcountries is often not relevant. In general, thebenefits to be obtained from effective treatment orprophylaxis within developing countries may be sohuge that the benefit-risk ratio is strongly positive,even when there is a substantial incidence ofadverse reactions. For example, in a country with ahigh mortality rate associated with reproduction, thebenefits of avoiding pregnancies are large, and willmore than offset the risk associated with oralcontraceptives. Moreover, many diseases, such astropical diseases, are only prevalent in developingcountries and the safety of innovative treatmentscan only be tested there.

In spite of budgetary constraints, several develop-ing countries have set up well-organized, well-runadverse drug reaction monitoring programmes.These are often driven by the strong motivation of ahandful of health professionals (10). Monitoring ofadverse drug reactions in developing countries is ofgreat importance. A good programme may detectsignals that are specific for that country, but also fordrugs — such as those used in tropical diseases(11) — that have often been on the market formany years in countries where there is no way ofproviding information on the potential risks.

Traditionally, the use of herbal medicines hasbeen high in developing countries and is now takingup an increasing share of the health care market ofthe developed world. One explanation may be thepopular belief that they do not cause adverse re-actions. None the less, some herbal medicines arequite active and may even contain toxic com-pounds. For example, cases of hepatic veno-occlusion attributed to pyrrolizidine alkaloids in teamade from Senecio and Symphytum (comfrey)species have been reported in several countries,and patients have died of hepatic necrosis followingoveruse of herbal medicines derived from theseplants. Attention must also be paid to possibleinteractions when administering other drug treat-ments. These safety aspects have resulted inrestrictive regulatory measures in a number ofMember States (12, 13).

Naturally occurring compounds may not be the onlycause of toxicity from herbal products. Sometimesherbal drugs are dangerously adulterated or en-riched by the addition of potent synthetic pharma-ceuticals such as anabolic steroids, sedatives andnonsteroidal anti-inflammatory agents. Severeadverse effects have been reported in patients afterconsumption of such adulterated medication (14,15). Continuous vigilance remains essential, butregistration of adverse reactions to herbal medi-cines is complicated because of the lack of con-sistency in the composition of a product consistingof the different parts of several different herbalspecies.

Recently, the world was shocked by reports ofmany young children in Haiti dying after consump-tion of a cough mixture which proved to containglycerol contaminated with diethylene glycol (16).This incident was not isolated; other cases involvingdiethylene glycol have been reported in the USA,India, Nigeria and Bangladesh, claiming the lives ofuncountable numbers of children, and intoxicatingmany others (17, 18, 19). Other instances ofcounterfeit or substandard medicines have beenreported such as antimalarials containing a traceamount of chloramphenicol, or eye drops manu-factured using tap-water instead of sterile water(20). In view of the huge amounts of moneyinvolved and the relative ease of manufacture,transport and sale of medicinal products — inparticular in insufficiently controlled markets — adecrease in the prevalence of counterfeits on thedrug market is not to be expected. Efforts areneeded to curb the problem, and drug monitoringprogrammes can be instrumental in this. For

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example, an unexpected lack of efficacy may bespotted in a product which is then found to have noactive ingredient, or unusual toxic effects may becaused by cheap adulterants inappropriately usedby unscrupulous manufacturers. Patients reactingin an unusual way to relatively standard treatmentshould be reported as this can lead to the de-tection of counterfeit or substandard drugs.

Often, counterfeit drugs do not contain sufficientamounts of the active substance. Apart fromproviding unsatisfactory treatment, this may alsolead to underdosing. In the case of infectiousdiseases, this can also contribute to the emer-gence of antibiotic resistance. Monitoring of thedevelopment of resistance is of vital importance,and national drug monitoring programmes can playan important role in this regard. Many othermechanisms may lead to antibiotic resistance andthis can pose a threat to public health. Alarmingoutbreaks of tuberculosis in the USA have latelystirred public interest and concern. In 1993, theWorld Health Organization declared tuberculosis aglobal emergency (21) and cited the danger ofmultidrug resistance. Once again, reporting theabsence of effect of long-established therapies mayprovide a clue to detection of a resistant strain.

Malaria kills between one and two million childrenevery year. However, the number of drugs availablefor treatment is remarkably small and multidrugresistance diminishes the already not so richarmamentarium even further. Almost all tropicalcountries are now faced with the problem of an in-creasing number of ineffective antimalarials andeven travellers returning from affected areas some-times fail to respond to medication (22). Simple andsustainable systems for identification and evalua-tion of adverse reactions as well as reporting onlack of efficacy associated with antimalarial drugsare needed, but many tropical countries do nothave the public health infrastructure to allowreporting (23).

Generally, vaccines are considered as safe and nomajor disasters have been reported. Sincevaccines are administered to healthy people,mostly children, the impact of a perceived problemcan be tremendous. Many will remember the scarewhen pertussis vaccine was reported to beassociated with brain damage. Vaccinationcoverage decreased in the United Kingdom from96% to 60% and only rose again when furtherstudies demonstrated the absence of a causalrelationship (24). It is consequently important to

collect information on the safety of vaccines toprovide sound reference data in the event of aproblem.

Because of these considerations, many countrieshave established a specific programme for themonitoring of adverse events following vaccination,and a field guide for vaccination programmemonitors has been published by WHO (25).

In line with the general trend in our society toautonomy and the need to keep public health costsunder control, more and more countries are allow-ing prescription-only drugs to be shifted to over-the-counter (OTC) status. This may result in adifferent rate of reporting of adverse effects, oreven lack of reporting altogether, and monitoringcentres should be on their guard.

Control of prescription medicines is the responsi-bility of the physician, or at least the dispensingpharmacist, whereas OTC drugs escape this kind ofcontrol (27). The possible risks associated with aswitch from prescription-only to OTC includeunexpected interactions when the product is usedin combination with other treatments, and themissed opportunity for diagnosis of a possibleserious ailment. This situation has primarilyeconomic advantages, but it also provides thepublic with easier access to medication which isnon-prescription (28). Consequences for drugmonitoring programmes have not been sufficientlyinvestigated, but initiatives are in hand to start thediscussion.

A number of issues in adverse drug reaction moni-toring have thus been identified that deserve moreattention than received so far. It is fortunate thatmany developing countries are beginning to realizethat they need to become active and collectinformation on the potential adverse effects of thedrugs in their markets.

Although these initiatives may not avoid anotherdisaster with absolute certainty, it is througheffective monitoring and application of WHOguidelines that the risk associated with the use ofmedicines will be reduced to a minimum.

References

1. Davies, D. M. Special Report. Adverse Drug Reactionsand Acute Poisoning, 3: 249–250 (1984).

2. Shapiro, S., Slone, D., Lewis, G. P., Jick, H. Fatal drugreactions amongst medical inpatients. Journal of the Ameri-can Medical Association, 216: 467-472 (1971).


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3. Classen, D.C., Pestotnik, S.L., Evans, R.S. et al.Adverse drug events in hospitalized patients. Journal ofthe American Medical Association, 277: 301–317 (1997).

4. Distillers Company Ltd. Distaval. Lancet, 2: 1262(1961).

5. Resolution WHA20.51. Handbook of resolutions anddecisions, 11th edition. World Health Organization,Geneva, 1971, p. 123.

6. Evreux, J.-C., Vidal, T. Le système francais de pharma-covigilance. Communication Partenaires Santé, 9–14(1992).

7. Royer, J.-R. Les différents systèmes de pharmaco-vigilance en Europe. Communication Partenaires Santé,25–28 (1992).

8. Edwards, I. R. The WHO database. Drug InformationJournal, 26: 477–480 (1992).

9. Gabrielian, A. Monitoring of adverse drug reactions inArmenia. Report of the Eighth International Conference ofDrug Regulatory Authorities, WHO, Geneva (in press).

10. Chaves, A. Drug monitoring in Latin America. DrugInformation Journal, 29: 87–89 (1995).

11. Darmansjah, I. Do signals differ in developingcountries? Adverse Drug Reactions: a global perspectiveon signal generation and analysis. Report of the WHOAnniversary Symposium, WHO, Geneva, 1988.

12. Vos, J. J., Wijnsma, R. Preparaten met pyrrolizidine-alkaloiden. Pharmaceutisch weekblad, 128, 1146–1152(1993).

13. Arrêt Royale, Ministère de la Santé Publique et del’Environnement, Royaume de Belgique, 1993.

14. Anonymous. Effets indésirables liés à un remède ditvégetal contre les rhumatismes en provenance de Hong-kong. Folia Pharmacotherapeutica Belgica, 20: 79 (1993).

15. Espinoza, E. O., Mann, M.-J., Bleasdell, B. Arsenicand mercury in traditional Chinese herbal balls. Lancet,333: 803–804 (1995).


16. Pan American Health Organization News Release,Washington, USA. 25 June 1996 and 3 July 1996.

17. Pandya, S. K. An unmitigated tragedy. British MedicalJournal, 297, 117–119 (1988).

18. Warning re batch of diethylene glycol mislabelled aspropylene glycol used in paracetamol syrup. PHA AlertIEA.13, World Health Organization, Geneva,1990.

19. Hanif, M., Mobarak, M. R., Ronan, A. et al. Renalfailure caused by diethylene glycol in paracetamol elixir:the Bangladesh epidemic. British Medical Journal, 311:88–91 (1995).

20. Sesay, M. M. Fake Drugs – a new threat to healthcare delivery. Africa Health, Number 13: 15 (1988).

21. Emerging Infectious diseases. World Health Day 1997— Information Kit. World Health Organization, Geneva.

22. White, N. Needs in developing countries: current stateof antimalarial resistance. Proceedings of the XXVIIthCIOMS Conference. CIOMS, Geneva, 1993.

23. Practical Chemotherapy of Malaria. WHO TechnicalReport Series, Number 805. World Health Organization,Geneva, 1990.

24. Rawlins, M.D. The broader perspective. Proceedingsof the XXVIIIth CIOMS Conference. CIOMS, Geneva,1993.

25. Field guide for managers of immunizationprogrammes: surveillance of adverse events followingimmunization. WHO/EPI/93.2, Geneva, 1993.

26. Stieve, G. Selbstmedikation im Spiegel von Zahlen.Trends und Meinungen. Pharmazeutische Zeitung, 141:3247–3251 (1996).

27. Anonymous. Automedicación: riesgos y beneficios.Boletín Terapeútica Andaluz, 12: 17-18 (1996).

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Reports on Individual Drugs

Rotavirus vaccinenearing registrationProfessor Timo Vesikari,University of Tampere Medical School,Tampere, Finland

Rotavirus is responsible for more diarrhoealdisease than any other single agent. Most of theresulting 600 000 deaths each year are in thedeveloping world, but rotavirus is a significantpathogen also in developed countries. Rotavirusdiarrhoea is highly contagious and cannot becontrolled by hygienic measures. This is a reasonwhy rotavirus vaccination is attractive for bothdeveloped and developing countries. After fifteenyears of studies, rotavirus vaccines are finally ap-proaching registration status and may soon beconsidered for inclusion in the immunization pro-grammes of many countries.

Rotavirus vaccination began by empirical use of thetissue-culture adapted bovine rotavirus strainRIT4237 in oral form. Studies in gnotobiotic pigletsfirst showed cross-protection between bovine andhuman rotaviruses (1) and, thereafter, the vaccinewas found safe, immunogenic, and efficacious dur-ing trials in human infants (2–3). In Finland, theRIT4237 vaccine induced 50–58% protectionagainst any rotavirus gastroenteritis, and 82–88%protection against clinically significant forms (4).Thus, a high level of protection against severe rota-virus disease, moderate protection against milddisease, and no protection against rotavirus infec-tion as such were seen. These findings have beenconsistent in most studies of oral rotavirusvaccines.

Despite the initial success in Finland, the RIT4237vaccine was withdrawn. A report of a small study inRwanda (5), and a preliminary analysis of a trial inLima, Peru, indicated little or no protection and thisled to the premature conclusion that the vaccinehad failed in developing countries. Subsequently, afull analysis of the Peruvian trial showed protectiveefficacy of 40 % against any rotavirus disease, and58–75% against severe forms (6) — which was in

fact only slightly less than in Finland. Anotherbovine rotavirus vaccine strain, WC3, showed apromising 76% protective efficacy in the UnitedStates (7), but was withdrawn because of un-satisfactory efficacy (17%) in another US trial (8)and virtually no efficacy when administered in theCentral African Republic (9).

A bovine-human reassortant rotavirus vaccinebased on the WC3 strain has been developed morerecently. This quadrivalent vaccine contains re-assortant rotaviruses expressing human rotavirussurface proteins VP7 (G types) G1, G2 and G4,and VP4 (P type) protein P[8] and has demonstrat-ed 67% protection against all rotavirus disease inone trial (10). The number of subjects studied so faris, however, insufficient to come to any firm con-clusions. A major advantage of the previous bovinerotavirus vaccines, as well as this reassortant vac-cine, is their lack of reactogenicity.

Rhesus rotavirus (RRV) vaccine is more immuno-genic than the bovine rotaviruses in humans (11).The vaccine titre is 104–105 per ml, as comparedwith 107 (WC3) or 108 (RIT4237) for the bovinerotavirus vaccines. RRV vaccine relies on virusmultiplication to produce a sufficient amount of viralantigens for induction of an immune response and,as a result, causes febrile reactions (but no diar-rhoea) at 3 to 4 days post-vaccination (12). Thereactions are more frequent and severe in childrenwho lack maternally acquired antibody, and aremore commonly observed in developed countrieswhere infants are less likely to receive rotavirusantibodies from the mother than in developingcountries. High titre RRV vaccine was, in fact,efficacious in a study in Sweden, but caused a highrate of reactions in 5–12-month-old children (13); inother studies there has been a great variation inefficacy (14–17).

RRV was further improved by development of therhesus-human reassortant rotaviruses (18), whichcontain 10 RNA segments from the rhesus rotavirusand one, encoding for the VP7 (G-type) surfaceprotein, from human rotaviruses corresponding tothe G-types 1, 2 or 4. Rhesus rotavirus itself isclose to the human G-type 3 rotavirus (18). A mix-ture of the four viruses is named the rhesus rota-virus tetravalent (RRV-TV) vaccine.© T. Vesikari 1997

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The performance of RRV-TV vaccine in clinicaltrials has been consistent. In a multicentre trial inthe USA, RRV-TV vaccine at titre level 4 x 104 PFUshowed a 57% protective efficacy against anyrotavirus diarrhoea, and up to 92 % protectionagainst severe forms (19). In order to furtherimprove vaccine efficacy a higher titre (4 x 105

PFU) RRV-TV vaccine was produced. In the USA,this high titre vaccine yielded a 49% efficacy for anyrotavirus diarrhoea and 100% efficacy for dehydrat-ing forms (20). In a recently completed trial inFinland, the high titre vaccine was 100% protectiveagainst hospitalization for rotavirus gastroenteritis*.In a large catchment trial in Caracas, Venezuela,the high titre RRV-TV vaccine showed goodprotection, with efficacy as high as in the USA andonly slightly lower than in Finland**. This is perhapsthe most encouraging result considering potentialuse in developing countries.

In contrast, the low titre RRV-TV was only 20% and35% efficacious against any rotavirus diarrhoea inpopulations of low socioeconomic status in Lima,Peru (21), and Belém, Brazil (22), respectively, and,at best, 50–60 % efficacious against severe diar-rhoea. An apparent reason was that the immuno-genicity was low at both of these study sites.

At the moment, field trials are the only way to judgethe performance of RRV-TV and other candidaterotavirus vaccines, as there is no satisfactorysurrogate marker for protection. Overall immuno-genicity is certainly of importance for clinical pro-tection, but the role of the human rotavirus G- orP-type surface antigens present in the RRV-TV orbovine reassortant vaccines is less clear (23).

It is likely that RRV-TV vaccine will be licensed inthe near future. Thereafter, the vaccine may beused by paediatricians in private practice in theUSA and, gradually, in Europe. Acceptance forpublic health immunization programmes will dependon national considerations of disease burden andcost-benefit in each country. For example, manyLatin American countries are likely to be interestedin the RRV-TV vaccine. In these countries, rotavirusdiarrhoea is a seasonal epidemic disease, causingconsiderable morbidity with some mortality. Many ofthe countries may be able to afford the vaccine ifthe price is reasonable. What may be needed toconvince the decision-makers is a large-scaledemonstration project showing effectiveness, ratherthan efficacy, and cost-benefit at the same time.

In many Asian and African developing countries,where rotavirus disease is less seasonal, trans-mission occurs by the faecal-oral route, and theinfectious dose is presumably large, the challengefor rotavirus vaccine is greater, but perhaps notimpossible to meet. Even an efficacy level of50–60% demonstrated by the low-dose RRV-TVagainst severe rotavirus disease — modest as itmay sound — could prevent a large number ofdeaths. It would, however, be crucial to identifymeans to further increase the uptake of the RRV-TV vaccine in developing-country conditions.

References

1. Zissis, G., Lambert, J.P., Marbehant, P. et al. Protectionstudies in colostrum deprived piglets of a bovine rotavirusvaccine candidate using human rotavirus strains forchallenge. Journal of Infectious Diseases, 148: 1061–1068 (1983).

2. Vesikari, T., Isolauri, E., Delem, A., et al. Immuno-genicity and safety of live attenuated bovine rotavirusvaccine strain RIT4237 in adults and young children.Lancet, 2: 807–811 (1983).

3. Vesikari, T., Isolauri, E., D'Hondt, E., et al. Protection ofinfants against rotavirus diarrhoea by RIT4237 attenuatedbovine rotavirus strain vaccine. Lancet, 1: 977–981(1984).

4. Vesikari, T., Joensuu, J. Review of rotavirus vaccinetrials in Finland. Journal of Infectious Diseases, 174(Suppl 1): S81–87 (1996).

5. De Mol, P., Zissis, G., Butzler, J.P., Mutwewingabo, A,.André, F.E. Failure of live, attenuated oral rotavirusvaccine. Lancet, 2: 108 (1986).

6. Lanata, C.F., Black, R.E., del Aguila, R., et al. Pro-tection of Peruvian children against rotavirus diarrhea ofspecific serotypes by the RIT4237 attenuated bovinerotavirus vaccine. Journal of Infectious Diseases, 159:452-459 (1989).

7. Clark, H.F., Borian, F.E., Bell, L.M., Modesto, K.,Gouvea, V., Plotkin, S.A. Protective effect of WC3 vaccineagainst rotavirus diarrhea in infants during a pre-dominantly serotype-1 rotavirus season. Journal ofInfectious Diseases, 158: 570-587 (1988).

8. Bernstein, D., Smith, V., Sander, D., Pax K., Schiff, G.,Ward, R. Evaluation of WC3 rotavirus vaccine andcorrelates of protection in healthy infants. Journal ofInfectious Diseases, 162: 1055-1062 (1990).

9. Georges-Courbot, M.C., Monges, J., Siopathis, M.R, etal. Evaluation of the efficacy of a low-passage bovinerotavirus (strain WC3) vaccine in children in CentralAfrica. Research of Virology, 142: 405–411 (1991).

* J. Joensuu and T. Vesikari, in press.** I. Perez-Schael, submitted for publication.

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10. Clark, H.F., Offit, P.A., Ellis, R.W., et al. The develop-ment of multivalent bovine rotavirus (strain WC3)reassortant vaccine for infants. Journal of InfectiousDiseases, 174 (Suppl 1): S73–80 (1996).

11. Kapikian, A.Z., Flores, J., Hoshino, Y., et al. Rotavirus:the major etiologic agent of severe infantile diarrhea maybe controllable by a Jennerian approach to vaccination.Journal of Infectious Diseases, 153: 815–822 (1986).

12. Vesikari, T., Kapikian, A.Z., Delem, A., Zissis, G. Acomparative trial of rhesus monkey (RRV-1) and bovine(RIT4237) oral rotavirus vaccines in young children.Journal of Infectious Diseases, 153: 832–839 (1986).

13. Gothefors, L., Wadell, G., Juto, P., et al. Prolongedefficacy of rhesus rotavirus vaccine in Swedish children.Journal of Infectious Diseases, 159: 753–757 (1989).

14. Flores, J., Perez-Schael, I., Gonzalez, M., et al.Protection against severe rotavirus diarrhea by rhesusrotavirus vaccine in Venezuelan infants. Lancet, 1: 882–884 (1987).

15. Christy, C., Madore, P., Pichichero, M., et al. Field trialof rhesus rotavirus vaccine in infants. Pediatric InfectiousDisease Journal, 7: 645–650, 1988.

16. Rennels, M., Losonsky, G., Young, A., et al. Anefficacy trial of the rhesus rotavirus vaccine in Maryland.American Journal of Diseases of Children, 144: 601–604,1990.

17. Madore, H.P., Christy, C., Pichichero, M., et al. Fieldtrial of rhesus rotavirus or human-rhesus rotavirusreassortant vaccine of VP7 serotype 3 or 1 specificity ininfants. Journal of Infectious Diseases, 166: 235–243,1992.

18. Kapikian, A.Z., Hoshino, Y., Chanock, R.M. et al.Efficacy of a quadrivalent rhesus rotavirus-based humanrotavirus vaccine aimed at preventing severe rotavirusdiarrhea in infants and young children. Journal ofInfectious Diseases, 174: 65-72 (1996).

19. Bernstein, D.I., Glass, R.I., Rodgers, G., et al. for theUS Rotavirus Vaccine Efficacy Group. Evaluation ofrhesus rotavirus monovalent and tetravalent reassortantvaccines in US children. Journal of the American MedicalAssociation, 273: 1191-1196 (1995).

20. Rennels, M.B., Glass, R.I., Dennehy, P.H., et al.Safety and efficacy of high-dose rhesus-humanreassortant rotavirus vaccines — report of the NationalMulticenter Trial. Pediatrics, 97: 7-13 (1996).

21. Lanata, C.F., Midthun, K., Black, R.E., et al. Safety,immunogenicity, and protective efficacy of one and threedoses of the tetravalent rhesus rotavirus vaccine in infantsin Lima, Peru. Journal of Infectious Diseases, 174: 268-275 (1996).

22. Linhares, A.C., Gabbay, Y.B., Mascarenhas, J.D.P., etal. Immunogenicity, safety and efficacy of tetravalentrhesus-human, reassortant rotavirus vaccine in Belém,Brazil. Bulletin of the World Health Organization, 74 (5):491-500 (1996).

23. Ward, R.L. Mechanisms of protection against rotavirusin humans and mice. Journal of Infectious Diseases, 174(Suppl1): S51-58.

24. Rotavirus vaccine for developing countries. WHOWeekly Epidemiological Record. No. 6, 7 February 1997.

Hearing loss from ototoxicsAndrew Smith, Prevention of Deafness and HearingImpairment, World Health Organization, Geneva,Switzerland

Ian Mackenzie, Hearing Impairment ResearchGroup, Liverpool School of Tropical Medicine,United Kingdom

Ototoxicity is the harmful effect of a drug or chemi-cal substance on the organs of hearing and/orbalance. Drugs and other chemicals that damagethe cochlea — the organ of hearing in the inner ear— do so by destroying sound-sensitive hair cells,usually starting at the basal turn and progressingtowards the apical turn. These drugs may alsodamage the end organs of balance in the semi-circular canals, utricle and saccule (vestibularapparatus). Ototoxic damage may be reversibleinitially but this generally depends on the particularagent and sometimes the dose. Aminoglycosideantibiotics, which are the commonest causes ofdrug-induced ototoxicity, usually produce per-manent damage.

Most studies of ototoxicity have been hampered bydifficulties in definition and measurement. A hearingloss of ≥15 dB at 2 or more frequencies or ≥20 dBat 1 or more frequencies following exposure to apotentially ototoxic substance is usually taken toindicate ototoxic damage. However, a recent studyof aminoglycoside ototoxicity suggests that theselevels could overestimate the incidence (1).

Cochlear toxicity often presents as tinnitus. Hearingloss may affect higher frequencies initially andpatients may only become aware of a problemwhen their loss is at least 30 dB at frequencies from3–4 kHz. Vestibular toxicity usually presents as un-steadiness (vertigo), or even oscillopsia (vertical“jiggling” of stationary objects). The vertigo may beso disabling that affected patients are often sickand bedridden (2).

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CausesThe table below indicates the major causes ofototoxicity. Among systemically administered drugs,the aminoglycosides are probably the commonestcause, and some persons may have an inheritedpredisposition. Damage may be increased by poorrenal function or during simultaneous administrationof loop diuretics, which alone can also be ototoxic,especially when given by bolus injection. There issome evidence that aminoglycosides, especiallystreptomycin, may damage the fetus when givenduring pregnancy. The likelihood of this occurringmay increase with the global resurgence oftuberculosis unless safer, alternative drug regimensare employed. Kanamycin given to pre-term infantshas caused hearing loss and pre-term infants arehypersensitive to aminoglycoside ototoxicity duringthe period of anatomical and functional maturationof the inner ear. Neomycin, when used in thetopical treatment of burns, may be absorbed andcan cause irreversible ototoxic damage. Netilmycinmay be less ototoxic than the otheraminoglycosides.

Macrolide antibiotics such as erythromycin, andpossibly azithromycin, can cause a reversiblehigh-tone sensorineural hearing loss and tinnitusafter high dosage (4 g/day for erythromycin). Therisk is greater in the elderly or where there is kidneyor liver dysfunction.

Salicylates, such as acetylsalicylic acid, have longbeen known to produce a reversible moderate

hearing loss and tinnitus. This is usually dose-dependent but idiosyncratic reactions haveoccurred. Some antimalarials are also ototoxic.Quinine, which is chemically similar to salicylates,can cause mild toxic symptoms — sometimesreferred to as “cinchonism” — such as tinnitus,high-tone hearing loss, visual disturbances,nausea, giddiness and tremors when administeredin therapeutic doses, and in excessive doses maycause permanent deafness or blindness as well asmyocardial conduction abnormalities, hypogly-caemia and coma (3, 4). With the increase ofchloroquine-resistant malaria, quinine is being usedon a larger scale and in higher dosage, especiallyfor cerebral malaria and the signs may be difficult todistinguish from quinine toxicity. Permanent hearingloss can also occur with high-dose chloroquine.

Anticancer agents, especially cisplatin, may beototoxic. The hearing loss may not commence untilmany days after therapy, and occurs more com-monly in adults with prior otologic disease. Affectedpatients may complain of otalgia, tinnitus andhearing loss. The chelating agent, deferoxamine,used to prevent iron overload in patients havingmultiple blood transfusions for conditions such asbeta-thalassaemia, may produce auditory andvisual neurotoxicity.

Many ototopical preparations, especially amino-glycosides, are potentially ototoxic. This has beendemonstrated in animal studies, but the evidence inhumans is less clear. Many otologists feel that the


Table of the main drugs causing ototoxicity

Aminoglycosides gentamicin, streptomycin, kanamycin, amikacin, tobramycin,neomycin, netilmicin, polymyxin B

Macrolides erythromycin, azithromycin, clarithromycinLoop diuretics furosemide, bumetanide, etacrynic acidSalicylates acetylsalicylic acid (aspirin)Antimalarials quinine, chloroquine (high dosage)Nonsteroidal anti-inflammatory drugs naproxen, indometacin (no definite findings)Antineoplastic drugs cisplatin, bleomycin, carboplatinChelating agents deferoxamineTopical otological preparations antibiotic solutions: aminoglycosides, polymyxin B,

chloramphenicol, fosfomycinanti-inflammatory: propylene glycol, hydrocortisoneantiseptic: chlorhexidine, povidone iodineacidifying: acetic acid (2% solution)

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risk of hearing loss from chronic otitis media isgreater than from the ototopical antibiotics used totreat it. In fact, the ototoxic risk may be greater ifsuch preparations are applied to a normal middle-ear mucosa, such as in a patient with a chronicperforation but only intermittent otorrhoea. Theototoxic potential of acetic acid and hydrocortisonehas been questioned. Some traditional medicinesmay be ototoxic. For example infusions of variousroots used as ear drops in Angola have beenreported to be ototoxic (2).

PreventionOtotoxic hearing loss and vestibulopathy are pre-dominantly iatrogenic or self-induced conditions.Once ototoxic damage has occurred, it is frequentlyirreversible, and expensive and time-consumingaudiological rehabilitation with hearing aids andspeech training may be required. However, there iswide scope for prevention, and this is where themain activities for control should be targeted.

1. Health education and promotionThere is a general lack of knowledge and aware-ness of the potential ototoxic effects of certaindrugs and chemicals. An increase in the public’sunderstanding of the risk factors for ototoxicity andthe improper use of such drugs could help toreduce the incidence of the problem, as was shownby a recent campaign in China (5).

2. Professional educationMuch of the problem of ototoxicity results from theinappropriate and indiscriminate use of ototoxicdrugs by health care providers, especially, but notonly, at primary levels. Information on the dangersof potentially ototoxic drugs and the strategies forcontrol should be included in basic and refreshertraining of all health professionals, particularlyprimary care workers, nurses, general practitioners,pharmacists, paediatricians, and internists. Theimportance of audiometric and other monitoring ofpatients at risk should be stressed. Lists of drugspublished for use by health professionals andindividual drug labelling and product informationshould include specific warnings of ototoxicpotential.

3. Regulation and legislationMany developing countries have inadequate controlof the availability of potentially ototoxic drugs. Insome countries, aminoglycosides and other anti-biotics are available over-the-counter without theneed for prescription. In others, there are regula-tions but they are not enforced. Regulations should

also include control of drugs donated for use inlarge-scale emergencies and disasters. Healthauthorities should ensure that adequate warningswritten in the local language are provided withdonated drugs.

4. Management and monitoringIf possible during treatment, ototoxic drugs shouldbe avoided, particularly where other risk factors forototoxicity are present. However this is not alwayspossible because of the lack of alternative andaffordable therapies. In situations where potentiallyototoxic drugs must be used, the followingprecautions should be observed:

• Use the minimum effective dose and duration oftherapy

• Use an appropriate route of drug administration;and

• Monitor the patient regularly and frequently.

This should be done by performing regular symp-tom checks, audiometric tests including high-frequency audiometry and otoacoustic emissions(if possible) and measurements of serum druglevels. Audiometry or serum testing may not bewidely available in some developing countries,hence the need for constant clinical vigilance.

5. National surveillance systemsThese should be set up, or integrated into othernetworks such as the WHO International DrugMonitoring Programme, in order to measure theextent and causes of the problem.

6. ResearchThe mechanism of ototoxicity and its incidence andprevalence, the development of affordable,alternative nontoxic drugs, and the need forsubstances that reduce damage caused by ototoxicdrugs should be determined by research. The safedosage and duration of treatment in high-riskpatients need to be evaluated, in particular forthose essential drugs that are potentially ototoxic.

References

1. Brummett, R.E., Morrison, R.B. The incidence of amino-glycoside antibiotic-induced hearing loss. Archives ofOtolaryngology, Head and Neck Surgery, 116: 406–4101990.

2. Chiodo, A.A., Alberti, P.W. Experimental, clinical andpreventive aspects of ototoxicity. European Archives ofOtorhinolaryngology, 251: 375–392 (1994).


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3. World Health Organization. Severe and complicatedMalaria. Transactions of the Royal Society of TropicalMedicine and Hygiene, 84 (suppl 2): (1990).

4. Harpur E. The pharmacology of ototoxic drugs. BritishJournal of Audiology, 16: 81–93 (1982).

5. Chan L. Status of ototoxic deafness in China. Strate-gies for prevention of hearing impairment from ototoxicdrugs. Unpublished background paper, PBL/WHO,Geneva, 1994.

International study of hormonereplacement therapy (HRT)announcedAn international study involving more than 30 000postmenopausal women will commence in 1997 toprovide data on the long-term benefits and risks ofHRT. The study is intended to complement therecent Women's Health Initiative study carried outin the United States. The Women‘s InternationalStudy of Long Duration Oestrogen after Menopause(WISDOM) will be coordinated in the United King-dom by the Medical Research Council‘s Epide-miology and Medical Care Unit and will extend over20 years.

Participants in the study will take HRT or placebofor 10 years, and be followed up for a further 10years. The first results of the trial are not expectedbefore 2012 and will study, in particular, the risksof developing heart and other cardiovasculardiseases, stroke, breast cancer and bone fracturescaused by osteoporosis, as well as provide informa-tion on the quality of life and economic implicationsof HRT.

Reference: Scrip, Number 2180, l996. p. 27.

Betacarotene, vitamin A and Emay not prevent cancer orcardiovascular diseasesObservations from epidemiological studies suggestthat the risk of cancer and cardiovascular diseasesis lower among persons who consume high dietarylevels of vegetables, fruits and grains (1). A com-monly accepted explanation for this, both amongscientists and the public has been that antioxidantvitamins in vegetables and fruits prevent carcino-genesis and atherogenesis by interfering passivelywith oxidative damage to DNA and lipoproteins.

These theories have also been supported by ob-servations in animal studies (2). As a result of thesebeliefs, many millions of dollars are spent annuallyon synthetic betacarotene and vitamin E (INN =tocofersolan) and A (INN = retinol) supplements.

Sceptics have long called for a large, long-termclinical intervention trial to demonstrate the benefitsand risks of these prevention practices. and theresults of four large-scale chemoprevention trials ofbetacarotene and related agents are now available.Their disappointing results reaffirm the importanceof solid scientific evidence as a sound basis for anydisease prevention strategies (3–6).

The Alpha-Tocopherol, Beta Carotene cancerprevention study (ATBC) (3) tested daily supple-mentation with 20 mg of betacarotene and 50 mg oftocofersolan in 29 133 male smokers (two-by-twofactorial design). A total of 876 new cases of lungcancer were diagnosed and no reduction in theincidence of lung cancer was found among malesmokers after five to eight years of dietary supple-mentation with tocofersolan or betacarotene. In factthe trial raised the possibility that these supple-ments may have both harmful and beneficialeffects.

The Physicians‘ Health Study (4) tested supple-mentation with 50 mg of betacarotene on alternatedays in 22 071 male physicians, 50% of whom wereformer smokers and 11 % of whom were currentlysmoking. In this trial, 170 new cases of lung cancerwere diagnosed and 12 years of supplementationwith betacarotene produced neither benefit norharm in terms of the incidence of malignant neo-plasms, cardiovascular disease, or death from allcauses.

The betacarotene and retinol efficacy trial (CARET)tested daily supplementation with a combination of30 mg betacarotene and 25 000 IU of retinol in atotal of 18 314 smokers, former smokers andworkers exposed to asbestos (5). There were 388new cases of lung cancer and, after an average offour years of supplementation, the combination ofbetacarotene and retinol had no benefit and mayhave had an adverse effect on the incidence of lungcancer and on the risk of death from lung cancer,cardiovascular disease, and any cause in smokersand workers exposed to asbestos.

Finally, a study conducted in 34 486 postmeno-pausal women with no cardiovascular diseasesuggested that the intake of vitamin E from food is


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inversely associated with the risk of death fromcoronary heart disease and that such women canlower their risk without using vitamin supplements(6). By contrast, the intake of retinol and ascorbicacid was not associated with lower risk of deathfrom coronary disease.

In summary, the studies did not prove the value ofantioxidant vitamin supplements for prevention ofcancer or cardiovascular disease in a well-nourished population. Instead of buying and con-suming antioxidant-vitamin supplements, peopleare advised to adhere to a healthy lifestyle. This isunderstood as eating sufficient fruit and vege-tables, taking enough exercise, avoiding becomingoverweight and refraining from smoking.

References

1. National Research Council. Committee on Diet andHealth, Food and Nutrition Board, Commission on LifeSciences. Diet and health: implications for reducingchronic disease risk. National Academy Press,Washington, DC, 1989.

2. Verlangieri, A.J., Bush, M.J. Effects of d-alpha-tocopherol supplementation on experimentally inducedprimate atherosclerosis. Journal of American College ofNutrition, 11:131–138 (1992).

3. The Alpha-tocopherol, beta carotene cancer preventionstudy group: Effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in malesmokers. New England Journal of Medicine, 331:141–147(1994).

4. Hennekens, C.H., Buring, J.E., Manson, J.E. et al. Lackof effect of long-term supplementation with beta caroteneon the incidence of malignant neoplasms and cardio-vascular disease. New England Journal of Medicine, 334:1145–1149 (1996).

5. Omenn, G.S., Buring, J.E., Mason, J.E. et al. Effects ofa combination of beta carotene and vitamin A on lungcancer and cardiovascular disease. New England Journalof Medicine, 334,1150–1155 (1996).

6. Kushi, L.H., Folsom, A.R., Prineas, R.J. et al. Dietaryantioxidant vitamins and death from coronary heartdisease in postmenopausal women. New EnglandJournal of Medicine, 334:1156–1162 (l996).

Driving ability in cancer patientstreated with morphineEven a small single dose of an opioid in opioid-naive healthy volunteers is reported to reducereaction speed and accuracy, muscular co-ordination, attentiveness and the ability to memor-ize, rendering the driver a traffic hazard. Thequestion of whether stable doses of opioids incancer treatment affect psychomotor functions inthe same way is now raised in a study reported inthe Lancet (1).

Two groups of cancer patients, one of 24 patientsusing slow-release morphine tablets in a mean dailydose of 209 mg, with dose stability established forat least two weeks, and a control group of 25patients who had no pain and used no analgesics,performed a series of psychological, psychomotorand neurological tests originally designed to meas-ure the vocational skills of professional drivers.

Although the morphine group did not perform quiteas well as the control group in the tests, there wereno significant differences between the two groupsas far as measurement of intelligence, attentive-ness, ability to concentrate, psychomotor speedand attention span were concerned. No significantdrug effects were demonstrated in neurologicaltests measuring reaction speed, sensitivity totemperature variation, and keeping one‘s balancewith the eyes open. The morphine group performedpoorer only in the test for keeping balance with theireyes closed.

The authors concluded that the long-term use ofstable doses of morphine does not essentiallyreduce driving skills. However, the observationrelevant to driving was that there is a slight dose-dependent effect on the performance of tasksdemanding special concentration.

References

1. Vainio, A., Ollila, J., Matikainen, E. et al. Driving abilityin cancer patients receiving long-term morphine analge-sia. Lancet, 346: 667 (l995).

2. Vainio, A., Kalso, E., Ollila, J. et al. Kan cancer-patienter som behandlas med morfin köra bil? Tabu, 6:50 (1996).


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General Information

The implications of the TRIPSAgreement for the protection ofpharmaceutical inventions*

Adrian Otten,World Trade Organization,Geneva, Switzerland*

The Agreement establishing the World TradeOrganization (WTO), including the Agreement onTrade-Related Aspects of Intellectual PropertyRights (TRIPS), came into force on 1 January 1995.The WTO is divided into three main parts: theAgreements on Trade in Goods, which includes anew General Agreement on Tarifs and Trade(GATT) and the various subsidiary agreements to it;a newly negotiated General Agreement on Trade inServices (GATS); and the Agreement on TRIPS.Any country wishing to be a Member of the WTO isobliged to accept all these agreements — as part ofa package which reflects the trade-offs made duringthe negotiating process.

The TRIPS Agreement covers all the main areas ofintellectual property — copyright and related rights,trademarks, geographical indications, industrialdesigns, patents, layout-designs of integrated cir-cuits and undisclosed information or trade secrets.In respect of these areas, the Agreement containsthree main sets of provisions.

StandardsThe Agreement lays down minimum standards ofsubstantive protection for each category of rightsthat must be provided in the national law of eachMember. It defines each of the main elements ofprotection, namely the subject matter to be pro-tected, the rights to be conferred and any permis-sible exceptions to those rights, and the minimumduration of protection. It does this by requiring thatthe substantive obligations of the World IntellectualProperty Organization (WIPO) Conventions, theParis Convention for the Protection of IndustrialProperty and the Berne Convention for the

Protection of Literary and Artistic Works, must becomplied with and by adding a substantial numberof additional obligations on matters where theseConventions are silent or were seen as beinginadequate. This is particularly the case in the areaof industrial property.

EnforcementThe second major characteristic of the Agreementis that, for the first time in international law, it re-quires Members to provide effective proceduresand remedies for the enforcement of intellectualproperty rights, whether through the normal civiljudicial process, through customs action againstimports of counterfeit and pirated goods or throughcriminal procedures in respect of wilful counter-feiting and piracy on a commercial scale.

Dispute settlementIt makes disputes between governments aboutwhether TRIPS obligations have been compliedwith subject to a strengthened version of the GATTdispute settlement system under the future WorldTrade Organization.

In addition the Agreement provides for certain basicprinciples, such as national treatment, and somegeneral rules to ensure that procedural difficulties inacquiring or maintaining international patent rightsdo not negate the protection due. The obligationsunder the Agreement will apply equally to all mem-ber countries, but developing countries will have alonger period to phase them in. Special transitionarrangements operate in the situation where adeveloping country does not presently provideproduct patent protection in the area of pharma-ceuticals (see page 15).

Another general point about the Agreement shouldalso be made. It is a minimum standards Agree-ment that leaves Members free to provide moreextensive protection of intellectual property if theyso wish — for purely domestic reasons or becausethey have concluded international agreements tothis effect, whether bilateral, regional, as forexample is the case in the European Communitiesand in the North American Free Trade Area(NAFTA), or multilateral, such as in WIPO. TheTRIPS Agreement does, however, require, as a

* The views presented in this article are the responsibilityof the author and should not be taken as necessarilythose of the World Trade Organization or its Secretariat.© A. Otten 1997

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general rule, that any more extensive protection soimplemented be extended to the nationals of allWTO Members on a national and most-favoured-nation treatment basis.

The TRIPS provisions onpharmaceutical patentsThe question of the protection of pharmaceuticalpatents was one of the key issues in the negoti-ations as a whole and perhaps the key issue in theNorth-South axis of the negotiations. It was the lastissue to be resolved in the negotiations prior to thetabling of the draft Agreement at the end of 1991.At that time, it was clear that there would be noTRIPS Agreement without a commitment to makeavailable patent protection for twenty years in virtu-ally all areas of technology, including pharma-ceuticals, and that without a TRIPS Agreement itwas doubtful that the Uruguay Round could beconcluded. The question therefore that all dele-gations were willing to consider was: on whatterms would they accept such an obligation, inparticular in regard to such matters as the exhaus-tion of rights, compulsory licensing, the control ofanti-competitive practices, test data protection andtransitional arrangements?

Patentable subject matterThe basic rule is that patents must be available forany inventions, whether products or processes, inall fields of technology without discrimination, sub-ject to the normal tests of novelty, inventiveness,industrial applicability and adequate disclosure.There are three exceptions to this basic rule.

• One is for inventions contrary to public order ormorality. This is subject to the condition that thecommercial exploitation of the invention must alsobe prevented and this prevention must benecessary for the protection of public order ormorality.

• The second exception is that Members mayexclude from patentability diagnostic, therapeuticand surgical methods for the treatment of humansor animals.

• The third is that Members may exclude plants andanimals other than microorganisms andprocesses for the production of plants or animalsother than non-biological and microbiologicalprocesses. It is worth noting that this exception isconsiderably broader than the exceptions for lifeforms found in the patent laws of the UnitedStates, European countries and Japan. This

reflected a concern on the part of manydeveloping countries not to be obliged to gofurther in this area of technology, at least for thetime being.

Patent rightsThe rights that must be conferred by a product pa-tent include the usual ones of making, using andselling. Process patent protection must give rightsover products obtained directly by the process.Patent owners must also have the right to preventimportation by third parties without their consent.The question of the international exhaustion ofrights, that is to say the extent to which a rightholder should have the possibility to assert hisrights in respect of goods that he had authorized tobe put on the market in another country, is ofcourse not only related to the importation right; itapplies equally in regard to the right to prevent saleor use of goods put on the market with his consentin another country. The negotiation on the issue ofexhaustion was between those who favouredcomplete silence on this issue and those whichwanted an explicit recognition of the right ofcountries to have their own exhaustion regimes.The outcome is the provision which makes it clearthat the issue of exhaustion cannot be addressed indispute settlement proceedings under the Agree-ment, except in regard to the national treatment andmost favoured nation obligations. Thus, subject tothese excep-tions, what a country does in the areaof exhaustion cannot be challenged through theWTO. However, the text does not specificallylegitimize national discretion in this area and isinterpreted by some as meaning that exhaustionpractices are not covered by the restraint on theuse of unilateral measures that the WTO disputesettlement provisions require.

Compulsory licensingThe main debate took place between those whowished to provide for a finite list of grounds onwhich compulsory licences could be granted, forexample limiting compulsory licensing to situationsof national emergency, anti-competi-tive practicesand public non-commercial use, and those who didnot consider such a finite list feasible or appro-priate. A further important element in the nego-tiations was the insistence by a large number ofcountries that government use practices — use byor on behalf of the government — should besubject to rules equivalent to those applying tocompulsory licensing. The outcome of thesedebates can be found in Article 31 of the TRIPStext. This contains a common set of rules applying

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to both forms of use without the authorization of theright holder — that is to say compulsory licensingand government use — and does not limit thegrounds on which compulsory licences can begranted. It does, however, contain, together withrelated provisions in Article 27.1, a number ofconditions that have to be respected in order to pro-tect the legitimate interests of the right holder. Anumber of these conditions are:

• Compulsory licences must not discriminate ac-cording to the field of technology. A number ofcountries have had special systems operating inthe area of pharmaceuticals. These will have tobe eliminated.

• Patents rights must be enjoyable without dis-crimination as to whether products are importedor locally produced. Failure to meet the reason-able needs of the market can remain a ground forthe grant of a compulsory licence. But the com-pulsory licensing system must not provide fordifferential treatment according to whether thepatent owner supplies the market through importsor local production.

• Applications for compulsory licences shall be con-sidered on their individual merits. This means thatcountries must not provide automatic licences ofright-type systems, but must consider each ap-plication in the light of the conditions set out in theTRIPS Agreement.

• As a general rule, applications must not be con-sidered unless an unsuccessful attempt has beenmade to obtain a voluntary licence on reasonableterms and conditions within a reasonable periodof time.

• The scope and duration of compulsory licencesare limited to the purpose for which they weregranted and such licences shall be liable, subjectto adequate protection of the legitimate interestsof the licensee, to be terminated if and when thecircumstances which led to their being grantedcease to exist and are unlikely to recur.

• The right holder shall be paid adequate remunera-tion in the circumstances of each case, taking intoaccount the economic value of the authorization.

• Decisions relating to remuneration and the legalvalidity of any decision to grant a licence shall besubject to judicial or other independent review.

• The requirements concerning the need to attemptfirst to negotiate a voluntary licence and theamount of remuneration are relaxed where acompulsory licence is granted to remedy apractice determined after judicial or administrativeprocess to be anti-competitive.

• Compulsory licences on dependent patentgrounds are permitted subject to a number ofadditional conditions.

Anti-competitive practicesThe TRIPS Agreement contains a Section on thecontrol of anti-competitive practices. This will be thefirst time that agreed language on such matters hasbeen incorporated in a binding multilateral instru-ment. The Section recognizes that some licensingpractices or conditions pertaining to IPRs whichrestrain competition may have adverse effects ontrade and impede the transfer and dissemination oftechnology. The Section further recognizes the rightof Members to adopt measures, consistently withthe provisions of the Agreement, to prevent orcontrol abusive anti-competitive practices andincludes an illustrative list of such practices. TheSection also establishes a consultation procedureby which a Member seeking to take action againstabusive anti-competitive practices may seek the co-operation of the home government of the companyin question, notably through the supply of informa-tion of relevance to the matter in question. Theseprovisions essentially reflect the concerns ex-pressed in the negotiations by representatives ofdeveloping countries. However, it is also worthnoting that attitudes towards a general considera-tion of matters of competition law, includingrestrictive business practices, as they relate to theconditions of international trade have evolved in theGATT/WTO recently. The December 1996Singapore Ministerial Conference decided toinclude this issue on the future work programme ofthe World Trade Organization.

Undisclosed information and test dataThe TRIPS Agreement contains obligations on theprotection of undisclosed information or tradesecrets. These are not treated as a form ofproperty; the protection that has to be given isagainst the use of such information in a mannercontrary to honest commercial practices, i.e.against acts of unfair competition. Although thematter was somewhat contentious at the outset ofthe negotiations, delegations generally recognizedthat such protection was desirable and in manycases was already available in one form or another

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through their national law. The information thatshould be protected is defined as information that issecret, that has commercial value because it issecret and that has been subject to reasonablesteps under the circumstances to keep it secret.

Undisclosed test data and other data whose sub-mission is required by a Member as a condition ofapproving the marketing of pharmaceutical oragricultural chemical products which use newchemical entities and whose origination involved aconsiderable effort must be protected against unfaircommercial use. Earlier drafts of the Agreementhad specified a period of time during which govern-ments should not rely on such data for the approvalof competing products without the agreement of thecompany submitting the original data. This, how-ever, was removed in the final stages of the nego-tiations.

Transitional arrangementsThe basic rule in this area is that, as of 1 January1995, the date of entry into force of the WTOAgreement, developed countries had a one-yeartransition period (i.e. until the beginning of thisyear), and developing and least-developedcountries generally have five- and eleven-yeartransition periods respectively in order to bring theirlegislation and practices into conformity with theirTRIPS obligations. Countries in transition to amarket economy may also benefit from a five-yeartransition period subject to certain conditions. AllWTO Members have had to comply with thenational treatment and most favoured nationobligations of the TRIPS Agreement since thebeginning of this year. These transition periods areoptional and many countries are making thenecessary changes to their legislation in advance.

At the end of the relevant transition period,Members have to apply the TRIPS standards notonly to new subject matter but also to existingsubject matter under protection on that date. Thus,for example, any patent still in force on that datewould benefit from the twenty-year term of protec-tion from filing, from the rights specified in theTRIPS text and from the conditions on the use ofcompulsory licensing. There are certain exceptionsto protect investments and arrangements alreadyinitiated prior to the acceptance of the WTOAgreement by a country; but, given the transitionperiod, these are likely to be applicable only indeveloped countries.

Special transitional arrangements apply in thesituation where a developing country does not

provide product protection in a given area oftechnology, such as pharmaceuticals, on thegeneral date of application of this Agreement forthat Member, i.e. in the year 2000. In such asituation, the country concerned may delay theapplication of the TRIPS obligations on productpatents to that area of technology for an additionalfive years (i.e. to the year 2005). If this was all theTRIPS Agreement said on this matter, the effectwould be that such a developing country would beobliged to start providing patent protection from theyear 2005 for pharmaceutical product inventionswhich will be “new” as of that date. Given the delaybetween the date of filing applications for patentsfor new pharmaceutical products and those pro-ducts receiving marketing approval, especially indeveloping countries, the practical commercialeffect of the TRIPS provisions in the pharma-ceutical sector would, in many such cases,nothave become apparent until the year 2015 or so.

This was clearly not a negotiable prospect in thecontext of the Uruguay Round. It is for this reasonthat the TRIPS text also includes additionaltransitional arrangements in the situation where acountry does not provide, as of the date of entryinto force of the WTO Agreement, patent protectionfor pharmaceutical (and agricultural chemical)products commensurate with the TRIPS provisions.In such a situation, the country concerned mustprovide, as from the date of entry into force of theWTO Agreement, a means by which patent appli-cations for such inventions can be filed.

These applications will not need to be examined fortheir patentability until the country starts applyingproduct patent protection in that area, i.e. for adeveloping country, at the end of the ten-yeartransition period. However, at that time, theapplication must be examined by reference to theprior art as it existed at the time the application wasmade. If the application is successful, productpatent protection would then have to be granted forthe remainder of the patent term counted from thefiling date of the application.

Given the lengthy delay between filing a patentapplication and obtaining marketing approval for apharmaceutical product, most products that are thesubject of this procedure would normally not belikely to get on the market in a developing countrybefore the expiry of the ten-year transition period.However, in the, perhaps. rather rare situationwhere such a product does obtain marketingapproval in a developing country benefiting from the

General Information

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ten-year transition period, provision is made for thegrant of an exclusive marketing right of up to fiveyears to tide over the gap. This is subject to anumber of safeguards to ensure that the productconcerned is a genuine invention: subsequent tothe entry into force of the WTO Agreement, apatent application must have been filed, a patentgranted and marketing approval obtained in anotherMember for the product in question.

The net effect of these arrangements is that, incountries that do not currently grant product pro-tection for pharmaceuticals, pharmaceutical inven-tions that meet the normal criteria for protection asof the date of entry into force of the Agreement forthat country (normally 1 January 1995) mustgenerally be protected, at least by the time thatprotection becomes of commercial significance.These transitional arrangements do not provide forpipeline protection, in the sense that there is noobligation for such countries to provide protection inrespect of pharmaceutical inventions no longermeeting the normal criteria for protection on thedate of entry into force, even if they have not yetbeen approved for marketing.

The TRIPS Agreement also regulates anothertransition issue, namely the extent to which patentsstill valid as of the end of a Member's transitionperiod will benefit from the standards under theAgreement. The basic rule is that the obligations inthe Agreement will apply to such patents. Forexample, an existing patent must benefit from theminimum term of 20 years from filing, even if it wasoriginally granted for a shorter period. There is,however, an exception in situations where an actwas commenced or in respect of which a significantinvestment was made before the date of accept-ance of the WTO Agreement by a Member. If suchan act becomes infringing as a result of the applica-tion of the rules of the Agreement, the MemberState concerned may limit remedies available to theright holder to the payment of equitable remunera-tion. There is also a provision which states that therules on compulsory licensing and government useneed not be applied to authorizations grantedbefore the date that the Agreement became known.In respect of patent applications pending at the endof the transition period, the applicant must beallowed to amend the application to claim anyenhanced protection available under the provisions

of the Agreement, provided such amendments donot include new matter.

Dispute settlementOne of the major innovations of the TRIPS Agree-ment is that treaty obligations in the area of intel-lectual property will be subject for the first time to afunctioning dispute settlement system. Under theWorld Trade Organization, an integrated disputesettlement system will apply to disputes in all of theareas covered. This system is a strengthenedversion of the existing GATT mechanism. Themajor element of strengthening has been theelimination of the means by which it has been pos-sible for losing parties to be able to delay or blockthe dispute settlement process. As under theexisting GATT system, any country which fails tobring itself into compliance with the findingsadopted under the system will run the risk of theaggrieved country being authorized to retaliate, i.e.to withdraw obligations or concessions made to theoffending country. Such retaliation can take placenot only in the area that is the subject of the disputebut also, subject to certain conditions, in otherareas covered by the WTO. Thus a country failingto live up to its TRIPS obligations would exposeitself to the risk of losing market access rights. Theissue of retaliation is important because it makesclear that in joining the WTO a country acceptsinternational liability for meeting its obligations.However, it is also important to appreciate thatretaliation has only once been authorized in thecontext of dispute settlement under the GATT andis more of a threat that gives credibility to the sys-tem than anything else.

Another important feature of the dispute settlementrules is that they contain commitments regardingthe use of unilateral methods of dealing withdisputes. WTO Members seeking redress of aviolation of TRIPS or other WTO obligations committhemselves to have recourse to, and abide by, themultilateral WTO dispute settlement procedures. Insuch cases, they undertake not to make a deter-mination that a violation has occurred except inaccordance with these procedures and only tomake such determinations consistent with thefindings resulting from them. Moreover, theyspecifically commit themselves not to retaliateexcept in accordance with authorization from theWTO.

General Information

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Regulatory Matters

Proposed withdrawal of terfenadineUnited States of America — The Food and DrugAdministration has announced its intention to with-draw approval of terfenadine (1), a non-sedatingantihistamine that is also marketed in genericversions and in combination with pseudoephedrine,and is available on prescription only.

The Agency has determined that terfenadine is nolonger the safest product available. Fexofenadine,an active metabolite of terfenadine, is now mar-keted and provides an alternative with essentiallysimilar therapeutic advantages, but lacking thecardiotoxic risks.

Cases of potentially fatal cardiac arrhythmias, suchas torsades de pointes or ventricular arrhythmias,have been reported in association with increasedterfenadine levels in plasma, leading to pro-longation of the QT interval (2). As a consequence,terfenadine is contraindicated in cases of hepaticdysfunction and when used concomitantly withdrugs such as oral ketoconazole, itraconazole,erythromycin, clarithromycin, or troleandomycin.The product is not recommended for use with oralimidazole, antifungals, macrolide antibiotics,potential arrhythmogenic drugs such as neuro-leptics and tricyclic antidepressants, or drugs whichcould produce an electrolyte imbalance (3).

The Food and Drug Administration advises patientscurrently taking terfenadine products to seek advicefrom their physicians concerning a change to alter-native medication.

References

1. FDA Talk Paper, T97–3, 13 January 1997.

2. Federal Register, 62: 1889–1892, 1997.

3. Nightingale, S.L. From the Food and Drug Administra-tion. FDA proposes to withdraw terfenadine approval.Journal of the American Medical Association, 277: 370(1997).

France — In line with an opinion delivered by theNational Pharmacovigilance Commission, the Medi-cines Agency has decided to suspend the productlicence for terfenadine.

In 1992, a preliminary inquiry concerning the risk ofrare but serious ventricular rhythm disorders led toa modification of the product information. Recentreappraisal has confirmed the continued risk ofserious effects in spite an information campaignaimed at correct use of the medication. It isconsequently considered that the benefit/risk ratiois no longer positive. The Medicines Agency hastherefore suspended the product licence in Franceand has initiated a procedure at the EuropeanCommunity level for reappraisal of terfenadine. Thisshould lead to a definitive and common positionbeing taken by all European Union members.

Reference: Agence du Médicament. Press release, 13February 1997.

European Union — The Committee for ProprietaryMedicinal Products (CPMP) has stated that a pro-cedure under Article 12 of Council Directive 75/319/EEC as amended, has been initiated by France.This procedure relates to terfenadine-containingmedicinal products, the marketing of which hasbeen suspended by France and Luxembourg.

Reference: Press Release, CPMP/182/97, February1997.

Japan — The Ministry of Health & Welfare hasadvised WHO that terfenadine, which has beenmarketed in Japan since 1990, is contraindicated inpatients with significant hepatic dysfunction or inconcomitant administration with itraconazole,miconazole, or erythromycin. A boxed warning of apossible risk of QT prolongation and/or ventriculararrhythmias including torsades de pointes has beenrequired since 1995.

Recent adverse reaction cases involving terfena-dine have now been analysed by the CentralPharmaceutical Affairs Council, which hasrecommended that additional precautions should beincluded as part of the package insert stating thatthe product should not be administered to patientsundergoing dialysis, or concomitantly withclarithromycin, antiarrythmic drugs except beta-adrenoreceptor antagonists, diuretics, psycho-tropics or probucol, and in patients with cardiacfailure, myocardial infarction or bradycardia.

18


The manufacturer has been requested to circulate adear doctor letter highlighting the cardiotoxicityconcerns.

Reference: Letter to WHO dated 13 February 1997 fromMinistry of Health & Welfare, Japan.

Restrictions on use of sotalolUnited Kingdom — The Medicines Control Agency(MCA) has re-evaluated the therapeutic indicationsfor sotalol following publication of findings from theSWORD (the Survival With Oral d-Sotalol) study(1). The study was set up to evaluate the survival ofpatients with left ventricular dysfunction after myo-cardial infarction treated with d-sotalol and wasdiscontinued for ethical and clinical reasons whenmortality soon proved to be significantly higher inthe treated group than in the placebo group (1).

Sotalol, a non-selective beta-adrenoreceptorantagonist, is known to have a dose-dependentarrhythmogenic effect. It prolongs the QT interval,which predisposes to the development of torsadesde pointes (2). Worldwide, sotalol has beenassociated with 123 spontaneous reports of thiscomplication.

In considering the available information, the MCAhas decided (2) that the use of sotalol should belimited to either the treatment of ventricular ar-rhythmias or prophylaxis of supraventricular tachy-arrhythmia. It should no longer be used for anginapectoris, hypertension, thyrotoxicosis or for second-ary prevention after myocardial infarction.

References

1. Waldo, A.L., Camm, A.J., de Ruyter, H. et al. Effect ofd-sotalol on mortality in patients with left ventriculardysfunction after recent and remote myocardial infarction.Lancet, 348: 7–12 (1996).

2. Committee on Safety of Medicines/Medicines ControlAgency. Current Problems in Pharmacovigilance, Volume22, July 1996.

Fluoroquinolones and tendon ruptureUnited States of America — The Food and DrugAdministration has requested manufacturers ofproducts containing ciprofloxacin, enoxacin, lome-floxacin, norfloxacin or ofloxacin to revise theproduct information and package inserts to includethe following warning: "Ruptures of the shoulder,hand, and Achilles tendons that required surgicalrepair have been reported with these drugs".

Treatment should be discontinued if the patientexperiences pain, inflammation or rupture of atendon. The patient should rest and refrain fromexercise until the diagnosis of tendinitis or tendonrupture has been confidently excluded. Tendonrupture can occur at any time during or aftertherapy with these fluoroquinolone derivatives.

Reference: FDA Medical Bulletin, Volume 26, October1996.

Fatal adverse drug reaction trendsUnited Kingdom — A total of 476 reports of fatalsuspected adverse reactions were reported to theCommittee on Safety of Medicines during 1995.408 reactions were reported in 1994 and 471 in1993. These figures relate to reports from healthprofessionals using the voluntary adverse drugreaction reporting scheme.

Those drug substances most frequently associatedwith fatal reactions during 1995 were clozapine (34cases), diclofenac (22), ethinylestradiol (21), fluoxe-tine (15), sertraline (12), paroxetine (12) amiod-arone (10), nicorandil (9) and ibuprofen (9). Cloza-pine and diclofenac were also the top two drugs inthe list for 1994.

Reference: The Pharmaceutical Journal, 257: 145 (1996).

Aspartame: no apparent linkwith brain tumoursUnited States of America — The Food and DrugAdministration has published a statement on thesafety of the artificial sweetener, aspartame. Arecently published medical journal article has againraised the possibility of a link with the incidence ofbrain tumours in the United States since 1981,when the FDA approved aspartame as a foodadditive.

A recent analysis of the public data base on cancerincidence in the United States (the SEER Programat the National Cancer Institute) did not support anassociation. Data showed an increase in overallincidence of brain tumours since 1973, which con-tinued up to 1985. However, since 1985 the trendline has flattened and in 1991 to 1993 the incidencedecreased slightly.

The FDA states that for the moment it upholds itsoriginal approval decision on aspartame, but re-mains ready to act on any credible scientific

Regulatory Matters

19


evidence — as it would in the case of any productwhich it has approved.

Reference: FDA Talk Paper, T 96-74, November 1996.

Anthranoids, herbal medicinesand carcinogenic potentialGermany — The Federal Institute for Drugs andMedical Devices has restricted the indications andrevised the contraindications of all medicinalproducts containing anthranoids (hydroxyanthra-cene derivatives) found in the plants Andira,Cassia, Rhamnus, Rheum and Aloe becauseexperimental studies have shown evidence ofpotential genotoxicity and carcinogenicity.

Reference: Notification from the Federal Institute forDrugs and Medical Devices, Berlin, enclosing a pressrelease of 31 July 1996.

Adrenal cortex extractassociated with infectionsUnited States of America — The Food and DrugAdministration has announced a nationwide alert oninjectable adrenal cortex extracts that have causedserious bacterial infections at the site of injection.Apparently these products may have been pre-pared from the adrenal glands of cattle, sheep orswine under conditions that could lead to conta-mination. The Food and Drug Administration hasnot approved adrenal cortex extract and is investi-gating how this product came to be manufacturedand distributed. The Agency has also taken steps toremove the product promptly from the market.

Reference: HHS News, P96-13, August 1996.

Herbal medicines adulteratedwith antirheumaticsSingapore — Four Chinese herbal medicines havebeen found to be adulterated with diclofenac — anonsteroidal anti-inflammatory drug. The productsinvolved were Ba Bace Fen Ski, Huo Luo Dan andShe Xiang Zhui Feng Ton Ou Wan, 101 Wei YaoLin (Mei Hua brand) and Zhen Zhu Tong Ling (FeiYien brand).

Reference: Communication from the Institute of Scienceand Forensic Medicine, Singapore, dated 18 July 1996.

Herbal hay-fever remedy andconventional drugsA remedy for hay fever under the name of "podi"which was purchased from a street stall in NewDelhi, India was analysed and found to containtablets of chlordiazepoxide, a benzodiazepine,5 mg, together with a packet of powder containingmaize flour mixed with theophylline 30 mg, clor-pheniramine 4 mg, and possibly prednisolone0.5 mg, per dose.

Reference: The Pharmaceutical Journal, 258: 105–106(1997).

Withdrawal of blood productsUnited States of America — Centeon, the manu-facturer of human albumin (Albuminar) and plasmaprotein fraction (Plasma Plex) has voluntarily with-drawn these two products as a precautionarymeasure because of possible contamination withbacterial agents.

Reference: FDA Talk Paper, T 96-69, October l996.

Benzodiazepines, drugdependence and rebound effectsSouth Africa — The Medicines Control Councilhas stated that package inserts of benzodiazepinesand benzodiazepine-like drugs should be revised toemphasize the risk of drug dependence duringprolonged use and at high doses, and in particularwhen prescribed for patients with a history ofalcohol or drug abuse.

The new information must state that a transientsyndrome with symptoms similar to those that occurat the outset of drug treatment can occur onwithdrawal. Mood changes, anxiety and restless-ness may accompany the reaction and the risk ofrebound effects is greater if treatment is discon-tinued abruptly. The duration of treatment should beminimized and should not exceed 4 weeks forinsomnia, and 8–12 weeks for anxiety disorders.

Reference: Communication from the Medicines ControlCouncil, Pretoria, 31 July 1996.

Carteolol and bronchial asthmaJapan — As in the case of other beta-adreno-receptor antagonists, carteolol-containing eye drops

Regulatory Matters

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have been reported to exacerbate bronchial asthmain patients with a history of this condition.

Reference: Information on Adverse Reactions to Drugs,Number 135, 1996.

Mucocutaneous reactionsand carbamazepineMalaysia — The Adverse Drug Reaction AdvisoryCommittee has received 103 reports, between 1988and 1996, associated with the use of carbamaze-pine. In 96 of the reports, carbamazepine wasidentified as the sole suspected drug.

Mucocutaneous reactions were the most commonlyreported findings ranging from maculopapular rash(25 cases) to more serious and potentially life-threatening reactions such as Stevens Johnsonsyndrome (48) and toxic epidermal necrolysis (2).Other reactions included exfoliative dermatitis (3),erythema multiforme (2), fixed eruption (2), bullouseruptions (2), angio-oedema (3), oral lesions (5),and ocular lesions (2).

Reference: Barita Ubat-Ubatan, Volume 10, l996.

Mebendazole deregulatedto over-the-counter (OTC) statusNorway — The anthelminthic, mebendazole, ineither mixture or tablet form is now available with-out prescription for treatment of various types ofintestinal worm infestations in adults and children.None the less, instruction or counselling by a physi-cian is still required for treatment during pregnancyor for use in children under two years of age.

Reference: Nytt on legemiddler, Number 4, 1996.

Donepezil: new treatment forAlzheimer diseaseUnited States of America — The Food and DrugAdministration has approved donepezil for thetreatment of mild to moderate symptoms ofAlzheimer disease.

Alzheimer disease is estimated to affect over fourmillion Americans and is a progressive conditionaffecting memory, judgement and the ability toreason. Donepezil is a cholinesterase inhibitor that

increases levels of acetylcholine, a neurotransmitterimportant in cognitive functions. Although the drughas not been shown to have an effect on the under-lying cause of the disease, it may moderate someof the symptoms.

Clinical trials reported side effects such asdiarrhoea, syncope and nausea. The labelling alsowarns that the drug has the potential to causebradycardia (arrhythmias), especially in patientswith underlying cardiac conduction conditions.

Following approval of tacrine in 1993, donepezil isonly the second drug available to treat thesymptoms of this disease.

Reference: FDA Talk Paper, T96–78, November 1996.

Whole-oat foods and heart diseaseUnited States of America — The Food and DrugAdministration will allow health claims on packagingof foods containing soluble fibre from whole oats(rolled oats, oat bran and oatflour) stating that whenused as part of a diet low in saturated fat and cho-lesterol, these foods may reduce the risk of heartdisease.

The Agency has concluded that the betaglucansoluble fibre of whole oats is the primary com-ponent responsible for the total and LDL bloodcholesterol-lowering effects of diets that containthese foods.

Reference: FDA Talk Paper, T97–5, 1997.

Nifedipine: restricted useIreland — Recent studies suggest that there is anincreased risk of cardiovascular events andmortality in patients treated with the short-actingcalcium channel blocker, nifedipine, for unstableangina pectoris or following myocardial infarction(1–3).

Following a review and evaluation of data, the IrishBoard of Medicines has recommended that use ofnifedipine in ischaemic heart disease should berestricted to the prophylaxis of stable angina and iscontraindicated in patients with unstable angina (4).

Prescribers are reminded that treatment of hyper-tension with short-acting nifedipine may induce anabrupt fall in blood pressure as well as tachycardia.

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References

1. Furberg, C.D. Nifedipine. Dose-related increase inmortality in patients with coronary heart disease.Circulation, 92: 1326–1331 (1995).

2. Psaty, B.M. The risk of myocardial infarction associatedwith antihypertensive drug therapies. Journal of theAmerican Medical Association, 275: 620–625 (1995).

3. Nifedipine: danger of short-acting formulations. WHODrug Information, 9: 220–221 (1995).

4. Irish Medicines Board. Drug Safety. Number 2, May1996.

Emergence of multidrug-resistant salmonellaWHO has issued a statement on the increasingresistance of Salmonellosis typhimurium to a rangeof antibiotics that threatens to become a seriouspublic health problem. Resistance is expected tocontinue to rise at a similar or even greater rate inthe future as antimicrobial agents lose theireffectiveness.

Multidrug-resistant Salmonella typhimurium DT 104initially emerged in cattle in 1988 in England andWales. Subsequently, the strain has been isolatedfrom poultry, sheep, pigs and horses. Antimicrobialtherapy is used extensively to combat salmonellainfection in animals. The evolution of a strain re-sistant to the commonly used antibiotics has madeinfection with S. typhimurium in food animalsdifficult to control and it will likely remain an animalhealth problem for quite some time.

The primary route by which humans acquire in-fection is by consumption of contaminated food ofanimal origin. Unlike S. enteritidis, which is mainlyassociated with poultry and eggs, multidrug-resistant S. typhimurium DT 104 can be found in abroad range of foodstuffs such as poultry, meat andmeat products, and unpasteurized milk. Humancases have also occurred where individuals havebeen in contact with infected cattle or pets.

An increase in the overall number and percentageof multidrug-resistant S. typhimurium DT 104 caseshas been reported from several Europeancountries. In England and Wales, a tenfold increasein the number of human cases of multidrug-resistant S. typhimurium DT 104 has beenreported during a six-year period from 1990 to 1996rising from 300 to 3500 cases per year. Resistance

has developed to some of the most commonantibiotics such as ampicillin, chloramphenicol,streptomycin, the sulfonamides and tetracycline.Since 1994, an increasing number of isolates withadditional resistance to trimethoprim and a few withadditional resistance to ciprofloxacin, have alsobeen reported. Moreover, infection with multidrug-resistant S. typhimurium DT 104 has been associat-ed with hospitalization rates which are twice that ofother zoonotic foodborne salmonella infections, withten times higher case-fatality rates.

In Germany, S. typhimurium DT 104 accounted forup to 10% of almost 10 000 salmonella samplesfrom human sources examined in 1995; and 18% ofthose examined in 1996. Almost all DT 104 isolateswere multidrug-resistant, with the same resistancepattern as in England and Wales — although re-sistance to ciprofloxacin has not yet been observedin Germany. DT 104 was recently detected in theUnited States but little is currently known concern-ing its prevalence and means of transmission. Arise in salmonellosis incidence has been reported inall countries in Europe and in a number of countriesin the Eastern Mediterranean and South-east Asia.

WHO‘s statement concludes that existing know-ledge and technology cannot provide consumerswith pathogen-free raw meat and poultry, and it isvery unlikely that the eradication of salmonellae indomestic animals is possible in the foreseeablefuture. The increased occurrence of drug-resistantpathogens in food of animal origin emphasizes theneed to cook foods thoroughly prior to con-sumption. Education of food-handlers in theprinciples of safe food-handling is an essential steptowards reducing the incidence of foodbornedisease resulting from cross-contamination duringprocessing and preparation of foods. Education offarmers and their families regarding the risks ofoccupationally acquired infections is also animportant step in the control of human infectionfrom S. typhimurium DT 104. Finally, the avoidanceof unnecessary antibiotic use in food animals isvital.

Reference: WHO Fact Sheet, Number 139, 1997.

Tolrestat: hepatic necrosisArgentina — Tolrestat is a new aldose-reductaseinhibitor indicated in the treatment of serious com-plications of diabetes such as neuropathy,retinopathy and nephropathy.

Regulatory Matters

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In March 1995, the National PharmacovigilanceSystem received notification of the death of a 41-year-old woman patient from hepatic necrosisfollowing treatment with tolrestat. The patient died80 days after treatment was started and 30 daysafter the drug was withdrawn because of abdominalpain and jaundice.

In October 1996, the manufacturer of tolrestat(John Wyeth Laboratory) withdrew the product fromthe market worldwide following reports of two otherdeaths from hepatic necrosis and poor efficacy inclinical trials.

Reference: Communication to WHO from theAdministración Nacional de Medicamentos, Alimentos yTecnología (ANMAT), Buenos Aires, 5 November 1996.

Somatropin for wastingsyndrome in AIDSUnited States of America — The Food and DrugAdministration has approved somatropin fortreatment of AIDS-wasting syndrome in HIV-infected patients to increase lean body mass. Thisillness is a metabolic disorder characterized byweight loss and leads to muscle weakness andorgan failure, contributing to a fatal outcome.

Reference: FDA Talk Paper, T96-59, August 1996.

Ivermectin approved for human useUnited States of America — The Food and DrugAdministration has approved ivermectin for treat-ment of two human parasitic infections: strongy-loidiasis and onchocerciasis.

Strongyloidiasis is an infection usually confined tothe small intestine. The disease is common in manytropical countries and, among Americans, it isusually a disease of immigrants, travellers, andformer prisoners of war — but it can occasionallybe acquired in some areas of the United States. Ifthe immune system is normal, the infection remainsin the intestine, often for years, causing abdominalpain, diarrhoea and blood eosinophilia. Theinfection can spread throughout the body and isfatal if the person has a weakened immune system.In controlled clinical trials a single dose of iver-mectin has cured between 64 and 100% of patientsinfected with intestinal strongyloidiasis, when theimmune system was normal.

Regulatory Matters

Onchocerciasis, also known as river blindness, isprevalent in many countries of Africa as well asSouth and Central America. The parasites canmigrate to the eyes, causing inflammation andblindness. In onchocerciasis, a single dose of iver-mectin reduced the number of larvae in the skin by83% at three days and 99.5 % at three monthsfollowing drug intake.

Reference: FDA Talk Paper, T96-77, November 1996.

Naproxen availableover-the-counter (OTC)Norway — The nonsteroidal anti-inflammatorydrug, naproxen, has been deregulated to non-prescription status and is available in tablet form inpackages containing a maximum of 20 tablets of250 mg each. The product is indicated for primarydysmenorrhoea or dysmenorrhoea associated withuse of an IUD.

Reference: Nytt on legemiddler, Number 3,1996.

Influenza virus vaccinesfor 1997–1998World Health Organization —The recommendedcomposition of influenza virus vaccines for use inthe 1997–1998 season has been announced as thefollowing:

Trivalent vaccines are recommended, with thefollowing composition:

• an A/Wuhan/359/95(H3N2)-like strain*

• an A/Bayern/7/95(H1N1)-like strain

• a B/Beijing/184/93-like strain.**

* The most widely used vaccine strain is A/Nanchang/933/95.

** The most widely used vaccine strain is B/Harbin/7/94.

Reference: Weekly Epidemiological Record, 28 February1997.

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Essential Drugs

WHO Model FormularySince publication of the first Model List of EssentialDrugs in 1977, WHO has made a significant contri-bution to rationalizing the use of drugs. The List hasnow been revised eight times and still includesfewer than 300 drugs which are consideredsufficient to satisfy the basic health needs of themajority of the population in most countries.

Needless to say, a list alone is not sufficient to en-sure good prescribing practice, and doctors andhealth care workers are in need of information onhow to use these drugs. Access to independent andaccurate information varies widely from one countryto another, and few countries have developedsources of independent information which are fullyconsistent with their needs.

Members of the WHO Expert Committee on theUse of Essential Drugs are aware of this situationand, at the last meeting in December 1995,discussed possible options available to furtherimprove the rational use of drugs. As a conse-quence, it was recommended that a WHO ModelFormulary should be developed to complement theModel List of Essential Drugs. The purpose of sucha formulary would be to provide general informa-tion, complemented by information on the prototypedrug as it appears in the List. Countries could thenadapt this information according to their own needs— thereby providing a key element in theimplementation of rational drug use.

This work is now in hand and draft texts of theWHO Model Formulary will be published regularlyin WHO Drug Information with a view to obtaininga response to the draft material proposed forpublication. Comments on the following sectionrelated to anticonvulsants/antiepileptics should beaddressed to: Drug Selection and Information(DSI), Division of Drug Management & Policies,World Health Organization, 1211 Geneva 27,Switzerland.

Anticonvulsants/antiepilepticsTreatment should always be started with a singledrug, but the choice of an anticonvulsant can only

be made on an individual basis and will depend onthe efficacy of the drug and the patient's toleranceof treatment. If one drug fails to control the seizuresafter it has been used in full therapeutic dosage foran adequate period, or if it is not well tolerated, itshould be gradually substituted with another. Ifmonotherapy is ineffective, two drugs should begiven in combination and several regimens mayneed to be tried before the most appropriate isdetermined.

Dosage should be increased gradually until aneffective response is obtained. Where the neces-sary laboratory facilities exist, it can be useful tomeasure plasma concentrations as an aid to doseadjustment or to determine whether the patient iscomplying with treatment. Patients should ideallyremain under supervision throughout treatment.

WithdrawalTreatment is normally continued for a minimum oftwo years after the last seizure. Withdrawal shouldbe extended over a period of several months sinceabrupt withdrawal can lead to complications suchas status epilepticus. Abrupt discontinuation istherefore never warranted. Many adult patientsrelapse once treatment is withdrawn and it may bejustified to continue treatment indefinitely,particularly when the patient’s livelihood can beendangered by recurrence of a seizure.

Pregnancy and lactationThere is an increased risk of birth defects with theuse of anticonvulsants, particularly carbamazepine,valproic acid and phenytoin. In view of the risks ofneural tube and other defects, patients who maybecome pregnant should be informed of the risksand referred for advice, and pregnant patientsshould be offered counselling and antenatalscreening. To counteract the risk of neural tubedefects, adequate folate supplements are advisedfor women before and during pregnancy. In view ofthe risk of neonatal bleeding associated withcarbamazepine, phenobarbital and phenytoin,prophylactic vitamin K

1 (INN = phytomenadione) isrecommended for the neonate and the motherbefore delivery. Antiepileptic drugs can be usedsafely during lactation, with the possible exceptionof phenobarbital and ethosuximide.

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Generalized tonic-clonic, simple partialand complex partial seizuresPhenobarbital, phenytoin, carbamazepine andvalproic acid are widely used in the treatment ofthese conditions. However, each of these drugs isassociated with dose-related and idiosyncraticadverse effects and monitoring of haematological,hepatic and renal function is advised.

Absence seizuresBoth ethosuximide and valproic acid are widelyused in the treatment of absence seizures and areusually well accepted. However, ethosuximide can,rarely, cause lupus erythematosus and psychoseswhich call for immediate, but cautious, discontinu-ation. Absence seizures are commonly associatedwith tonic-clonic seizures and valproic acid ispreferred since it is effective in both disorders.

Tonic, atonic and atypical absence seizuresPhenobarbital or phenytoin is widely used for tonicseizures, valproic acid or clonazepam for atonicseizures, and clonazepam for atypical absenceseizures.

Myoclonic seizuresValproic acid is widely used for juvenile myoclonicseizures. Although this drug is the most effective, itis associated with a high relapse rate and it is oftennecessary to continue therapy indefinitely. Othermyoclonic seizures are often resistant to treatmentand some do not have an epileptic basis. Valproicacid or clonazepam can be of value in this caseand other antiepileptic drugs may be useful inintractable cases. Both drugs are generally wellaccepted, although tolerance to clonazepam hasbeen reported.

Infantile spasm (infantile myoclonic epilepsy)Infantile spasms, which are often associated withsevere brain damage, can be resistant to anti-epileptic drugs. However, they may be responsiveto intramuscular adrenocorticotrophic hormone(ACTH) which holds advantage over cortico-steroids. Clonazepam is sometimes of value inresistant cases.

Febrile convulsionsFebrile convulsions usually respond to spongingwith tepid water and antipyretics such as paraceta-mol. Rectal diazepam is needed for severe attacks.Prolonged treatment is advisable when repeatedseizures occur during the first 18 months of life orwhen the child has evident neurological abnormal-ities. Phenobarbital is used for this purpose but

careful clinical monitoring and dosage adjustmentare necessary to minimize the risk of adverseeffects. Valproic acid, although also effective, is notrecommended because of the greater risk ofhepatotoxicity in this age group. Alternatively,intermittent prophylaxis with rectal diazepam duringfebrile episodes can also be effective.

Status epilepticusStatus epilepticus is a medical emergency whichcarries a high mortality rate. Maintenance of theairway and assisted ventilation are crucial evenwhen the seizures are controlled, since the drugsused in its management may also depress res-piration. Unresponsive patients require intensivecare. Intravenous diazepam or clonazepam is ofteneffective. Diazepam, which is rapid-acting, can beadministered first and should be followed imme-diately by phenytoin which has a longer-actingeffect. When cannulation is impossible, diazepammay be administered rectally. Intravenous pheno-barbital is also effective and is preferred whenstatus epilepticus occurs during withdrawal of oralphenobarbital. If seizures continue despite treat-ment, general anaesthesia may be required. Theunderlying cause must be identified and remediedin all cases.

CARBAMAZEPINEAnticonvulsant agentScored tablets: 100 mg, 200 mg

Uses: Generalized tonic-clonic, simple partial andcomplex partial seizures.

Dosage: Adults: Initially 100 mg twice daily, or 50mg twice daily in frail or elderly patients. This isincreased gradually according to response, to amaximum of 2 g daily in divided dosage. Excep-tionally, even higher doses have been used.Children: Daily maintenance doses usually liebetween 10 and 20 mg/kg. Twice daily dosage isoften adequate but six or eight-hourly administra-tion is advisable at higher dosages to avoid largefluctuations in plasma concentrations. Therapeuticplasma concentrations are in the region of 4–12mg/ml (17–50 micromol/l). Lower blood levels areattained when carbamazepine is used with pheny-toin or phenobarbital as a result of increased ratesof inactivation of the liver.

Contraindications: Known hypersensitivity to car-bamazepine or tricyclic antidepressants; atrio-ventricular conduction abnormalities, concomitantuse with monoamine oxidase (MAO) inhibitors orwithin two weeks of using the latter.

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Precautions: See notes on page 23 for pre-cautions concerning pregnancy. The white bloodcell count should be monitored during the firstmonth. Patients should be asked to report sorethroat or fever to the physician since this may beindicative of bone-marrow depression and maymean that medication should be changed.

Adverse effects: Dose-related reactions includegastrointestinal intolerance, dryness of the mouth,drowsiness, dizziness, blurred vision, diplopia andataxia. Frequently, cutaneous eruptions and,rarely, more serious skin conditions such asStevens-Johnson syndrome occur. Severe idiosyn-cratic reaction usually presents with dermatitis, inwhich case hospitalize the patient immediately.Rarely, bone-marrow depression or hepaticdysfunction is reported.

Drug interactions: Plasma concentrations ofclonazepam, ethosuximide, phenytoin and valproicacid may be lowered. Other important interactionswill appear in tabulated form in the appendix of thepublished edition of the model formulary.

CLONAZEPAMAnticonvulsant agent.Scored tablets: 0.5 mg

Uses: Atonic and myoclonic seizures, atypicalabsence seizures, absence seizures resistant toethosuximide or valproic acid; infantile spasms.

Dosage:Adults: Initially 1 mg at night for 4 days or 0.5 mgin frail or elderly patients. The dosage is increasedgradually over 2–4 weeks to 4–8 mg daily in divid-ed doses depending on the patient’s response.Children under 1 year: 0.25 mg initially, and up to0.5–1 mg daily. Children 1–5 years: 0.25 mg initiallyand up to 1–3 mg daily. Children 5–12 years: 0.5mg initially and up to 3 mg daily.

Contraindications: Known hypersensitivity tobenzodiazepines.

Precautions: Use with caution in patients withrenal or hepatic impairment. Avoid alcohol. Do notoperate machinery. Avoid abrupt withdrawalbecause of status epilepticus.

Adverse effects: Frequently drowsiness, lethargy,ataxia and, less frequently, aggression, irritabilityand mental changes are reported. Rarely, blooddisorders and abnormal hepatic function tests orexcessive salivation may occur.

Drug interactions: These will appear in tabulatedform in the appendix of the published edition of themodel formulary.

DIAZEPAMAnticonvulsant agentInjection: 5 mg/ml in 2-ml ampoule(intravenous or rectal)

Uses: Status epilepticus, emergency manage-ment of recurrent seizures including febrile con-vulsions, seizures associated with poisoning anddrug withdrawal, symptomatic treatment of alcoholwithdrawal.

Dosage:Status epilepticusAdults: Initially 10–20 mg (0.15–0.3 mg/kg) by slowintravenous injection at a rate of 5 mg per minute.This can be repeated, if necessary to a maximum of50 mg over a 60-minute period. In resistant cases,a slow IV infusion of up to 3 mg/kg over a 24-hourperiod may be necessary provided that facilities forassisted ventilation in the event of hypotension anddysrhythmia are immediately available.Children: 0.2–0.3 mg/kg by slow intravenous in-fusion or, as necessary, to a maximum of 5 mg aday in children less than 3 years and 10 mg a dayin children over 3 years.Diazepam may alternatively be administered rec-tally at a dosage of 0.2–0.4 mg/kg, up to a maxi-mum of 10 mg a day, using a cannula or catheterfitted to the syringe.

Emergency treatment of rapidly recurrent (orclosely spaced) seizures.Adults: 10–20 mg (0.15–0.3 mg/kg) by slow intra-venous injection or rectally.Children: (1–3 years) and elderly patients: 0.2–0.3mg/kg by slow intravenous injection or rectally.

Febrile convulsions0.5 mg/kg administered rectally. This may be re-peated, if necessary, after 30 minutes up to a maxi-mum of 10 mg a day.

Seizures associated with poisoning, drug andalcohol withdrawal.10 mg IV repeated, if necessary, after 4 hours.

Contraindications, precautions and adverseeffects will appear in the section on psychothera-peutic drugs of the published edition of the modelformulary.

Essential Drugs

26


Drug interactions: These will appear in tabulatedform in the appendix of the published edition of themodel formulary.

ETHOSUXIMIDEAnticonvulsant agentCapsule: 250 mgSyrup: 250 mg/ 5 ml

Uses: Generalized absence seizures

Dosage: The optimum plasma concentration liesbetween 50 and 100 mg/ml (350 and 700 micro-mol/l). Inadequate dosage is the major cause oftherapeutic failure.Adults and children over 6 years: Initially, 500 mgdaily, subsequently adjusted according to response.Increments should be made in steps of 250 mgevery 4 to 7 days to a maximum of 2 g daily, or untilan adequate response is obtained. The daily main-tenance dose is usually within the range 20–30 mg/kg. Amounts of 1g or more should be taken in 2 ormore divided doses.Children under six years: Infants and young child-ren metabolize ethosuximide more rapidly thanadults. They therefore require relatively higher andmore frequent dosage: initially, 10 mg/kg dailyadjusted as above according to requirements to amaximum of 40 mg/kg daily.

Contraindications: Hypersensitivity to ethosux-imide, mesuximide or phensuximide.

Precautions: Monitor plasma concentrations inpatients with impaired hepatic or renal function.See notes on page 23 for precautions concerningpregnancy.

Adverse effects: Gastrointestinal disturbancesinclude anorexia, hiccoughs, nausea and vomiting,epigastric pain (particularly during the initial phasesof treatment); weight loss, drowsiness, dizziness,ataxia, headache, depression and mild euphoriamay be troublesome. Rarely, psychotic states,rashes including erythema multiforme and the moreserious Stevens Johnson syndrome, lupus erythe-matosus, disturbances of liver function and haema-tological disorders, including leukopenia, agranulo-cytosis and bone-marrow depression have beenreported.

Drug interactions: Plasma concentrations ofphenytoin may be raised. Other interactions willappear in tabulated form in the appendix of thepublished edition of the model formulary.

PHENOBARBITALAnticonvulsant agentInjection: 60 mg/mlTablet: 15 –100 mgElixir: 15 mg /5ml

Uses: Generalized tonic-clonic seizures, simplepartial and complex partial seizures, neonatalseizures and febrile seizures, status epilepticusoccurring only during withdrawal of phenobarbital,in patients unresponsive to diazepam or phenytoin.

Dosage:All indications other than status epilepticus.Oral dosage forms.The optimum plasma concentration usually liesbetween 10 and 30 mg/ml (45 and 130 mmol/l).Adults: Initially 2 mg/kg daily (to a maximum of 100mg) as a single dose at night. If necessary, thismay be increased incrementally, according to theresponse, to a maximum of 6 mg/kg daily in 2 ormore divided doses.Children: Initially 3–4 mg/kg, but in infants up to8 mg/kg may be required in order to achieve thera-peutic plasma concentrations.

Status epilepticus.Injectable dosage formsAdults and children: 10–20 mg/kg is infused intra-venously at a rate not exceeding 30 mg per minuteuntil an adequate response is obtained. Careshould be taken that hypotension and respiratorydepression do not occur. In general, children andneonates tend to require higher dosages. Intra-venous therapy should be discontinued as soon asseizures are controlled.

Contraindications: Hypersensitivity to barbitur-ates, MAO inhibitors. Acute intermittent porphyria.

Precautions: Avoid driving or operating machinerybecause of sedative effects. The use of pheno-barbital in children needs to be considered withregard to the possibility of behavioural changes andhyperactivity. Monitor dosage in the elderly and inpatients with reduced respiratory capacity or renalinsufficiency. See notes on page 23 for precautionsconcerning pregnancy.

Adverse effects: Dose-related reactions includesedation, nystagmus and ataxia. Impairment oflearning ability and understanding, irritability, be-havioural problems and hyperactivity may occur inchildren. Commonly, confusion in the elderly,rashes and other signs of allergy may occur.

Essential Drugs

27


Rarely, serious hypersensitivity reactions includingexfoliative dermatitis. Occasionally, megaloblasticanaemia and osteomalacia (resulting from pro-longed therapy), phenobarbital dependence, statusepilepticus (on discontinuation of treatment). As aresult of local extravasation, extensive necrosisand, during injection, spasm, severe pain andpossibly gangrene. On rapid intravenous injection,respiratory depression or hypotension.

Drug interactions: Plasma concentrations ofcarbamazepine, ethosuximide, phenytoin andvalproic acid may be lowered. Other interactionswill appear in tabulated form in the appendix of thepublished edition of the model formulary.

PHENYTOINAnticonvulsant agentCapsule or tablet: 25 mg, 50 mg, 100 mg(sodium salt)Injection: 50 mg (sodium salt)/ml in 5-ml vial

Uses: Generalized tonic-clonic, simple partial andcomplex partial seizures; status epilepticus.

Dosage:All indications other than status epilepticusOral dosage formsAdults: Initially 4–5 mg/kg/day. This is frequentlygiven as 100 mg two or three times daily. However,many seizures in adult patients can be adequatelycontrolled on one daily dose. This should beincreased by 25 mg daily at two-weekly intervals,according to the response, to a maximum of about8 mg/kg daily.Children: Initially 5 mg/kg daily administered in twodivided doses and increased gradually to amaximum of 8 mg/kg.The optimum plasma concentration usually liesbetween 10 and 20 mg/ml (40–80 micromol/l).Protein binding is reduced in neonates and patientswith impaired renal or hepatic function and lowerplasma concentrations are generally effective.

Status epilepticus:Injectable dosage forms:Administration of phenytoin is normally preceded byan initial IV injection of diazepam.Adults: 15–18 mg/kg as a loading dose by IV injec-tion at a rate not exceeding 50 mg per minute. Anadditional 5 mg/kg may be given after 12 hours ifnecessary.Children: 10–15 mg/kg by IV injection at a rate of0.5–1.5 mg/kg per minute. In refractory cases, use

of IV barbiturates, rectal paraldehyde or generalanaesthesia should be considered.

Contraindications: Hypersensitivity to hydantoins.Avoid parenteral phenytoin in patients with sinusbradycardia, sino-atrial block, or second or thirddegree atrioventricular block.

Precautions: Diplopia and ataxia are indications forlowering dosage. Withdraw or reduce dosage at arate not greater than 25 mg in any 7-day period.Preferably, a plan should be adopted to phase outdosage over a 6-month period. See notes on page23 for precautions concerning pregnancy.

Adverse effects: Gastric intolerance, sleepless-ness and agitation are sometimes troublesome(during the initial phases of treatment), dose-relatedfunctional neurological disturbances including seda-tion, confusion, blurred vision, ataxia, nystagmus,diplopia, vertigo, cerebellar-vestibular symptoms,behavioural disturbances and hallucinations, non-dose-related adverse effects include mucocuta-neous changes (gingival hyperplasia, skin erup-tions, coarse facies, hirsutism), neurologicalchanges (peripheral neuropathy, choreiform move-ments, impaired learning and understanding),osteomalacia and occasionally rickets associatedwith reduced plasma calcium levels, hyper-glycaemia, megaloblastic anaemia, hypersensitivityreactions including erythema, generalized lymph-node enlargement and, very rarely, Stevens-Johnson syndrome, systemic lupus erythematosus,hepatic necrosis, nephrosis and polyarthropathy,haematological reactions including leukopenia andrarely, thrombocytopenia, agranulocytosis andbone-marrow depression; hypotension andventricular dysrhythmias (resulting from parenteraladministration).

Drug interactions: Plasma concentrations may belowered of carbamazepine, clonazepam, ethosux-imide, and valproic acid. Other interactions willappear in tabulated form in the appendix of thepublished edition of the model formulary.

VALPROIC ACIDAnticonvulsant agentEnteric coated tablet: 200 mg, 500 mg(sodium salt)

Uses: Generalized absence seizures; generalizedtonic-clonic, simple partial and complex partialseizures, myoclonic and atonic seizures.

Essential Drugs

28


Dosage:All indicationsAdults: Initially 15 mg/kg in one or two divideddoses increased, according to the response, by200 mg daily at twice weekly intervals. Daily dosesin excess of 30 mg/kg are rarely needed.Infants and children: Initially 15 mg/kg daily individed doses, increasing according to response.Rarely, daily doses of more than 30 mg/kg areneeded in children and infants may require up to40 mg/kg. The effective plasma concentration is inthe region of 40–100 mg/ml (280–690 micromol/l).However, the correlation between therapeuticefficacy and plasma levels is poor and the latterhave limited value in management, except as anindication of noncompliance or to monitor theeffects of a change in dosage or the addition ofanother drug to the regimen.

Contraindications: Hypersensitivity to valproicacid, pre-existing impaired hepatic or pancreaticfunction, bleeding disorders. First trimesterpregnancy.

Precautions: Increased risk of neural tube defectsif given during the first trimester of pregnancy. See

notes on page 23 for other precautions concerningpregnancy. Because of the risk of hepatic failure,which can be fatal, hepatic function should bemonitored and the drug withdrawn if there are signsof loss of seizure control, malaise, weakness,lethargy, facial oedema and vomiting. Withdraw thedrug immediately if spontaneous bruising or bleed-ing indicative of thrombocytopenia occurs. Monitorthe bleeding time and platelet count before surgeryor anticoagulant administration.

Adverse effects: Rarely, potentially fatal hepaticfailure, thrombocytopenia, pancreatitis; otheradverse effects include weight gain resulting fromincreased appetite, partial or complete hair loss,tremor, paraesthesia, drowsiness and ataxia;commonly, sedation (when used with pheno-barbital).

Drug interactions: Plasma concentrations ofethosuximide, phenobarbital and phenytoin may beraised. Other interactions will appear in tabulatedform in the appendix of the published edition of themodel formulary.

Essential Drugs

29


Recent Publications

A standard list of terms was therefore drawn upafter a comparison had been made of terminologiesused around the world. Despite the diversity of thereferences, it soon became evident that the vastmajority of terms could be traced back to a dozenor so internationally recognized reference sources.It furthermore became apparent that nuances inmeaning were usually attached to the terms usedby individuals so that while concepts were largelycomparable, the specific terms were no longersynonymous. As a consequence, a cumulative listof terms with an accompanying grouping byconcept was felt necessary. In each conceptualgroup, a candidate preferred term has beenselected.

The current list therefore features preferred terms,printed in bold, arranged in alphabetical order inEnglish, French and Spanish. The correspondingequivalents are listed and any synonyms — as theyappear in the literature — are set out below. Simplerules were followed to ensure maximum consis-tency in the selection of preferred terms. To beconcise, single-word terms were chosen wheneverpossible. For example, the action exerted onvarious receptors is described as “agonist” or“antagonist”. “Inhibitor” is used to describe theaction on enzymes, and “hormone inhibitor” and“enzyme inhibitor” refer to general action. Specifichormone or enzyme names should be used todescribe the corresponding action. Finally, thesystemic impact of a given drug is implied by itsspecific therapeutic use. Additional qualifications inthe form of adjectives may be added, as necessary,for further accuracy.

Pharmacological action and therapeutic use of drugs —list of terms, (WHO/PHARM/97.594) can be obtained freeof charge in English, French and Spanish from theProgramme on International N onproprietary Names,Division of Drug Management & Policies, WHO, 1211Geneva 27, Switzerland.

Nordic statistics on medicines:1993–1995National consumption statistics have been pub-lished for the Nordic countries by the NordicCouncil on Medicines (NLN) covering Denmark,Finland, Iceland, Norway and Sweden. Theirpurpose is to make data on drug consumption moregenerally available. The new publication providescomparative data between countries, and illustratestrends in drug consumption with emphasis onnational differences. In order to give a perspectiveto the data, the statistics are compared to those ofAustralia, Estonia and Spain.

NLN Publication No. 43. Nordiska Läkemedelsnämnden,Nordic Council on Medicines, Uppsala, Sweden.ISBN 91-86432-42-7

Pharmacological action andtherapeutic use of drugs –list of termsSince 1989, members of the WHO Expert AdvisoryPanel on the International Pharmacopoeia andPharmaceutical Preparations designated to dealwith the selection of INNs have recognized that theterms describing the pharmacological action andtherapeutic use of pharmaceuticals were in need ofharmonization.

A review of the situation has indicated that the lackof a unique, generally accepted reference list canlead to use of various terminologies originating fromdifferent sources of information. This diversity isreflected in inconsistencies in numerous documentsand information material issued such as drugmonitoring reports and newsletters, and many otherdocuments and publications related to pharma-ceuticals.

30


Please note that henceforth lists ofrecommended International Nonproprietary

Names (INNs) will appear twice yearly, inalternance with the proposed INNs.

An added feature of the lists will be theinclusion of graphic formulae.

WHO Programme on International NonproprietaryNames (INN) for Pharmaceutical Substances

Division of Drug Management & PoliciesWorld Health Organization

1211 Geneva 27, Switzerlande mail: [email protected]

Fax: +41 22 791 0746Telephone: +41 22 7913636

31

WHO Drug Information, Vol. 11, No. 1, 1997 RECOMMENDED INN: List 37

International Nonproprietary Names for Pharmaceutical Substances (INN) RECOMMENDED International Nonproprietary Names (Rec. INN): List 37

Notice is hereby given that, in accordance with paragraph 7 of the Procedure for the Selection of Recommended International Nonproprietary Names for Pharmaceutical Substances [Off. Rec. Wld Health Org. 1955, 60, 3 (Resolution EB15.R7): 1969. 173, 10 (Resolution EB43.R9)], the following names are selected as Recommended International Nonproprietary Names. The inclusion of a name in the lists of Recommended International Nonproprietary Names does not imply any recommendation of the use of the substance in medicine or pharmacy. Lists of Proposed (1-73) and Recommended (1-35) International Nonproprietary Names can be found in Cumulative List No. 9. 1996.

Dénominations communes internationales des Substances pharmaceutiques (DCI)

Dénominations communes internationales RECOMMENDÉES (DCI Rec): Liste 37

Il est notifié que, conformément aux dispositions du paragraphe 7 de la Procédure à suivre en vue du choix de Dénominations communes internationales recommandées pour les Substances pharmaceutiques [Actes off. Org. mond. Santé, 1955, 60, 3 (résolution EB15.R7); 1969.173, 10 (résolution EB43 R9)] les dénominations ci-dessous sont mises à l'étude par l'Òrganisation mondiale de la Santé en tant que dénominations communes internationales proposées. L'inclusion d'une dénomination dans les listes de DCI proposées n'implique aucune recommandation en vue de l'utilisation de la substance correspondante en médecine ou en pharmacie. On trouvera d'autres listes de Dénominations communes internationales proposées (1-73) et recommandées (1-35) dans la Liste récapitulative No. 9, 1996.

Denominaciones Comunes Internacionales para las Sustancias Farmacéuticas (DCI)

Denominaciones Comunes Internacionales RECOMENDADAS (DCI Rec): Lista 37

De conformidad con lo que dispone el párrafo 7 del Procedimiento de Selección de Denominaciones Comunes Internacionales Recomendadas para las Sustancias Farmacéuticas [Act. Of. Mund. Salud, 1955, 60, 3 (Resolución EB15.R7); 1969,173,10 (Resolución EB43.R9)], se comunica por el presente anuncio que las denominaciones que a continuación se expresan han sido seleccionadas como Denominaciones Comunes Internacionales Recomendadas. La inclusión de una denominación en las listas de las Denominaciones Comunes Recomendadas no supone recomendación alguna en favor del empleo de la sustancia respectiva en medicina o en farmacia. Las listas de Denominaciones Comunes Internacionales Propuestas (1-73) y Recomendadas (1-35) se encuentran reunidas en Cumulative List No. 9. 1996.

RECOMMENDED INN: List 37 WHO Drug Information, Vol 11, No. 1, 1997

MODIFICATION

This is to inform you that WHO will henceforth publish lists of recommended INNs twice a year.

This new measure is intended to provide information as soon as possible on the names that have reached the status of recommended INNs.

MODIFICATION

L'OMS publiera désormais les listes des DCI recommandées deux fois par an.

Cette nouvelle mesure est destinée à informer les lecteurs dès que possible au sujet des dénominations ayant atteint le statut de DCI recommandée.

MODIFICACION

De ahora en adelante, la OMS publicará dos veces por año las listas de DCI recomendadas.

Con esta nueva medida se quiere facilitar lo antes posible la información sobre las denominaciones a las que se ha asignado la condición de DCI recomendadas.

32


Latin, English, French, Spanish Recommended INN

DCI Recommandée

DCI Recomendada

Chemical name or description; Molecular formula; Graphic formula

Nom chimique ou description; Formule brute; Formule développée

Nombre químíco o descripción; Fórmula empírica; Fórmula desarrollada

agomelatinum

agomelatine

agomélatine

agomelatina

N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide

N-[2-(7-méthoxynaphtalén-1-yl)éthyl]acétamide

N-2-(7-rnetoxi-1-naftil)etiI]acetamida

C15H17NO2

alatrofloxacinum alatrofloxacin

alatrofloxacine

alatrofloxacino

7-[(1R,5S,6s)-6-[(S)-2-[(S)-2-aminopropionamido}propianamido]-3-azabicyclo[3.1.0]hex-3-yl]-1-(2.4-difluorophenyI)-6-fluoro-1,4-dihydro-4-oXo-1,8-naphthyridine-3-carboxylic acid

acide 7-[(1R,5S,6s)-6-[[(2S)-2-[[(2S)-2-aminopropanoyl]amino]propanoyl]= amino]-3-azabicyclo[3.1.0]hex-3-yl]-1-(2,4-difluorophényl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphtyridine-3-carboxyIique

ácido 7-[(1R.5S,6s)-6-[(S)-2-[(S)-2-aminopropionamido]prapionamido]-3-azabiciclo[3.1.0]hex-3-il]-1-(2.4-difluorofenil)-6-fluoro-1,4-dihidro-4-oxo-1.8-naftindina-3-carboxílico

C26H25F3N6O5

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RECOMMENDED INN: List 37 WHO Drug Information, Vol. 11, No. 1, 1997

aripiprazolum aripiprazole

aripiprazole

aripiprazol

7-[4-[4-(2.3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril

7-[4-[4-(2.3-dichlorophényl)pipérazin-1-yl]butoxy]-3,4-dihydroquinoléin-2(1H)-one

7-[4-[4-(2,3-diclorofenil)-1-piperazinil]butoxi]-3,4-dihidrocarbostiril

C23H27Cl2N3O2

arofyllinum

arofylline

arofylline

arofilina

3-(p-chlorophenyl)-1-propylxanthine

3-(4-chlorophényl)-1 -propyl-3,7-dihydro-1H-purine-2,6-dione

3-(p-clorofenil)-1 -propilxantina

C 1 4 H 1 3 CIN 4 O 2

atiprimodum

atiprimod

atiprirnod

atiprimod

2-[3-(diethylamino)propyl]-8,8-dipropyl-2-azaspiro[4.5]decane

3-[8,8-dipropyl-2-azaspiro[4 5]déc-2-yl]-N,N-diéthylpropan-1-amine

2-[3-(dietilamino)propil]-8,8-dipropil-2-azaspiro[4.5]decano

C22H44N2

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WHO Drug Information, Vol. 1 1 , No. 1, 1997 RECOMMENDED INN List 37

bectumomabum bectumomab

bectumomab

bectumomab

immunoglobulin G 2a (mouse monoclonal IMMU-LL2 Fab' fragment γ-chain anti-human antigen CD 22), disulfide with mouse monoclonal IMMU-LL2 light chain

immunoglobuline G 2a (chaîne γ du fragment Fab' de l'anticorps monoclonal de souris IMMU-LL2 anti-antigène CD 22 humain), disulfure avec la chaîne légère de l'anticorps monoclonal de souris IMMU-LL2

inmunoglobulina G 2a (cadena γ del fragmento Fab' del anticuerpo monoclonal de ratón IMMU-LL2 anti-antígeno CD 22 humano), disulfuro con la cadena ligera del anticuerpo monoclonal de ratón IMMU-LL2

beloxepinum

beloxepin

béloxépine

beloxepina

(±)-cis-1,3,4,13b-tetrahydro-2,10-dimethyldibenz[2.3:6,7]oxepino= [4,5-c]pyridin-4a(2H)-ol

(4aRS,13bRS)-2,10-diméthyl-1.3,4,13b-tétrahydrodibenzo[2,3:6,7]oxépino= [4,5-c]pyridin-4a(2H)-ol

(±)-cis-1,3,4.13b-tetrahidro-2.10-dimetiIdibenz[2.3:6,7]oxepino= [4,5-c]piridin-4a(2H)-ol

C19H21NO2

bemiparinum natricum bemiparin sodium

bémiparine sodique

Sodium salt of depolymerized heparin obtained by alkaline degradation of quaternary ammonium salt of heparin from pork intestinal mucosa; the majority of the componen ts have a 2-O-sulfo-4-enepyranosuronic acid structure at the non-reducing end and a 2-N.6-O-disulfo-o-glucosamine structure at the reducing end of their chain; the average relative molecular mass is about 3600 (3000 to 4200); the degree of sulfatation is about 2 per disaccharidic unit.

Sel de sodium d'héparine dépolymérisée obtenue par fragmentation alcaline d'un sel d'ammonium quaternaire d'héparine de muqueuse intestinale de porc. La majorité des composants présentent une structure acide 2-O-sulfo-4-ènepyranosuronique à l'extrémité non réductrice et une structure 2-N,6-O-disulfo-D-glucosamine à l'extrémité réductrice de leur chaîne La masse moléculaire relative moyenne est voisine de 3600 (3000 à 4200). Le degré de sulfatation est voisin de 2 par unité disaccharide

and enantiomer et l'énantiomère y enantiómero

35


bemiparina sódica Sal de sodio de heparina despolimerizada obtenida por fragmentación alcalina de una sal de amonio cuaternario de heparina de mucosa intestinal de cerdo. La mayoría de los componentes presentan una estructura ácido 2-O-sulfo-4-enopiranosurónico en el extremo no reductor y una estructura 2-N.6-O-disulfo-D-glucosamina en el extremo reductor de su cadena. La masa molecular relativa media es aproximadamente 3600 (de 3000 a 4200). El grado de sulfatación es aproximadamente 2 por unidad de disacárido.

cemadotinum cemadotin

cémadotine

cemadotina

N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-N-benzyl-L-prolinamide

(N,N-diméthyl-L-valyl)-L-valyl-(N-méthyl-L-valyl)-L-prolyl-(N-benzyl-L-prolinamide)

N,N-dimetil-L-valil-L-valil-N-metil-L-valil-L-prolil-N-bencil-L-prolinamida

C35H56N6O5

choriogonadotropinum alfa choriogonadotropin alfa

choriogonadotropine alfa

coriogonadotropina alfa

human chorionic gonadotropin (protein moiety reduced), glycoform α α-subunit: chorionic gonadotropin (human α-subunit protein moiety reduced) β-subunit: chorionic gonadotropin (human β-subunit protein moiety reduced)

gonadotropine chorionique humaine (partie protéique réduite), forme glycosylée α sous-unité α gonadotropine chorionique (partie protéique réduite de la sous-unité α humaine) sous-unité β: gonadotropine chorionique (partie protéique réduite de la sous-unité β humaine)

gonadotropina coriónica humana (fracción proteica reducida), glucoforma α subunidad α: gonadotropina coriónica (fracción proteica reducida de la subunidad α humana) subunidad β: gonadotropina coriónica (fracción proteica reducida de la subunidad β humana)

α: C437H682N122O134S13

β: C668H1090N196O203S13

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WHO Drug Information Vol. 11, No. 1, 1997 RECOMMENDED INN. List 37

APDVQDCPEC TLQENPFFSQ PGAPILQCMG CCFSRAYPTP LRSKKTMLVQ KNVTSESTCC VAKSYNRVTV MGGFKVENHT ACHCSTCYYH KS

SKEPLRPRCR PINATLAVEK EGCPVCITVN TTICAGYCPT MTRVLQGVLP ALPQVVCNYR DVRFESIRLP GCPRGVNPVV SYAVALSCQC ALCRRSTTDC GGPKDHPLTC DDPRFQDSSS SKAPPPSLPS PSRLPGPSDT PILPQ

clevidipinum

clevidipine

clévidipine

clevidipino

(±)-hydroxymethyl methyl 4-(2,3-dichIorophenyl)-1,4-dihydro-2.6-dimethyl-3,5-pyridinedicarboxylate, butyrate (ester)

(4RS)-4-(2,3-dichlorophény[)-2,6-diméthyl-1.4-dihydropyndine-3,5-dicarboxylate de bulanoyloxyméthyle et de méthyle

(±)-4-(2,3-diclorofenil)-1,4-dihidro-2.6-dimetil-3,5-piridinadicarboxilato de butiriloximetilo y metilo

C21H23CI2NO6

and enantiomer al l'énantiomère y enantiómero

domitrobanum

domitroban

domitroban

domitrobán

(+)-(Z)-7-[(1R,2S,3S,4S)-3-benzenesulfonamido-2-norborny]]-5-heptenoic acid

acide (+)-(Z)-7-[(1R,2S,3S,4S)-3-[(phénylsulfonyl)amino]bicyclo[2.2.1]hept-2-yl]hept-5-énoique

ácido (+)-(Z)-7-[(1R,2S,3S,4S)-3-bencensulfonamido-2-norbornil]-5-heptenoico

C20H27NO4S

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RECOMMENDED INN: List 37 WHO Drug Information, Vol. 11, No 1, 1997

donepezilum donepezil

donépézil

donepezilo

(±)-2-[(1-benzyl-4-piperidyl)methyl]-5,6-dimethoxy-1-indanone

(2RS)-2-[(1-benzylpipéridin-4-yl)méthyl]-5,6-diméthoxy-2,3-dihydro-1H-indén-1-one

(±)-2-[(1-bencil-4-piperidil)metil]-5,6-dimetoxi-1-indanona

C24H29NO3

and enantiomer et l'énantiomère y enantiómero

dronedaronum

dronedarone

dronédarone

dronedarona

N-[2-butyl-3-[p-[3-(dibutylamino)propoxy]benzoyl]-5-benzofuranyl]= methanesulfonamide

N-[2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]benzofuran-5-yl]méthanesulfonamide

N-(2-butil-3-[p-[3-(dibutilamino)propoxi]benzoil]-5-benzofuranil]= metanosulfonamida

C31H44N2O5S

ecamsulum

ecamsule

écamsule

ecamsul

(±)-(3E,3'E)-3,3'-(p-phenylenedímethylidyne)bis[2-oxo-10-bornanesulfonic acid]

acide [[1,4-phénylènediméthylidyne]bis[(3E,3'E)--7,7--dírriéthyl-2-oxobicyclo[2.2 1]heptan-3,1-diyl]]diméthanesulfonique

(±}-(3E,3'E)-3,3'-(p-fenilenodimetilidino)bis[ácido 2-oxo-10-bornanosulfónico]

C28H34O8S2

38


efepristinum efepristin

éfépnstine

efeprístina

N-[(6R,9S,10R,13S,15aS,22S,24aS)-6-ethyldocosahydro-10,23-dimsthyl-22-[p-(methylamino)benzyl]-5,8,12,15,17,21,24-heptaoxo-13-phenyl-12H-pyirido[2,1-f]pyrrolo[2,1-/][1,4,7,10,13,16]oxapentaazacyclononadecin-9-yl]-3-hydroxypicolanamide

N-[(6R,9S,10R,13S,15aS,22S,24aS)-6-éthyI-10,23-diméthyl-22-[4-(méthyl= amino)benzyl]-5,8,12,15,17,21,24-heptaoxo-13-phény]docosahydro-12H-pyrido[2,1-f]pyrrolo[2,1-/][1,4,7,10,13,16]oxapentaazacyclonanadécén-9-yl]-3-hydroxypyridine-2-carboxamide

N-[(6R,9S,10R,13S,15aS,22S,24aS)-6-8tildocosahidro-10,23-dimetil-22-[p-(metilamino)bencil]-5,8,12,15,17,21,24-heptaoxo-13-fenil-12H-pirido[2,1-f]pirrolo[2,1 -/][1,4,7,10.13,16]oxapentaazaciclononadecin-9-il]-3-hidroxipicolinamida

C 4 4 H 5 2 N 8 O 1 0

elinafidum elinafide

élinafide

elinafida

N,N '-[trimethylenebis(iminoethylene)]dinaphthalimide

2,2'-[propane-1.3-diylbis(iminoéthylène)]bis[1H-benzo[de]isoquinoléine-1,3(2H)-dione]

N,N'-[trimetilenobis(iminoetiIeno)]dinaftalirnida

C31H28N4O4

39


filaminastum

filaminast

filaminast

filaminast

3'-(cyclopentyloxy)-4'-methoxyacetophenone (E)-O-carbamoyloxime

1-[3-(cyclopentyloxy)-4-méthoxyphényl]éthanone (E)-O-carbamoyloxime

3'-(ciclopentiloxi)-4'-metoxiacetofenona (E)-O-carbamoiloxima

C15H20N2O4

flibanserinum flibanserin

flibansérine

flibanserina

1-[2-[4-(α,α,α-trifluoro-m-tolyl)-1-piperazinyl]ethyl]-2-benzimidazolinone

1 -[2-[4-[3-(trifluorométhyl)phényl]pipérazin-1-yl]éthyl]-1,3-dihydro-2H-benzimidazol-2-one

1-[2-[4-(α,α,α-trifluoro-m-tolil)-1-piperazinil]etil]-2-benzimidazolinona

C20H21F3N4O

fludarabinum

fludarabine

fludarabine

fludarabina

9-β-D-arabinofuranosyl-2-fluoroadenine

9-(β-D-arabinofuranosyl)-2-fluoro-9H-purin-6-amine

9-β-D-arabinofuranosil-2-fluoroadenina

C10H12FN5O4

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WHO Drug information, Vol . 11, No. 1, 1997 RECOMMENDED INN List 37

fomivirsenum fomivirsen

fomivirsen

fomivirseno

foropafantum

foropafant

foropafant

foropafant

2'-deoxy-P-thioguanylyl-(5'→3')-2'-deoxy-P-thiocytidylyl-(5'→3')-2'-deoxy-P-thioguanylyl-(5'→3')-P-thiothymidylyl-(5'→3')-P-thiothymidylyI-(5'→3')-P-thiothymidylyl-(5'→3')-2'-deoxy-P-thioguanylyl-(5'→3')-2'-deoxy-P-thiocytidylyl-(5'→3')-P-thiothymidylyl-(5'→3')-2'-deoxy-P-thiocytidylyl-(5'→3')-P-thiomymidylyl-(5'→3')-P-thiothymidylyl-(5'→3')-2'-deoxy-P-thiocytidylyl-(5'→3')-P-thiothymidylyl-(5'→3')-P-thiothymidyiyl-(5'→3')-2'-deoxy-P-thiocytidylyl-(5'→3')-P-thiothymidylyl-(5'→3')-P-thiothymidylyl-(5'→3')-2'-deoxy-P-thioguanylyl-(5'→3')-2'-deoxy-P-thiocytidylyl-(5'→3')-2'-deoxyguanosine

2'-désoxy-P-thioguanylyl-(5'→3')-2'-désoxy-P-thiocytidylyl-(5'→3')-2'-désoxy-P-thioguanylyl-(5'→3')-P-thiothymidyIyl-(5'→3')-P-thiothymidylyl-(5'→3')-P-thiothymidylyl-(5'→3')-2-désoxy-P-thioguanylyl-(5'→3')-2-désoxy-P-thiocytidylyl-(5'→3')-P-thiothymidylyl-(5'→3')-2'-désoxy-P-thiocytidylyl-(5'→3')-P-thiothymidylyl-(5'→3')-P-thiothymidylyl-(5'→3')-2'-désoxy-P-thiocytidyIyI-(5'→3')-P-thiothymidyIyl-(5'→3')-P-thiothymidylyl-(5'→3')-2'-désoxy-P-thiocytidylyI-(5'→3')-P-thiothymidylyl-(5'→3')-P-thiothymidylyl-(5'→3')-2'-désoxy-P-thioguanylyl-(5'→3')-2'-désoxy-P-thiocytidyIyl-(5'→3')-2'-désoxyguanosine

2'-desoxi-P-tioguanilil-(5'→3')-2'-desoxi-P-tiocitidilil-(5'→3')-2'-desoxi-P-tioguanilil-(5'→3')-P-tiotimidilil-(5'→3')-P-tiotimidilil-(5'→3')-P-tiotimidilil-(5'→3')-2'-desoxi-P-tioguanilil-(5'→3')-2'-desoxi-P-tiocitidilil-(5'→3')-P-tiotimidiIil-(5'→3')-2'-desoxi-P-tiocitidilil-(5'→3')-P-tiotimidilil-(5'→3')-P-tiotimidilil-(5'→3')-'2-desoxi-P-tiocitidiIil-(5'→3')-P-tiotimidilil-(5'→3')-P-tiotimidilil-(5'→3')-2'-desoxi-P-tiocitidilil-(5'→3')-P-tiotimidilil-(5'→3')-P-tiotimidilil-(5'→3')-2'-desoxi-P-tioguanilil-(5'→3')-2'-desoxi-P-tiocitidilil-(5'→3')-2'-desoxiguanosina

C 2 0 4 H 2 6 3 N 6 3 O 1 1 4 P 2 0 S 2 0

3-[[[2-(dimethylamino)ethyl][4-(2,4,6-triisopropylphenyl)-2-thiazolyl]amino]= methyl]pyridine

N,N-diméthyl-N'-[(pyridin-3-yl)méthy]]-N-[4-[2,4,6-tris(1-méthyléthyl)= phényl]thiazol-2-yl]éthane-1,2-diamine

3-[[[2-(dimetilamino)etil][4-(2,4,6-triisopropilfenil)-2-tiazolil]amino]= metil]piridina

C28H40N4S

41

RECOMMENDED INN: List 37 WHO Drug Information, Vol. 11, No 1, 1997

icopezilum

icopezil

icopézil

icopezilo

3-[2-(1-benzyl-4-piperidyl)ethyl]-5,7-dihydro-6H-pyrrolo[3,2-f]-1,2-benzisoxazol-6-one

3-[2-(1-benzylpipéridin-4-yl)éthyl]-5,7-dihydro-6H-pyrrolo[3,2-f]-1,2-benzisoxazol-6-one

3-[2-(1-bencil-4-piperidil)etil]-5,7-dihidro-6H-pirrolo[3,2-f]-1,2-benzisoxazol-6-ona

C 2 3 H 2 5 N 3 O 2

ioflupanum (123I) ioflupane (123l)

ioflupane (123l)

ioflupano (123l)

methyl 8-(3-fluoropropyl)-3β-(p-iodo-123/-phenyl)-1αH,5αH-nortropane-2β-carboxylate

(1R,2S,3S,5S)-8-(3-fluoropropyl)-3-[4-[123/]iodophényl]-8-azabicyclo[3.2.1]octane-2-carboxylate de méthyle

8-(3-fluoropropil)-3β-(p-iodo-123/-fenil)-1αH,5αH-nortropano-2β-carboxilato de metilo

C18H23F123INO2

ivabradinum ivabradine

ivabradine

ivabradina

3-[3-[[[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl]= methylamino]propyl]-1,3,4,5-tetrahydro-7,8-dimethoxy-2H-3-benzazepin-2-one

3-[3-[[[(7S)-3,4-diméthoxybicyclo[4 2.0]octa-1,3,5-trién-7-yl]méthyl]= méthylamino]propyl]-7,8-diméthoxy-1,3,4,5-tétrahydro-2H-3-benzazépín-2-one

3-[3-[[[(7S)-3,4-dimetoxibiciclo[4.2.0]octa-1,3,5-trien-7-il]metil]rnetilamino] propil]-1,3,4,5-tetrahidro-7,8-dimetoxi-2H-3-benzazepin-2-ona

42

WHO Drug Information, Vol. 11, No. 1, 1997 RECOMMENDED INN List 37

C2 7H3 6N2O5

lagatidum

lagatide

lagatide

lagatida

L-prolyl-L-valyl-L-threonyl-L-lysyl-L-prolyl-L-glutaminyl-D-alaninamide

L-prolyl-L-valyl-L-thréonyl-L-lysyl-L-prolyl-L-glutaminyl-D-alaninamide

L-prolil-L-valil-L-treonil-L-lisil-L-prolil-L-glutaminil-D-alaninamida

C33H58N10O9

H-Pro—Val-Thr-Lys-Pro-Gln-D-Ala-NH2

landiololum

landiolol

landiolol

landiolol

(-)-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl-p-[(S)-2-hydroxy-3-[[2-(4-morpholinecarboxamido)ethyl]amino]propoxy]hydrocinnamate

(-)-3-[4-[(2S)-2-hydroxy-3-[[2-[(morpholin-4-ylcarbonyl)amino]éthyI]amino]= propoxy]phényl]propanoate de [(4S)-2,2-diméthyl-1,3-dioxolan-4-yl]rnéthyle

p-[(S)-2-hidroxi-3-[[2-(4-morfolinacarboxamido)etil]amino]propoxi]-hidrocinnamato de (-)-[(S)-2,2-dimetil-1,3-dioxolan-4-il]metil

C25H39N3O8

lefradafibanum lefradafiban

lefradafiban

lefradafiban

(3S,5S)-5-[[[4'-(carboxyamidino)-4-biphenylyI]oxy]rnethyI]-2-oxo-3-pyrrolidineacetic acid, dimethyl ester

2-[(3S,5S)-5-[[[4'-[imino[(méthoxycarbonyl)amino]méthyl]biphényl-4-yl]oxy]méthyl]-2-oxopyrrolidin-3-yl]acétate de méthyle

éster dimetilico del ácido(3S,5S)-5-[[[4'-(carboxiamidino)-4-bifenilil]oxi]metili]-2-oxo-3-pirrolidinacético

43

RECOMMENDED INN: List 37 WHO Drug Information. Vol. 11, No. 1, 1997

C 2 3 H 2 5 N 3 O 6

marimastatum

marimastat

marimastat

marimastat

(2S,3R)-3-[[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]carbamoyl]-2-hydroxy-5-methylhexanohydroxamic acid

(2R,3S)-N1-[(1S)-2,2-diméthyl-1-(méthylcarbamoyl)propyl]-N4,3-dihydroxy-2-(2-méthylpropy])butanediamide

ácido (2S,3R)-3-[[(1S)-2,2-dimetil-1-(metilcarbamoil)propil]carbamoil]-2-hidroxi-5-metilhexanohidroxámico

C15H29N3O5

maxacalcitolum

maxacalcitol

maxacalcitol

maxacalcitol

(+) (5Z,7E,20S)-20-(3-hydroxy-3-methylbutoxy)-9,10-secopregna-5,7,10(19)-triene-1α,3β-diol

(+)-(5Z,7E)-(20S)-20-(3-hydroxy-3-méthylbutoxy)-9,10-sécoprégna-5,7,10(19)-triène-1α,3β-diol

(+)-(5Z,7E,20S)-20-(3-hidroxi-3-metilbutoxi)-9,10-secopregna-5,7,10(19)-trieno-1α,3β-diol

C 2 6 H 4 2 O 4

44

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WHO Drug Information, Vol. 11 , No. 1, 1997 RECOMMENDED INN: List 37

mazokalimum

mazokalim

mazokalim

mazokalim

ethyl 5-[(3S,4R)-4-[(1,6-dihydro-6-oxo-3-pyridazinyl)oxy]-3-hydroxy-2,2,3-trimethyl-6-chromanyl]-1H-tetrazole-1-butyrate

4-[5-[(3S,4R)-3-hydroxy-2,2,3-triméthyl-4-(6-oxo-1,6-dihydropyridazin-3-yloxy)-3,4-dihydro-2H-chromén-6-yl]-1H-tétrazol-1 -yl]butanoate d'éthyle

5-[(3S,4R)-4-[(1,6-dihidro-6-oxo-3-piridaziniI)oxi]-3-hidroxi-2,2,3-trimetil-6-cromaniI]-1H-tetrazol-1-butirato de etilo

C23H28N6O6

nifekalantum nifekalant

nifékalant

nifekalant

6-[[2-[(2-hydroxyethyl)[3-(p-nitrophenyI)propyl]amino]ethyl]amino]-1.3-dimethyluraciI

6-[[2-[(2-hydroxyéthyl)[3-(4-nitrophényl)propyl]amino]éthyl]amino]-1 3-diméthylpyrimidin-2.4(1H,3H)-dione

6-[[2-[(2-hidroxietil)[3-(p-nitrofenil)propil]amino]etil]amino]-1,3-dimetiluracilo

C19H27N5O5

nolpitantii besilas nolpitantium besilate

bésilate de nolpitantium

besilato de nolpitantio

1-[2-[(S)-3-(3,4-dichlorophenyl)-1-[(m-ísopropoxyphenyl)acetyl]-3-piperidyl]ethyl-4-phenylquinuclidinium benzenesulfonate

benzènesulfonate de 1-[2-[(3S)-3-(3,4-dichlorophényl)-1-[2-[3-(1-méthyléthoxy)phényl]acétyl]pipéridin-3-yl]éthyl]-4-phényl-1-azoniabicyclo[2.2.2]octane

bencenosulfonato de 1-[2-[(S)-3-(3,4-diclorofenil)-1-[(m-isopropoxifenil)acetil]-3-piperidil]etil-4-fenilquinuclidinio

45


C43H50CI2N2O5S

orbofibanum orbofiban

orbofiban

orbofibán

N-[[(3S)-1-(p-amidinophenyl)-2-oxo-3-pyrrolidinyl]carbamoyl]-β-alanine, ethyl ester

3-[3-[(3S)-1-(4-carbamimidoylphényl)-2-oxopyrrolidin-3-yl]uréido]propanoate d'éthyle

éster etílico de la N-[[(3S)-1-(p-amidinofenil)-2-oxo-3-pirrolidinil]carbamoil]-β-alanina

C17H23N5O4

pranazepidum pranazepide

pranazépide

pranazepida

(-)-N-[(S)-1-(o-fluorophenyl)-3,4,6,7-tetrahydro-4-oxopyrrolo= [3,2,1-jk][1,4]benzodiazepin-3-yl]indole-2-carboxamide

(-)-N-[(3S)-1-(2-fluorophényl)-4-oxo-3,4,6,7-tétrahydropyrrolo= [3,2,1-jk][1,4]benzodiazépin-3-yl]-1H-indole-2-carboxamide

(-)-N-[(S)-1-(o-fluorofenil)-3,4,6,7-tetrahidro-4--oxopirrolo-= [3,2,1-jk][1,4]benzodiazepin-3-il]indol-2-carboxamida

C26H19FN4O2

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WHO Drug Information, Vol. 1 1 , No. 1, 1997 RECOMMENDED INN: List 37

rizatriptanum

rizatriptan

rizatriptan

rizatriptán

3-[2-(dimethylamino)ethyl]-5-(1H-1,2,4-triazol-1-ylmethyl)indole

N,N-diméthyl-2-[5-[(1H-1,2,4-triazol-1-yl)méthyl]-1H-indol-3-yI]éthanamine

3-[2-(dimetilamino)etil]-5-(1H-1,2,4-triazol-1-ilmetil)indol

C1 5H1 9N5

saredutantum

saredutant

sarédutant

saredutant

N-[(S)-β-[2-(4-acetamido-4-phenylpiperidino)ethyl]-3,4-dichlorophenethyl]-N-methylbenzamide

N-[(2S)-4-[4-(acétylamino)-4-phénylpipéridin-1-yl]-2-(3,4-dichlorophényl)butyl]-N-méthylbenzamide

N-[(S)-β-[2-(4-acetamido-4-fenilpiperidino)etil]-3,4-diclorofenetil]-N-metilbenzamida

C31H35CI2N3O2

sitafloxacinum

sitafloxacin

sitafloxacine

sitafloxacino

(-)-7-[(7S)-7-amino-5-azaspiro[2.4]hept-5-yl]-8-chloro-6-fluoro-1 -[(1R,2S)-2-fluorocyclopropyI]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid

acide (-)-7-[(7S)-7-amino-5-azaspiro[2.4]hept-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoIéin-3-carboxylique

ácido (-)-7-[(7S)-7-amino-5-azaspiro[2.4]hept-5-il]-8-cloro-6-fluoro-1-[(1R,2S)-2-fluorociclopropil]-1,4-dihidro-4-oxo-3-quinoIinacarboxilico

47

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C19H18CIF2N2O3

sulesomabum sulesomab

sulésomab

sulesomab

immunoglobulin G 1 (mouse monoclonal IMMU-MN3 Fab' fragment γ-chain anti-human NCA-90 granulocyte cell antigen), disulfide with mouse monoclonal IMMU-MN3 light chain

immunoglobuline G 1 (chaîne γ du fragment Fab' de l'anticorps monoclonal de souris 1MMU-MN3 anti-antigène de granulocyte humain NCA-90), disulfure avec la chaîne légère de l'anticorps monoclonal de souris IMMU-MN3

inmunoglobulina G 1 (cadena γ del fragmento Fab' del anticuerpo monoclonal de ratón IMMU-MN3 anti-antígeno de granulocito humano NCA-90), disulfuro con la cadena ligera del anticuerpo monoclonal de ratón IMMU-MN3

taltirelinum

taltirelin

taltiréline

taltirelina

(-)-N-[[(S)-hexahydro-1-methyl-2,6-dioxo-4-pyrimidinyl]carbonyl]-L-histidyl-L-prolinamide

(-)-(2S)-1 -[(2S)-3-(1H-imidazol-4-yl)-2-[[[(4S)-1-méthyl-2,6-dioxohexahydro= pyrimidin-4-y]]carbonyl]amino]propanoyl]pyrrolidine-2-carboxamide

(-)-N-[[(S)-hexahidro-1-metil-2,6-dioxo-4-pirimidinil]carbonil]-L-histidil-L-prolinamida

C17H23N7O5

taIviralinum talviraline

talviraline

isopropyl (2S)-3,4-dihydro-7-methoxy-2-[(methylthio)methyl]-3-thioxo-1 (2H)-quinoxalinecarboxylate

(2S)-7-méthoxy-2-[(méthylsulfanyl)méthyl]-3-thioxo-3,4-dihydroquinoxaline-1(2H)-carboxylate de 1-méthyléthyle

46

WHO Drug Information, Vol. 11, No. 1, 1997 RECOMMENDED INN List 37

talviralina (2S)-3,4-dihidro-7-metoxi-2-[(metiltio)metil]-3-tioxo-1(2H)-quinoxalinacarboxilato de 1-metiletilo

C15H20N2O3S2

technetium (99mTc) pintumomabum technetium (99mTc) pintumomab

technétium (99mTc) pintumomab

technetium (99mTc) pintumomab

immunoglobulin G 1 (mouse monoclonal 170 γ-chain anti-human adenocarcinoma antigen), disulfide with mouse monoclonal 170 κ-chain, dimer, [99mTc] technetium salt

sel de [99mTc] technétium de l'immunoglobuline G 1 (chaîne γ de l'anticorps monoclonal de souris 170 anti-antigène associé à l'adénocarcinome humain), dimère du disulfure avec la chaîne κ de l'anticorps monoclonal de souris 170

sal de [99mTc] technetium del inmunoglobulina G 1 (cadena γ del anticuerpo monoclonal de ratón 170 anti-antígeno asociado al adenocarcinoma humano), dírnero del disulfuro con la cadena κ del anticuerpo monoclonal de ratón 170

terbogrelum terbogrel

terbogrel

terbogrel

(5E)-6-[m-(3-tert-butyl-2-cyanoguanidino)phenyl]-6-(3-pyridyl)-5-hexenoic acid

acide (5E)-6-[3-[2-cyano-3-(1,1-diméthyléthyi)guanidino]phényl]-6-(pyrid-3-yl)hex-5-énoíque

ácido (5E)-6-[m-(3-terc-butil-2-cianoguanidino)fenil]-6-(3-piridil)-5-hexenóico

C23H27N5O2

tresperimusum tresperimus [4-[(3-aminopropyl)amino]butyI]carbamic acid, ester with

N-(6-guanidinohexyl)glycolamide

49


trespérimus

tresperimus

[4-[(3-aminopropyl)amino]butyl]carbamate de 2-[(6-guanidinohexyl)amino]-2-oxoéthyle

[4-[(3-aminopropil)amino]butil]carbamato de [(6-guanidinohexil)carbamoil]= metilo

C17H37N7O3

vinfluninum

vinflunine

vinflunine

vinflunina

4'-deoxy-20',20'-difluoro-8'-norvincaleukoblastine

20',20'-difluoro-4'-désoxy-8'-norvincaleucoblastine

4'-desoxi-20',20'-difluoro-8'-norvincaleucoblastina

C45H54F2N4O8

zanamivirum zanamivir

zanamivir

zanamivir

5-acetamido-2,6-anhydro-3,4,5-trideoxy-4-guanidino-D-glycero-D-galacto-non-2-enonic acid

acide (4S,5R,6R)-5-(acétylamino)-4-guanidino-6-[(1R,2R)-1,2,3-trihydroxypropyl]-5,6-dihydro-4H-pyrane-2-carboxylique

ácido 5-acetamido-2,6-anhidro-3,4,5-tridesoxi-4-guanidino-D-glicero-D-galacto-non-2-enónico

C12H20N4O7

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

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

Les textes de la Procédure à suivre en vue de choix de dénominations communes internationales recommandées pour les substances pharmaceutiques et des Directives générales pour la formation de dénominations communes internationales applicables aux substances pharmaceutiques seront publiés seulement dans les listes impaires des DCI proposées.

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

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