WHO DRUG INFORMATION · 1 WHO Drug Information Vol. 13, No. 1, 1999. General Policy Issues. WHO roundtable with industry. On 21 October 1998, Dr Gro Harlem Brundtland, the newly elected

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R E C O M M E N D E D I N N L I S T 41 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

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WHO Drug Information Vol. 13, No. 1, 1999

General Policy Issues

WHO roundtable with industryOn 21 October 1998, Dr Gro Harlem Brundtland, the newly elected Director-General of WHO, met with keyfigures of the research-based pharmaceutical industry to explore ways in which access to affordable,innovative and essential drugs can be improved. The roundtable was attended by members of majorpharmaceutical companies which included American Home Products, Glaxo Wellcome, Novartis, Pasteur-Mérieux-Connaught and SmithKline Beecham, together with representatives of the International Federa-tion of Pharmaceutical Manufacturers Associations (IFPMA).

The meeting offered an opportunity for both sides to address issues of public health concern and todetermine common ground. WHO's goal is to build a constructive dialogue with the private sector, andharness support to improve access to drugs and vaccines for populations in need.

Global partnerships for health

Gro Harlem BrundtlandDirector-GeneralWorld Health Organization

A roundtable, as we intend to apply the word inWHO, is not a single event but a method of work. Itderives from our commitment to meet with broadconstituencies involved in public health at the globallevel and address key issues relevant to the fulfil-ment of our mandate in combating ill-health andbuilding healthy populations.

I have invited representatives of the research-based pharmaceutical industry to a roundtablebecause I believe that we have a common aim inhealth. I am convinced that we can collaborateeffectively if we deal with our differences andaddress them directly and openly as we did in themeeting on the Revised Drug Strategy held earlierin October*. Then, after an initial breakdown incommunication, Members States reached a con-sensus on important issues which are also ofconcern to the pharmaceutical industry. How didthis come about? Because of broader access toinformation, more time to listen, and a greatercommitment to build bridges.

Let me underline where WHO stands: we arecommitted to national drug policies and the conceptof essential drugs and vaccines. The Action Pro-gramme on Essential Drugs has been our maininstrument in helping governments implement theseconcepts. When the action programme was estab-lished in 1975, very few countries had adoptednational drug policies. The developing countrieswere faced with serious problems of availability,cost, quality, and rational use of drugs. Today,nearly 90 countries have national drug policies inplace or in preparation. The WHO Model List ofEssential Drugs has been widely adapted by na-tional authorities and three out of every four coun-tries in the world now have an essential drugs list.

WHO plays a key supporting role by helping coun-tries to assess their needs, identify problems andfind solutions. WHO sets norms, standards andregulations for implementation by regulatory au-thorities, while quality assurance of pharmaceuti-cals is an overriding concern. Nowhere is theresponsibility or challenge greater. Of course,operational research is a core function and so issafety monitoring. The two are closely linked. WHOworks with partners around the world to monitor theuse of drugs — not only to sound the alarm whenfaced with emergencies and outbreaks but to sharethe good news when progress has been madeagainst a major disease.

WHO's global vaccination programme has achievedan immunization rate of 80% for all children in the

* Meeting of the ad hoc Working Group on the RevisedDrug Strategy convened by WHO from 13 to 16 October1998. WHO Drug Information, 12(4): 209 (1998).

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WHO Drug Information Vol. 13, No. 1, 1999General Policy Issues

world. This is a success both from an industry anda public health perspective. However, we need tomove on with new vaccine research and develop-ment and WHO is actively engaged with the WorldBank, UNICEF, leading foundations and industry topave the way to new breakthroughs in vaccinedevelopment and delivery. This kind of joint projecthas also been established in other areas. Forexample, the Medicines for Malaria Venture hasrecently been set up and will be incorporated intothe Roll Back Malaria initiative. I hope that WHOand the pharmaceutical industry can work togetherto strengthen this particular component.

Still much remains to be done. One-third of theworld's population lacks access to essential drugs.Those concerned with public health or equity willagree that this is truly unacceptable. Despite thelarge sums spent on research and development,less than 1% is directed to providing treatment forthose diseases that strike developing countries.Frankly, this does not make sense. The price ofdrugs — especially for the newer products — putsthem out of reach in the majority of developingcountries. We must work together to ensure devel-opment of new drugs for major public healththreats. The challenge is there. But we must alsocreate an infrastructure to ensure that drugs forkiller diseases like tuberculosis and malaria areprovided to those in need.

Emerging diseases, growing drug resistance, globaleconomic instability and uncertainty about thepublic health impact of new trade agreements areall relevant key issues. WHO will be present in all ofthese arenas. Health is an integral part of our wayof life, how our world evolves, how human re-sources are nurtured, how trade expands andeconomies grow, and how environments perish orsurvive. The pharmaceutical industry has theresponsibility for developing, producing and sellingpharmaceutical products — drugs and vaccines.WHO has the responsibility for helping countriesacquire access to essential drugs. The pharmaceu-tical industry is in the business of making a profit.But we are in the business of seeing to it that themost vulnerable — who have little or no purchasingpower — are allowed equitable access to medi-cines.

WHO sees great potential in this roundtable as afirst step in a serious attempt to build a sustainablemechanism and provide affordable, essential drugsof quality to the needy. We look forward to forging astrong, durable and committed partnership withthose having a common purpose in health.

Public health andthe pharmaceutical industry

Richard B. Sykes, President, InternationalFederation of Pharmaceutical ManufacturersAssociations and Chairman, Glaxo Wellcome,United Kingdom

The research-based pharmaceutical industry andthe World Health Organization share a commongoal of fighting disease and improving health. Withthis essential unity of purpose, it seems clear thatwe should be working closely together wherever itis feasible to do so. I am confident that the discus-sions which have taken place during this WHOroundtable will be a first step towards a closerpartnership based on dialogue and mutual under-standing.

We all agree that medicines have made a tremen-dous contribution to the improvement of health careduring the 20th century, and particularly during the50 years that WHO has existed. Of course, mucheffort still needs to be concentrated on ensuringthat the benefits of modern medicine are madeavailable to all in need. The pharmaceutical indus-try will play its part in helping to achieve this goal.However, our primary focus is and will continue tobe the scientific and technological research neededto produce new medicines to respond to healthproblems that have so far eluded treatment.

As we go forward into the 21st century, we haveevery reason to be confident that the medicalprogress witnessed so far will continue and acceler-ate. Prospecting for new medicines has entered anera of unprecedented opportunity and offers newinsights into areas unimagined until now. Within theindustry, much is being done to ensure that weharness this new science and technology anddeliver medicines of real value.

The contribution of geneticsGenetics is a vital newcomer to the drug discoveryprocess and helps explain many things that wehave observed in practice. The study of geneticsoffers an entirely new approach by identifyingfactors that influence an individual's susceptibility toa certain disease. This new knowledge derives fromthe international human genome project devoted tosequencing the three billion DNA bases in humans.

This tremendous effort will bring about significantimprovements in the provision and practice ofhealth care. Intransigent health problems such as

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WHO Drug Information Vol. 13, No. 1, 1999 General Policy Issues

asthma and heart disease, which are increasing atan alarming rate throughout the world, will beunderstood. Genetic testing will enable individualpatients to be targeted for specific treatment tomaximize efficacy and minimize side-effects. Inother words, drugs can be tailored to people formaximum response.

Effective preventionIn the future, the use of genetics will allow us toscreen for susceptibility and we will be able toidentify which individuals will develop diseases longbefore the symptoms appear. This genetic informa-tion can then be combined with known conventionalrisk factors. Although in many cases these benefitscan only be provided within a sophisticated medicalinfrastructure, this new understanding of geneticswill prove of great potential value in the fight againstdiseases of the developing world.

For example, the complete Mycobacterium tubercu-losis genome sequence has now been published,and the sequence of every potential drug target andantigen is now available. Sequencing of the Plas-modium falciparum genome will be of great signifi-cance in paving the way for the development of aDNA vaccine against malaria. What, then, needs tobe done to ensure that the tremendous potential forthe development of new and better medicines isactually realized and that people throughout theworld will benefit from them?

The realities of research and developmentFrom an industry perspective, effective protection ofintellectual property is essential if billions of dollarsare to be invested each year in the research anddevelopment of new medicines. Currently usedtechniques are vastly more efficient and productivethan ever before, but the technology that underpinsthese is very expensive. By contrast, copying andmanufacturing medicines are very cheap. Unlesscompanies are assured of intellectual propertyprotection during the limited period conferred bypatents, they simply will not be able to find thefunds to pay for future research and development.The industry is pleased that progress was made inthis regard during the meeting of the ad hoc Work-ing Group on the Revised Drug Strategy convenedby WHO from 13 to 16 October 1998*.

There is growing recognition that special measuresare needed to encourage research and develop-ment for diseases such as malaria and tuberculo-sis. The involvement of the International Federationof Pharmaceutical Manufacturers Associations(IFPMA) in the new WHO Medicines for MalariaVenture demonstrates industry's willingness to findnew ways forward. Similarly, legislation has suc-cessfully been introduced in the United States toprovide incentives to companies developing orphandrugs and the European Union is now setting up asimilar system. Regulatory authorities and WHOmay wish to explore such an approach for tropicaldiseases since this would harness the industry'sskills and resources for new drug development inan important area.

With regard to the problem of ensuring access topatented medicines, we need to look at ways toencourage companies to offer prices which reflectthe economic reality of individual countries. Thiscould be done by offering prices which are lower indeveloping countries than in more affluent parts ofthe world. However, if customers in the better-offcountries were to import the lower priced medi-cines, industry would be unable to bear the burden.Parallel trading has understandable attractions forhealth care providers faced with tight budgets, butits long-term consequences can only be damaging.

Adequate funding is a key precondition for success-ful public health management and for the continuingsupply of new medicines. Equally, there has to be aclear recognition from health care providers that theprice paid for medicines will ultimately affect thefunds available for further research and develop-ment. The pharmaceutical industry cannot beexpected to take sole responsibility for ensuringthat the least well-off have access to their medi-cines. This is a vital role for multilateral agencieswho must work in close partnership with us. TheUNAIDS HIV Drug Access Initiative and the newMedicines for Malaria Venture offer examples ofpotential opportunities for this kind of partnership.

These are exciting times for the research-basedpharmaceutical industry. It is our desire to shareour achievements through true partnerships —particularly with WHO — and to ensure that thebenefits of modern science and technology are trulyavailable to all peoples of the world.

* See WHO Drug Information, 12(4): 209 (1998).

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International harmonizationof safety information:a CIOMS initiative

Jens S. SchouFaculty of Health SciencesCopenhagen, Denmark andmember of CIOMS Working Group

The Council for International Organizations ofMedical Sciences (CIOMS) was constituted inBrussels in 1949 as a nongovernmental organiza-tion under an agreement between UNESCO andWHO to facilitate the coordination of the planningand timing of international medical congresses, andwith a mandate to collaborate with its two foundingorganizations and other United Nations agencies.However, it soon became clear that CIOMS alsoprovided an ideal forum for joint projects in thecomplementary fields of medicine, the social andlife sciences, philosophy, ethics and law.

One important project which has developed overthe years is a joint CIOMS–WHO programme onthe medical, social and economic implications ofdrug development and use. As an independentorganization, CIOMS is well placed to bring to-gether experts from the research-based pharma-ceutical industry, national regulatory control agen-cies and academia to discuss issues of immediateconcern.

Many achievements of public health importancehave resulted from this joint venture. In particular,attention has been focused on the harmonization ofdrug safety monitoring and, specifically, terminol-ogy. As the use of drugs becomes more globalized,national regulatory agencies demand increasingamounts of foreign and domestic data before theywill authorize marketing in their country. This cancause a considerable burden to manufacturers andthe time taken to comply with different countryprocedures holds up the availability of new medi-cines. The introduction of uniform procedures isthus considered beneficial to regulators, manufac-turers and patients alike.

In an effort to address this and similar issuesconcerning international harmonization, CIOMS

working groups on drug safety have been consti-tuted, and are made up of specialist representativesof drug regulatory authorities, academia and thepharmaceutical industry. The system of compact,focused working groups has been very productive,and has also been adopted for use within theInternational Conference on Harmonization (ICH)process. Furthermore, many of the initiatives pro-posed by the CIOMS working groups have gone onto be incorporated into ICH guidelines. It is thehope of members of the working groups that theirproposals for the international harmonization ofdrug safety information will be accepted throughoutthe world.

Model form for suspect adverse reactionsIn 1985, an overall plan to improve the monitoringand assessment of adverse drug reactions wasmapped out and working group I was set up tostudy how the international reporting of post-mar-keting adverse drug reactions could be improved(1). With the collaboration of five regulatory authori-ties and six pharmaceutical manufacturers, a pilotinternational reporting system was successfullyimplemented. As a result, the Model Form forSuspect Adverse Reactions was published in 1987(2).

International reporting of adversedrug reactions: terminologyWork continued on promoting the application ofCIOMS recommendations and the reporting form,and on devising a standard reporting language.Internationally-agreed terms were needed to deter-mine the severity of adverse drug reactions andharmonize postmarketing surveillance reporting.Additionally, many countries required manufactur-ers to report adverse drug reactions to their regula-tory authority. A standardized process of reportingusing the model form accompanied by a set ofdefinitions, procedures and methods was devised(3). These methods were tested by seven multina-tional pharmaceutical companies with 40 affiliatedbranches in six countries. The rapid collection andtransmission of safety information is vital to the safeand proper use of medicines and the project alsodemonstrated the feasibility and utility of reportingadverse drug reactions occurring anywhere in theworld.

Personal Perspectives

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Periodic drug safety update summaryIn 1989, working group II was established to harmo-nize reporting of periodic drug safety updates. Asafety update provides a review of informationaccumulated from various sources since the previ-ous report. The usefulness of this project wasparticularly appropriate, since the USA was the onlycountry at that time to formally require submissionof a drug safety update summary prior to filing for amarketing application. In order for safety informa-tion to be harmonized, a CIOMS pilot study wascarried out to assess the feasibility and utility of asingle periodic drug safety update summary con-taining both foreign and domestic reports (4). Aftermuch work and refinement, the final proposal waspublished in 1992. The periodic safety updatereport has been extensively implemented, andmany of the recommendations proposed by CIOMShave now been incorporated into European Unionlegislation.

Core data sheetIn order to ensure availability of a central referencemanufacturers document, the concept of the coredata sheet was pursued by CIOMS. This is a docu-ment prepared by the pharmaceutical manufacturerand contains critical information which the manufac-turer will include in the labelling or package insert ofa medicinal product (5). In devising the Core DataSheet, the working group took into considerationregulatory requirements of the Summary of ProductCharacteristics (SPC) of the European Union andthe FDA's General Requirements on Content andFormat of Labelling for Human Prescription Drugsand Specific Requirements on Content and Formatfor Human Prescription Drugs.

Core safety information is not meant to be static:the initial information will undergo changes as newknowledge becomes available. The actual momentwhen new information is to be incorporated into thecore data sheet is determined by a "threshold".During discussion of threshold requirements, theCIOMS working group identified a new and impor-tant area for future work: how to evaluate thebenefit/risk ratio for a marketed medicinal productwhen a significant new safety signal is identified.

Benefit-risk evaluation reportDiscussions were held at great length on this topicand examined the theoretical and practical aspectsof reassessment and how a potentially major, new

safety signal impacts upon the relationship betweenbenefit and risk, bearing in mind how a standardreport should describe this. The working groupreviewed a number of case histories to evaluatehow major safety concerns had been handled in thepast. As a result, the CIOMS Working Group IVreport (6) sets out the standard format and contentof a benefit-risk evaluation report with details ofimplementation and a detailed discussion of topics,including decision making, benefit/risk metrics, andthe value and limitations of information reporting. Adiscussion of terminology and a definition of termsare also provided.

A key element to the consistent success of thisimportant long-term venture has been the dedica-tion of working group members and the CIOMSsecretariat, and their recognition of the globalimportance of the task. Another contributing factorhas been the focused scope of working groupactivities and the neutral platform provided byCIOMS.

References :

1. Council for International Organizations of MedicalSciences. Monitoring and assessment of adverse drugeffects. CIOMS Working Group Report. CIOMS, Geneva,1986.

2. Council for International Organizations of MedicalSciences. International reporting of adverse drug reac-tions. CIOMS Working Group Report. CIOMS, Geneva,1987.

3. Council for International Organizations of MedicalSciences. International reporting of adverse drug reac-tions. CIOMS Working Group Report. CIOMS, Geneva,1990.

4. Council for International Organizations of MedicalSciences. International reporting of periodic drug-safetyupdate summaries. CIOMS Working Group II Report.CIOMS, Geneva, 1992.

5. Council for International Organizations of MedicalSciences. Guidelines for preparing core clinical safetyinformation on drugs. CIOMS Working Group III Report.CIOMS, Geneva, 1995.

6. Council for International Organizations of MedicalSciences. Benefit-risk balance for marketed drugs:evaluating safety signals. CIOMS Working Group IVReport. CIOMS, Geneva, 1998.

Personal Perspectives

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Reports on Individual Drugs

Short-course zidovudinein perinatal HIV transmissionIn 1994, a reduction of 67.5% in the relative risk ofmother-to-child transmission of HIV was demon-strated in newborn infants treated before, duringand after birth with zidovudine. (1). Further datafrom a recent trial in Thailand suggest that an ab-breviated regimen of oral zidovudine from 36 weeksof gestation until delivery, with no neonatal compo-nent, can reduce the relative risk of transmission byapproximately 50% (2). Although the decrease wassignificant, it was understandably lower than the re-duction in the relative risk of perinatal transmissionreported in the 1994 study.

The results of a new study undertaken in the USAsuggests that more abbreviated zidovudine prophy-laxis can reduce the rates of perinatal transmissionof HIV even further (3). The timing and response ofzidovudine therapy was analysed in 939 HIV ex-posed infants below 180 days of age. When treat-ment was begun in the prenatal period, the rate ofHIV transmission was 6.1%. However, when zido-vudine was begun intrapartum the rate was 10%;begun within the first 48 hours of life 9.3%; and onday 3 of life or later 18.4%. In the absence of zido-vudine prophylaxis, the rate of HIV transmission is26.6.%. These results confirm the efficacy of zido-vudine prophylaxis and suggest that reductions inthe rates of perinatal transmission of HIV can beachieved even with the use of abbreviated regi-mens that begin during labour or the first 48 hoursof life.

These findings require further confirmation but,even without confirmation, the study offers hopethat HIV infection can be prevented after exposure.It also indicates that HIV-infected women who donot receive zidovudine during pregnancy should beidentified so that they can receive antiretroviralsduring delivery and their infants can begin receivingzidovudine at birth. This study demonstrates that aninexpensive preventive regimen (4) is available forroutine use in many parts of the world, includingthose areas where HIV prevalence is high but re-sources are severely limited (5).

References

1. Connor, E.M., Sperling, R.S., Gelber, R. et al. Reduc-tion of maternal-infant transmission of human immunodefi-ciency virus type 1 with zidovudine treatment. New Eng-land Journal of Medicine, 331: 1173–1180 (1994).

2. Centers for Disease Control and Prevention. Adminis-tration of zidovudine during late pregnancy to prevent peri-natal HIV transmission — Thailand 1996–1998. Morbidityand Mortality Weekly Report, 47: 151–153 (1998).

3. Wade, N.A., Birkhead, G.S., Warren, B.L. et al. Abbre-viated regimens of zidovudine prophylaxis and perinataltransmission of the human immunodeficiency virus.New England Journal of Medicine, 339: 1409–1414(1998).

4. McIntosh, K. Short (and shorter) courses of zidovudine.New England Journal of Medicine, 339: 1467–1468(1998).

5. World Health Organization. Recommendations on thesafe and effective use of short-course ZDV for preventionof mother-to-child transmission of HIV. Weekly Epidemio-logical Record, 73: 313-320 (1998).

Vitamin D supplements in adultsVitamin D is an essential precursor of 1,25-dihydroxyvitamin D, the steroid hormone necessarynot only for bone development and growth in chil-dren but maintenance of bone in adults. In particu-lar, vitamin D deficiency is a risk factor for boneloss in osteoporosis and fracture. Correction of aneven slightly low concentration of serum 25-hydroxyvitamin D with vitamin D and calcium sub-stantially reduces the risk of osteoporosis fracturesand hip fractures (1, 2). The prevalence of hypovita-minosis D in residents of retirement and nursinghomes and people over the age of 65 is between25 and 54%, but can be as high as 79% (3, 4).

A recent study of 152 male and 138 female hospi-talized patients with a mean age of 62 years (range18 to 95 years) had measured low serum 25-hy-droxy-vitamin D at 57% (3). In 22%, hypovitamino-sis D was severe. Patients hospitalized in Marchhad more hypovitaminosis than those hospitalizedin September. The patients in this study wereyounger than those in many previous studies and

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only a minority were housebound or residents of anursing home. Thus the patients may have beenmore representative of the general population.

Hypovitaminosis D is associated with conditionssuch as poor dietary intake, inadequate sun expo-sure, chronic liver and renal diseases, malabsorp-tion, and therapy with drugs that impair vitamin Dactivation or accelerate its clearance such asglucocorticoids, phenytoin, carbamazepine and ri-fampicin.

Increased calcium intake by older people has animportant role in prevention of osteoporosis but it isapparent that attention should also be focused onthe need for increased intake of vitamin D (4). Vita-min D stimulates calcium absorption, thereby in-creasing the benefit of supplemental calcium. It alsoslows bone resorption and increases bone forma-tion.

It is evident that more widespread screening for vi-tamin D deficiency is required especially in elderlypeople, and more frequent routine vitamin D sup-plementation should be considered. An increase invitamin D intake is likely to have a greater effect onosteoporosis and fractures than many other inter-ventions (4).

References

1. Chapuy, M.C., Arlot, M.E., Duboeuf, F. et al. Vitamin Dand calcium to prevent hip fracture in elderly women. NewEngland Journal of Medicine, 327: 1637–1642 (1992).

2. Chapuy, M.C., Arlot, M.E., Delmas, P.D. et al. Effect ofcalcium and cholecalciferol treatment for three years onhip fractures in elderly women. British Medical Journal,308: 1081–1082 (1994).

3. Thomas, M.K., Lloyd-Jones, D.M., Thadhani, R.I. et al.Hypovitaminosis D in medical inpatients. New EnglandJournal of Medicine, 338: 777–783 (1998)

4. Utiger, R.D. The need for more vitamin D. New EnglandJournal of Medicine, 338: 828–829 (1998).

Tacrine and Alzheimer diseaseThe present ageing of the world's population willlead to an increase in cases of elderly dementia, ofwhich Alzheimer disease is a common form. Thepossibilities for prevention of Alzheimer are limitedby the major determinants — age and geneticmakeup — which cannot be modified. As a result,

treatment has thus far been directed to the sympto-matic relief of the disease.

Although an effective treatment for Alzheimer dis-ease has yet to be marketed, potent acetylcho-linesterase inhibitors have been the dominanttherapeutic strategy. Tacrine hydrochloride was thefirst in the generation of cholinesterase inhibitors tobe widely marketed for impaired memory and rea-soning ability of patients with Alzheimer disease.Several other drugs, such as donepezil,rivastigmine and metrifonate, have a similar mecha-nism of action.

Using the Cochrane Dementia Group registry ofclinical trials, the Dementia Trialists CollaborationGroup has now carried out a meta analysis oftacrine in patients with Alzheimer disease (1). Theaim was to determine the effects of tacrine onsymptoms in terms of cognitive performance, clini-cal global impression of change, behaviour andfunctional autonomy. The study analysed 12 rand-omized, double-blind, placebo controlled trials total-ling 1984 patients. All patients enrolled in the trialshad been diagnosed as having "probable" Alzhe-imer disease according to commonly accepted cri-teria (2). Duration of treatment varied from 3 and 36weeks.

Cholinesterase inhibition with tacrine appears to re-duce deterioration in cognitive performance duringthe first 3 months of treatment and an increase inthe odds of overall clinical improvement. However,as measured by behavioural disturbances, the ben-eficial effects were of questionable clinical signifi-cance and functional autonomy was not signifi-cantly affected. Early withdrawal from studies wasmuch higher for patients receiving tacrine com-pared with placebo and elevated transaminase lev-els were cited as the main reason for this in the twolargest trials.

The benefits of cholinesterase inhibition remaincontroversial, and long-term trials with clinically rel-evant end points are required. Only 2 of the 12 tri-als had assessments beyond 12 weeks and it wastherefore not possible to make reliable estimates ofthe long-term effects of tacrine. Neither was it pos-sible to assess whether beneficial effects are ob-tained from continuous therapy, how long they en-dure, or when it is best to withdraw treatment. Ef-forts should thus continue to define the types of pa-tients and the circumstances in which the newercholinesterase inhibitors may be beneficial.


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References

1. Qizibash, N., Whitehead, A. Higgins, J. et al.Cholinesterase inhibition for Alzheimer disease. Journal ofthe American Medical Association, 280: 1777–1782(1998).

2. McKanna, G. Drachman, D. Folstein, M. et al. Clinicaldiagnosis of Alzheimer disease: report of the NINCDS-ADRDA Working Group. Neurology, 4: 939–944 (1984).

Anti-ulcer drugs may maskearly gastric cancerDyspepsia, typically presenting as heartburn orgastrointestinal discomfort, is responsible for about2–5% of patient visits to general health care physi-cians. In over 50% of cases, no firm diagnosis ispossible because symptoms are of an uncertain ori-gin. However, a significant proportion of patientswith early gastric cancer experience symptoms typi-cal of dyspepsia.

Following the availability of H2 receptor antagonistssuch as cimetidine, famotidine, nizatidine and raniti-dine to treat gastric ulcer, it became evident thattheir use may mask symptoms of cancer and delaydiagnosis and appropriate treatment (1). Further-more, the recently introduced and more powerfulproton pump inhibitors such as omeprazole, lanso-prazole, and pantoprazole produce significantlymore rapid symptom control and healing of benigngastric ulcer.

It would appear that the action of these drugs masksymptoms of gastric cancer to such an extent thatendoscopic diagnosis is difficult, thereby alteringthe prognosis from probable to incurable disease(2–4). In some cases, ulcerated lesions which werevisible at an initial gastroscopy are virtuallyundetectable less than four-weeks later after treat-ment with a proton pump inhibitor (5). Patients withmissed early cancers may alternatively be labelledas having non-ulcer dyspepsia and receive re-peated courses of antisecretory drugs which will actto delay diagnosis even further (4, 5).

Antisecretory drugs, including H2 receptor antago-nists, are available in lower doses without prescrip-tion. At present, no studies are available to showwhether these low-dose drugs are also able to healthe mucosal lesions associated with early gastriccancer.

In conclusion, it is recommended that dyspeptic pa-tients over 45 years of age should undergo endos-copy before any antisecretory ulcer drugs arestarted (5). Inappropriate use and prescription ofanti-ulcer drugs may delay or even prevent diagno-sis of early gastric ulcer in two ways. The rapid con-trol of dyspepsia may lead the patient or generalpractitioner to underestimate the importance of thesymptoms and referral for endoscopy will be de-layed or even deferred. If the patient should laterundergo a gastroscopy, the prior treatment withantisecretory drugs could also mask signs. It re-mains to be seen whether the increased availabilityof these drugs over-the-counter and their expand-ing use for self medication requires reassessment.

References

1. Taylor, R.H., Menzies-Gow, N., Lovell, D. et al. Mis-leading response of malignant gastric ulcers to cimetidine.Lancet, 686–687 (1978).

2. Wayman. J., Hayes N. Proton pump inhibitors delay thediagnosis of gastric cancer. British Journal of Surgery,84(Suppl. 1): 62 (1997).

3. Wayman, J., Hayes, N., Griffin, S.M. The response ofearly gastric cancer to proton-pump inhibitors. New Eng-land Journal of Medicine, 338: 1924–1925 (1998).

4. Suvakovic, Z., Bramble, M.G., Jones, R. et al. Improv-ing the detection rate of early gastric cancer requires morethan open access gastroscopy: a five year study. Gut, 41:308–313 (1997).

5. Griffin, S.M., Raimes, S.A. Proton pump inhibitory maymask early gastric cancer. British Medical Journal, 317:1606–1607 (1998).


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Current Topics

WHO develops artesunate foremergency treatment of malaria

Artesunate Task Force, World HealhOrganizaion, Geneva*

Traditionally, the development of new drugs reliesheavily on the ability of the pharmaceutical industryto carry out scientific and technological research onbehalf of public health. In such a setting, drugdevelopment tends to be directed to health prob-lems which give returns on the significant invest-ment of time and money needed to obtain a com-mercially successful product. The provision of newmedicines for diseases endemic in developingcountries where a commercial gain is not possibleremains a dilemma (1).

A new initiative in public health delivery has re-cently been launched by WHO with the develop-ment of the drug artesunate. The pace of artesu-nate development has been fast, focused andtargeted and the potential beneficiaries arepopulations at risk of severe malaria. For the rea-sons described below, WHO has extended its usualdrug development process one step further byinitiating registration of rectal artesunate for theemergency treatment of malaria in patients.

Although the strategy of artesunate developmentwas orchestrated from within WHO's Special Pro-gramme for Research and Training in TropicalDiseases, it relies heavily upon an alliance ofscientists, laboratories, industry, regulators andministries of health to ensure the public healthoutcome. This change in development strategy has

transformed the way in which WHO does business.In essence, each and every player has been ralliedto the challenge of reducing the discrepancy be-tween need and availability of an important drug.

The malaria settingIt is estimated that malaria is responsible for up to500 million episodes of clinical infection annually,killing 2.7 million people with severe and cerebraldisease. Existing data indicate that in some Africansettings, 44% of all mortality in children under theage of 5 is associated with malaria and 82% ofthese deaths occur at home. The commonestpresenting symptoms associated with significantmortality are cerebral malaria, recurrent convul-sions, metabolic dysfunction, or symptomaticanaemia (2). In the population most at risk of death— infants and children in Africa — a significantnumber soon become too ill to take any form ofmedication orally and they must be referred tohospital for parenteral treatment if they hope tosurvive.

For those children fortunate enough to reach ahospital, data confirm that the illness progressesrapidly. Children with severe anaemia may presentwith longer histories of illness, although acutedecompensation, manifesting as respiratory dis-tress, often precipitates admission to hospital. Therisk of death at hospital is highest within the first 24hours after admission, and varies from 10–40%.Survival will depend on two factors: the timeelapsed between first symptoms and initiation oftreatment, and the health facility's ability to managecomplications.

It follows that the earlier a patient receives thera-peutic concentrations of an effective antimalarial,the lower the risk of mortality. Since the publichealth need is to provide early, affordable treatmentto patients who do not have easy access to hospi-tal, it was urgent for WHO to develop a product tomeet these criteria.

The artesunate storyThe clinical efficacy of currently marketed antima-larials is generally demonstrated by parasite clear-ance rates. However, the circumstances of malariaillness are more complicated. Survival will often

Members of the Artesunate Task Force: P. Folb, Profes-sor of Pharmacology, University of Cape Town, SouthAfrica (Chairman), formerly Chairman, Medicines ControlCouncil, South Africa; S. Krishna, St. George's HospitalMedical School, London, United Kingdom; M.E. Molyneux,Wellcome Trust Centre, University of Malawi, Malawi; V.Navaratnam, Director, Dentre for Drug Research,Universiti Sains Malaysia, Malaysia; N. White, Director,Wellcome Trust Foundation, Mahidol University, Bangkok,Thailand; M. Gomes and P.Olliaro, WHO Special Pro-gramme for Research and Training in Tropical Diseases,World Health Organization, Geneva.

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depend on early efficacious treatment of a patienttoo ill to take oral medication. A priority for WHO istherefore to develop an effective, rapidly actingtreatment for administration to non per os patientsat high risk of mortality and unable to reach hospitalquickly.

The drug formulation identified to meet the chal-lenges of this setting is rectal artesunate. This canbe administered easily and safely by untrainedhealth workers and is acceptable to young children.WHO's intention is thus to achieve full developmentand distribution of artesunate in suppository formfor emergency treatment of patients during the timeneeded to reach hospital. Once the patient hasreached an equipped health facility, a more precisediagnosis can be made and treatment administeredas required.

The development strategyThe Artesunate Task Force was set up in 1996 tooperate as a "virtual" pharmaceutical company. Itmeets twice a year to oversee the development ofthe registration dossier with its sights firmly on theneed to urgently provide national programmes withadditional means to control malaria. It is comprisedof a core group of 4 members with ad hoc consulta-tion among other experts, regulatory officials andthe scientific community. This approach, aside frombeing flexible, has many advantages:

• A plan of work is created with the ultimate goal ofproviding national programmes with access to anantimalarial with life-saving qualities.

• World experts in chemotherapy, toxicology, chem-istry, regulatory affairs, and pharmacokinetics(nonlinear mixed effects modelling) can be calledupon on an expenses-only basis (although manygive advice and evaluate material for a symbolicfee).

• The pace of drug development is spurred by anurgent public health need for the product.

• A high level of collaboration can be achievedwhen parties are engaged in a common aim.

• Research capacity for related public health drugdevelopment is established in many areas involv-ing safety monitoring, good clinical practice andlaboratory capacity.

Demonstration of benefitThere are several reasons why rectal artesunatewas identified for development. A sharp decline inmalaria levels following introduction of the artemisi-nin derivatives in Viet Nam provided evidence ofthe potential role of these drugs in the control ofsevere malaria and associated mortality.

Although artesunate is widely regarded as the mostefficacious of the artemisinin derivatives, it is notunder patent and has not been subject to full regis-tration by a highly-developed regulatory authority.Furthermore, no pharmaceutical company hasshown willingness to do this in light of the invest-ment needed to constitute a registration dossier.WHO was thus able to fill the gap in drug develop-ment by taking the product to full registration status.

Raw data on the safety of artesunate, which hasbeen collected by investigators working on malariaover the past ten years in South-East Asia hasbeen made available and clinical data has beengenerated by WHO through studies of hospital-based patients with moderately severe malaria.However, the burden of proof for effectiveness in anemergency situation will fall upon the communitytrials now beginning in several countries. Thesetrials will be crucial in demonstrating whether earlytreatment halts severe disease and prevents a fataloutcome. Additionally, they will define the condi-tions of use and follow-up treatment, and provide aplatform for subsequent development of healtheducation programmes.

Regulatory mechanismsWHO will be the sole applicant for marketing ofrectal artesunate for the emergency treatment ofsevere malaria. Registration dossiers will be sub-mitted in Switzerland, the United Kingdom and theUnited States of America in late 1999 and registra-tion elsewhere is likely to be made by mutualagreement with the national drug regulatory author-ity.

The new drug application to be submitted to theFDA will be filed under orphan drug status andwithin the expedited approval process. Orphandrugs are those drugs that involve a condition ordisease affecting less than 200 000 diagnosedcases in the USA and expedited approval is re-served for products addressing serious or life-threatening illnesses. In these circumstances,approval is based on evidence of benefit on asurrogate endpoint pending the outcome of com-

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munity based studies designed to provide definitivesurvival data.

WHO's relationship with regulatory authorities inEurope and the USA has been one of partnership inachieving a public health benefit. Dialogue hastaken the form of evaluating an emergency productfor life-threatening suspected malaria. The highlevel of technical input by regulatory authorities andtheir understanding of the global impact of malariahas been appreciated by the Artesunate TaskForce. Above all, the development plan for artesu-nate has profited from the ability of drug regulatoryauthorities to look beyond immediate nationalresponsibilities towards the broader goal of globalpublic health.

A direct subsmission by WHO to regulatory authori-ties for registration of an amtimalarial is unprec-edented. In the past, WHO has undertaken focusedstudies with private-sector partners in various areasof drug development but has not assumed respon-sibility for the regulatory aspects. It is highly unlikelythat a fully registered artesunate product wouldhave been developed if WHO had not responded tothe need

Elements of a model strategyCollaboration is possible wherever parties benefitmutually and share a common aim. The followingsteps outline how WHO achieved this goal byexploiting its unique international role and expertisein public health.

• A common aim to develop and register a productof public health benefit was identified.

• Collaborative links were established with thepharmaceutical industry, regulatory authorities,scientists, experts, national authorities and com-munity health centres in endemic areas.

• Global expertise was harnessed cost-effectively.

• On behalf of WHO, scientific experts planned,gave advice and executed components of thestrategy.

• Industrial partners manufactured a final product incompliance with the highest quality, safety andefficacy requirements.

• A simple and focused path to registration wasplanned by the application of orphan drug statusand accelerated approval.

• Postmarketing surveillance and health educationprogrammes are planned to enable optimal use ofthe final product by public health agencies such asUNICEF, Roll Back Malaria, and national controlprogrammes.

References

1. Garattini, S. Financial interests constrain drug develop-ment. Science, 275: 287 (1997).

2. Newton, C.R., Krishna, S. Severe falciparum malaria inchildren: current understanding of pathophysiology andsupportive treatment. Pharmacology and Therapeutics,79(1): 1–53 (1998).

Vitamin Asupplementation strategiesVitamin A deficiency has been identified as aproblem of public health importance in over 60countries worldwide and about 250 million childrenare estimated to be at risk of this deficiency. Amongchildren under 5 years of age, some 3 million haveclinical signs of xerophthalmia.

Reducing vitamin A deficiency requires long-termapproaches which include food fortification orincreased dietary intake of foods rich in vitamin A.Periodic supplementation is a rapid, low-cost way toensure that children at risk receive enough vitaminA. The Expanded Programme on Immunization(EPI) is now linking delivery of vitamin A to itsroutine and supplementary immunization pro-grammes (1).

In the correct dosage, vitamin A is safe and has nonegative effect on seroconversion rates for OPV ormeasles vaccine. Occasionally, side effects such asheadache, loss of appetite, vomiting, or a bulgingfontanelle in infants may occur the day followingvitamin A administration. These symptoms areminor and transitory. Vitamin A supplements shouldnot be given to any pregnant woman or a woman ofreproductive age because of the risk of teratogenic-ity (2).

To avoid multiple dosing, vitamin A supplementa-tion should be recorded on the child's health card.Children aged 6 months and above should ideallyreceive high-dose supplements at intervals of 4–6months. If infants under 6 months are not breast-fed, they should receive one 50 000 IU supplementas a preventive measure, and if they show signs ofclinical vitamin A deficiency they should receive

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treatment of one 50 000 IU dose on 2 successivedays. The recommendation for postpartum supple-mentation for mothers is one 200 000 IU dose to beadministered within 6 weeks after delivery, which isusually a period of infertility in breastfeeding moth-ers (2).

Vitamin A supplementation is the easiest interven-tion to add to routine EPI schedules or nationalimmunization days and requires a minimum oftraining and equipment. Good planning is essentialfor the successful integration of vitamin A supple-mentation in national immunization events. Thefollowing are useful steps to follow when undertak-ing such an event.

1. Define whether the area or region has a vitaminA deficiency problem. Indications of this may behigh infant mortality and high measles casefatality rates.

2. Convince decision-makers of the importance ofvitamin A supplementation and engage partnerssuch as WHO, UNICEF, the Red Cross or non-governmental organizations and aid agencies.

3. Inform and educate the public, health care work-ers and politicians about the advantages ofsupplementation and the dangers of deficiency.

4. Evaluate success and use this information toimprove delivery of vitamin A in subsequentevents.

References

1. World Health Organization. Integration of vitamin Asupplementation with immunization. Weekly Epidemio-logical Record, 4: 1–8 (1999).

2. Expanded Programme on Immunization. EPI UpdateNo. 33. November 1998.

The microbial threat:Copenhagen recommendationsThe implications to human health of the increasingresistance of microorganisms to antimicrobialagents is a major public health problem in Europe.The international spread of microorganisms whichhas recently been recorded indicates that this canno longer be regarded as a national, but an inter-national problem and requires a common, globalsolution.

In September 1998, Ministers of Health fromEuropean Union countries met at a conference inCopenhagen, Denmark, to address the growingproblem of antimicrobial resistance within Europe.Recommendations from the conference weresubsequently drafted and transmitted to all Minis-ters of Health in the European Union. A summaryof their conclusions and recommendations follows.

Participants at the conference agreed that there isan established but complex link between theconsumption of antimicrobial agents and the preva-

Schedule for vitamin A supplementation (3)

Target group Encounter point Vitamin A dose

All mothers irrespective of mode of BCG, OPVO, DTPI 200 000 IUinfant feeding up to 6 weeks postpartum immunization scheduleif no vitamin A supplement received afterdelivery

Infants 9–11 months Measles vaccination 100 000 IUChildren 12 months and older schedule 200 000 IU

Children 1–4 years Booster doses* 200 000 IUSpecial campaigns*Delayed primary immunization

* The minimum interval between doses is1 month (exceptionallly the interval my be reduced in the case of clinicalvitamin A deficiency: see above).

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lence of drug resistance. Although the full extent ofthe problem is as yet unknown, resistance is lead-ing to increased deaths and illness, with conse-quential health expenditure. Although the pharma-ceutical industry is making great efforts to developnew antimicrobials, innovative medicines cannot beexpected to solve the immediate problem. It is thusa priority to introduce policies which govern therational use of the antimicrobials which are avail-able.

The provision of good quality data on resistancepatterns which are clinically and epidemiologicallyrelevant is essential if effective interventions are tobe implemented. A European surveillance systemshould be established based on existing nationalsystems to monitor trends in antimicrobial resist-ance of microorganisms of both human and animalorigin and the European Union should coordinatethe medical and veterinary sectors and seek theactive involvement of all parties.

Rational use of antimicrobial agentsEducational initiatives for both health professionalsand the general public are of major importance forimproving the use of antimicrobial agents. Antimi-crobials for therapeutic use should be prescription-only medicines and as such should not be adver-tised to the public. Guidelines for the rational use ofantimicrobials should be introduced into medicaland veterinary practice. Guidelines on good prac-tice in prescribing antimicrobials should be drawnup which set out (i) the conditions under whichantimicrobials should be prescribed; and (ii) theimportance of patient compliance and how this canbe achieved. Laboratories carrying out antimicrobialtesting should be strengthened.

The majority of participants at the conferenceconsidered that use of antimicrobials as growth

promoters was not justified and that safer non-antimicrobial alternatives should be developed,including improved farming practice. It was alsoconsidered urgent to conduct a full risk assessmentand coordinated research on antimicrobial resist-ance should be igiven high priority.

Recommendations

• Antimicrobial resistance is a major European andglobal problem.

• Pharmaceutical companies should be encouragedto develop new antimicrobial agents.

• The European Union and member states shouldset up a European surveillance system of antimi-crobial resistance.

• The European Union and member states shouldcollect data on the supply and consumption ofantimicrobial agents.

• The European Union and member states shouldencourage the adoption of a wide range of meas-ures to promote prudent use of antimicrobialagents.

• The European Union, member states and nationalresearch councils should make coordinatedresearch on antimicrobial resistance a highpriority.

• A way should be found to review progress ofthese recommendations and proposals.

Reference : Ministry of Health & Ministry of Food, Agricul-ture and Fisheries, Denmark. European Union Confer-ence, The Microbial Threat. "The Copenhagen Recom-mendation". 10 September 1998.

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General Information

The International Pharmacopoeia:50 years onIn countries with a robust pharmaceutical market,regulatory control measures ensure that drugs areefficacious, safe and of good quality. However, theextent to which a national health authority is able toprovide adequate regulatory control will depend onprevailing conditions, experience and the resourcesavailable to it. A prime consideration for WHO is tosupport national health authorities with reliableexpertise, information and technology. One impor-tant tool in the overall task of assuring quality is apharmacopoeia.

A pharmacopoeia is an official, legally bindingdocument which, in the majority of countries, isincorporated into the framework of national healthlegislation. This means that any pharmaceuticalproduct being manufactured within its boundariesmust conform to the nationally adopted pharmaco-poeia which will contain quality specifications forthe determination of finished drug products, drugsubstances and excipients. A quality specificationdescribes appropriate tests to confirm the identityand purity, and to determine the strength or con-tent, of an active substance.

The underlying principles of a pharmacopoeia arethat pharmaceutical substances and productsintended for human use should be manufactured inadequately equipped facilities which are managedby competent professionals and operated by quali-fied staff. General rules governing pharmaceuticalmanufacture are contained in good manufacturingpractices (GMP). Processes, premises, and instal-lations should also comply with regulations underwhich the product licence or marketing authoriza-tion has been granted and with any binding interna-tional standards in the case of those productsdestined for export.

Pharmaceutical preparations are usually producedon a large scale and are stored while they awaittransport. During storage, pharmacopoeial testingshould be undertaken to verify physical and chemi-cal stability during the claimed shelf-life. Suchpharmacopoeial tests will allow for the inevitable

variations that occur during production and packag-ing as well as for subsequent degradation duringstorage.

The following important principles should be consid-ered when pharmacopoeial standards are used toestablish compliance with regulatory requirements:

• the application of a monograph is understood ascompliance with all general requirements containedtherein and testing methods, texts, or noticespertaining to it;

• a product is not of pharmacopoeial quality unlessit complies with all the stated requirements.

A clear distinction exists between pharmacopoeialstandards and release specifications, although bothcomprise identical or similar tests. Release specifi-cations are applied by the manufacturer of a phar-maceutical product to confirm quality. However,since the manufacturer is also responsible for thequality of the product throughout its shelf-life, testsmust also be predictive. Thus, manufacturers’release specifications are generally more exactingthan the corresponding pharmacopoeial require-ments. As a general rule, quality must be built intoa product throughout the manufacturing processand cannot be added at a later stage of production.

The International PharmacopoeiaThe history of the International Pharmacopoeiadates back to 1874 when the strengths and compo-sition of drugs and their terminology were docu-mented in the Unification of the Formulae of PotentDrugs. In 1929, an agreement drawn up between19 countries proposed that the League of Nationsshould collaborate in the task of preparing an“international pharmacopoeia”.

In 1948, the First World Health Assembly approvedthe establishment of an expert committee to sup-port the work of the International Pharmacopoeia.Within the same context, the Programme on Inter-national Nonproprietary Names (INN) for Pharma-ceutical Substances was created in 1950 to createa single nonproprietary name to identify pharma-ceutical substances unambiguously on a worldwidebasis.

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In collaboration with national pharmacopoeia com-missions, the first edition of the International Phar-macopoeia was prepared by adapting and harmo-nizing monographs which were already published inmajor pharmacopoeias, or by the development ofnew standards. Drug substances were chosen withthe needs of developing countries in mind, and withemphasis on treatments for tropical diseases. Thefirst edition of the International Pharmacopoeia ap-peared in English, French and Spanish, and wassubsequently translated into German and Japa-nese. It comprised 422 monographs and 59 appen-dices, including monographs on pharmaceuticalstarting materials.

The second edition of the International Pharmaco-poeia saw the addition of a number of new mono-graphs. Specifications were tested by nationalpharmacopoeia commissions, national qualitycontrol laboratories, pharmaceutical manufacturersand national institutes and 162 pharmaceuticalpreparations were added, while 114 monographswere deleted. The appendices included a numberof new analytical control methods using infraredspectrophotometry, chromatography (column,paper and thin-layer), non-aqueous titration, andradioactivity.

By 1975, a trend was developing among the majorpharmacopoeias to include techniques requiring ex-pensive analytical instrumentation of the kind that isnot readily available in smaller drug testing labora-tories operating on low budgets. In response, it wasdecided that the International Pharmacopoeiashould focus on providing information adapted tothe needs of developing countries and recommendonly simple, classical techniques which would givea reasonable assurance of identity and quality.Henceforth priority was given to monographs forthose drugs that are most widely available through-out the world, such as those used in national con-trol programmes or contained in the Model List ofEssential Drugs. Information was also provided ondrugs likely to contain impurities arising from degra-dation during storage or difficult to manufacture.

Volume 5 of the third edition is now in the finalstages of preparation. It contains additions to thelist of monographs for active pharmaceutical sub-stances and a number of important general texts ondissolution tests, nomenclature and specificationsfor tablets. A section will include the newly devel-oped antimalarial drug substances arteether, arte-mether, artemisinin, artesunate, anddihydroartemisinin.

Future activitiesIn the future, work on dissolution tests for predictingthe capacity of equivalence testing of groups ofdrug products will be undertaken. WHO will alsocontinue to provide monographs for starting materi-als using simple test methodologies. The impor-tance of this activity was emphasized following inci-dents of contamination of pharmaceutical productswith diethylene glycol.

Future activities of the International Pharmacopoeiashould be regarded in the context of quality controlof pharmaceuticals in general. Many countries stilldo not have their own national pharmacopoeia anddepend either totally or in part on the monographsincluded in the International Pharmacopoeia.

It must be emphasized that the trend of advocatingexpensive methods for drug testing is driven by in-creasingly large-scale drug manufacture and doesnot consider the more varied practical needs oflesser developed countries. This renders the majorpharmacopoeias less and less adapted for thepractice of drug quality control in countries thatneed drug testing methods for various other rea-sons, such as on-the-spot identification of counter-feit pharmaceuticals. If the International Pharmaco-poeia is abandoned, WHO would lose all potentialinfluence in this field.

Artemisinin: guidelines for useArtemisinin products, including artesunate, arte-mether, and arteether, were first developed as anti-malarials in China. They resolve fever and clearparasites more rapidly than any other known anti-malarial agent. Moreover, they are the only group ofantimalarial drugs to which resistance of P. falci-parum has not yet developed and, as such, play anessential role in malaria control. Protection of thisproduct from resistance will depend on controlled,rational use requiring the urgent development andimplementation of global and national policies con-cerning management, availability and prescription.

In order to address these issues, a meeting washeld in Geneva from 10–12 June 1998 to review theuse of artemisinin products in the light of experi-ence now available from several countries. Partici-pants at the meeting gave advice on policy anddrafted guidelines for the selection and correct useof artemisinin products in different epidemiologicalsituations. A summary of the report of the meetingfollows. More concise information is available from

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the report itself and includes information on recom-mended regimens and clinical use of artemisininproducts as well as priority areas for further re-search*.

In practice, the process of registration and availabil-ity of artemisinin products varies depending on theparticular circumstances of each country. Somecountries, such as Bangladesh and the Philippines,do not have a problem with multidrug resistant ma-laria and have not allowed these drugs onto themarket. Others, such as Myanmar and Viet Nam,face problems of resistance to antimalarials andconsequently allow artemisinin products to betraded by pharmacies and market sellers wherepopulations do not have access to public healthservices.

Thailand was one of the first countries outsideChina and Viet Nam to use artemisinin products inthe public sector. During the early 1990s, it wasfacing acute problems of multidrug resistance withfailure rates of antimalarials, and particularly meflo-quine, reaching over 50% in some areas. In view ofthe lack of full registration of artemisinin products inany highly-developed country, the Thai authoritiesallowed probational use of the drug in the publichealth sector only on the understanding that rein-forced postmarketing surveillance would be carriedout. All batches of imported artemisinin productswere controlled for quality by the Thai Food andDrug Administration.

Faced with an unacceptable level of chloroquinefailures, Papua New Guinea has also revised itsantimalarial drug policy. A combination of chloro-quine plus sulfadoxine/pyrimethamine is the first-line drug of choice with oral artesunate in reserve.Parenteral or rectal artesunate is available for thetreatment of severe malaria. In Brazil, dispensing ofartemisinin products is restricted to approved publicsector hospitals, but only for the treatment of se-vere malaria.

By contrast, artemisinin products are widely avail-able in Africa despite warnings recommending cau-tion. Injectable artemether and oral artesunate pro-duced by French-based companies have now beenregistered in 38 countries in Africa. Formulationsfrom China are also circulating.

A weak regulatory system is one of the greatest ob-stacles to the correct deployment and rational useof antimalarials. Even in countries where regulatorymechanisms are well established, the system is by-passed by illegal activities which lead to the sale ofsubstandard and counterfeit drugs. The WHO Cer-tification Scheme is a useful way of verifying thestatus of imported products. Alternatively, manycountries insist on the provision of a certificate ofregistration and free sale from the country of origin.However, a free-sale certificate will not give infor-mation on the quality and stability of the productunder local conditions.

Essential requirements for the rational use of ar-temisinin products are:

• A drug registration authority which will regulatethe import and distribution of drugs and will beable to resist commercial pressure to make drugsfreely available.

• Development of a sound national antimalarialdrug policy and inclusion in the national essentialdrugs list.

• Awareness campaigns to prescribers on the ra-tional use of drugs.

• Information, education and communication on ap-propriate treatment seeking behaviour to the gen-eral public.

An assessment of the quality of artemisinin prod-ucts can be made using several methods, rangingfrom the relatively cheap thin-layer chromatography(TLC), to the high-performance liquid chromatogra-phy (HPLC) with ultraviolet detector allowing accu-rate quantitation of diluents and breakdown prod-ucts. The former system may be used at entryports or for on-the-spot testing, with confirmationfrom the second method situated, for example, in anational control laboratory when regulatory actionneeds to be taken. WHO is presently developing invitro dissolution profiles for dosage forms, andquality specifications for the artemisinin productswill soon be published in the International Pharma-copoeia.

Recommendations

1. Use• Artemisinin is a safe and effective alternative to

quinine for the treatment of severe malaria . In ar-

General Information

*World Health Organization. The use of artemisinin and itsderivatives as antimalarial drugs. Report of a joint CTD/DMP/TDR Informal Consultation. Unpublished documentWHO/MAL/98.1086.

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eas where sensitivity to quinine is reduced, artem-isinin is the treatment of choice. In other areas, achange from quinine to artemisinin may not nec-essarily improve survival, but may be preferred inview of ease of administration and lessened sideeffects.

• Artemisinin is a potent and effective drug for thetreatment of uncomplicated malaria. However,use should be limited to patients with multidrug-resistant malaria.

• To improve efficacy of the drug and delay onsetof resistance artemisinin should always be usedin combination with another effective antimalarial.Under certain circumstances, such as a history ofadverse reactions to the combination, mono-therapy may be indicated. In this case, a 7-daycourse of treatment is recommended as long ascompliance can be assured.

• In areas where mefloquine is the first-line drug ofchoice, or a change to mefloquine is being consid-ered, a 3-day course of artemisinin in combinationwith mefloquine is recommended.

• Combination therapy using artemisinin and arte-misinin derivatives could slow resistance to eachcomponent and is a promising strategy. However,studies have not yet evaluated the tolerability, effi-cacy, effectiveness and cost benefit of this ap-proach.

• The use of parenteral preparations of artemisininin patients able to take oral medication is not indi-cated.

• Artemisinin or its derivatives should not be usedfor chemoprophylaxis.

2. Registration• National authorities should develop policies re-

garding the manufacture, import, distribution, pro-motion and use of artemisinin products with a viewto preventing or delaying the development of re-sistance. It is important that health care providers,together with those involved in distribution andsale of these products, health organizations andcommunity service agencies should comply withnational policy.

• Only artemisinin products manufactured accordingto good manufacturing practices (GMP) should beused.

• In order to ascertain the regulatory and GMP sta-tus of products, the WHO Certification Schememay be used by governments to provide informa-tion on the status of the product in the exportingcountry.

• Governments lacking expertise may call on theassistance of WHO when developing systems ofGMP, quality assurance or testing.

• In order to maintain stability, special attentionshould be paid to conditions of transport, distribu-tion and storage.

3. Drug susceptability monitoring• Monitoring is the responsibility of the national con-

trol programme and should be conducted in senti-nel sites on a regular and sustained basis. Patientresponse should be monitored to detect changesin susceptibility.

• Wherever artemisinin products are used, post-marketing surveillance should be in place. Al-though there is now a body of information confirm-ing the safety of standard artemisinin regimens,information is still needed on the long-term effects,particularly among pregnant women and followingrepeat treatments.

4. Information• Guidelines on the use of artemisinin products

should be made available by national authoritiesand distributed to all health care providers, dis-tributors and sales outlets. This information maycomplement the national formulary, prescribing in-formation or guidelines for pharmacists.

• To avoid consumer misuse, it is important to edu-cate the general public on the correct use andneed for compliance when taking these products.

• Donor agencies, consumer service organizationsand pharmaceutical companies should be discour-aged from promoting or importing these drugs out-side of official channels.

• Countries facing problems of multidrug resistanceshould develop mechanisms whereby they mayshare information and experience with other coun-tries.

In order to achieve implementation of these recom-mendations, collaboration will be required not onlyfrom the public and private health care sectors butthe community at large.

General Information

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Regulatory Matters

Tolcapone and fatal liver injuryEuropean Union — The European Agency for theEvaluation of Medicinal Products (EMEA) hasissued a recommendation to suspend the marketingauthorization for tolcapone, a catechol-O-methyltransferase (COMT) inhibitor indicated as adjunc-tive treatment for Parkinson disease. The productwas approved by the CPMP in August 1997.

The Manufacturer has reported 9 cases of seriousabnormal hepatic function, 2 of which were fatal.Monitoring of liver function did not predict thesereactions, and the Agency has also identified a riskof rhabdomyolysis and neuroleptic malignant syn-drome. The latter reaction may be associated withabrupt discontinuation of therapy.

The EMEA advises patients taking tolcapone toconsult their physician immediately to initiate dis-continuation which should be undertaken over 3–6days under medical supervision.

Reference : Press release from EMEA. CPMP/2457/98:Recommendation for the suspension of the marketingauthorization for Tasmar® (tolcapone). 17 November1998.

United States of America — The Food and DrugAdministration and the manufacturer of tolcaponehave advised physicians to carefully follow newwarnings added to the labelling. The warning callsfor liver monitoring tests fortnightly and suggestsself-monitoring by patients for signs of liver disease,including jaundice, fatigue and loss of appetite. Thewarning also states that if a patient fails to showsubstantial clinical benefit within three weeks ofinitiating treatment they should be withdrawn fromthe drug under medical supervision.

Reference : FDA Talk Paper, T98–81, November 1998.

Entacapone labelling strengthenedEuropean Union — The European Agency for theEvaluation of Medicines has requested reinforcedpatient information from the manufacturer of enta-capone, a COMT inhibitor which was approved inSeptember 1998 for Parkinson disease (1, 2), that

the product must not be used if there is a history ofneuroleptic malignant syndrome or non-traumaticrhabdomyolysis, and that if the drug is stoppeddiscontinuation should be carried out under medicalsupervision.

These changes have been made based on thepossibility that abrupt discontinuation may beassociated with adverse reactions such as thosereported with another COMT inhibitor, tolcapone.

The Committee for Proprietary Medicinal Products(CPMP) has concluded that the most recent safetydata for entacapone show that the product does notappear to be hepatotoxic. Rare reports of an in-crease in liver enzymes have been received butthese cases involved patients with an underlyingdisease which could have been the cause.

References

1. Press release from EMEA. CPMP/2178/98. December,1998.

2. WHO Drug Information, 12(4), 242 (1998).

Rituximab: newrecommendationsEuropean Union — The European Agency forEvaluation of Medicinal Products (EMEA) hasreceived reports of severe adverse reactions,including 8 fatal cases of cytokine release syn-drome, associated with the monoclonal antibody,rituximab. The product was approved in June 1998for treatment of patients with stage III and IV follicu-lar lymphoma who are chemoresistant, although 3of the fatal cases were receiving the medication fora different indication (1).

It is estimated that some 14 000 patients have beentreated worldwide. A common feature of the fatalcases was the development of severe reactionsduring the first infusion. Cytokine release syndromeis characterized by dyspnoea accompanied bybronchospasm or hypoxia.

New recommendations have been provided by themanufacturer in a circular letter, outlining the

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WHO Drug Information Vol. 13, No. 1, 1999 Regulatory Matters

changes and emphasizing that rituximab shouldonly be prescribed for its approved indication.Patients with a history of cardiac disease should bemonitored closely (2).

References

1. Press Release. Mabthera® (Rituximab): Reports ofadverse reactions – new recommendations for use.EMEA/40532/98, 30 November 1998

2. SCRIP No. 2393, 4 December 1998.

United States of America — The Food and DrugAdministration and the manufacturer of rituximabhave informed physicians that, since its approval inNovember 1997, approximately 70 cases of seriousinfusion-related events have been reported. Areview of reports seems to suggest that patientswith a high tumour burden or with a high number ofcirculating malignant cells may be at higher risk.Such patients should be treated with extremecaution and be closely monitored throughout eachinfusion. The package insert was revised in Sep-tember 1998 to include additional information in thewarnings section regarding tumour lysis syndrome.

Reference : Communication from FDA Medwatch trans-mitting letter from Genentech, Inc. and IDEC Pharmaceu-ticals Corporation. 5 December 1998. http://www.fda.gov/medwatch/safety/1998/rituxa.htm

Montelukast and eosinophiliaUnited States of America — Montelukast is aselective leukotriene (LTD4) receptor antagonistthat was approved by the Food and Drug Adminis-tration in February 1998 for the prophylaxis andchronic treatment of asthma in adults and paediatricpatients over 6 years of age.

The FDA, in collaboration with the manufacturer,has informed physicians that therapy withmontelukast has been associated rarely with sys-temic eosinophilia, presenting on occasions clinicalfeatures of vasculitis consistent with Churg-Strausssyndrome. This adverse reaction has been associ-ated with a reduction in concomitant oral corticos-teroid therapy. Physicians should be alert to pa-tients developing eosinophilia, vasculitis rash,worsening of pulmonary symptoms, cardiac compli-cations or neuropathy (1).

Leukotriene antagonists are also marketed in manyEuropean countries (2).

Reference :

1. Communication from FDA Medwatch transmitting letterfrom Merck & Co, Inc. December 1998. http://www.fda.gov/medwatch/safety/1998/singul.htm

2. WHO Drug Information, 12(4): 241 (1998).

Amineptine and dependenceFrance — In collaboration with the manufacturer,the Medicines Agency has decided to suspend themarketing authorization of amineptine followingreports of drug abuse and dependence.

Amineptine is an antidepressant which inhibits thereuptake of dopamine and is indicated in majordepressive episodes. It has been available inFrance since 1978, but is also marketed in 66 othercountries worldwide, particularly Africa, Asia andSouth America . After suspension, amineptine willbe available through compassionate use in hospi-tals until June 1999 for addicted patients who needgradual discontinuation.

The risk of dependence with amineptine is wellknown and the two major complications are signifi-cant weight loss and micro- and macrocystic acne.Dependence always results in major withdrawaldifficulties, including agitation, mania, confusionand relapse of depression.

Reference : Communication to WHO from the Agence duMédicament, 22 January 1999.

Cosmetic containspharmaceutical substancesGermany — The Federal Institute for Drugs andMedical Devices has withdrawn a range of skinproducts, Psorigon®, from the market after formula-tions were found to contain unlabelled cortisonederivatives and tretinoin. Neither of these sub-stances has been approved for use in cosmeticsand are available on prescription only in Germany.

Reference : PIC Rapid Alert, Federal Institute for Drugsand Medical Devices, Berlin, 6 November 1998.

United Kingdom — The Medicines Control Agencyis currently analysing samples of Psorigon® for thepresence of undeclared corticosteroids. This prod-uct is advertised as a treatment for psoriasis and isavailable through the Internet. The distributor has

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WHO Drug Information Vol. 13, No. 1, 1999Regulatory Matters

agreed to withdraw the product, which is manufac-tured in Germany and provided through a supplierin Gibraltar.

Reference : Defective Medicines Report Centre, Medi-cines Control Agency, Communication to WHO.

Sweden — The Medical Products Agency haswithdrawn a range of skin products, Psorial®. Theproducts did not have a marketing authorizationalthough they contained the corticosteroids triam-cinolone and halcinonide. The products werelabelled to treat psoriasis and various types ofeczema. Many patients had purchased the productsin order to avoid corticosteroid use.

Reference : Information från Läkemedelsverket, 9(7): 3(1998).

Jurisdiction over cloningtechnologyUnited States of America — The Food and DrugAdministration has issued a letter to all institutionalreview boards (IRBs) confirming that the agencyhas jurisdiction over clinical research involvinghuman cloning technology and informing IRBs ofthe FDA regulatory process that is required beforean investigator can proceed with such a clinicalinvestigation.

Before any research using cloning technology tocreate a human being can begin, the sponsor of theresearch is required to submit to FDA an Investiga-tional New Drug (IND) application describing theproposed research plan; obtain authorization from aproperly constituted and functioning IRB; and toprovide a commitment from the investigators ofinformed consent from all human subjects involvedin the research.

Reference : Letter from FDA communicated through http://www.fda.gov/oc/oha/irbletr.html

Contaminated hydrocortisoneFrance/Belgium — Following a request by theUniversity Hospital of Kamenge, Burundi, theAgence du Médicament has analysed a 200 mg/20ml preparation of injectable solution hydrocortisonemanufactured in China by Shanghai Sine Pharma-ceutical Company and distributed by Exphar,Belgium.

Analysis demonstrated an unacceptably highethanol content of 52% v/v or 41% m/v. Patientshad experienced a burning sensation and beensubject to behavioural disturbances on injection ofthe solution.

Reference : Communication to WHO from the GeneralPharmaceutical Inspectorate, Belgium enclosing conclu-sions of analysis from the Agence du Médicament,France. 29 October 1998.

Intravenous immune globulinand acute renal failureUnited States of America — The Center forBiologics Evaluation and Research of the Food andDrug Administration has circulated a warning tophysicians concerning the potential risk of acuterenal failure associated with the intravenous admin-istration of human immunoglobulin products. Sinceintroduction in 1981, the FDA has gathered over114 reports, including 80 reports from the USA,associated with renal dysfunction or acute renalfailure. Of the 17 fatal cases, many were due toserious underlying conditions.

Preliminary evidence suggests that products whichalso contain sucrose may present a greater risk andrenal histopathological examinations have indicatedan osmotic injury to the proximal renal tubules.

In order to avoid these reactions the FDA recom-mends adequate hydration prior to infusion, andparticular caution in patients with preexisting renalinsufficiency, diabetes, volume depletion, sepsis,concomitant use of nephrotoxic drugs and over 65years of age.

Reference : Dear Doctor letter from the Center for Biolog-ics Evaluation and Research, November 1998.

Sertindole suspendedpending evaluationUnited Kingdom — The Committee on Safety ofMedicines has informed physicians that the manu-facturer of sertindole, an antipsychotic agent indi-cated for the treatment of schizophrenia, has volun-tarily suspended availability of the product becauseof reports of cardiac arrhythmias and sudden deathassociated with its use.

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WHO Drug Information Vol. 13, No. 1, 1999 Regulatory Matters

Sertindole was approved by the European Union in1996. It is now suspended pending a full evaluationof risks and benefits in collaboration with the Medi-cines Control Agency.

Physicians are advised to recall all patients usingsertindole and to propose alternative treatment ifpossible. Discontinuation should be initiated undermedical supervision and tapered over a period oftwo weeks while other antipsychotic treatment isintroduced.

Reference : Communication from the Committee onSafety of Medicines, 2 December 1998.

Labelling information forpaediatric useUnited States of America — The Food and DrugAdministration has issued a final rule requiring thatapplications for new drugs and biological productscontain sufficient data and information to supportdirections for paediatric use. This action cameabout to ensure adequate medical care for children.Paediatricians often stated that they were requiredto prescribe drugs to young children that were notlabelled for children and for which paediatric dos-age forms did not exist.

Most drugs and biologicals have not been ad-equately tested in the paediatric subpopulation andproduct labelling frequently fails to provide direc-tions for safe and effective use in children. Manu-facturers of certain products already marketed willnow be required to provide data and information tosupport paediatric use. Manufacturers have 20months to submit the required assessment. Thenew rule should significantly improve paediatriclabelling.

Reference : Federal Register, Volume 63(231): 66631–66672 (1998).

Tryptophan prescribing warningSweden — The Medical Products Agency hasinformed physicians that tryptophan is not author-ized as a medical product and can be prescribedonly in the context of clinical trials as a supplemen-tary medication for sleeping disorders or depres-sion.

The Agency also reminds physicians of an adversereaction syndrome involving muscle and leg pains,fever, skin rash and eosinophilia that has beenreported in association with high doses of tryp-tophan.


Impurities in dietarytryptophan productsUnited States of America — The Food and Drugadministration has confirmed the presence ofimpurities in some 5-hydroxy-L-tryptophan (5HTP)products promoted for use as aids for insomnia,depression, obesity and for children with attentiondeficit disorders.

One of the impurities is known as peak X. Althoughthe significance of peak X is unknown, past experi-ence with these products has shown that eosi-nophilia-myalgia syndrome is associated with 5HTPand L-tryptophan. It has not yet been resolvedwhether EMS cases were caused by L-tryptophanor 5HTP, one or more impurities, or other factors.The Centers for Disease Control and Preventionhas identified more than 1500 cases of EMS,including at least 38 deaths, associated with theuse of L-tryptophan.

Eosinophilia-myalgia syndrome is a serious sys-temic illness characterized by elevations of certainwhite blood cells and severe muscle pain. At thepresent time, the Agency is unaware of any recentillnesses associated with 5HTP products. However,the widespread sale of these products has onlyrecently begun.

Reference : FDA Talk Paper, T98–48, 1998.

Chlormezanone withdrawnZimbabwe — The Medicines Control Authority hascancelled the marketing authorization for productscontaining chlormezanone following internationalregulatory action based on safety evaluations. Thedrug has been associated with an unacceptableincidence of Stevens-Johnson syndrome.

Reference : Drug Information Bulletin, Volume 2(1), 1998.

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WHO Drug Information Vol. 13, No. 1, 1999Regulatory Matters

New home screening testfor abuse drugsUnited States of America — The Food and DrugAdministration has approved a nonprescription testfor drugs of abuse that can be performed at homeand gives preliminary results in minutes. However,conclusive results can only be provided by a labora-tory.

The Quickscreen At-Home Drug Test® comes intwo models. One tests for cocaine, marijuana,opiates, amphetamine and phencyclidine and thesecond for cocaine, marijuana, opiates, ampheta-mines and metamfetamine. Some drugs can bedetected within two hours of use and remain detect-able for several days or more. Other drugs have adifferent timing.

If the initial results are "negative" nothing furtherneeds to be done, but if the results are "inconclu-sive" the urine sample is placed into a mailer pro-vided with the kit and sent to a designated labora-tory for confirmatory testing. The results are avail-able in three days. Numerous factors can affect testresults. For example, certain foods and medicinesand being in the presence of a heavy marijuanasmoker may give a positive result.

Reference : FDA Talk Paper, T98-74, October 1998.

High-dose terfenadine withdrawnEuropean Union — The Commission for Propri-etary Medicinal Products (CPMP) has decided towithdraw 120 mg strength terfenadine productsfrom the market because of a higher risk of over-dose (1). The labelling for lower dose products hasalso been changed to reflect age and weight restric-tions and to emphasize contraindications.

Terfenadine has been associated with serious,fatal, cardiac adverse reactions when metabolismof the drug is reduced by disease or interaction withother drugs influencing the same metabolizingenzymes (2).

References

1. The Pharmaceutical Journal, 261: 658 (1998).

2. WHO Drug Information, 11: 17, 11:67 and 11.68 (1997).

Liquid ecstasy (GHB)trading investigatedUnited Kingdom — The Medicines Control Agencyis investigating the illegal trading and promotion ofgamma hydroxybutyrate (GHB), a drug known as"liquid ecstasy". The drug has been promoted forbody building, claiming that it stimulates the body'sproduction of growth hormone (1). It has also beenused as a sleeping aid and reports have beenreceived of overdosing and abuse and as a recrea-tional drug used with other substances (2). Thedrug is legally manufactured within the EuropeanUnion as a general anaesthetic but is not licensedin the United Kingdom.

Overdosing with GHB causes severe intoxication.Cases of poisoning have been reported (57 cases)over a three month period in the USA, as well as inthe United Kingdom.

References :

1. Liquid ecstasy trading to be investigated. British Medi-cal Journal, 317: 1035 (1998).

2. Thomas, G. Bonner, S., Gascoigne, A. Coma inducedby abuse of gamma-hydroxybutyrate (GBH or liquidecstasy): a case report. British Medical Journal, 314: 35(1997).

2. WHO Drug Information, 12(4): 229 (1998).

Metamizole sodium withdrawnZimbabwe — The Medicines Control Agency hascancelled the marketing authorization for all phar-maceutical products containing metamizole sodiumbecause of the potential risk of fatal agranulocyto-sis.

Reference : Drug Information Bulletin, Volume 2(1), 1998.

Medication guidesUnited States of America — The Food and DrugAdministration has issued a final rule on require-ments for the distribution of patient labelling forselected prescription products used primarily on anoutpatient basis. Medication Guides will now beprovided with certain products that pose a seriousor significant public health concern. They will con-tain information necessary for the safe and effectiveuse of the medication.

23


A Medication Guide will be required when: (1) thedrug product is one for which the information couldhelp prevent serious adverse effects; (ii) the drugproduct has serious risks and these risks couldaffect the patient's decision to use or continue touse the product; and (iii) the drug product is impor-tant to health, and compliance with the directionsfor use is crucial to effectiveness of the treatment.

Reference : Federal Register, 63(230): 66377–664001(1998).

Streptokinase: severe back painSweden — The Medical Products Agency hasreceived reports of severe acute back pain in sixpatients treated with streptokinase infusion. Thepain occurred when 10–15 ml of streptokinase hadbeen given to patients requiring a further dose.


Sildenafil: revised labellingUnited States of America — In collaboration withthe manufacturer, the Food and Drug Administra-tion is advising doctors of new warnings and infor-mation which have been added to the productlabelling for sildenafil (Viagra®).

Over 6 million prescriptions have been written forsildenafil, and adverse events constitute only asmall fraction of these. The updated informationincludes information on cardiovascular events, riskof sexual activity and underlying cardiovascularstatus, vasodilatory effects and priapism. Severalgroups of patients were not studied in the clinicaltrials for sildenafil and these include patients withcardiovascular problems, hypotension or hyperten-sion, and retinitis pigmentosa. Such patientsshould be prescribed sildenafil with extreme cau-tion.

Reference : FDA Talk Paper, T98-83, 1998.

Chlorzoxazone and hepatotoxicityChile — The product information and labelling forproducts containing chlorzoxazone, a musclerelaxant, have been revised to include a warning of

severe hepatic damage. This is a rare, but unpre-dictable occurrence and will depend on the suscep-tibility of the patient. A physician should be con-tacted immediately if fever, nausea or vomitingoccur.

Reference : Boletin Informativo sobre Medicamentos, 15(1), 1998.

Mislabelling of glucose

Belgium — Two premature infants have died afterbeing administered potassium chloride (KCl) takenfrom containers labelled "glucose 5% 10-ml sterilesolution for injection". The manufacturer and dis-tributor reports that one batch, number 97H21C and7344C16, is implicated and may be circulating inBelgium Luxembourg, Slovak Republic and Ger-many. The product may have been exported toother countries.

Reference : EU Rapid Alert, General PharmaceuticalsInspectorate, Brussels, 20 January 1999.

Internet sale ofgamma butyrolactone (GBL)

United States of America — Products containinggamma butyrolactone (GBL) are being sold via theinternet, in health food stores, gymnasiums andfitness centres under various brand names such asBlue Nitro, or GH Revitalizer. These products, whilelabelled as dietary supplements, are unapprovednew drugs and have not been approved for mar-keting.

When taken orally, GBL — which is converted inthe body to gamma hydroxybutyrate (GHB) hasserious side effects (see page 22). Reported effectsinclude seizures, vomiting, slow heart rate anddeath. In some cases consumers became uncon-scious or comatose and several required intubationfor respiratory assistance.

Consumers are advised to dispose of any productsof this type in their possession and companies arebeing requested to voluntarily recall such products.

Reference : FDA Talk Paper, T99-5, January 1999.

Regulatory Matters

24


New ATC level codes (other than 5th level)Selective estrogen receptor modulators G03XCCOX-2 specific inhibitors M01AH

New ATC 5th level codesabacavir J05AF06azelastine S01GX07basiliximab L04AA09becaplermin D03AX06betaxolol, combinations S01ED52budipine N04BX03celecoxib M01AH01clobetasol and antibiotics D07CD01combinations G04BE30dexketoprofen M01AE17finasteride D11AX10fluconazole D01AC15fluocortolone and antibiotics D07CC06flurithromycin J01FA14fomivirsen S01AD08fosphenytoin N03AB05insulin lispro A10AC04insulin lispro A10AD04ioflupane (123I) V09AB03lansoprazole, amoxicillin and metronidazole A02BD03lansoprazole, tetracycline and metronidazole A02BD02levacetylmethadol N02AC06loperamide, combinations A07DA53mannitol A06AD16metoprolol, combination packages C07AB52nonacog alfa B02BD09

The following temporary classifications were agreed at a meeting of the WHO International Working Groupfor Drug Statistics Methodology which took place on 12–14 October 1998 in Geneva. Comments on orobjctions to the classification should be forwarded to the WHO Collaborating Centre for Drug StatisticsMethodology, P.O. Box 100, Veivet, 0518 Oslo, Norway (telephone: 0047 22 16 9811, fax: 0047 22 169818, e-mail: [email protected]) before 15 April 1999 . A final list of classifications will be publishedsubsequently in this journal. The inclusion of a substance in the lists does not imply any recommendationof use in medicine or pharmacy.

ATC Level INN/common name ATC code

ATC/DDD Classification (temporary)

25


perindopril and diuretics C09BA04potassium permanganate D08AX06pramocaine D04AB07raloxifene G03XC01rizatriptan N02CC04sertaconazole D01AC14sevelamer V03AE02sodium hypochlorite D08AX07technetium (99mTc) depreotide V09IA05telmisartan C09CA07temocapril C09AA14tilactase A09AA04tirofiban B01AC17trovafloxacin J01MA13trypsin, combinations M09AB52valsartan and diuretics C09DA03voglibose A10BF03ziprasidone N05AE04

ATC code changesPrevious: ferric ammonium citrate B03AB10New: ferric ammonium citrate V08CA07

Change of level name

Previous: Imidazole derivativesNew: Imidazole and triazole derivatives D01ACPrevious: Drugs for treatment of hyperkalaemiaNew: Drugs for treatment of hyperkalaemia V03AE and hyperphosphataemia

New DDDs:

INN/common name DDD Unit Route of ATC codeadministration

balsalazide 6.75 g O A07EC04clopidogrel 75 mg O B01AC04dexketoprofen 75 mg O M01AE17*dihydroergotamine 1 mg N N02CA01fenofibrate 0.2 g (micronised) O C10AB05finasteride 1 mg O D11AX10*fosphenytoin 0.45 g P N03AB05*mometasone 0.2 mg N R01AD09ondansetron 16 mg R A04AA01orlistat 0.36 g O A08AB01


ATC/DDD Classification

26


New DDDs (continued):

INN/common name DDD Unit Route of ATC codeadministration

pantoprazole 40 mg P A02BC02propiverine 30 mg O G04BD06quetiapine 0.4 g O N05AH04raloxifene 60 mg O G03XC01*riluzole 0.1 g O N07XX02rivastigmine 9 mg O N07AA06rizatriptan 10 mg O N02CC04*temocapril 10 mg O CO9AA14*triamcinolone 0.22 mg N R01AD11trovafloxacin 0.2 g O,P J01MA13*ziprasidone 80 mg O N05AE04*

* temporary ATC code

Change of DDDs:

dalteparin 2.5 TU (antiXa) P B01AB04danaparoid 1.5 TU (antiXa) P B01AB09dexibuprofen 0.8 g O M01AE14dolasetron 0.1 g P A04AA04enoxaparin 2.0 TU (antiXa) P B01AB05fluticasone 0.2 mg N R01AD08nandroparin 2.85 TU (antiXa) P B01AB06parnaparin 3.2 TU (antiXa) P B01AB07reviparin 1.43 TU (antiXa) P B01AB08tinzaparin 3.5 TU (antiXa) P B01AB10

Temporary ATC codes and DDDs under evaluation:

INN/common name ATC code DDD

follitropin beta G03GA06 75 U* Pmemantine N06BX21*propentofylline N06BC02*


27


New ATC level codes (other than 5th level):Helicobacter pylori, combinations for eradication of A02BDAntipsoriatics, other, for systemic use D05BXGynecologicals, other G02CX

New ATC 5th level codes:

azidamfenicol S01A A25albumin tannate, combinations A07X A51balsalazide A07E C04benzoyl peroxide, combinations D10A E51brimonidine S01E A05candesartan C09C A06candesartan and diuretics C09D A06canrenone C03D A03carbamide, combinations D02A E51charcoal, medicinal, combinations A07B A51cefdinir J01D A42cefprozil J01D A41cinolazepam N05C D13delavirdine J05A G02diphtheria-haemophilus influenzae B- pertussis-poliomyelitis-tetanus J07C A06efavirenz J05A G03emedastine S01G X06ethambutol, combinations J04A M03etilefrine, combinations C01C A51ferric oxide dextran complex B03A C06ferric proteinsuccinylate B03A B09fluocinonide and antibacterials D07C C05fumaric acid derivatives, combinations D05B X51gadoversetamide V08C A06

The following classifications were agreed at a meeting of the WHO International Drug Utilization WorkingGroup which took place on 30 and 31 March 1998 in Oslo.They came into force on 15 November 1998 . Allrequests for classification should be forwarded to the WHO Collaborating Centre for Drug StatisticsMethodology, P.O. Box 100, Veivet, 0518, Oslo, Norway (telephone: 00 47 22 16 9811, fax: 0047 22 169818, e-mail: [email protected]). The inclusion of a substance in the lists does not imply any recommendationof use in medicine or pharmacy.


ATC/DDD Classification (final)

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heparin S01X A14hexamidine R01A X07hydrocortisone, combinations R01A D60hydroxocobalamin, combinations B03B A53ibopamine S01F B03imiquimod D06B B10immunocyanin L03A X10interferon alfa-2a L03A B04interferon alfa-2b L03A B05interferon alfa-n1 L03A B06interferon beta-1a L03A B07interferon beta-1b L03A B08isoprenaline, combinations R03C B51isopropanol D08A X05kanamycin S01A A24ketamine N01A X14levobupivacaine N01B B10levofloxacin J01M A12macrogol, combinations A06A D65melitracen and psycholeptics N06C A02mometasone R01A D09nystatin, combinations G01A A51omeprazole, amoxicillin, and metronidazole A02B D01oprelvekin L03A C02penciclovir J05A B13phenylephrine, combinations R01B A53propanol, combinations D08A X53quetiapine N05A H04ramipril and calcium channel blockers C09B B05reboxetine N06A X18rivastigmine N07A A06salicylic acid S01B C08salmeterol and anti-asthma R03A K06sibutramine A08A A10sildenafil G04B E03tazarotene D05A X05tretinoin, combinations D10A D51triamcinolone R01A D11zaleplon N05C F03combinations A07B C30combinations S02D A30

Change of ATC code:previous: zolpidem N05C G01new: zolpidem N05C F02

Deleted ATC level:imidazopyridines N05CG



29


Change of level name:

cyclopyrrolones benzodiazepine-related drugs N05CFdiazepines and oxazepines diazepines, oxazepines and

thiazepines N05AHferric oxide polymaltose complex dextriferron B03AB05interferon alfa interferon alfa natural L03A B01interferon beta interferon beta natural L03A B02

New DDDs:

INN/common name DDD Unit Route of ATC code administration

brimonidine 0.2 ml S01E A05*candesartan 8 mg O C09C A06*cefdinir 0.6 g O J01D A42*cidofovir 25 mg P J05A B12eprosartan 0.6 g O C09C A02follitropin beta 75 IU P G03G A06grepafloxacin 0.4 g O J01M A11irbesartan 0.15 g O C09C A04levofloxacin 0.25 g O, P J01M A12*montelukast 10 mg O R03D C03pilocarpine 15 mg O N07A X01polycarbophil calcium 2.5 g O A06A C08reboxetine 8 mg O N06A X18*saquinavir 1.8 g O J05A E01tolcapone 0.45 g O N04B X01tolterodine 4 mg O G04B D07zolmitriptan 2.5 mg O N02C C03

Change of DDDs:

INN/common name DDD Unit Route of ATC code administration

risperidone 5 mg O N05A X08

Previous New ATC code


30


Essential Drugs

As described in previous issues of this journal, work is now under way on the WHO ModelFormulary and draft texts will be published regularly to obtain comments on the materialproposed for publication. Observations concerning the following sections should be addressedto: Department of Essential Drugs and Other Medicines (EDM), World Health Organization,1211 Geneva 27, Switzerland.

WHO Model Formulary

DiureticsDiuretics are employed to increase urinary excre-tion in the treatment of hypertension and oedemadue to congestive heart failure, or chronic renal orhepatic disease. They reduce extracellular fluidvolume by decreasing total body sodium chloridecontent and modify renal handling of other cations,thereby enhancing potassium and magnesiumexcretion, and decreasing calcium and urate.

Thiazide diuretics, such as hydrochlorthiazide, aremoderately potent but are not effective if theglomerular function rate is less than 30 ml/minute.They inhibit sodium and chloride resorption at thebeginning of the distal convoluted tubule and actwithin one to two hours of oral administration. Mosthave a duration of action from 12–24 hours.

In mild to moderate high blood pressure, thiazidesare often used at low dose to produce a maximal ornear-maximal blood pressure lowering effect withvery little biochemical disturbance. Higher doses donot necessarily increase the hypotensive responsebut may cause marked changes in plasma potas-sium, magnesium, uric acid, glucose and lipids.Thiazides are also used in combination with otherantihypertensives to reduce higher blood pressureand in the management of oedema due to mild tomoderate congestive heart failure. Oedema due tokidney or hepatic diseases may also respond tothiazides, although the oedema secondary to thenephrotic syndrome may require more potent loopdiuretics. Paradoxically, thiazides are used in thetreatment of diabetes insipidus, by reducing urinevolume up to 50%. Another less common use ofthiazides is treatment of hypercalciuria in patientswith calcium-containing renal calculi.

Thiazides often cause potassium depletion whichincreases ventricular irritability and may lead tocardiac arrhythmias. The avoidance of potassiumdepletion is particularly important in patients takingcardiac glycosides, such as digoxin, since hypoka-laemia potentiates cardiac toxicity of these drugs.

Loop diuretics, or high-ceiling diuretics, such asfurosemide, are highly potent diuretics which rapidlyproduce an intense dose-dependent diuresis ofshort duration. They inhibit resorption from theascending loop of Henle in the renal tubule and areuseful, particularly in situations where rapid andeffective diuresis is needed such as reduction ofacute pulmonary oedema due to left ventricularfailure or in hypertensive crises. Loop diuretics arealso used to treat oedema in chronic renal insuffi-ciency and nephrotic syndrome. Oral furosemideproduces diuresis within 30 minutes to 1 hour ofadministration, with the maximum diuretic effect in1–2 hours. The diuretic action lasts for 4–6 hours.Intravenous furosemide produces diuresis within 5minutes, with the maximum diuretic effect in 20–60minutes and diuresis is complete within 2 hours.Because loop diuretics are highly potent, over-treatment of oedema with loop diuretics can pro-duce severe dehydration and circulatory collapse.Hypokalaemia and other electrolyte disturbancesmay also develop. Rapid high dose injection orinfusion of furosemide may cause tinnitus and evenpermanent deafness.

Potassium-sparing diuretics, such as amiloride andspironolactone, are relatively weak diuretics andare usually used in combination with thiazide orloop diuretics. They cause retention of potassium,and amiloride causes a small increase in sodiumchloride excretion and mild natriuresis. Amiloride

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WHO Drug Information Vol. 13, No. 1, 1999 Essential Drugs

and spironolactone are often used in combinationwith thiazides or loop diuretics to conserve potas-sium in patients at risk from hypokalaemia duringthe long-term treatment of oedema associated withheart failure or hepatic cirrhosis, including ascites.Spironolactone requires multiple doses over 2–3days to achieve the maximum diuretic effect. Thediuretic activity stops 2–3 days after cessation oftreatment. Spironolactone is also used in the treat-ment of hyperaldosteronism and refractory oedemaassociated with secondary aldosteronism.

The most dangerous adverse effect of potassium-sparing diuretics, such as amiloride or spironolac-tone, is hyperkalaemia, which can be life threaten-ing. These diuretics are thus contraindicated inpatients with hyperkalaemia or who may develophyperkalaemia, with renal failure, those receivingother potassium sparing diuretics, and patientstaking ACE inhibitors or potassium supplements.

Osmotic diuretics such as mannitol are adminis-tered in sufficiently large doses to raise the osmo-larity of plasma and renal tubular fluid. With ad-equate rehydration, mannitol is mainly used toincrease urine flow in patients with acute renalfailure. Osmotic diuretics are used to reduce orprevent cerebral oedema, to reduce raisedintraocular pressure or to treat dialysis disequilib-rium syndrome. Mannitol is also used to controlintraocular pressure during acute attacks of glau-coma, and is particularly useful in reducingintraocular pressure before or after eye surgery.

AMILORIDETablet: 5 mg (hydrochloride)

Uses: Oedema associated with heart failure andhepatic cirrhosis (with or without ascites). Alsoused in combination with thiazide or loop diureticsto conserve potassium.

Dosage: 10 mg daily adjusted according to re-sponse (maximum 20 mg).

Used in combination with thiazides or loop diureticsto treat congestive heart failure and hypertension:Initial oral dose, 5 mg daily. Increase to 10 mg ifnecessary.

Used in combination with thiazides or loop diureticsto treat hepatic cirrhosis with ascites: Initial oraldose, 5 mg daily.

Contraindications: Hyperkalaemia, renal failure.

Precautions: Pregnancy, breastfeeding, in elderly,diabetes mellitus. Monitor serum electrolytes, inparticular potassium.

Adverse effects: Nausea, vomiting, abdominalpain, diarrhoea, constipation, and anorexia. Head-ache, dizziness and minor psychiatric or visualchanges. Skin rashes, pruritus, muscle cramps,orthostatic hypotension. Hyperkalaemia (elevatedpotassium) and hyponatraemia (decreased so-dium). Signs of hyperkalaemia include irregularheartbeat, confusion, nervousness, numbness ortingling in hands, feet or lips, shortness of breath ordifficult breathing, unusual tiredness or weakness,and weakness or heaviness of legs. Signs of hy-ponatraemia include drowsiness, dry mouth, in-creased thirst and lack of energy.

Drug interactions: Other potassium-sparingdiuretics, patients taking potassium supplements orpatients taking ACE inhibitors increases risk ofhyperkalaemia.

FUROSEMIDETablet: 40 mgInjection: 10 mg/ml in 2-ml ampoule

Uses: Oedema due to congestive heart failure orrenal or hepatic disease.

Dosage:OralAdults: Initial oral dose of 40 mg daily on rising:Maintenance dose of 20 mg daily or 40 mg onalternate days. Resistant cases may need 80 mgdaily.

Children: 1–3 mg/kg daily.

Intramuscular injection or slow intravenousinjectionReserved for emergency use only. Do not exceedinjection rate of 4 mg/minute.

Adults: 20–50 mg; can be increased in 20 mgincrements every 2 hours.

Children: 0.5–1.5 mg/kg up to 20 mg daily.

By intravenous infusion for oedema: If theeffective single dose is more than 50 mg, considerusing a slow intravenous infusion. Do not exceedinfusion rate of 4 mg/minute.

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WHO Drug Information Vol. 13, No. 1, 1999Essential Drugs

Treatment of oliguria: In patients where glomerularfiltration rate is less than 20 ml/minute:• dilute furosemide 250 mg in 250 ml of infusionfluid. Infuse over 1 hour.

• if no response to first infusion, dilute furosemide500 mg in appropriate amount of infusion fluid,depending on hydration state of patient. Infusionover 2 hours.

• If no response to second infusion, dilute furosem-ide 1000 mg (1 gram) in appropriate amount ofinfusion fluid, depending on hydration state ofpatient. Infusion over 4 hours.

• If no response to third infusion, patient probablyrequires dialysis

Contraindications: Severe hyperkalaemia, hy-ponatraemia, renal failure with anuria andprecomatose states associated with liver cirrhosis.

Precautions: Monitor serum electrolytes, espe-cially potassium, calcium, chloride and bicarbonatebefore beginning furosemide therapy and regularlyduring therapy.Reduce dosage in elderly. In diabet-ics or suspected diabetics, monitor urine glucoseand blood glucose.

Adverse effects: Hyponatraemia, hypokalaemiaand hypomagnesaemia. Hypochloraemic alkalosis,increased calcium excretion, hypovolaemia andhypotension. Nausea, gastrointestinal disturbances,hyperuricaemia and gout are reported less com-monly. Hyperglycaemia: but less often than withthiazide diuretics. Temporary increase in plasmacholesterol and triglyceride concentration. Rashes,photosensitivity, bone marrow depression, pancrea-titis, tinnitus and deafness are reported rarely.Tinnitus and deafness may be experienced withlarge parenteral doses and rapid administration offurosemide, and in patients with renal impairment orin patients taking other ototoxic drugs.

HYDROCHLOROTHIAZIDETablet: 25 mg, 50 mg

Uses: Oedema, mild to moderate hypertension.

Dosage: Hypertension: 12.5–25 mg daily.

Adults with oedema: Initial oral dose to be taken onrising of 25 mg daily. If necessary, increase to 50mg daily.

Elderly: Initial oral dose of 12.5 mg daily.

Adults with severe oedema or toxaemia of preg-nancy: 100 mg oral daily or intermittently, at inter-vals of up to 4 days.

Adults with nephrotic diabetes insipidus: initial oraldose of 100 mg daily

Contraindications: Severe kidney or severe liverimpairment. Refractory hypokalaemia, hyponatrae-mia, hypercalcaemia, symptomatic hyperuricaemia,Addison’s Disease, porphyria.

Precautions: In elderly, pregnancy,breastfeeding, renal or hepatic impairment. Mayreduce potassium levels and aggravates diabetesand gout. May exacerbate systemic lupus ery-thematosus.

Adverse effects: Hypokalaemia and hypomagne-saemia are the most important adverse effects.Other common adverse effects include lethargy,drowsiness, hyperglycaemia, hyperuricaemia, gout,gastrointestinal adverse effects (anorexia, nausea,vomiting, constipation and diarrhoea), hyponatrae-mia, hypercalcaemia, hypochloraemic alkalosis,rashes and photosensitivity. Rare adverse effectsinclude impotence, blood disorders (includingneutropenia and thrombocytopenia), pancreatitis,hepatitis, intrahepatic cholestasis, hypersensitivityreactions and acute renal failure.

Drug interactions: Digitalis and digitalis glycosides(digoxin, digitoxin) will increase the risk of toxicity ifhypokalaemia occurs.

MANNITOLInjectable solution: 10% and 20%

Uses: To treat raised intracranial pressure, intra-cranial oedema, intraocular pressure and oedemain glaucoma, or for administration in preparation forintraocular surgery.

Dosage:Adults: Use slow infusion rate (not rapid?

Cerebral oedema (other indications?Adults: 1.5–2.0 g/kg as 20% solution administeredover 30–60 minutes. (as injection?Children: Dose of 0.25–2.0 g/kg.

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WHO Drug Information Vol. 13, No. 1, 1999 Essential Drugs

Contraindications: Pulmonary congestion, pulmo-nary oedema, intracranial bleeding except duringcraniotomy, severe congestive heart failure, severedehydration and metabolic oedema with abnormalcapillary fragility. Patients with renal failure unless atest dose has produced diuresis. Hyperkalaemia,hypokalaemia or hypovolaemia.

Precautions: Extravasation. Never add mannitol towhole blood for transfusion. Never give mannitolusing the same set through which blood is beinginfused. Monitor renal function, fluid balance andelectrolytes. Solutions containing more than 15%mannitol may crystallize during storage. Redissolvecrystals by warming before use. Do not use solutionif all crystals do not completely dissolve. All intrave-nous administration sets should have a filter.

Adverse effects: Extravasation may causeoedema, skin necrosis, inflammation and throm-bophlebitis. Fluid and electrolyte imbalance, includ-ing circulatory overload and acidosis. Expansion ofextracellular volume can cause pulmonary oedema,particularly in patients with diminished cardiacreserve. Intravenous infusions have been reportedto cause nausea, vomiting, headache, dizziness,chills fever, tachycardia, chest pain, blurred vision,urticaria, hypotension, hypertension and allergicreactions.

SPIRONOLACTONETablet: 25 mg

Uses: Refractory oedema in patients with conges-tive heart failure, nephrotic syndrome, hepaticcirrhosis (with or without ascites) and in ascitesassociated with malignancy. Diagnosis and treat-ment of primary hyperaldosteronism.

Dosage:OedemaAdults: 100 mg daily, which may be increased inresistant cases to 400 mg daily.

Children: 3 mg/kg in divided doses.Primary hyperaldosteronism:Diagnosis (do you mean prophylaxis?) 400 mg dailyin 4 divided doses, for 3–5 weeks.Treatment: 100–400 mg daily.

Contraindications: Hyperkalaemia, hyponatrae-mia. Severe renal impairment, diabetes with renalimpairment. Addison’s disease.

Precautions: Monitor serum electrolytes andblood urea nitrogen periodically during therapyespecially in the elderly and in patients with de-crease in renal or hepatic function, diabetes melli-tus, or patients at risk of hyperkalaemia.

Adverse effects: Gynaecomastia, impotence,menstrual irregularities, gastrointestinal distur-bances, including cramps and diarrhoea, skinrashes, hyponatraemia, dehydration, headaches,drowsiness, ataxia, mental confusion, fever, andhepatoxicity. Transient increase in blood ureanitrogen. Reversible hyperchloraemia metabolicacidosis. Severe hyperkalaemia in patients withimpaired renal function or in patients receivingsupplemental potassium.

Drug interactions: ACE inhibitors combined withspironolactone may produce hyperkalaemia. Otherinteractions will appear in tabulated form in theappendix of the published edition of the WHOModel Formulary.

Anti-allergics anddrugs used in anaphylaxisAlthough there are three types of histamine recep-tors H1, H2 and H3 it is the H1 receptor antagonistswhich are generally referred to as antihistamines.These are responsible for a histamine-inducedincrease in capillary permeability and sensory nervestimulation, thus inhibiting the wheal, pruritus,sneezing and mucous secretion responses that arecharacteristic of allergy. H1 receptor antagoniststhus relieve the symptoms of allergic reactions,such as urticaria, angioedema, allergic rhinitis, andallergic conjunctivitis. They are also used to treatdrug allergies, food allergies and insect stings andsome of the symptoms of anaphylaxis. Antihista-mines also control the pruritus in skin disorders,such as eczema. However, they are ineffective inthe treatment of acute asthmatic attacks.

Drowsiness and sedation are particular disadvan-tages of the early antihistamines and the patientshould be warned against driving or operating anytype of machinery. Other central nervous depres-sants, including alcohol, barbiturates, hypnotics,opioid analgesics, anxiolytic sedatives and neu-roleptics may enhance the sedative effects ofantihistamines. Since they interfere with skin testsfor allergy, therapy should be stopped at least oneweek before conducting a skin test. Rashes and

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WHO Drug Information Vol. 13, No. 1, 1999Essential Drugs

photosensitivity reactions, palpitations and arrhyth-mias have also been reported.

Chlorphenamine is considered the prototype forantihistamine H1 antagonists. This class includesdrugs with less sedative action than the traditionalantihistamines or with different therapeutic poten-cies. In practice, all antihistamines are equallyeffective in relieving the symptoms of allergicreactions and differ mainly in the intensity of seda-tive and anticholinergic effects. Selection of drugsin this class should thus be based on the intendedtherapeutic uses, the adverse reaction profile andthe cost.

Corticosteroids, such as dexamethasone, hydrocor-tisone, or prednisolone suppress or prevent almostall symptoms of inflammation associated withallergy. The route of administration should dependon the particular type of allergic condition. Forexample, in the case of a mild allergic skin reaction,the best therapy may be to apply a glucocorticoidointment or cream. If the skin reaction does notrespond to topical corticosteroid therapy, it may benecessary to give corticosteroids orally. Allergicdiseases of limited duration and with mild reactions,such as urticaria or allergic rhinitis, usually requireno treatment. If, on the other hand, symptomsbecome persistent, antihistamines constitute themainstay of treatment.

Corticosteroids should be considered as supple-ments to primary therapy and used to reduceinflammation. Oral corticosteroids may be requiredfor a few days in an acute attack of urticaria. Oralcorticosteroids are also used to relieve severeexacerbations in chronic urticaria, but long-term useof oral corticosteroids should be avoided. Corticos-teroids may be used topically to reduce inflamma-tion in allergic rhinitis but should not be used orallyor parenterally for this condition.

The adverse effects of corticosteroids includeinhibition of growth in children, disturbances of theelectrolyte balance leading to oedema and hyper-tension and to potassium loss, production of oste-oporosis and spontaneous fractures, skin thinning,increased susceptibility to infection, mental distur-bances and diabetes.

Allergic emergenciesAnaphylactic shock is a medical emergency thatcan result in cardiovascular collapse and death. Itrequires prompt treatment of possible laryngealoedema, bronchospasm or hypotension. Atopic

individuals are particularly susceptible. Insect bitesand certain foods including eggs, fish, peanuts andnuts are also a risk for sensitized persons. Drugsparticularly associated with anaphylaxis includeblood products, vaccines, antibiotics (especiallypenicillins), iron injections, heparin and neuromus-cular blocking agents. Acetylsalicylic acid and otherNSAIDs, may cause bronchoconstriction inleukotreine-sensitive patients. In the case of drugallergy, anaphylaxis is more likely to occur afterparenteral administration. Resuscitation facilitiesshould always be available if injection of a drug isassociated with a certain risk.

First-line treatment includes administering epine-phrine, keeping the airway open (assisted respira-tion may be necessary) and restoring blood pres-sure. Epinephrine should immediately be given bydeep intramuscular or subcutaneous injection toproduce vasoconstriction and bronchodilation andinjections should be repeated every ten minutesuntil blood pressure and pulse have stabilized. Ifthere is complete cardiovascular shock, epine-phrine must be given by slow intravenous injection.

Further treatment of anaphylaxis often includesintravenous corticosteroids such as hydrocortisone,intravenous antihistamines, such as chlorphen-amine, and may include intravenous fluids, oxygen,an intravenous vasopressor agent, such asdopamine, intravenous aminophylline, and aninjected or nebulized bronchodilator, such assalbutamol. Chlorphenamine is a useful adjunctivetreatment given after epinephrine injection andcontinued for 24 to 48 hours to reduce the severityand duration of symptoms and to prevent relapse.An intravenous corticosteroid such as hydrocorti-sone has an onset of action that is delayed severalhours, but should be given to help prevent laterdeterioration in severely affected patients.

Steps in anaphylactic shock management

1. Epinephrine:

• 0.1 ml/10 kg (strength 1:1000, 1 mg/ml) by deepintramuscular injection; the dose can be repeated10-30 minutes later.

• If the patient is in shock: Adult:s 1–3 ml (strength 1:10 000, 0.1 mg/ml) by

slow intravenous infusion. Children: 0.1–0.5 ml (strength 1:10 000, 0.1 mg/

ml) by slow intravenous infusion.

35


2.Vital functions: maintain an open airway; giveoxygen by mask.

3. Corticosteroids–hydrocortisone

Adult: 250–500 mg intravenously

Child: 10 mg/kg intravenously.

4. Intravenous fluids: start infusion with sodiumchloride (500–1000 ml during the first hour).

5. If the patient has asthma-like symptoms, giveaminophylline: 5 mg/kg by slow intravenousinjection.

6. Antihistamine orally.

CHLORPHENAMINETablet: 4 mg (hydrogen maleate)Injection: 10 mg (hydrogen maleate) in 1-mlampoule

Uses: Symptomatic relief of allergy, hay fever,allergic rhinitis and conjunctivitis, urticaria, insectstings, pruritus of allergic origin and angioedema.Adjunct in the emergency treatment of anaphylacticshock or in the emergency treatment of severeangioedema.

Dosage:Adults: 4 mg every 4–6 hours, maximum 24 mgdaily.

Emergencies: by subcutaneous or intramuscularinjection or slow intravenous injection:

Adults: 5–20 mg, repeated if required (max 40 mgin 24 hours).

Children: 1–2 years: 1 mg twice daily. 2–5 years:1 mg every 4–6 hours (max 6 mg daily). 6–12years: 2 mg every 4–6 hours (max 12 mg daily).

Contraindications: Patients with prostate enlarge-ment since chlorphenamine may cause urinaryretention. Patients with ileus or pyloric stenosis.Glaucoma. Children under one year.

Precautions: Use with caution in patients withepilepsy, hepatic disease and severe cardiovascu-lar disorders. Ability to drive or operate machinerymay be impaired.

Adverse effects: Drowsiness, hypotension, head-ache, palpitations, psychomotor impairment, urinaryretention, dry mouth, blurred vision and gastrointes-tinal disturbances. Other adverse effects includerash and photosensitivity reactions, sweating andtremor. Injections may be irritant and may causeparadoxical central nervous system stimulation andhypotension.

Drug Interactions: Effects of alcohol and otherCNS depressants may be additive. Other druginteractions will appear in tabulated form in theappendix of the published edition of the WHOModel Formulary.

DEXAMETHASONETablet: 0.5 mg, 4 mgInjection: 4 mg dexamethasone phosphate(as disodium) in 1-ml ampoule

Uses: Adjunct in the emergency treatment of ana-phylaxis. Short-term suppression of inflammation inallergic disorders.

Dosage:Orally: usual range 0.5–10 mg daily.

By intramuscular injection or slow intravenousinjection or infusion:Adults: 0.5–20 mg daily.Children: 200–500 micrograms/kg daily.

Contraindications, precautions and adverseeffects: Because rare instances of anaphylactoidreactions such as bronchospasm have occurred inpatients receiving parenteral corticosteroid treat-ment, appropriate precautionary measures shouldbe taken prior to administration, especially whenthe patient has a history of allergy to drugs.

EPINEPHRINE (ADRENALINE)Injection: 1 mg (as hydrochloride or hydrogentartrate) in 1-ml ampoule

Uses: Severe anaphylactic reaction or severeangioedema.

Dosage:Caution: Different dilutions of epinephrine solutionare used for different routes of administration. Use1:1000 epinephrine solution for intramuscular orsubcutaneous injection.

Essential Drugs

36


Anaphylaxis

Age volume of epinephrine1: 1 000 (1 mg/ml solution)

under 1 year 0.05 ml1 year 0.1 ml2 years 0.2 ml3–4 years 0.3 ml5 years 0.4 ml6–12 years 0.5 mlAdult 0.5–1.0 ml

Repeat the dose every 10 minutes as necessary,according to blood pressure and pulse, until im-provement occurs.

Use 1:10 000 epinephrine solution for slow intrave-nous injection.

This route should be reserved for severely ill pa-tients when there is doubt about the adequacy ofcirculation and absorption from the intramuscularsite.

Adults: 500 µg (0.5 mg), i.e., 5 ml of a dilute 1:10000 epinephrine injection solution given at aninjection rate of 100 µg (1 ml of a dilute 1:10 000epinephrine injection solution)/minute, stoppingonce a response is obtained.

Children: 10 micrograms/kg (0.1 ml/kg of a dilute1:10 000 epinephrine injection solution) given overseveral minutes.

Contraindications: Hyperthyroidism, hyperten-sion, diabetes mellitus, ischaemic heart disease,hypertension and closed angle glaucoma. Chronicbronchial asthma and substantial emphysema.Elderly patients.

Adverse effects: Tachycardia and arrhythmias,hypertension, tremor, anxiety, sweating, nausea,vomiting, weakness, dizziness and pulmonaryoedema have all been reported. Headache iscommon.

Drug interactions: These will appear in tabulatedform in the appendix of the published edition of theWHO Model Formulary.

HYDROCORTISONEPowder for injection, 100 mg(as sodium succinate) in vial

Uses: Adjunct in the emergency treatment ofanaphylaxis.

Dosage: Anaphylactic emergency: By slow intra-venous injection: Adult: 100+300 mg three to fourtimes in 24 hours as required. Children: < 1 year 25mg, 1-5 years 50 mg, 6-12 years 100 mg.

Contraindications, precautions and adverseeffects: Because rare instances of anaphylactoidreactions such as bronchospasm have occurred inpatients receiving parenteral corticosteroid therapy,appropriate precautionary measures should betaken prior to administration, especially when thepatient has a history of allergy to drugs.


PREDNISOLONETablet, 5 mg

Uses: Short-term suppression of inflammation inallergic disorders.

Dosage: Initial dose up to 10–20 mg daily. Se-vere allergy may require up to 60 mg daily. Themaintenance dose is 2.5–15 mg daily. Higherdoses may be necessary.

Contraindications

Adverse effects


Essential Drugs

37


Recent Publications and Documents

The New Emergency Health Kit 98The provision of health care is difficult and demand-ing in the aftermath of large scale emergencies anddisasters. In collaboration with a large number ofinternational agencies, WHO has developed theEmergency Health Kit. The Kit is available from anumber of major pharmaceutical suppliers and thenewly-revised publication explains how to use thestandardized packages of essential drugs, suppliesand equipment. Development of the Kit was basedon priority health needs and is designed to expeditethe provision of supplies, in particular by emer-gency relief agencies.

A complete emergency health kit contains twoseparate sets of drugs and supplies. The main setis intended for use by health workers located inremote areas or operating under isolated condi-tions, and the supplementary kit contains drugs,renewable supplies and equipment needed bydoctors working in first level health facilities.

The concept of an emergency health kit has beendeveloped over years of study and field testing.Information has been drawn from epidemiologicaldata, population profiles and specific diseasepatterns following emergencies. A description of thecontents of the health kit, treatment guidelines andchecklists for suppliers and prescribers is alsoincluded as part of the publication. Useful annexeshave been integrated into the book including theModel Guideline for the International Provision ofControlled Medicines for Emergency Medical Care,and Guidelines for Drug Donations.

The New Emergency Health Kit 98. WHO/DAP/98.10.Available from: World Health Organization, Geneva,Switzerland. Price Sw.Fr. 8.-

Tuberculosis and air travelIn recent years, several episodes of potentialtransmission of tuberculosis infection during airtravel have been reported. Although the risk oftransmission during air travel has been docu-mented, it seems to be relatively low. Nonetheless,within the next decade, it is expected that more

than two billion passengers per year will travel byscheduled air traffic. Because airlines, passengers,physicians and health authorities need to know therisk of tuberculosis transmission and how to takeproper measures, WHO has issued guidelinesendorsed by the Aerospace Medical Associationand the Airline Medical Directors Association.

The guidelines were produced in collaboration withinternational health experts, civil aviation authoritiesand airline company representatives. The guide-lines give recommendations for collaboration be-tween physicians, health authorities and airlinecompanies. Advice is given on prevention andmanagement of infectious passengers, contacttracing, conducting investigations, reducing the riskof exposure, and improving air quality and ventila-tion.

Tuberculosis and Air Travel: Guidelines for Preventionand Control. WHO/TB/98.258. Available from: WorldHealth Organization, Geneva, Switzerland.

Effects of antimicrobialsused in food-producing animalsThe US Food and Drug Administration has recentlyissued A Proposed Framework for Evaluating andAssuring the Human Safety of the Microbial Effectsof Antimicrobial New Animal Drugs Intended forUse in Food-Producing Animals. This is the secondstep in the Agency's efforts to develop policies todeal with the problem of antimicrobial resistance.The FDA is particularly concerned that significanthuman antimicrobial therapies are not lost as aresult of the overuse of antimicrobials in food-producing animals.

As a first step, the Agency has produced the draftguidance document Evaluation of the HumanHealth Impact of the Microbial Effects of Antimicro-bial New Animal Drugs Intended for Use in Food-Producing Animals. This document set out twocriteria for evaluation (i) the quantity of antimicrobialdrug resistant enteric bacteria formed in the ani-mal's intestinal tract following exposure to theantimicrobial; and (ii) any changes in the number ofenteric bacteria in the animals intestinal tract that

38


cause human illness (pathogenic load). Its aim isalso to address the risk of increased human infec-tions as a result of disturbance of the normal intesti-nal microbial ecosystem causing an increase inpathogens in the animal.

A Proposed Framework for Evaluating and Assur-ing the Human Safety of the Microbial Effects ofAntimicrobial New Animal Drugs Intended for Usein Food-Producing Animals. Available from theFood and Drug Administration. http://www.fda.gov./cvm/fda/infores/vmac/ANTIM18.htm

Quality control methodsfor medicinal plant material

Because of their increasing use worldwide, moreand more attention is being paid to the quality ofplant materials used in over-the-counter prepara-tions, home remedies or as raw materials for phar-maceutical preparations.

This book has been prepared in response to theneed for international harmonization in qualitycontrol testing of medicinal plant materials. It con-tains descriptions of recommended test methods foridentity, purity and content, together with a detailedlist of the reagents and solutions necessary to carrythese out. The purpose of the tests is twofold, tofulfil the needs of quality control laboratories and toprovide a basis for the development of nationalstandards.

The book will be useful for national drug regulatoryauthorities, the pharmaceutical industry and phar-macists working with medicinal plant materials.

Quality control methods for medicinal plant materials.Available from: World Health Organization, Geneva,Switzerland. E-mail: [email protected]. Price Sw.Fr.35.- (Price in developing countries: Sw.Fr. 24.50).

Basic Tests for DrugsBasic tests represent one of the many elements ofquality assurance for pharmaceutical products. Thebasic test series has been developed by WHO toprovide a simple method to confirm the identity of a

Recent Publications and Documents

substance or indicate whether gross degradationhas occurred. The tests described in the latestmanual, Basic Tests for Drugs: PharmaceuticalSubstances, Medicinal Plant Materials and DosageForms, are meant to complement the previouslypublished Basic Tests for Pharmaceutical Sub-stances and Basic Tests for Pharmaceutical Dos-age Forms.

The book describes test procedures for 23 pharma-ceutical substances and 58 pharmaceutical dosageforms, including basic tests for confirming theidentity of 4 commonly used medicinal plant materi-als. A description of other tests is made, includingthin-layer chromatography and volumetric or spec-trophotometric analysis which can be useful inscreening. The book concludes with a cumulativeindex of test procedures contained in this and theprevious two related publications.

Basic Tests for Drugs: Pharmaceutical Substances,Medicinal Plant Materials and Dosage Forms. Availablefrom: World Health Organization, Geneva, Switzerland.E-mail: [email protected]. Price Sw.Fr. 26.- (Price indeveloping countries: Sw.Fr. 18.20).

Information data basefor dietary supplementsCurrently, the term dietary supplement is used for awide array of products available in health foodstores, pharmacies or by mail order which containvitamins, minerals, nutrients and herbals as well asingredients and extracts of animal and plant origin.Given the growing problems surrounding the termi-nology used to describe the ingredients of dietarysupplements, the National Institutes of Health haslaunched a database for access via the internet toprovide scientific information on supplements. Thesite will assist health experts and the public todetermine the status of substances with referenceto published scientific literature and will providedefinitions on what a dietary supplement is consid-ered to be.

National Institutes of Health Office of Dietary Supple-ments. Available on: http://odp.od.nih.gov/ods

35

WHO Drug Information, Vol. 13, No. 1, 1999 RECOMMENDED INN: List 41

International Nonproprietary Names forPharmaceutical Substances (INN)RECOMMENDED International Nonproprietary Names (Rec. INN): List 41

Notice is hereby given that, in accordance with paragraph 7 of the Procedure for the Selection of Recommended InternationalNonproprietary 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 recommendationof 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 CumulativeList No. 9, 1996.

Dénominations communes internationalesdes Substances pharmaceutiques (DCI)

Dénominations communes internationales RECOMMENDÉES (DCI Rec): Liste 41

Il est notifié que, conformément aux dispositions du paragraphe 7 de la Procédure à suivre en vue du choix de Dénominationscommunes 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 choisises par l’Organisationmondiale de la Santé en tant que dénominations communes internationales recommandées. L’inclusion d’une dénominationdans les listes de DCI recommandées n’implique aucune recommandation en vue de l’utilisation de la substancecorrespondante 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 Internacionalespara las Sustancias Farmacéuticas (DCI)

Denominaciones Comunes Internacionales RECOMENDADAS (DCI Rec.): Lista 41

De conformidad con lo que dispone el párrafo 7 del Procedimiento de Selección de Denominaciones ComunesInternacionales Recomendadas para las Sustancias Farmacéuticas [Act. Of. Mund. Salud, 1955, 60, 3 (ResoluciónEB15.R7); 1969, 173, 10 (Resolución EB43.R9)], se comunica por el presente anuncio que las denominaciones que acontinuación se expresan han sido seleccionadas como Denominaciones Comunes Internacionales Recomendadas. Lainclusión de una denominación en las listas de las Denominaciones Comunes Recomendadas no supone recomendaciónalguna 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 encuentranreunidas en Cumulative List No. 9, 1996.

36

WHO Drug Information, Vol. 13, No. 1, 1999RECOMMENDED INN: List 41

An ongoing review is under way of the long-standing objections to proposed Interna-tional Nonproprietary Names (INN). As a result, objections have been withdrawn to thefollowing names which are now included in this list of recommended INNs:

aspartic acid, amiprilose, dinaline, flumoxonide, mebeverine, megestrol, miroprofen,piridicillin, teclozan, thiram

Les objections formulées de longue date contre des Dénominations communesinternationales (DCI) proposées sont examinées. Des objections ont été retirées à lasuite de cet examen et les noms suivants sont donc inclus dans cette liste des DCIrecommandées:

acide aspartique, amiprilose, dinaline, flumoxonide, mébévérine, mégestrol,miroprofène, piridicilline, téclozan, thirame

Se ha emprendido un examen de las objeciones que se vienen formulando desde hacetiempo a las denominaciones comunes internacionales (DCI) propuestas. Comoresultado, se han retirado las objeciones a las denominaciones siguientes, que ahoraestán incluidas en la presente lista de DCI recomendadas:

ácido aspártico, amiprilosa, dinalina, flumoxónida, mebeverina, megestrol, miroprofeno,piridicilina, teclozán, tiramo

37


acidum asparticumaspartic acid L-aspartic acidnootropic agent

acide aspartique acide (2S)-2-aminobutanedioïquenootrope

ácido aspártico ácido L-aspárticonootropo

C4H7NO4

HO2CCO2H

NH2H

alvamelinumalvameline 3-(2-ethyl-2H-tetrazol-5-yl)-1,2,5,6-tetrahydro-1-methylpyridinenootropic agent

alvaméline 3-(2-éthyl-2H-tétrazol-5-yl)-1-méthyl-1,2,5,6-tétrahydropyridinenootrope

alvamelina 3-(2-etil-2H-tetrazol-5-il)-1,2,5,6-tetrahidro-1-metilpiridinanootropo

C9H15N5

N

CH3

N N

NN CH3

7732amediplasumamediplase 173-L-serine-174-L-tyrosine-175-L-glutamine-173-275-plasminogen activator

(human tissue-type reduced), fusion protein with urokinase (human urineβ-chain reduced)fibrinolytic

amédiplase [173-L-sérine-174-L-tyrosine-175-L-glutamine]173-275-activateur duplasminogène (type tissulaire humain réduit)-159-411-urokinase (chaîneβ urinaire humaine réduite)fibrinolytique

amediplasa 173-L-serina-174-L-tirosina-175-L-glutamina-173-275-activador delplasminógeno(tipo tisular humano reducido), proteína de fusión conurokinasa (orina humana cadena β reducida)fibrinolítico

Latin, English, French, Spanish:Recommended INN Chemical name or description; Molecular formula; Graphic formula

DCI Recommandée Nom chimique ou description; Formule brute; Formule développée

DCI Recomendada Nombre químico o descripción; Fórmula empírica; Fórmula desarrollada

38


SYQGNSDCYF GNGSAYRGTH SLTESGASCL PWNSMILIGK

VYTAQNPSAQ ALGLGKHNYC RNPDGDAKPW CHVLKNRRLT

WEYCDVPSCS TCGLRQYSQP QFRIIGGEFT TIENQPWFAA

IYRRHRGGSV TYVCGGSLIS PCWVISATHC FIDYPKKEDY

IVYLGRSRLN SNTQGEMKFE VENLILHKDY SADTLAHHND

IALLKIRSKE GRCAQPSRTI QTICLPSMYN DPQFGTSCEI

TGFGKENSTD YLYPEQLKMT VVKLISHREC QQPHYYGSEV

TTKMLCAADP QWKTDSCQGD SGGPLVCSLQ GRMTLTGIVS

WGRGCALKDK PGVYTRVSHF LPWIRSHTKE ENGLAL

7751amiprilosumamiprilose 3-O-[3-(dimethylamino)propyl]-1,2-O-isopropylidene-α-D-glucofuranoseantiviral

amiprilose 3-O-[3-(diméthylamino)propyl]-1,2-O-(1-méthyléthylidène)-α-D-glucofuranoseantiviral

amiprilosa 3-O-[3-(dimetilamino)propil]-1,2-O-isopropilideno-α-D-glucofuranosaantiviral

C14H27NO6

O

O

O

O

HO

CH3

CH3

HO H NCH3

CH3

amprenavirumamprenavir (3S)-tetrahydro-3-furyl [(S)-α-[(1R)-1-hydroxy-

2-(N1-isobutylsulfanilamido)ethyl]phenethyl]carbamateantiviral

amprénavir [(1S,2R)-3-[[(4-aminophényl)sulfonyl](2-méthylpropyl)amino]-1-benzyl-2-hydroxypropyl]carbamate de (3S)-tétrahydrofuran-3-yleantiviral

amprenavir [(S)-α-[(1R)-1-hidroxi-2-(N1-isobutilsulfanilamido)etil]fenetil]carbamato de(3S)-tetrahidro-3-furilantiviral

39


C25H35N3O6S

NH

NS

H OH

HO

CH3

H3C

OO

NH2

O

O

H

7655anatumomabum mafenatoxumanatumomab mafenatox immunoglobulin G 1, anti-(human tumor-associated glycoprotein 72) (human-

mouse clone pMB125 Fab fragment γ1-chain) fusion protein with enterotoxinA (227-alanine) (Staphylococcus aureus) complex with mouse clonepMB125 κ-chain)immunomodulator

anatumomab mafénatox immunoglobuline G1 (chaîne γ1 du fragment Fab de l'anticorps monoclonal desouris humanisé, clone pMB125, dirigé contre la glycoprotéine 72 humaineassociée aux tumeurs)-[227-alanine]entérotoxine A (Staphylococcusaureus), complexée à la chaîne κ de l'anticorps monoclonal de souris clonepMB125immunomodulateur

anatumomab mafenatox inmunoglobulina G 1 (cadena γ1 del anticuerpo monoclonal quiméricohombre-ratón pMB125 dirigido contra la glicoproteina 72 asociada a tumorhumano) proteina de fusión con enterotoxina A de Staphylococcus aureus(227-alanina) con el clón de pMB125 cadena κ del anticuerpoinmunomodulador

ancestimumancestim N-L-methionyl-1-165-hematopoietic cell growth factor KL (human clone

V19.8:hSCF162), dimerantianaemic

ancestim dimère du N-L-méthionyl-1-165-facteur de croissance KL de celluleshématopoïétiques (clone humain V19.8:hSCF162)antianémique

ancestim N-L-metionil-1-165-factor de crecimiento celular hematopoietico KL (clonhumano V19.8:hSCF162), dímeroantianémico

C1662H2650N422O512S18

EGICRNRVTN

NIVDDLVECV

NVKDVTKLVA NLPKDYMITL KYVPGMDVLP

QLSDSLTDLL

KENSSKDLKK SFKSPEPRLF TPEEFFRIFN

RSIDAFKDFV SSTLSPEKDS RVSVTKPFML

PPVAA

M

SNYSIIDKLVDKFSNISEGLSHCWISEMVV

VASETSDCVV

2

40


ascorbylum gamolenasascorbyl gamolenate L-ascorbic acid, 6-[(6Z,9Z,12Z)-6,9,12-octadecatrienoate]diabetic antineuropathic agent

ascorbyl gamolénate (6Z,9Z,12Z)-octadéca-6,9,12-triénoate de (2S)-2-[(2R)-3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl]-2-hydroxyéthyleagent de traitement de la neuropathie diabétique

gamolenato de ascorbilo 6-[(6Z,9Z,12Z)-6,9,12-octadecatrienoato] de ácido L-ascórbicoagente para el tratamiento de la neuropatía diabética

C24H36O7

OO

O

OHH

OHHO

O

H3C

7733calcobutrolumcalcobutrol calcium hydrogen 10-[(1RS,2SR)-2,3-dihydroxy-1-(hydroxymethyl)propyl]-

1,4,7,10-tetraazacyclododecane-1,4,7-triacetatepharmaceutical aid

calcobutrol hydrogéno 2,2',2'’-[10-[(1RS,2SR)-2,3-dihydroxy-1-(hydroxyméthyl)propyl]-1,4,7,10-tétraazacyclododécane-1,4,7-triyl]triacétate de calciumauxiliaire pharmaceutique

calcobutról 10-[(1RS,2SR)-2,3-dihidroxi-1-(hidroximetil)propil]-1,4,7,10-tetraazaciclododecano-1,4,7-triacetato de hidrógeno y calcioexcipiente

C18H32CaN4O9

and enantiomeret énantiomèrey enantiómero

Ca

OHH

H OH

HO2C

-O2COH

CO2-

N N

N N2+

77347726dextioproninumdextiopronin N-[(R)-2-mercaptopropionyl]glycineanti-inflammatory agent

dextiopronine acide [[(2R)-2-sulfanylpropanoyl]amino]acétiqueanti-inflammatoire

dextiopronina N-[(R)-2-mercaptopropionil]glicinaantiinflamatorio

C5H9NO3S

H3C

HN CO2H

SHH

O

41


dinalinumdinaline 2',4-diaminobenzanilideanti-inflammatory agent

dinaline 4-amino-N-(2-aminophényl)benzamideanti-inflammatoire

dinalina 2',4-diaminobenzanilidaantiinflamatorio

C13H13N3O

HN

H2N

O

NH2

edodekinum alfaedodekin alfa interleukin 12 (human)immunomodulator

édodékine alfa interleukine 12 humaineimmunomodulateur

edodekina alfa interleuquina 12 (humana)inmunomodulador

IWELKKDVYV VELDWYPDAP GEMVVLTCDT PEEDGITWTL

KTLTIQVKEF GGEVLSHSLLDQSSEVLGSG GDAGQYTCHK

LLHKKEDGIW STDILKDQKE PKNKTFLRCE AKNYSGRFTC

TFSVKSSRGS ATLSAERVRGWWLTTISTDL SDPQGVTCGA

DNKEYEYSVE CQEDSACPAA DAVHKLKYEN

IKPDPPKNLQ EVSWEYPDTW

EESLPIEVMV

LKPLKNSRQV

STPHSYFSLT FCVQVQGKSK REKKDRVFTD KTSATVICRK

RYYSSSWSEWNASISVRAQD ASVPCS

YTSSFFIRDI

RNLPVATPDP GMFPCLHHSQ NLLRAVSNML QKARQTLEFY

DITKDKTSTV NESCLNSRETPCTSEEIDHE EACLPLELTK

SFITNGSCLA SRKTSFMMAL CLSSIYEDLK MYQVEFKTMN

IFLDQNMLAV NSETVPQKSSAKLLMDPKRQ IDELMQALNF

LEEPDFYKTK IKLCILLHAF TSYLNASRIRAVTIDRV

7749eniporidumeniporide N-(diaminomethylene)-5-(methylsulfonyl)-4-pyrrol-1-yl-o-toluamideNa+/H+ antiport inhibitor

éniporide N-(diaminométhylène)-2-méthyl-5-(méthylsulfonyl)-4-(1H-pyrrol-1-yl)benzamideinhibiteur de l’échange Na+/H+

eniporida N-(diaminometileno)-5-(metilsulfonil)-4-pirrol-1-il-o-toluamidainhibidor del transporte activo Na+/H+

42


C14H16N4O3S

O

N NH2

NH2

SH3C

OO

CH3N

7766esomeprazolumesomeprazole 5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]=

sulfinyl]benzimidazoleantiulcer agent

ésoméprazole 5-méthoxy-2-[(S)-[(4-méthoxy-3,5-diméthylpyridin-2-yl)méthyl]sulfinyl]-1H-benzimidazoleantiulcéreux

esomeprazol 5-metoxi-2-[(S)-[(4-metoxi-3,5-dimetil-2-piridil)metil]sulfinil]benzimidazolantiulceroso

C17H19N3O3S

S

NH

N

N

CH3

OCH3

OCH3

H3CO

7697esonarimodumesonarimod (±)-3-mercapto-2-(p-methylphenacyl)propionic acid acetateimmunomodulator

ésonarimod acide (2RS)-2-[(acétylsulfanyl)méthyl]-4-(4-méthylphényl)-4-oxobutanoïqueimmunomodulateur

esonarimod acetato del ácido (±)-3-mercapto-2-(p-metilfenacil)propiónicoinmunomodulador

C14H16O4S

CO2H

H3C

H S

O

H3C

O


flumoxonidumflumoxonide 6α,9-difluoro-11β,16α,17-trihydroxy-3,20-dioxopregna-1,4-dien-21-al

21-(dimethyl acetal) cyclic 16,17-acetal with acetoneimmunomodulator

flumoxonide 6α,9-difluoro-11β-hydroxy-21,21-diméthoxy-16α,17-O-(1-méthyléthylidène)prégna-1,4-diène-3,20-dioneimmunomodulateur

flumoxónida 6α,9-difluoro-11β,16α,17-trihidroxi-3,20-dioxopregna-1,4-dien-21-al21-(dimetil acetal) cíclico 16,17-acetal con acetonainmunomodulador

43


C26H34F2O7

CH3

HCH3

OO

HF

HOH

O

H

CH3

CH3

O

H F

O

O

CH3

CH3

iturelixumiturelix [N-acétyl-3-(naphtalén-2-yl)-D-alanyl]-p-chloro-D-phenylalanyl-3-(3-pyridyl)-

D-alanyl-L-seryl-N6-nicotinoyl-L-lysyl-N6-nicotinoyl-D-lysyl-L-leucyl-N6-isopropyl-L-lysyl-L-prolyl-D-alaninamideluteinizing hormone-releasing-hormone (LHRH) antagonist

iturélix [N-acétyl-3-(naphtalén-2-yl)]-D-alanyl]-(4-chloro-D-phénylalanyl)-[3-(pyridin-3-yl)-D-alanyl]-L-séryl-[N6-(pyridin-3-ylcarbonyl)-L-lysyl]-[N6-(pyridin-3-ylcarbonyl)-D-lysyl]-L-leucyl-[N6-(1-méthyléthyl)-L-lysyl]-L-prolyl-D-alaninamideantagoniste de l’hormone de libération de la lutéostimuline

iturelix N-acetil-3-(2-naftil)-D-alanil-p-cloro-D-fenilalanil-3-(3-piridil)-D-alanil-L-seril-N6-nicotinoil-L-lisil-N6-nicotinoil-D-lisil-L-leucil-N6-isopropil-L-lisil-L-prolil-D-alaninamidaantagonista de la hormona de liberación de hormona luteinizante

C82H108ClN17O14

N6 N63 4 3D-Ala NH2ProLys

CH3H3C

LeuD-LysLys

N

Cl

D-Ala SerH3C

O

D-Ala D-Phe

O

N

NO

N6

7736mebeverinummebeverine 4-[ethyl(p-methoxy-α-methylphenethyl)amino]butyl 3,4-dimethoxybenzoateNMDA receptor antagonist

mébévérine 3,4-diméthoxybenzoate de 4-[éthyl[(1RS)-2-(4-méthoxyphényl)-1-méthyléthyl]amino]butyleantagoniste des récepteurs du NMDA

mebeverina 3,4-dimetoxibenzoato de 4-[etil(p-metoxi-α-metilfenetil)amino]butiloantagonista de los receptores de NMDA

C25H35NO5

ON

O

H3CO

H3CO

CH3

CH3HOCH3


44


megestrolummegestrol 17-hydroxy-6-methylpregna-4,6-diene-3,20-dioneNMDA receptor antagonist

mégestrol 17-hydroxy-6-méthylprégna-4,6-diène-3,20-dioneantagoniste des récepteurs du NMDA

megestrol 17-hidroxi-6-metil-4,6-pregnadieno-3,20-dionaantagonista de los receptores de NMDA

C22H30O3

CH3

HCH3

CH3

OCH3

HH

OH

O

midafotelummidafotel (-)-(R)-4-[(E)-3-phosphonoallyl]-2-piperazinecarboxylic acidNMDA receptor antagonist

midafotel (-)-acide (2R)-4-[(2E)-3-phosphonoprop-2-ényl]pipérazine-2-carboxyliqueantagoniste des récepteurs du NMDA

midafotel ácido (-)-(R)-4-[(E)-3-fosfonoalil]-2-piperazincarboxílicoantagonista de los receptores de NMDA

C8H15N2O5P

HN

N

CO2HH

P

O

OH

OH

7641midaxifyllinummidaxifylline 8-(1-aminocyclopentyl)-1,3-dipropylxanthineadenosine receptor antagonist

midaxifylline 8-(1-aminocyclopentyl)-1,3-dipropyl-3,7-dihydro-1H-purine-2,6-dioneantagoniste de récepteur adenosine

midaxifilina 8-(1-aminociclopentil)-1,3-dipropilxantinaantagonista del receptor adenosina

C16H25N5O2

N

N

HN

N

O

O

CH3

NH2H3C

45


midostaurinummidostaurin N-[(9S,10R,11R,13R)-2,3,10,11,12,13-hexahydro-10-methoxy-9-methyl-

1-oxo-9,13-epoxy-1H,9H-diindolo[1,2,3-gh:3',2',1'-lm]pyrrolo[3,4-j]=[1,7]benzodiazonin-11-yl]-N-methylbenzamideantineoplastic

midostaurine N-[(9S,10R,11R,13R)-10-méthoxy-9-méthyl-1-oxo-2,3,10,11,12,13-hexahydro-9,13-époxy-1H,9H-diindolo[1,2,3-gh:3’,2’,1’-lm]pyrrolo[3,4-j]=[1,7]benzodiazonin-11-yl]-N-méthylbenzamideantinéoplasique

midostaurina N-[(9S,10R,11R,13R)-2,3,10,11,12,13-hexahidro-10-metoxi-9-metil-1-oxo-9,13-epoxi-1H,9H-diindolo[1,2,3-gh:3',2',1'-lm]pirrolo[3,4-j]=[1,7]benzodiazonin-11-il]-N-metilbenzamidaantineoplásico

C35H30N4O4

N N

HN

OCH3H

NCH3

O

H

O

H

OCH3

7646miroprofenummiroprofen p-imidazo[1,2-a]pyridin-2-ylhydratropic acidNMDA receptor antagonist

miroprofène acide (2RS)-2-[4-(imidazo[1,2-a]pyridin-2-yl)phényl]propanoïqueantagoniste des récepteurs du NMDA

miroprofeno ácido p-imidazo[1,2-a]piridin-2-ilhidratrópicoantagonista de los receptores de NMDA

C16H14N2O2

CO2H

CH3H

N

N


morolimumabummorolimumab human monoclonal IgG1 antibody against human Rhesus-D antigenimmunomodulator

morolimumab immunoglobuline G 1 (anticorps monoclonal humain dirigé contre l’antigèneRhésus-D humain)immunomodulateur

morolimumab inmunoglobulina G 1 (anticuerpo monoclonal humano dirigido contra elantígeno Rhesus-D humano)inmunomodulador

46


natalizumabumnatalizumab immunoglobulin G 4 (human-mouse monoclonal AN100226 4-chain anti-

human integrin 4), disulfide with human-mouse monoclonal AN100226 lightchain, dimerimmunomodulator

natalizumab immunoglobuline G 4 (chaîne γ de l’anticorps monoclonal de souris humaniséAN100226 dirigé contre l’intégrine 4 humaine), dimère du disulfure avec lachaîne légère de l’anticorps monoclonal de souris humanisé AN100226immunomodulateur

natalizumab inmunoglobulina G 4 (cadena γ del anticuerpo monoclonal humanizado deratón AN100226 dirigido contra la integrina 4 humana), dímero del disulfurocon la cadena ligera del anticuerpo monoclonal humanizado de ratónAN100226inmunomodulador

7740olamufloxacinumolamufloxacin (-)-5-amino-7-[(S)-7-amino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-

1,4-dihydro-8-methyl-4-oxo-3-quinolinecarboxylic acidantibacterial

olamufloxacine (-)-acide 5-amino-7-[(7S)-7-amino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-8-méthyl-4-oxo-1,4-dihydroquinoléine-3-carboxyliqueantibactérien

olamufloxacina ácido (-)-5-amino-7-[(S)-7-amino-5-azaspiro[2.4]hept-5-il]-1-ciclopropil-6-fluoro-1,4-dihidro-8-metil-4-oxo-3-quinolinacarboxílicoantibacteriano

C20H23FN4O3

N

CO2H

O

F

CH3

NH2

NH

H2N

7753palivizumabumpalivizumab immunoglobulin G 1 (human-mouse monoclonal MEDI-493 γ1-chain anti-

respiratory syncytial virus protein F), disulfide with human-mouse mono-clonal MEDI-493 κ-chain, dimerimmunomodulator

palivizumab immunoglobuline G 1 (chaîne γ1 de l’anticorps monoclonal de sourishumanisé MEDI-493 dirigé contre la protéine F du virus syncytialrespiratoire), dimère du disulfure avec la chaîne κ de l’anticorps monoclonalde souris humanisé MEDI-493immunomodulateur

palivizumab inmunoglobulina G 1 (cadena γ1 del anticuerpo monoclonal humanizado deratón MEDI-493 dirigido contra la proteína F del virus respiratorio sincitial),dímero del disulfuro con la cadena κ del anticuerpo monoclonal humanizadode ratón MEDI-493inmunomodulador

47


piboserodumpiboserod N-[(1-butyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-

10-carboxamideserotonin receptor antagonist

pibosérod N-[(1-butylpipéridin-4-yl)méthyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamideantagoniste de la sérotonine

piboserod N-[(1-butil-4-piperidil)metil]-3,4-dihidro-2H-[1,3]oxazino[3,2-a]indol-10-carboxamidaantagonista de los receptores de la serotonina

C22H31N3O2

HN

O

N

O

N CH3

7600piridicillinumpiridicillin (2S,5R,6R)-6-[(R)-2-[6-[p-[bis(2-hydroxyethyl)sulfamoyl]phenyl]-

1,2-dihydro-2-oxonicotinamido]-2-(p-hydroxyphenyl)acetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acidserotonin receptor antagonist

piridicilline acide (2S,5R,6R)-6-[[(2R)-2-[[[6-[4-[bis(2-hydroxyéthyl)sulfamoyl]phényl]-2-oxo-1,2-dihydropyridin-3-yl]carbonyl]amino]-2-(4-hydroxyphényl)acétyl]=amino]-3,3-diméthyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxyliqueantagoniste de la sérotonine

piridicilina ácido (2S,5R,6R)-6-[(R)-2-[6-[p-[bis(2-hidroxietil)sulfamoil]fenil]-1,2-dihidro-2-oxonicotinamido]-2-(p-hidroxifenil)acetamido]-3,3-dimetil-7-oxo-4-tia-1-azabiciclo[3.2.0]heptano-2-carboxílicoantagonista de los receptores de la serotonina

C32H35N5O11S2

N

S CH3

CH3

CO2HH

HH

HN

O

NHH

OHN

S

N

HO

OH

OO

O

HOO

repinotanumrepinotan (-)-2-[4-[[(R)-2-chromanylmethyl]amino]butyl]-1,2-benzisothiazolin-3-one

1,1-dioxideserotonin receptor agonist

répinotan (-)-2-[4-[[[(2R)-3,4-dihydro-2H-chromén-2-yl]méthyl]amino]butyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxydeagoniste de la sérotonine

repinotán (-)-2-[4-[[(R)-2-cromanilmetil]amino]butil]-1,2-benzisotiazolin-3-ona1,1-dióxidoagonista de los receptores de la serotonina

48


C21H24N2O4S

HN

NS

OO

O

O

H

7678sardomozidumsardomozide urea azine with 1-oxo-4-indancarboxamidineantineoplastic

sardomozide [(4-carbamimidoyl-2,3-dihydro-1H-indén-1-ylidène)amino]guanidineantinéoplasique

sardomozida azina de la urea con 1-oxo-4-indancarboxamidinaantineoplásico

C11H14N6

HN

NH2

NN NH2

NH2

7752stannsoporfinumstannsoporfin dihydrogen (OC-6-13)-dichloro[7,12-diethyl-3,8,13,17-tetramethylporphyrin-

2,18-dipropionato(4-)-N21,N22,N23,N24]stannate(2-)bilirubin inhibitor

stannsoporfine dihydrogéno (OC-6-13)-dichloro[7,12-diéthyl-3,8,13,17-tétraméthyl=porphyrine-2,18-dipropanoato(4-)-N21,N22,N23,N24]stannate(2-)inhibiteur de la bilirubine

estannsoporfina (OC-6-13)-dicloro[7,12-dietil-3,8,13,17-tetrametilporpirina-2,18-dipropionato(4-)-N21,N22,N23,N24]estannato(2-) de dihidrógenoinhibidor de la bilirubina

C34H36Cl2N4O4Sn

N N

NN

H3CHO2C

CH3

CH3

CH3

CH3H3CHO2C

Sn

Cl

Cl

7606teclozanumteclozan N,N’-(p-phenylenedimethylene)bis[2,2-dichloro-N-(2-ethoxyethyl)acetamide]serotonin receptor antagonist

téclozan N,N’-[1,4-phénylènebis(méthylène)]bis[2,2-dichloro-N-(2-éthoxyéthyl)acétamide]antagoniste de la sérotonine

teclozán N,N’-(p-fenilenodimetileno)bis[2,2-dicloro-N-(2-etoxietil)acetamida]antagonista de los receptores de la serotonina

49


C20H28Cl4N2O4

NO CH3

NOH3C O

OCl

Cl

Cl

Cl

tegaserodumtegaserod 1-[[(5-methoxyindol-3-yl)methylene]amino]-3-pentylguanidineserotonin receptor antagonist

tégasérod N-[[(5-méthoxy-1H-indol-3-yl)méthylène]amino]-N'-pentylguanidineantagoniste de la sérotonine

tegaserod 1-[[(5-metoxiindol-3-il)metilen]amino]-3-pentilguanidinaantagonista de los receptores de la serotonina

C16H23N5O

NNH

NH

HN

H3CO

NH

CH3

7769tenecteplasumtenecteplase 103-L-asparagine-117-L-glutamine-296-L-alanine-297-L-alanine-298-L-alanine-

299-L-alanineplasminogen activator (human tissue-type)antithrombotic

ténectéplase [103-L-asparagine-117-L-glutamine-296-L-alanine-297-L-alanine-298-L-alanine-299-L-alanine]activateur du plasminogène (type tissulairehumain)antithrombotique

tenecteplasa 103-L-asparagina-117-L-glutamina-296-L-alanina-297-L-alanina-298-L-alanina-299-L-alanina-activador del plasminógeno (de tipo tisular humano)antitrombótico

C2558H3872N738O781S40

7758thiramumthiram bis(dimethylthiocarbamoyl)disulfideantiarrhythmic

thirame bis(diméthylthiocarbamoyl)disulfaneantiarythmique

tiramo disulfuro de bis-(dimetiltiocarbamoilo)antiarrítmico

C6H12N2S4

H3CN S

S NCH3

S

S

CH3

CH3

50


trecetilidumtrecetilide (-)-4'-[(S)-4-[ethyl(6-fluoro-6-methylheptyl)amino]-

1-hydroxybutyl]methanesulfonanilideantiarrhythmic

trécétilide (-)-N-[4-[(1S)-4-[éthyl(6-fluoro-6-méthylheptyl)amino]-1-hydroxybutyl]phényl]méthanesulfonamideantiarythmique

trecetilida (-)-4'-[(S)-4-[etil(6-fluoro-6-metilheptil)amino]-1-hidroxibutil]metanosulfonanilidaantiarrítmico

C21H37FN2O3S

H3CS

NH

NCH3

CH3FOHH

OO

CH3

7750valrubicinumvalrubicin (8S,10S)-8-glycoloyl-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-

10-[[2,3,6-trideoxy-3-(2,2,2-trifluoroacetamido)-α-L-lyxo-hexopyranosyl]oxy]-5,12-naphthacenedione 82-valerateantineoplastic

valrubicine pentanoate de 2-oxo-2-[(2S,4S)-2,5,12-trihydroxy-7-méthoxy-6,11-dioxo-4-[[3-[(trifluoroacétyl)amino]-2,3,6-tridésoxy-α-L-lyxo-hexopyranosyl]oxy]-1,2,3,4,6,11-hexahydrotétracén-2-yl]éthyleantinéoplasique

valrubicina 82-valerato de (8S,10S)-8-glicoloil-7,8,9,10-tetrahidro-6,8,11-trihidroxi-1-metoxi-10-[[2,3,6-tridesoxi-3-(2,2,2-trifluoroacetamido)-α-L-lixo-hexopiranosil]oxi]-5,12-naftacenodionaantineoplásico

C34H36F3NO13

O

OOCH3

OH

OH O

HN

CH3

HO

OH

OH

O

O

O

CH3

O

CF3

51


AMENDMENTS TO PREVIOUS LISTSMODIFICATIONS APPORTÉES AUX LISTES ANTÉRIEURES

MODIFICACIONES A LAS LISTAS ANTERIORES

Recommended International Nonproprietary Names (Rec. INN): List 8

(WHO Chronicle, Vol. 22, No. 10, 1968)

p. 466 hypromellosum

hypromellose replace the chemical name by the following:

a mixed methyl and 2-hydroxypropyl ether of cellulose

Dénominations communes internationales recommendées (DCI Rec.): Liste 8

(Chronique OMS, Vol. 22, No. 10, 1968)


hypromellose remplacer le nom chimique par le suivant:

mélange d'éthers méthyliques et 2-hydroxypropyliques de cellulose

Denominaciones Comunes Internacionales Recomendadas (DCI Rec.): Lista 8

(Crónica de la OMS, Vol. 22, No. 10, 1968)


hipromelosa sustitúyase el nombre quimico por el siguiente:

mezcla de éteres metílicos y 2-hidroxipropílicos de celulosa


(WHO Chronicle, Vol. 28, No. 10, 1974)

p. 2 calcitoninum

calcitonin replace the description by the following:

a polypeptide hormone that lowers the calcium concentration

(the species specificity should be indicated in brackets behind the name)

e.g.

calcitonin (human)C151H226N40O45S3

Cys Gly Asn Leu Ser Thr Cys Met Leu Gly Thr Tyr Thr

Gln Asp Phe Asn Lys Phe His Thr Phe Pro Gln Thr Ala

Ile Gly Val Gly Ala Pro NH2

10

20

30

52


calcitonin (salmon)C145H240N44O48S2

Cys Ser Asn Leu Ser Thr Cys Val Leu Gly Lys Leu Ser

Gln Glu Leu His Lys Leu Gln Thr Tyr Pro Arg Thr Asn

Thr Gly Ser Gly Thr Pro NH2

10

20

30


(Chronique OMS, Vol. 28, No. 10, 1974)

p. 2 calcitoninum

calcitonine remplacer la description par la suivante:

hormone polypeptidique qui abaisse le taux de calcium

(la spécifité de l'espèce doit être indiquée entre parenthèses derrière la

dénomination), ex.:

calcitonine (humaine)C151H226N40O45S3




10

20

30

calcitonine (saumon)C145H240N44O48S2




10

20

30


(Crónica de la OMS, Vol. 28, No. 10, 1974)

p. 3 calcitoninum

calcitonina sustitúyase la descripción por la siguiente:

hormona polipeptídica que disminuye la concentración del calcio

(la especifidad de especie debe estar indicada entre paréntesis después

de la denominación) p. ej.

53


calcitonina (humana)C151H226N40O45S3




10

20

30

calcitonina (salmón)C145H240N44O48S2




10

20

30


(WHO Drug Information, Vol. 7, No. 3, 1993)

p. 1 altumomabum

altumomab replace the description by the following:

immunoglobulin G1, anti-(human carcinoembryonic antigen) (mouse

monoclonal ZCE025 γ1-chain), disulfide with mouse monoclonal ZCE025

light chain, dimer

p. 7 satumomabum

satumomab replace the description by the following:

immunoglobulin G1, anti-(human tumor-associated glycoprotein 72) (mouse

monoclonal B72.3 light chain), disulfide with mouse monoclonal B72.3 light

chain, dimer


(Informations Pharmaceutiques OMS, Vol. 7, No. 3, 1993)

p. 1 altumomabum

altumomab remplacer la description par la suivante:

immunoglobuline G1, anti-(antigène associé aux carcinomes embryonnaires

humains) (chaîne γ1 de l'anticorps monoclonal de souris ZCE025), dimère

du disulfure avec la chaîne légère de l'anticorps monoclonal de souris

ZCE025

54


p. 8 satumomabum

satumomab remplacer la description par la suivante:

immunoglobuline G1, anti-(glycoprotéine 72 humaine associée aux tumeurs)

(chaîne légère de l'anticorps monoclonal de souris B72.3), dimère du

disulfure avec la chaîne légère de l'anticorps monoclonal de souris B72.3


(Información Farmacéutica OMS, Vol. 7, No. 3, 1993)

p. 1 altumomabum

altumomab sustitúyase la descripción por la siguiente:

inmunoglobulina G1, anti-(antígeno carcinoembrionario humano) (cadena γ1

del anticuerpo monoclonal de ratón ZCE025), dímero del disulfuro con la

cadena ligera del anticuerpo monoclonal de ratón ZCE025

p. 7 satumomabum

satumomab sustitúyase la descripción por la siguiente:

inmunoglobulina G1, anti-(glicoproteína 72 humana asociada al tumor)

(cadena ligera del anticuerpo monoclonal de ratón B72.3), dímero del

disulfuro con la cadena ligera del anticuerpo monoclonal de ratón B72.3





p. 2 abciximabum

abciximab replace the description by the following:

immunoglobulin G1, anti-(human integrin αIIbβ3) Fab fragment (human-

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

mouse monoclonal c7E3 clone p7E3VκhCκ κ-chain

abciximab remplacer la description par la suivante:

immunoglobuline G1, anti-(intégrine αIIbβ3 humaine) fragment Fab (chaîne

γ1 de l’anticorps monoclonal chimérique homme-souris c7E3 clone

p7E3VHhCγ1), disulfure avec la chaîne κ de l’anticorps monoclonal

chimérique homme-souris c7E3 clone p7E3VκhCκ

abciximab sustitúyase la descripción por la siguiente:

inmunoglobulina G1, anti-(integrina αIIbβ3 humana) fragmento Fab (cadena

γ1 del anticuerpo monoclonal hombre-ratón c7E3 clon p7E3VHhCγ1),

disulfuro con la cadena κ del anticuerpo monoclonal hombre-ratón c7E3

clon p7E3VκhCκ

55


p. 5 capromabum

capromab replace the description by the following:

immunoglobulin G1, anti-(human prostatic carcinoma cell) (mouse mono-

clonal 7E11-C5.3 γ1−chain), disulfide with mouse monoclonal 7E11-C5.3 light

chain, dimer

capromab remplacer la description par la suivante:

immunoglobuline G1, anti-(cellules du carcinome prostatique humain)

(chaîne γ1 de l'anticorps monoclonal de souris 7E11-C5.3), dimère du

disulfure avec la chaîne légère de l'anticorps monoclonal de souris 7E11-

C5.3

capromab sustitúyase la descripción por la siguiente:

inmunoglobulina G1, anti-(células de carcinoma prostático humano) (cadena

γ1 del anticuerpo monoclonal de ratón 7E11-C5.3), dímero del disulfuro con

la cadena ligera del anticuerpo monoclonal de ratón 7E11-C5.3

p. 8 detumomabum

detumomab replace the description by the following:

immunoglobulin G1, anti-(human B lymphoma cell) (mouse monoclonal

SPECIFID heavy chain), disulfide with mouse monoclonal SPECIFID light

chain, dimer

détumomab remplacer la description par la suivante:

immunoglobuline G1, anti-(cellules de lymphome B humain) (chaîne lourde de

l'anticorps monoclonal de souris SPECIFID), dimère du disulfure avec la

chaîne légère de l'anticorps monoclonal de souris SPECIFID

detumomab sustitúyase la descripción por la siguiente:

inmunoglobulina G1, anti-(células de linfoma B humano) (cadena pesada del

anticuerpo monoclonal de ratón SPECIFID), dímero del disulfuro con la

cadena ligera del anticuerpo monoclonal de ratón SPECIFID

p. 8 edobacomabum

edobacomab replace the description by the following:

immunoglobulin M, anti-(endotoxin) (mouse monoclonal XMMEN-0E5

µ-chain), disulfide with mouse monoclonal XMMEN-0E5 light chain,

pentameric dimer

édobacomab remplacer la description par la suivante:

immunoglobuline M, anti-(endotoxine) (chaîne m de l'anticorps monoclonal

souris XMMEN-0E5), dimère pentamérique du disulfure avec la chaîne

légère de l'anticorps monoclonal de souris XMMEN-0E5

edobacomab sustitúyase la descripción por la siguiente:

inmunoglobulina M, anti-(endotoxina) (cadena µ del anticuerpo monoclonal

de ratón XMMEN-0E5), dímero pentamérico del disulfuro con la cadena

ligera del anticuerpo monoclonal de ratón XMMEN-0E5

56


p. 9 enlimomabum

enlimomab replace the description by the following:

immunoglobulin G2a, anti-(human CD54 (antigen)) (mouse monoclonal BI-

RR-1 γ2a−chain), disulfide with mouse monoclonal BI-RR-1 light chain, dimer

enlimomab remplacer la description par la suivante:

immunoglobuline G2a, anti-(antigène CD54 humain) (chaîne γ2a de

l'anticorps monoclonal de souris BI-RR-1), dimère du disulfure avec la

chaîne légère de l'anticorps monoclonal de souris BI-RR-1

enlimomab sustitúyase la descripción por la siguiente:

inmunoglobulina G2a, anti-((antígeno) CD54 humano) (cadena γ2a del

anticuerpo monoclonal de ratón BI-RR-1), dímero del disulfuro con la cadena

ligera del anticuerpo monoclonal de ratón BI-RR-1

p. 21 votumumabum

votumumab replace the description by the following:

immunoglobulin G3, anti-(human carcinoma-associated antigen) (human

monoclonal 88BV59 γ3−chain), disulfide with human monoclonal 88BV59

κ-chain, dimer

votumumab remplacer la description par la suivante:

immunoglobuline G3, anti-(antigène associé aux carcinomes humains)

(chaîne γ3 de l'anticorps monoclonal humain 88BV59), dimère du disulfure

avec la chaîne κ de l'anticorps monoclonal humain 88BV59

votumumab sustitúyase la descripción por la siguiente:

inmunoglobulina G3, anti-(antígeno asociado a los carcinomas humanos)

(cadena γ3 del anticuerpo monoclonal humano 88BV59), dímero del

disulfuro con la cadena κ del anticuerpo monoclonal humano 88BV59

p. 22 zolimomabum aritoxum

zolimomab aritox replace the description by the following:

immunoglobulin G1, anti-(human CD5 (antigen) heavy chain) (mouse

monoclonal H65-RTA γ1−chain), disulfide with mouse monoclonal H65-RTA

light chain, dimer, disulfide with ricin (castor bean A-chain)

zolimomab aritox remplacer la description par la suivante:

immunoglobuline G1, anti-(chaîne lourde de l’antigène CD5 humain) (chaîne

γ1 de l’anticorps monoclonal de souris H65-RTA), dimère du disulfure avec

la chaîne légère de l’anticorps monoclonal de souris H65-RTA, disulfure

avec la chaîne A de la ricine

zolimomab aritox sustitúyase la descripción por la siguiente:

inmunoglobulina G1, anti-(cadena pesada del antígeno humano CD5)

(cadena γ1 del anticuerpo monoclonal de ratón H65-RTA), dímero del

disulfuro con la cadena ligera del anticuerpo monoclonal de ratón H65-RTA,

disulfuro con ricina (cadena A de la judía de ricino)

57






p. 3 afelimomabum

afelimomab replace the description by the following:

immunoglobulin G3, anti-(human tumor necrosis factor α) F(ab')2 fragment

(mouse monoclonal LU54107 γ3-chain), disulfide with mouse monoclonal

LU54107 κ-chain, dimer

afélimomab remplacer la description par la suivante:

immunoglobuline G3, anti-(facteur de nécrose tumorale α humain) fragment

F(ab’)2 (chaîne γ3 de l’anticorps monoclonal de souris LU54107), dimère du

disulfure avec la chaîne κ de l’anticorps monoclonal de souris LU54107

afelimomab sustitúyase la descripción por la siguiente:

inmunoglobulina G3, anti-(factor de necrosis tumoral α humano) fragmento

F(ab')2 (cadena γ3 del anticuerpo monoclonal de ratón LU54107), dímero

del disulfuro con la cadena κ del anticuerpo monoclonal de ratón LU54107

p. 13 inolimomabuminolimomab replace the description by the following:

immunoglobulin G1, anti-(human interleukin 2 receptor α-chain) (mouse

monoclonal B-B10 γ1-chain), disulfide with mouse monoclonal B-B10

κ-chain, dimer

inolimomab remplacer la description par la suivante:

immunoglobuline G1, anti-(chaîne α du récepteur de l'interleukine 2 humain)

(chaîne γ1 de l'anticorps monoclonal de souris B-B10), dimère du disulfure

avec la chaîne κ de l'anticorps monoclonal de souris B-B10

inolimomab sustitúyase la descripción por la siguiente:

inmunoglobulina G1, anti-(cadena α del receptor de interleukina 2 humano)

(cadena γ1 del anticuerpo monoclonal de ratón B-B10), dímero del disulfuro

con la cadena κ del anticuerpo monoclonal de ratón B-B10

58


p. 18 nacolomabum tafenatoxum

nacolomab tafenatox replace the description by the following:

immunoglobulin G1, anti-(human colorectal tumor antigen C242) Fab

fragment (mouse monoclonal r-C242Fab-SEA clone pkP941 γ1-chain) fusion

protein with enterotoxin A (Staphylococcus aureus), disulfide with mouse

monoclonal r-C242Fab-SEA clone pkP941 κ-chain

nacolomab tafénatox remplacer la description par la suivante:

protéine de fusion entre l'immunoglobuline G1, anti-(antigène C242 associé

aux tumeurs colorectales humaines) fragment Fab (chaîne γ1 de l'anticorps

monoclonal de souris r-C242Fab-SEA clone pkP941) et l'entérotoxine A

(Staphylococcus aureus), disulfure avec la chaîne κ de l'anticorps

monoclonal de souris r-C242Fab-SEA clone pkP941

nacolomab tafenatox sustitúyase la descripción por la siguiente:

inmunoglobulina G1, anti-(antígeno C242 de tumor colorrectal humano)

fragmento Fab (cadena γ1 del anticuerpo monoclonal de ratón r-C242Fab-

SEA clon pkP941) proteína de fusión con la enterotoxina A (Staphylococcus

aureus), disulfuro con la cadena κ del anticuerpo monoclonal de ratón

r-C242Fab-SEA clon pkP941

p. 22 priliximabum

priliximab replace the description by the following:

immunoglobulin G1, anti-(human CD4 (antigen)) (human-mouse monoclonal

cm-T412 γ1-chain), disulfide with human-mouse monoclonal cm-T412

κ-chain, dimer

priliximab remplacer la description par la suivante:

immunoglobuline G1, anti-(antigène CD4 humain) (chaîne γ1 de l’anticorps

monoclonal chimérique homme-souris cm-T412), dimère du disulfure avec la

chaîne κ de l’anticorps monoclonal chimérique homme-souris cm-T412

priliximab sustitúyase la descripción por la siguiente:

inmunoglobulina G1, anti-((antígeno) CD4 humano) (cadena γ1 del

anticuerpo monoclonal hombre-ratón cm-T412), dímero del disulfuro con la

cadena κ del anticuerpo monoclonal hombre-ratón cm-T412

59


p. 23 regavirumabum

regavirumab replace the description by the following:

immunoglobulin G1, anti-(human herpesvirus 5 glycoprotein B) (human

monoclonal γ1-chain), disulfide with human monoclonal κ-chain, dimer

régavirumab remplacer la description par la suivante:

immunoglobuline G1, anti-(glycoprotéine B du virus de l'herpès 5 humain)

(chaîne γ1 de l'anticorps monoclonal humain), dimère du disulfure avec la

chaîne κ de l'anticorps monoclonal humain

regavirumab sustitúyase la descripción por la siguiente:

inmunoglobulina G1, anti-(glicoproteina B del virus del herpes 5 humano)

(cadena γ1 del anticuerpo monoclonal humano), dímero del disulfuro con la

cadena κ del anticuerpo monoclonal humano

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 PharmaceuticalSubstances and General Principles for Guidance in Devising International Nonproprietary Names for PharmaceuticalSubstances will be reproduced in uneven numbers of proposed INN lists only.

Les textes de la Procédure à suivre en vue du choix de dénominations communes internationales recommandées pourles substances pharmaceutiques et des Directives générales pour la formation de dénominations communes internatio-nales applicables aux substances pharmaceutiques seront publiés seulement dans les numéros impaires des listesdes DCIs proposées.

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