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INFORMATION V O L U M E 1 1 - N U M B E R 3 • 1 9 9 7

R E C O M M E N D E D I N N L I S T 3 8 I N T E R N A T I O N A L N O N P R O P R I E T A R Y N A M E S F O R P H A R M A C E U T I C A L S U B S T A N C E S

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

Volume 11, Number 3, 1997 World Health Organization, Geneva

WHO Drug Information

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Contents

General Policy IssuesThe dangers of counterfeit and substandard

active pharmaceutical ingredients 123

Quality Assurance IssuesThe importance of analytical procedures

in regulatory control 128

Reports on Individual DrugsSimplified treatment for leprosy 131Should antibiotics be indicated for children

with acute otitis media? 131Acetylsalicylic acid: confirmed efficacy

after stroke 132Antiretroviral therapy for HIV: latest guidelines 134

General InformationBiological standardization: report of the

Expert Committee 138

Regulatory MattersIrinotecan-associated mortality 141HIV protease inhibitors associated with

diabetes 141Valvular heart disease associated with

fenfluramine and phentermine 141Withdrawal of antidiarrhoeal paediatric product 142Dangerous products promoted on the Internet 142Health risks of herbal products containing

ephedrine 142Photoallergic and phototoxic reactions

associated with fibrates 143Restriction on sale of high-dose vitamin B6

products 143First-year safety reports with triple component

pertussis vaccine 143

Essential DrugsWHO Model FormularyAntiprotozoal drugsDrugs used in amoebiasis 144

Diloxanide 144Drugs used in giardiasis

Metronidazole 145Drugs used in leishmaniasis 145

Meglumine antimoniate & sodium stibogluconate 146Pentamidine 147Amphotericin B 148

Drugs used in trypanosomiasis 148Melarsoprol 148Pentamidine 149Suramin sodium 149Eflornithine 151

Drugs used in American trypanosomiasis 151Benznidazole 151Nifurtimox 152

ATC/DDD Classification(temporary) 153

Recent Publications and DocumentsDrugs for the elderly 155Rapid examination methods against counterfeit

and substandard drugs 155Countering counterfeiting 155Malaria: a manual for community health

workers 156Guidelines for the management of

drug-resistant tuberculosis 156

Recommended InternationalNonproprietary Names: List 38 157

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WHO Drug Information Vol. 11, No. 3, 1997

General Policy Issues

The dangers of counterfeitand substandard activepharmaceutical ingredientsWHO was first alerted to the circulation of counter-feit pharmaceuticals at the Conference of Expertson the Rational Use of Drugs held in Nairobi, in1985. Since then, concern about the situation hasbeen voiced repeatedly by delegations at the WorldHealth Assembly and this has been reflected inseveral resolutions. The most important wasadopted in May 1988 (1) and requested WHO "toinitiate programmes for the prevention anddetection of the export, import and smuggling offalsely labelled, spurious, counterfeited orsubstandard pharmaceutical preparations and tocooperate with the Secretary-General of the UnitedNations in such cases when the provisions ofinternational drug treaties are violated".

The WHO Secretariat has implemented theseresolutions through its normative activities as wellas in the formulation of guidelines. It has set out tostimulate collaboration between regulatory authori-ties, and a data base has been created within WHOwhich contains some 700 case reports on counter-feit finished dosage forms. Information and newsare exchanged regularly with other interestedparties and drug alerts are circulated to drugregulatory authorities. Particular importance isplaced on the promotion of training for drugregulators and inspectors in those countries whichare most vulnerable to counterfeiting and relatedactivities.

The report of a WHO/IFPMA workshop held in 1992(2) defines a counterfeit medicine as one which isdeliberately and fraudulently mislabelled withrespect to identity and/or source. This definition isalso relevant to active pharmaceutical ingredients(APIs) and underscores the need to establish theirtrue origin and to have this information reflected onthe label. Furthermore, it has become evident thatboth developed and developing countries alike areconfronted with similar problems. Counterfeits canrange from highly sophisticated copies which arealmost indistinguishable from the authentic brandedproduct, to potentially dangerous substandard orspurious preparations sold under branded orgeneric labels.

In countries where there is strong regulation,counterfeits are fewer in number, but highlysophisticated. Where the risk of detection is lower,the infringements increase in number and themisrepresentations become more crude. In thedeveloping countries, it is the essential life-savingdrugs such as antibiotics and antiparasitics that aremost commonly counterfeited. Many developingcountries are heavily reliant on imports of finisheddosage forms and active pharmaceutical ingredi-ents. As a result of the attention that has repeatedlybeen drawn to the extent of counterfeit andsubstandard products, including APIs, circulatingwithin these countries, the WHO CertificationScheme is being extended to include activepharmaceutical ingredients.

It must be underscored that, at present, the legalstatus of APIs differs fundamentally from that offinished dosage forms. APIs are not subject tomarketing authorization, although they are regulat-ed indirectly through the drug master file (DMF).However, this mechanism is only applied in highlydeveloped countries and, even there, marketingand labelling are not always regulated. Finisheddosage forms, on the other hand, are subject tomarketing authorization, and their labelling is strictlyregulated and requires display of the marketingauthorization holder, even when this is not themanufacturer.

Because of the present lack of regulation of APIs, itis unclear whether the definition manufacture andmanufacturer — as set out, for example, in theWHO/GMP text (3) and in Directive 75/319/EEC —also covers APIs. If it does, the opportunity arisesfor a company or an individual involved in “partialmanufacture” — perhaps only repackaging — toplace their name on the label without furtherreference to the manufacturer responsible for thechemical synthesis. In many instances, this practiceprovides a means to deliberately obscure the trueprovenance and quality of the material.

Case reportsThe following reports on counterfeit APIs have beenprovided to WHO, and several of them clearlyillustrate the problem of labelling.

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WHO Drug Information Vol. 11, No. 3, 1997General Policy Issues

AustraliaIn February 1997, the Therapeutic Goods Ad-ministration of Australia drew the attention of thePharmaceutical Inspection Convention (PIC-PIC/S)Committee of Officials (4) to the practice of sub-stitution. The following cases, concerning APIsmanufactured and supplied from Asia, are drawnfrom the evidence provided.

An API, sulfamethoxazole, manufactured in Indiaand delivered to an Australian firm, was partiallysubstituted with sugar in the same particle size. Thesubstitution involved three of every 10 containers inthe delivery. In another incident, inferior grade andrejected APIs were deliberately being placed at thebottom of every third or fourth drum. During sub-sequent investigations, it came to light that thissubstitution often takes place immediately followingdeparture of the consignment from the premises ofthe legitimate manufacturer. Substitution racket-eers also gain access to sophisticated packagingtechnology, including access to “tamper-proof”security devices through co-opting companyemployees into providing packaging information, orexamples of the security, or the actual packagingmaterial from either the manufacturing plant or theprinter of the labels.

Information on this particular situation was passedon to all members of the PIC-PIC/S, and inspector-ates were requested to report any similar problemsoccurring in their own country. They were alsoasked whether a provision for “top, middle andbottom” sampling of each container of API receivedfrom specified countries should be implemented.

The Therapeutic Goods Administration has alsoinvestigated the following cases.

• An antibiotic API exported to Australia from acountry in Western Europe was in fact manu-factured in Central America, then sent to theEuropean company where it was repackaged,reanalysed and issued with a new certificate ofanalysis before being shipped to an affiliate inAustralia. The label and documentation gave theimpression that the API originated in Europe. TheAustralian company only discovered the origin ofthe product after an investigation.

• An orphan drug API, documented as originatingfrom a Western European country, was actuallyproduced in Eastern Europe. The practice wentundetected by the Australian affiliate company forabout a decade until the Western European plantwas closed down and information was disclosed.

The argument provided by these companies was

that the value-added nature of the work conductedin Western Europe was greater than 50% of thecost of the drug provided to Australia and hence thecompany was entitled to claim that it was “made” inthat particular country. No action could be takensince the Australian companies had not committedan offence, and no prosecution of the overseascompanies from within Australia was possible.However, because of lack of regulation of either themanufacturing process, de novo synthesis, orrepackaging, and the routing of subsequentexports, it is unlikely that the authorities in any ofthe countries involved would have had a basis forlegal intervention.

Many similar cases involve substitution, dilution oradulteration, including the addition of subpotentmaterial to normal material in such a way as to bejust able to pass pharmacopoeial specifications,and the switching of technical grade for pharma-ceutical grade substances.

United States of AmericaInformation has also been received from the USFood and Drug Administration's Office of CriminalInvestigation (5) regarding recent cases involvingAPIs. The following investigation was carried outjointly with the US Customs Service.

In 1991, chemists at SmithKline Beecham Labora-tories notified the FDA of the delivery of counterfeitoxytetracycline at their Animal Health Facility inNebraska. Investigations discovered a conspiracyto import and distribute counterfeit bulk drugs. As aconsequence, a company and three individualswere fined for drug counterfeiting and moneylaundering.

The investigation determined that companyemployees were switching national drug codes(NDCs) and producing counterfeit certificates ofanalysis (COAs) reflecting false codes, falsemanufacturers and false batch-code information. Inessence, the legitimate API was replaced withcounterfeit API, or repackaged into drums that weredifferent from those used by the legitimate manu-facturer. The legitimate drug was therefore replacedwith a drug which purported to be the approved USAPI, when in fact it was not.

Surprisingly, legitimate firms receiving the counter-feit products did not bother to challenge thedeliveries, even when they observed unusual ormismatched drums. The drugs involved werechlortetracycline, oxytetracycline, tetracycline,

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chloramphenicol, gentamicin, neomycin sulfate,sulfadimidine, and methyldopa.

United KingdomExamples of prosecuted cases (6) on whichinformation is provided from the United Kingdominvolve pharmaceutical products and not APIs.However, the way in which they were handled couldequally apply to APIs and the following examplesmay be of interest.

• A licensed UK wholesale distributor was found tohave stocks of pharmaceutical products on pre-mises other than those declared on the licence.These products were imports for which thecompany did not have marketing authorization.The products had been removed from originalcontainers and repackaged to disguise the origin,and the expiry dates were extended beyond theshelf-life. As a consequence of this investigation,the operating licence was withdrawn and thecompany and its owner successfully prosecuted.

• An unlicensed trader was found to import largequantities of pharmaceutical products from outsidethe European Union, and manufactured onunlicensed sites. These were sold to pharmacies“from the back of a van”. The trader was arrestedand the stock seized, as were the proceeds of thesales. Both the trader and an accomplice weresuccessfully prosecuted and pharmacists pur-chasing the products were reported to theirprofessional association.

• A licensed wholesaler who substituted batchnumbers on a substantial quantity of stock he wasnot licensed to sell was successfully prosecuted.

Cases still under investigation in the UK involveillicit manufacture, obtaining APIs from unlicensedsites in the Far East, assembling products andproposing these as the genuine product, andassembling products containing only 50% of theAPI.

A counterfeit product in the UK tends to be aprescription-only medicine and one for which eitherdemand and sale price are high, or for which thereis a specialized highly-priced demand.

Prosecutions generally result in fines and,occasionally, a prison sentence. United Kingdomlegislation permits sequestration of assets gainedby unlawful activity, and the Medicines Control

Agency can request courts to confiscate property,money and other assets. Consignments ofpharmaceutical products are also seized. Theseactions are intended to make counterfeitingactivities unrewarding and, as a deterrent, can bemore effective than fines or even imprisonment.

Contamination with diethylene glycolExperience with this compound indicates thatsafeguards need to be applied to all materialsincluded in formulated dosage forms and not justAPIs. Contamination or substitution with diethyleneglycol in the manufacture of pharmaceutical pro-ducts has resulted in the loss of over 500 lives —mostly children — in Argentina, Bangladesh, India,Nigeria and, now, Haiti. WHO has sent warnings todrug regulatory authorities in all Member Statesfollowing these incidents.

Over 80 children died in the Haiti incident last year(7), and the case was investigated by the Haitianauthorities with the assistance of the US Food andDrug Administration (FDA), the US Centers forDisease Control (CDC) and WHO/PAHO. A specialworkshop on diethylene glycol contamination wassubsequently held and a report will soon be issuedwith recommendations on this particular problem. Itwill also include simple analytical test proceduresthat allow the detection of diethylene glycol down toa low content limit.

Despite the fact that the pharmaceutical companyin Haiti ordered glycerol from a company inGermany, the material was originally shipped fromXiangang (China) via the free port in Rotterdam(Netherlands) to Port-au-Prince. It is clear thatthroughout a series of complicated and numeroustransactions, vital information on the provenanceand nature of the material was obliterated ondocuments and product containers.

The pharmaceutical company in Haiti used theproduct traded in this way for the preparation ofparacetamol syrup and oral drops for neonates.Following the incident, the manufacturer was visitedby an FDA inspector and found to be in violation ofbasic GMP principles, since the incoming startingmaterials were not being tested, no in-processquality control was implemented, and certificates ofanalysis were not always available. According to anewspaper article on this case, the manufacturerstated that he had ordered the material fromGermany to be certain of its quality.

What can be done?


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There is now sufficient evidence of the internationalcirculation of counterfeit and substandard APIs andother starting materials used in the manufacture ofmedicines. The magnitude of this trade may beunknown, but it is certainly far greater than is evi-dent from the case histories that have filteredthrough into the public domain. The range andextent of illicit activities, even in highly regulatedcountries, points to an urgent need for counter-measures which should be coordinated on a globalbasis. The following recommendations may provideways to consolidate efforts against unlawful anddangerous activities.

Drug regulatory authorities should:

• extend their regulatory mandate to cover manu-facturers of APIs — particularly with regard toinspection of GMP compliance, and imposerigorous requirements for labelling and certificatesof analysis for consignments moving in interna-tional commerce.

• introduce regulations that require APIs and allother starting materials intended for the formu-lation of medicinal products to be clearly labelled“for pharmaceutical use” or with a suitablepictogram.

• establish within the regulatory authority a multi-disciplinary group to investigate illicit activitiespromptly and professionally.

• monitor free ports and strengthen collaborationwith law enforcement agencies including customsofficials, and offices of criminal investigation, atnational and international level.

• seek to enact legislation that permits seques-tration of assets gained by unlawful activity andseizure and destruction of products involved.

WHO should:

• develop a network of technically competentofficials within national drug regulatory authoritieswith a view to ensuring timely exchange ofinformation, both on cases of counterfeiting andon any countermeasures taken at national level.

• act as a clearinghouse for the exchange ofinformation on counterfeit pharmaceuticals andAPIs.

• develop guidelines for the certification of APIsmoving in international commerce and strengthenGMP.

• continue to promote the use of WHO guidelines

on GMP, inspection and drug registration.

Pharmaceutical manufacturers,wholesalers and traders should:

• be cautious in the procurement of APIs andfinished products, and when introducing productsinto the distribution chain.

• maintain vigilance in detecting counterfeiting orsubstitution of dosage forms and APIs.

• share information with regulatory authorities. Thisinformation should be handled with due discretionto avoid loss of confidence in legitimate products.

• rigorously implement GMP in the manufacture ofAPIs (3).

Manufacturers of finished dosage formsshould:

• buy APIs, whenever possible, from the originalmanufacturer or, when through traders, insist ontransparent and full documentation concerning theorigin, and demand certificates of analysis.

• be aware of their responsibility and liability inassessing and ensuring the quality of the APIsand other starting materials that they use, and therigorous conditions, as outlined in GMP (3), to beapplied in those exceptional situations wherereliance is vested in the supplier’s certificate ofanalysis in place of a full re-analysis.

Interested parties must decide to what extent theserecommendations are realistic. The impact ofadditional laws and regulations will depend on theirimplementation, and this will require increasedinspection capacity and more resources. The fullresponsibility of the manufacturer cannot beoverstressed and the supplier must inform themanufacturer of the true origin of the API. Manysmall manufacturers in developing countries mayhave little bargaining power to insist on this trans-parency, and action needs to be considered withurgency to protect all concerned.

References

1. World Health Assembly resolution WHA 41.16.

2. World Health Organization. Counterfeit drugs: report ofa joint WHO/IFPMA workshop. WHO/DMP/CFD/92. WHO,Geneva 1992.

3. WHO Expert Committee on Specifications for Pharma-


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ceutical Preparations, Thirty-second Report. WHOTechnical Report Series, Number 823, WHO, Geneva,1992.

4. Note from the Therapeutics Goods Administration(TGA) entitled Substitution of Active PharmaceuticalIngredients, distributed during PIC-PIC/S meeting ofofficials in Geneva in February 1997. Communication fromthe TGA addressed to WHO dated 3 and 25 March 1997.

5. Letters from the US FDA Office of Criminal Investiga-

tions addressed to WHO dated 28 February and 7 April1997.

6. Letter from Medicines Control Agency, United Kingdomto WHO dated 2 June 1997.

7. Pan American Health Organization. Deaths in Haitirenal failure epidemic. PAHO News Release, 7 August1996.


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Quality Assurance Issues

The importance of analyticalprocedures in regulatory control

Thomas LayloffDivision of Drug AnalysisUnited States Food and Drug AdministrationSt Louis, MO, USA

A regulatory authority responsible for the quality ofthe pharmaceutical products distributed within itsjurisdiction is confronted with many challenges in itsefforts to assure the public health of its citizens.One of the primary tasks of regulation is to deter-mine which products can safely be allowed onto themarket. This is usually accomplished through adrug registration system.

The laboratory resources needed to support theregulation of any given market will depend heavilyon whether or not the products are manufacturedwithin that market area or whether they are largelyimported. Consequently, if the market is importantand handles large quantities of products, the officiallaboratory will need sufficient resources to providean analytical service which will assure the quality ofthese products. This is especially important whenproducts proposed for entry into the area havebeen manufactured in facilities which have not haddirect inspection for compliance with good manu-facturing practice (GMP).

In many developing countries, however, anunfortunate combination of two factors exists. Onthe one hand, there is a predominance of importedfinished products and on the other, a lack ofadequate analytical services. Product quality canbe better assured if an inspection force is availableto periodically visit manufacturing sites and reviewproduction records. Although the United Statesmarket is supplied mainly by manufacturersoperating within its borders, the number of finisheddosage forms entering the country is steadilyincreasing. It is furthermore expected that thecurrent globalization of the pharmaceutical marketwill also give impetus to increased trading infinished dosage forms and this situation willdemand even greater efforts by inspection andlaboratory services.

Once drug registration has been established,compliance of the approved products with qualitystandards must be sought. In some instances,where a country depends largely on importedfinished products, a regulatory authority will applythe same methods of analysis and qualitystandards as those in the country of product origin.Since little harmonization has so far taken placeamong the major pharmacopoeias, this could giverise to a situation where several different qualitystandards and methods of analysis are in use forthe same product within a given country or marketarea.

The multiplicity of standards and methods applic-able to the same product can result in an extremelycomplicated situation for the regulatory controlservices, such as the need to have access to eachpharmacopoeia and the specific equipment andreagents used in the country of origin. In an effortto remedy this situation, it has been suggested thatthe establishment of a unique analytical monographfor registration purposes and an accompanyingquality standard for each finished dosage formwould help to ensure that the approved productconforms to the same standards. However, thisundertaking would constitute an immense task, andan easier solution may be the adoption of specificmonographs and quality standards for eachapproved product based on existing pharmaco-poeias.

When a pharmaceutical product is received at aport of entry, it is subject to controls to determine itsmarketing status, labelling, and claimed ingredients.These determinations should be made on allproducts entering the market area. In order not tohold up shipments, analytical tests to substantiatethe claimed product characteristics are neededrapidly and as near to the port of entry as possible.However, this is not always possible, since amarket area can very often be serviced by multipleports of entry and standard laboratory services arenot necessarily available at all of them. In thissituation, a preliminary screening can be made ofthe product to ascertain the presence of the activeingredient and the claimed amount. In order to beeffective, this analysis must be carried out before

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release of the goods. If this is not the case, theproducts will be distributed throughout the countryand regulatory controls would be ineffective in theevent that a product needs to be withdrawn. Anarray of chemical methods of analysis are availableto provide information on the quality of a productand ensure that it complies with the regulatoryrequirements in force. This availability is, however,dependent on many factors such as funding andthe extent to which these services are required.Consideration must additionally be addressed tosources of funding for staff, training, equipment,maintenance, supplies and running costs.

A preliminary screening at a port of entry willprovide information on whether a product isapproved for distribution, is properly labelled,contains the correct ingredient in the claimedamount and complies with legal specifications. It isat this point that counterfeit products can mostconveniently be identified. Screening techniquesinclude WHO basic tests, and other simple testmethods. However, the use of thin layer chroma-tography (TLC) has been shown to be particularlyuseful during this preliminary screening phase. Thetests are cheap and quick, require a low capitalinvestment and have low operating costs. TLCrequires minimum laboratory resources and analystskills, which means that competent personnel canbe easily trained in their use. Any sample found tofail the necessary tests using this method couldthen be subjected to analysis according to the legalreference methods (LRM) carried out by theregulatory control laboratory. Notwithstanding thesimplicity of the method, TLC is reliable enough tosupport decisions on whether entry should bedenied for products which fail significantly.

Once a product has entered the market and hasbeen distributed, it falls within the jurisdiction of thatmarket. This generally means that any regulatoryaction taken against the product must be based onLRM as determined by legislation. Thus, in additionto providing preliminary screening of importedproducts, regulatory authorities must maintain, orhave access to, facilities suitable for conductingLRM which will confirm or refute the preliminaryscreening results. These facilities are also useful forcarrying out special surveillance activities. Prelimi-nary screening, with possible confirmatory LRMactivities, is therefore essential before a productcan be released into the market area, and to ensurethat the product will comply with the claimed expirydate and required quality standards.

Unfortunately, in the case of the LRM, several daysor weeks may be needed to set up the analyticalequipment and prepare the reagents. In addition,many LRM use liquid chromatography (LC) or gas-liquid chromatography (GLC) methods. The UnitedStates Pharmacopeia, for example, contains over800 monographs requiring LC and 150 monographsrequiring GLC. As can be imagined, equipment forthis type of analysis requires a relatively largecapital investment, with the related costs for trainedoperators and maintenance staff. In the UnitedStates, a high-performance liquid chromatographwill cost approximately $25 000 to $65 000depending on the accessories and attachments,and a gas-liquid chromatograph will cost between$15 000 and $70 000, although less expensiveequipment may be available in other regions of theworld. In order to keep the equipment operationaland to replace worn parts, a laboratory will need anadditional 5–10% of the initial cost for maintenance.It is important to have easy access to parts andcircuit boards in addition to the necessary reagents,reference standards and supplies, the cost of whichmay represent a further 5–10% of the initial outlay.Furthermore, operation of the equipment can beaffected by environmental factors such astemperature and humidity.

Experience with running an LRM facility suggeststhat, in order to be efficient, it should be equippedand staffed at a level over and above minimumrequirements and it is often preferable to have threeor more units of identical equipment so that aber-rant results can be confirmed by a second appara-tus. Also, modules can be switched around orexchanged when defective parts are identified.Multiple units of identical apparatus will also reducethe need for space to house spare parts andconsumable supplies required to keep the equip-ment operational.

The acquisition of expertise is also an importantfactor if the laboratory is to be run successfully. Incontrast to the minimum skills needed for applyingthe preliminary testing methods, personnel carryingout LRM need higher levels of training. In the morecomplex laboratory environments, it is useful tohave several persons skilled in the same tech-niques working together in order to stimulate thefunctioning of the laboratory and discuss details ofthe work. This strengthens the analytical capabilityof the services provided and assists in the applica-tion of the more complicated instrumentaltechniques.


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Because of the costs involved, LRM testing canonly be performed on a fraction of the productsactually in circulation and in many cases this isbelow 1% of the total. For example, in a countrywhere 35 000 prescription-only medicines and115 000 over-the-counter products are on themarket, there would be 150 000 batch samples tobe collected and analysed. For each product,analysis would include assay, content uniformity,release rate and identity and an approximate totalof 30 analytical results would eventually beproduced taking approximately one week persample to complete. For the sake of statistics, itmay be worth while for a regulatory authority tocollaborate with industry in estimating the numberof batches manufactured annually within theterritory in order to compare these figures with thenumber of batches tested for compliance.

In some special cases, a product may need furthertesting using advanced analytical methods. Forexample, in the case of an epidemiologicalaberration associated with a specific product or indetection of counterfeit or spurious products. Thesemethods will also provide a means of verification ofthe techniques proposed by manufacturers in theregistration dossiers and may assist in carrying outresearch into detecting unexpected impurities,undeclared or substituted excipients or othercharacteristics which need examination. In thiscase, mass spectrometric, nuclear magneticresonance, or X-ray powder diffraction analysismay be required. This can only be carried out byskilled staff backed by an armamentarium ofsophisticated equipment normally available only atuniversities and research institutes. Access to thisexpertise should be facilitated whenever possibleby the authorities.

It is therefore important that the regulation ofpharmaceutical products in every country shouldinclude responsibility for the quality of products

circulating within its boundaries and those enteringthe market area from other parts of the world. Thiscan only be achieved through a three-tiered systemof preliminary and legally required methods (LRM)backed up by advanced analytical methods. Thiswill enable large numbers of products to bescreened to ensure identity and content amount,with an LRM level to validate the results of thesetechniques, confirm marginal findings anddetermine conformity with legal requirements.Advanced analytical methods will be relied on whensophisticated counterfeit products need to beidentified or to confirm or refute circumstances ofproduct-related, epidemiological events.

Further reading

1. Vincent-Ballereau, F. et al. Contrôle de qualité desmédicaments essentiels dans les pays en développe-ment. Méthodes standardisées (Standardized methods forthe quality control of essential drugs in developingcountries). GEEP, Centre Hospitalier, Villeneuve St-Georges, France, 1993.

2. World Health Organization. Basic tests forpharmaceutical substances. WHO, Geneva, 1986.

3. World Health Organization. Basic tests forpharmaceutical dosage forms. WHO, Geneva, 1991.

4. Drug identification and assay sheets, 1988—1991.Syndicat National de l’Industrie Pharmaceutique (SNIP),France, 1992.

5. Ministry for Health, Cairo, Egypt. Analytical mono-graphs of essential drugs. Pharmaco Information Centre,National Organization for Drug Control and Research(NODCAR), Ministry for Health, Cairo, Egypt, 1994.

6. Kenyon, T.A., Kenyon, A.S., Sibiya, T. Drug qualityscreening in developing countries: Establishment ofan appropriate laboratory in Swaziland. Bulletin of theWorld Health Organization, 72: 615–620 (1994).


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Reports on Individual Drugs

has shown that one dose of rifampicin 600 mg,ofloxacin 400 mg and minocycline 100 mg issufficient to cure patients with PB leprosy exhibitinga single skin lesion, and provides an acceptableand cost-effective alternative regimen. For PBleprosy patients with more than one skin lesion,the standard treatment of rifampicin 600 mg oncemonthly and dapsone 100 mg daily for a durationof six months is still recommended. WHO iscurrently providing these drugs in blister packs, freeof charge and in sufficient quantities to treat about800 000 patients per year. This treatment hassuccessfully been used to cure 8.4 million sufferersof all forms of the disease since 1981.

Unfortunately, for many years to come, countrieswill still be confronted with the problem of rehabili-tation for those people who suffered severe dam-age to limbs or eyes through lack of treatment inthe past. However, provided the political will andthe resources needed for treatment are maintained,it is reasonable to envisage the total eradication ofleprosy as a disease in the not so distant future.

Reference: World Health Organization. Action Pro-gramme for the Elimination of Leprosy. Status report:update 1997. WHO/LEP/97.4.

Should antibiotics be indicated forchildren with acute otitis media?Acute upper respiratory infections (URI) that affectthe ear, nose and throat are common worldwide,particularly among children under 5 years of age.Although they are seldom life-threatening indeveloped countries, this is not always the caseelsewhere (1). In disability-adjusted life years(DALYs), otitis media is estimated to cause aburden of over 50 million DALYs, and over 90% ofthis disease burden falls on developing countries(2, 3).

Chronic otitis media is a serious problem because itcan retard language development and the educa-tional progress of children. It therefore requiresproper detection and consistent follow-up ofaffected children (4). Acute otitis media is normallya bacterial or viral infection of the middle ear, and isusually secondary to URI or a complication of

Simplified treatment for leprosyLeprosy is caused by a bacillus, Mycobacteriumleprae, which multiplies very slowly in the body andaffects the skin, nerves and mucous membranes. Inmany cases, symptoms do not become visible formany years. If left untreated, the disease can causeprogressive and permanent damage to skin,nerves, limbs and eyes.

The WHO Action Programme for the Eliminationof Leprosy has been set up to actively seek re-sources and assist in elimination activities in the 55countries which have been identified as endemic.Of these, only 16 are rated as "most endemic", butthey account for 91% of all cases. Provided thatthese countries are able to maintain and intensifycase-finding and treatment, and that resourcescontinue to be available, WHO is confident thatleprosy will soon be eliminated as a public healthproblem.

Multidrug therapy (MDT) has been used againstleprosy since 1981, and is a combination of threepowerful drugs — dapsone 100 mg daily, rifampicin600 mg once monthly, and clofazimine 300 mgonce monthly and 50 mg daily. This treatmentregimen will effectively kill the bacteria and preventdrug resistance. The drugs are highly acceptableto patients, causing very few side-effects and thereis virtually no relapse. Because the treatment hasproven to be so effective, a WHO ExpertCommittee has now agreed that the course oftreatment for multibacillary leprosy may beshortened to 12 months rather than the current 24months.

With the early detection and increasing coverageof patients by MDT, the cases diagnosed each yearare increasingly milder and, currently, multibacillaryleprosy constitutes a very small proportion of thetotal disease burden. Newly detected skin-smearpositive cases have fallen sharply from close to onemillion ten years ago to an estimated 70 000worldwide in 1996.

In patients with paucibacillary (PB) leprosy, havingfew bacteria in the body and only one skin lesion, itis now considered sufficient to use a single dose ofthree antileprosy drugs. A recent multicentre trial

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measles or pertussis. In children, the incidencepeaks between 6 and 15 months. By the age of 3months, 10% will have suffered at least oneepisode (5).

The use of antibiotics for acute otitis media inchildren varies between countries — from as low as31% in the Netherlands to as high as 98% inAustralia, the United Kingdom and the UnitedStates (6). A meta analysis of randomized,controlled trials has now been completed todetermine the usefulness and effect of antibiotictreatment in acute otitis media in children (7).

Six studies in children aged between 7 months and15 years with acute otitis media were evaluated.Pain, deafness and other symptoms related toacute otitis media were used as main outcomemeasures. The evaluation showed that as many as60% of placebo-treated children were pain-freewithin 24 hours of presentation and at 2–7 daysafter presentation, antibiotics reduced pain in theremaining children. Early antibiotic use (mostcommonly penicillin or amoxicillin) reduced pain by41%. Antibiotics also reduced contralateral acuteotitis media by 43%, but seemed to have noinfluence on subsequent attacks of acute otitismedia or deafness at one month, although therewas a trend for improvement of deafness at threemonths. On the other hand, antibiotics wereassociated with a near doubling of the risk ofvomiting, diarrhoea or rashes.

Only one study (8) has investigated the possibleconsequences of not using antibiotics. For a periodof 17 months, 60 general practitioners in theNetherlands had used nose drops and analgesicsalone for initial treatment of acute otitis media in4860 children aged between 2 and 12 years of age.Only 126 (2.7%) of these children suffered a severecourse of illness, which was measured by third orfourth-day illness, or ear discharge for more than 14days. One hundred of these patients with severesymptoms entered the trial treatment schedule,which showed antimicrobial treatment, either aloneor in combination, to be more effective thanmyringotomy alone. Two of the children developedmastoiditis, but this settled uneventfully aftertreatment with amoxicillin.

This study indicated that acute otitis media in child-ren can be treated with nose drops and analgesicsalone for the first three to four days but if this is noteffective, antibiotics should then be administered.From the above studies, it can be concluded thatearly use of antibiotics provides only modest benefitfor acute otitis media.

None the less, it must be pointed out that studieshave so far only been conducted in developedcountries. The results may therefore not begenerally indicative of the situation in developingcountries where a far greater risk of seriouscomplicated suppuration may support the routineearly use of antibiotics (1). Perhaps the bestapproach is still to regard antibiotics as an optionaltreatment for early acute otitis media and, wherepossible, physicians should discuss with thepatients and their parents the risks and benefitsassociated with this and other optional treatment.

References

1. Berman, S. Otitis media in developing countries.Pediatrics, 96: 126–131 (1995).

2. World Health Organization. The World Health Report1996, WHO, Geneva, 1996, p.25.

3. World Bank. World Development Report 1993:Investing in health. Tables B.2 and B.3. Oxford UniversityPress, New York, 1994, pp. 216 and 218.

4. World Health Organization. The World Health Report1997, WHO, Geneva, p.71.

5. Klein, J. Epidemiology of acute otitis media. InfectiousDisease, 8 (suppl 1): 89 (1989).

6. Froom, J., Culpepper, L., Grob, P. et al. Diagnosis andantibiotic treatment of acute otitis media: report from theInternational Primary Care Network. British MedicalJournal, 300: 582–586 (1990).

7. Del Mar, C., Glasziou, P., Hayem, M. Are antibioticsindicated as initial treatment for children with acute otitismedia? A meta analysis. British Medical Journal,314:1526–1529 (1997)

8. van Buchem, F.L., Peeters, M.F., van 'T Hof, M.A.Acute otitis media: a new treatment strategy. BritishMedical Journal, 290: 1033–1037 (1985).

Acetylsalicylic acid: confirmedefficacy after strokeStroke and other cerebrovascular diseases killabout 4 million people a year, and this figurerepresents 7.5% of total global deaths from allcauses (1). Stroke is also a major cause ofhandicap in middle-aged and elderly people, andattacks can cause partial paralysis or impairment ofspeech and other mental faculties. The care ofthese patients thus poses a growing problem forhealth services in both developed and developingcountries.

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Stroke is caused by acute occlusion of a cerebralartery. Anticoagulants have been widely used(2–4) to facilitate early clot lysis, to inhibit clotpropagation in cerebral arteries and to prevent earlyarterial re-embolization and venous thrombo-embolism originating in immobile limbs (5).

Acetylsalicylic acid (ASA) has been shown to beeffective in the treatment of acute myocardialinfarction (6). Moreover, long-term antiplatelettherapy among patients with a history of myocardialinfarction, stroke or transient ischaemic attack hasshown that about 40 similar types of seriousvascular events are avoided per 1000 patients iftreatment with ASA was begun some years pre-viously. However, until now, only limited clinicaltrials have compared antithrombotic therapy groupsversus control groups in acute ischaemic strokeand none has been large enough to provide reliableevidence on the safety and effectiveness of earlyASA for acute ischaemic stroke.

Two large multicentre trials, which have been setup to investigate the usefulness of antithrombotictherapy in acute ischaemic stroke, have nowreported their findings. The International StrokeTrial (IST) (7) was a randomized, open trial ofacetylsalicylic acid, subcutaneous heparin, both, orneither, among some 20 000 patients from 467hospitals in 36 countries. The Chinese Acute StrokeTrial (CAST) (8) was a randomized placebo-controlled trial of early ASA use (160 mg/day) in20 000 patients with acute ischaemic stroke in 413Chinese hospitals. Both trials applied computedtomographic (CT) scanning to confirm the diagnosisof ischaemic stroke. In the IST, 67% had a CT scanbefore randomization, a further 29% were scannedafter randomization, and 4% never had a CT scan.In the CAST, 87% had had a CT scan beforerandomization, and 94% had at least one CT scanin hospital.

In the IST, neither of the heparin regimens (5000 IUor 12 500 IU twice daily) offered any clinical advan-tage at 6 months. For ASA taken at 300 mg dailythe IST showed a small but worthwhileimprovement at 6 months. There was already asignificant reduction of 11 (SD 5) deaths or non-fatal recurrent strokes within 14 days per 1000patients. In CAST, there was a significant 14%(SD 7) promotional reduction in mortality duringthe scheduled treatment period of 343 deaths(3.3%) among ASA-allocated patients versus 398deaths (3.9%) among placebo-allocated patients.

There were significantly fewer recurrent ischaemicstrokes in the ASA-allocated, rather than in theplacebo-allocated group (167 and 1.6% versus 215and 2.1%), but slightly more haemorrhagic strokes.

These results match those of the small MAST-Istudy, which is the only previously published studyon ASA in acute stroke. The authors of the CASTstudy analysed all three trials: MAST-I, CAST andIST. In CAST, there were 11 (SD 6) fewer patientseither deceased or dependent at discharge per1000 allocated ASA; in IST, with assessed disabilityat 6 months, there was a similar benefit of 13 per1000. For these two trials, together with MAST-I,the benefit is 13 (SD 5) fewer dead or dependentper 1000. This finding also provides substantialreassurance that the early use of ASA does notincrease the prevalence of serious disability amongsurvivors.

The results of IST provide evidence against theroutine use of heparin as an intensive or sub-cutaneous medium-dose regimen in patients withacute ischaemic stroke. The hypothesis that ASAplus low-dose heparin is better than ASA aloneremains unresolved by this trial given the relativelysmall number of patients, since it was concludedthat a trial of at least 20 000 patients would berequired. Because the evidence from ASA trialsinvolved some 40 000 randomized patients, it ismore reliable than the conclusions which could bedrawn for use of heparin.

Unless there are clear contraindications, immediateuse of ASA in an initial dose of 300 mg —though alower maintenance dose might suffice — should beconsidered in all patients with acute ischaemicstroke, especially if a CT scan has excluded intra-cerebral haemorrhage. Long-term low-dose ASA,continued for some years after the stroke, willimprove the prognosis for many patients and ISTand CAST showed a slight improvement in prog-nosis if ASA is started at the beginning rather thanat the end of the hospital stay.

The results of these large clinical trials and thetreatment recommendations made by the authorshave been reviewed extensively (9–11), and moreinvestigations may be needed to draw conclusionson the value of heparin and other thrombolytictherapies, such as alteplase (1). None the less,CAST and IST are particularly relevant since thetrials were conducted in a wide variety of specialistand non-specialist hospitals in 37 different countriesthroughout the world.


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Acetylsalicylic acid treatment can be usedadvantageously in countries where there are limitedmedical resources since laboratory monitoring isnot necessary. It is also important to note that forabout 800 of the 40 000 patients in CAST and IST,the initial diagnosis was wrong and these patientshad cerebral haemorrhage. However, there was noindication in either trial that these misdiagnosedpatients were somehow damaged by ASA and, ifthere were any side effects at all, they were notsignificant enough to report.

References

1. World Health Organization. The World Health Report1995, WHO, Geneva, 1995, p.32.

2. Marsh, E.F., Adams, H.P., Biller, J. et al. Use of anti-thrombotic drugs in the treatment of acute ischaemicstroke. Neurology, 39: 1631–1634 (1989).

3. Lindley, R.I., Amayo, E.O., Marshall, J. et al. Acutestroke treatment in UK hospitals: the Stroke Associationsurvey on consultant opinion. Journal of the Royal Collegeof Physicians of London, 26: 479–484 (1995).

4. Chen, Z.M., Xie, J.X., Collins, R. et al. Survey ofhospital care of patients with acute stroke in China.Cerebrovascular Disease, 5: 228 (1995).

5. Sandercock, P.A.G., van den Belt, A.G.M., Hindley, R.I.et al. Antithrombotic drugs in acute ischaemic stroke: anoverview of the completed randomized trials. Journal ofNeurology, Neurosurgery and Psychiatry, 56: 17–25(1993).

6. ISIS-2 (Second International Study of Infarct Survival)Collaborative Group. Randomized trial of intravenousstreptokinase, oral aspirin, both, or neither among 17 187cases of suspected acute myocardial infarction: ISIS 2.Lancet, 2: 349–360 (1988).

7. CAST (Chinese Acute Stroke Trial) CollaborativeGroup. CAST: randomized placebo-controlled trial of earlyaspirin use in 20 000 patients with acute ischaemic stroke.Lancet, 349: 1641–1649 (1997).

8. International Stroke Trial Collaborative Group. TheInternational Stroke Trial (IST): a randomized trial ofaspirin, subcutaneous heparin, both, or neither among19 435 patients with acute ischaemic stroke. Lancet, 349:1569–1581(1997).

9. Bousser, M-G. Aspirin or heparin immediately after astroke? Lancet, 349: 1564–1566 (1977).

10. Editorial: a better future in stroke? Lancet, 349: 1563(1997).

11. James, A. Stroke treatment trials yield disappointingresults. Lancet, 349: 1673 (1997).

Antiretroviral therapy for HIV:latest guidelinesThe United States Department of Health andHuman Services (DHHS) has recently publishedguidelines on the use of antiretroviral agents in HIV-infected adults and adolescents and laboratorymonitoring methods in the treatment of HIV-infectedindividuals (1). These have been developed by anexpert panel brought together by the DHHS and theHenry J. Kaiser Family Foundation. The guidelinesare directed to physicians and other health careproviders and are intended as a companiondocument to the therapeutic principles formulatedby the National Institutes of Health (NIH) Panel (2).

The guidelines address the following issues:

• testing for plasma HIV RNA levels (viral load) andCD4+ T lymphocyte count;

• when to initiate therapy in established HIVinfection;

• therapy in patients with advanced stage disease;

• interruption of therapy;

• changing therapy and available therapeuticoptions;

• treatment of acute HIV infection; and

• antiretroviral therapy in pregnancy.

These guidelines differ in many respects from thoseissued in April 1997 by the British HIV Associationand published in the previous issue of this journal(3, 4). This reflects the evolution of current therapyand the urgency with which information fromongoing clinical trials is communicated to healthcare professionals. Practitioners caring for HIV-infected persons must keep abreast of thesedevelopments in order to offer the latest advice onthe safe and effective use of the new therapies.

The following is a selected summary of the mainrecommendations from the guidelines.

Testing for HIVDecisions regarding initiation or changes in anti-retroviral therapy should be guided by monitoring ofthe laboratory parameters of viral load (plasma HIVRNA), the CD4+ T lymphocyte count and theclinical condition of the patient. Confirmatory labo-ratory tests should be performed wheneverpossible.


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In previously untreated patients, viral load (plasmaHIV RNA levels) and CD4+ T lymphocyte countsshould be measured at the time of diagnosis andgenerally every 3–4 months thereafter. Viral loadshould also be measured immediately prior to and 4weeks after initiation of antiretroviral therapy. Thisallows the clinician to evaluate the initial effective-ness of therapy. The absence of a large decrease(less than 10-fold) in viral load by 4 weeks shouldprompt the physician to reassess patient adher-ence, rule out malabsorption, consider repeat RNAtesting to document lack of response, and considera change in drug regimen. With optimal therapy andusing currently available assays, viral levels inplasma should be undetectable at 6 months fromstart of treatment.

A minimally significant change in plasma viraemiais considered to be a 3-fold increase or decrease,and in CD4+ T lymphocyte count, a drop of morethan 30% from baseline for absolute cell numbersand a drop of more than 3% from baseline inpercentages of cells.

Therapy in asymptomatic HIVAntiretroviral therapy provides clinical benefit inHIV-infected individuals with advanced HIV diseaseand immunosuppression. Although there is atheoretical benefit in treating patients with a CD4+ Tcell count greater than 500 cells/mm3, no long-termclinical benefit has yet been demonstrated.

Factors outweighing initiation of early treatment inthe asymptomatic stable patient include potentialadverse effects of the drugs on the quality of life, arisk of drug resistance limiting future treatmentoptions, the risk of dissemination of virus resistantto protease inhibitors and other agents, theunknown durability of effect of currently availabletherapies, and the unknown long-term toxicity ofsome drugs. The guideline lists several factors tobe considered, including the willingness of theindividual, after counselling and education, toadhere to a complicated prescribed therapy and toaccept the side-effects of treatment.

Once the patient and physician have decided toinitiate therapy, this should preferably beaggressive, with the intention of suppressing theplasma viral load to undetectable levels. In general,any patient with fewer than 500 CD4+ T cells/mm3

or more than10 000 (bDNA) or 20 000 (RT-PCR)copies of HIV RNA per ml of plasma should beoffered therapy.

The preferred regimen in established HIV infectionis two nucleoside analogues (NRTIs) and onepotent protease inhibitor selected from the followingcolumns where drugs are listed in random, notpriority, order:

Protease inhibitors Nucleoside analogues

indinavir ZDV (zidovudine) +ddI (didanosine)

nelfinavir d4T (stavudine) + ddIritonavir ZDV + ddC (zalcitabine)

ZDV+ lamivudine (3TC )d4T+ 3TC

Therapy in advanced HIV infectionAll patients with advanced HIV infection should betreated with antiretroviral therapy, as should allpatients with symptomatic HIV infection defined asthe presence of thrush or unexplained fever, butwithout progression to AIDS.

Once therapy is initiated, a maximum suppressiveregimen, such as two nucleoside analogues andone protease inhibitor should be used as set outabove. Advanced-stage patients maintained on anantiretroviral regimen should not have therapydiscontinued during an acute opportunistic infectionor malignancy unless there are concerns regardingdrug toxicity, intolerance, or drug interactions.Patients who have progressed to AIDS are oftentreated with complicated combinations of drugs andthe potential for multidrug interactions must becarefully considered. The table on page 136 listssome of the known major potential interactions.

In this regard, the use of rifampicin to treat activetuberculosis is problematic in a patient receiving aprotease inhibitor, which adversely affects themetabolism of rifampicin. However, this treatment isfrequently needed to effectively suppress viralreplication in patients with advanced disease.Conversely, rifampicin lowers the blood level ofprotease inhibitors which may result in suboptimaltherapy. While rifampicin is contraindicated withprotease inhibitors, one might consider usingrifabutin at a reduced dose.

Other factors complicating advanced-stageinfection are wasting and anorexia, which mayprevent patients from adhering to the dietaryrequirements for efficient absorption of certainprotease inhibitors. Bone-marrow suppressionassociated with zidovudine and neuropathic effectsof zalcitabine, stavudine and didanosine maycombine with the direct effects of HIV to render the


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Known potential interactions of protease inhibitors*

indinavir• inhibits cytochrome P450 • not recommended for concurrent use: rifampicin, terfenadine, astemizole,cisapride, razolam, midazolam, ergot alkaloids • indinavir levels increased by ketaconazole • indinavirlevels reduced by rifampicin, rifabutin • didanosine reduces indinavir absorption unless taken > 2 hoursapart.

ritonavir• inhibits cytochrome P450 (potent inhibitor) • ritonavir increases levels of multiple drugs that are notrecommended for concurrent use • reduced ritonavir absorption with didanosine unless taken > 2 hoursapart • ritonavir decreases levels of ethinylestradiol, theophylline, clarithromycin, sulfamethoxazole andzidovudine.

saquinavir• inhibits cytochrome P450 • saquinavir levels increased by ritonavir, ketoconazole, grapefruit juice• saquinavir levels reduced by rifampicin, rifabutin and phenobarbital, phenytoin, dexamethasone andcarbamazepine • not recommended for concurrent use with terfenadine, astemizole, cisapride, ergotalkaloids.

nelfinavir• inhibits cytochrome P450 • nelfinavir levels reduced by rifampicin, rifabutin • not recommended forconcurrent use with rifampicin, triazolam, midazolam, ergot alkaloids, terfenadine, astemizole, cisapride• nelfinavir decreases levels of ethinylestradiol and norethindrone and increases ketoconazole level.


Known adverse effects of protease inhibitors*

indinavir• nephrolithiasis — gastrointestinal intolerance • increased indirect bilirubinaemia (inconsequential)• headache, asthenia, blurred vision, dizziness, rash, metallic taste, thrombocytopenia • new orexacerbated diabetes mellitus, hyperglycaemia1

ritonavir• gastrointestinal intolerance, nausea, vomiting, diarrhoea • paraesthesia (circumoral and extremities• asthenia • taste perversion • triglycerides increase > 200%, transaminase elevation, elevated CPK anduric acid • new or exacerbated diabetes mellitus, hyperglycaemia1

saquinavir• gastrointestinal intolerance, nausea, diarrhoea • headache • elevated transaminase enzymes • new orexacerbated diabetes mellitus, hyperglycaemia1

nelfinavir• diarrhoea • new or exacerbated diabetes mellitus, hyperglycaemia1

* Taken from Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-infectedadults and adolescents Table IX (draft document). See reference 1.

1 FDA Talk Paper, T7–23 1997 (see page 141).

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drugs intolerable. Hepatotoxicity associated withcertain protease inhibitors may limit their use,especially in underlying liver dysfunction. Theabsorption and half-life of certain drugs may bealtered by antiretroviral agents. Some interactionscan result in life-threatening drug toxicity.

Health care providers should inform their patients ofthe need to discuss any new therapy, including theneed to consider the effects of over-the-countermedicines and alternative medications. Carefulattention should be given to the relative risks ofspecific combinations of agents.

Interruption of antiretroviral therapyThere are multiple reasons for temporary dis-continuation of antiretroviral therapy, includingintolerable side-effects, drug interactions, firsttrimester pregnancy and unavailability of the drug.There are no reliable studies or estimates of thenumber of days, weeks or months that constitute aclinically important interruption of one or morecomponents of a therapeutic regimen that wouldincrease the likelihood of drug resistance. If there isa need to discontinue antiretroviral medication foran extended time, clinicians and patients should beadvised of the theoretical advantage of stopping allantiretroviral agents simultaneously, rather thancontinuing one or two agents, to minimize theemergence of resistant viral strains.

Changing a failing regimenWhen considering a change in therapy, it isimportant to distinguish between drug failure anddrug toxicity. In the latter case, it is appropriate tosubstitute one or more alternative drugs of thesame potency and from the same class of agentsas that suspected of causing toxicity. Optimally, andwhenever possible, the regimen should be changedentirely to drugs that have not previously beentaken.

With combination therapy, at least two, andpreferably three, new agents must be used. This isbased on current understanding of strategies toprevent drug resistance. Special criteria that mayprompt consideration for changing therapy includethe following:

• less than 10-fold reduction in the plasma viral loadby week 4 following initiation of therapy;

• failure to suppress plasma viral load to undetect-able levels within 4–6 months of initiating therapy;

• repeated detection of virus in plasma after initialsuppression to undetectable levels;

• any reproducible significant increase, defined as3-fold or greater, of plasma viral load not attribut-able to intercurrent infection, vaccination or thetest method;

• persistent declining CD4+ cell numbers; and

• clinical deterioration.

Other important aspectsThe guidelines also discuss the treatment of acuteHIV infection, treatment regimens for primary HIVinfection, patient follow-up, duration of therapy forprimary HIV infection and antiretroviral therapy inthe HIV-infected pregnant woman includingtreatment of HIV-infected children.

The panel responsible for drafting the guidelineshas reiterated its commitment to revising recom-mendations as new data become available.

References

1. Department of Health and Human Services. Guidelinesfor the use of antiretroviral agents in HIV-infected adultsand adolescents (draft document). The Federal Register,19 June 1997.

2. National Institutes of Health. Report of the NIH panel todefine principles of therapy of HIV infection. Draftdocument provided to WHO on 1 July 1997.

3. British HIV Association guidelines for anti-retroviraltreatment of HIV seropositive individuals. Lancet, 349:l086–1092 (l997).

4. WHO Drug Information, 11( 2): 63–64 (1997).


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General Information

Biological standardization:report of the Expert CommitteeThe WHO Expert Committee on Biological Stan-dardization recommends procedures for assuringthe quality, safety and efficacy of biological medici-nal products. It also reviews and discusses issuesrelated to the standardization and control of bio-logicals and establishes international referencematerials. Requirements and guidelines are alsodeveloped for the production and control of bio-logicals including vaccines, plasma products anddiagnostic agents.

The rapid expansion and increasing diversity of thebiologicals sector, together with the development ofnovel biotechnological methods, raise new and veryspecific challenges for product safety and efficacy,and call for the establishment and implementationof effective control measures. In this respect, areview of the scientific basis of the standardizationand quality control of biologicals has recently beenconducted on behalf of the National BiologicalStandards Board of the United Kingdom. Thereview was undertaken in collaboration with WHOand with support from the European MedicinesEvaluation Agency and the EuropeanPharmacopoeia. Because the report has importantimplications at international level, the Committeehas recommended its issue by WHO to assuremaximum dissemination (1).

At the latest meeting of the Expert Committee inOctober 1996, important changes in recommenda-tions regarding residual DNA in biological productsderived from continuous cell lines were agreed anda relaxation was allowed on the extent of chromo-somal recharacterization required for well-established diploid cell-lines used in production andtumorigenicity testing. The report of the meeting,which will be published soon in the WHO TechnicalReport Series, will cover the following issues indetail.

The use of International Reference Materialsestablished by WHO for designating the activity oridentity of biological preparations used in prophy-laxis, therapy or diagnosis ensures comparability ofsubstance activity, as well as reliability of diagnostic

procedures. Their extensive use attests the key rolethat these materials play in harmonizing the qualityof biologicals at international level. The eight new orreplacement standards established in 1996 by theCommittee are set out in the table on page 139Additionally, six International Reference Materialshave been discontinued, a number of these beingantibiotics where the microbiological assay has nowbeen replaced by a physicochemical assay method.

With regard to the supply of International ReferenceMaterials, a decision has been taken by the StatensSeruminstitut, Copenhagen, to relinquish responsi-bility for this service to the National Institute forBiological Standards and Control (NIBSC) in theUnited Kingdom. Stocks of reference materialshave now been transferred to the NIBSC, andconditions of distribution will be the same as forother International Reference Materials alreadyprovided. Tribute was paid to the long and valuablecontribution by the Statens Seruminstitut to WHOactivities.

Twelve interim Reference Reagents were alsoestablished by the Committee (see page 139). Thisconstitutes a new class of reference materialswhich have been developed — albeit on limiteddata — to provide rapidly expanding areas, such ascytokine production, with a means for standardiza-tion in measurement prior to the establishment ofan International Standard. The availability of theseReference Reagents was considered vital for useduring the transitional period between laboratoryand clinical work.

Three new documents were adopted at themeeting. Revised requirements for cell substratesto be used for the production of biologicals coveruse of animal cells as in vitro substrates for theproduction of biologicals, and incorporate the latestavailable data relating to cell substrates. They havebeen adopted following worldwide consultation anddiscussion at the International symposium on thesafety of biological products prepared frommammalian cell culture, held in Annecy, France, inSeptember 1996. The requirements cover thecharacterization and testing of continuous cell linesand diploid cell lines for the production of both viralvaccines and other biologicals, such as monoclonalantibodies and recombinant DNA products, as well

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as some general manufacturing requirements whichapply also to primary cells. Considerable emphasisis placed on testing for extraneous agents andmanufacturers are clearly encouraged, whereverpossible, to use cell substrates for productiongenerated from cell banks which have beenthoroughly characterized, rather than from primarycells. In the revised requirements for diploid celllines the extent of chromosomal recharacterization

needed for well established diploid cell lines, suchas MRC-5 and WI-38, as well as the extent ofroutine tumorigenicity testing has been relaxed.

There is also a major departure from previousrequirements published by WHO concerning theamount of residual cellular DNA permitted inproducts derived from continuous cell lines. In1986, a WHO Study Group advised on the levels of

International Biological Standards and Reference Reagents established by the46th WHO Expert Committee on Biological Standardization, 1996

AntibodiesAnti-rubella immunoglobulin, human First International StandardBlood ProductsBlood Coagulation Factors IX concentrate, human Third International StandardBlood Coagulation Factors II, VII, IX, X plasma, human Second International StandardFerritin, human recombinant Third International StandardWhole Blood Folate First International StandardThromboplastin, human recombinant, plain Third International StandardCytokines▲

Interleukin-5 First Reference ReagentInterleukin-7 First Reference ReagentInterleukin-9 First Reference ReagentInterleukin-11 First Reference ReagentInterleukin-12 First Reference ReagentInterleukin-13 First Reference ReagentInterleukin-15 First Reference ReagentLeukaemia Inhibitory Factor First Reference ReagentOncostatin M First Reference ReagentTumour Necrosis Factor, beta First Reference ReagentNerve Growth Factor First Reference ReagentEndocrinological Substances▲

Thyroid Stimulating Hormone, human recombinant First Reference ReagentMiscellaneousEndotoxin Second International StandardMAPREC analysis of poliovirus type 3 First International Standard(Sabin)DiscontinuationsAnti-rubella serum, human Second International ReferencePreparationFactor IX component of blood coagulation Second International Reference Standard factors II, IX and X concentrate, humanOleandomycin First International StandardSpectinomycin First International ReferenceTriacetyloleandomycin First International Reference PreparationViomycin Second International Reference PreparationEndotoxin for limulus gelation tests First International StandardThromboplastin, human, plain Second International Reference Preparation

▲These reference materials are Interim Reference Reagents, as distinct from International Reference Reagents, andare established on the basis of limited data for certain rapidly developing fields where there is a need forstandardization in measurement before an International Standard can be established.

General Information

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contaminating DNA deriving from continuous celllines. Based on evidence available at that time, itwas concluded that the risk associated withresidual DNA is negligible when the amount of suchDNA is l00 picograms or less in a single dose. Areassessment of this situation has led to DNA beingconsidered now more as a cellular contaminant. Inview of this reassessment, the recommendationshave been revised so that up to l0 nanograms ofresidual DNA from continuous cell lines per dose ofa purified product are acceptable. Of course, thepurification process should be validated todemonstrate its capacity to remove cellular DNA,including spiking studies.

Requirements for acellular pertussis vaccines werealso discussed by the Expert Committee. Based onthe outcome of two recent international meetings, itwas clear that a consensus had not yet beenreached on the antigenic composition of an idealacellular pertussis vaccine. The need for continuedresearch to identify immune markers of protectionand rigorous post-marketing surveillance of vaccinesafety and effectiveness was emphasized. Becauseof the urgent need for guidance, the Committeeagreed that the Guidelines for the production andcontrol of the acellular pertussis component ofmonovalent or combined vaccines should beadopted. It also recommended that a WHO WorkingGroup should be set up to discuss the issues and toconsider how the guidelines could be extended.

Guidance concerning DNA-vaccines was also onthe agenda of the meeting. This new approach tovaccination involves direct introduction into hosttissue of plasmid DNA which contains the geneencoding the antigen against which an immuneresponse is sought. Although this approach offers anumber of advantages, there are several potential

issues of safety. The injected DNA taken up by thecells may integrate into the host's chromosomesand cause an insertional mutagenic event. Equally,the long-term expression of a foreign antigen mayresult in an undesired immunopathological reaction.It is not yet known whether the use of genesencoding cytokines or co-stimulating moleculesmay pose extra risks. Antibodies against theinjected DNA may be formed and contributetowards undesired autoimmune reactions, or theexpressed antigen may itself have biologicalactivity.

The purpose of the document Guidelines forassuring the quality of DNA vaccines is thus meantto indicate appropriate methods for the manufactureand testing of plasmid DNA vaccines and the in-formation specific to plasmid DNA vaccines thatshould be included in submissions by manufac-turers to national control authorities when applyingfor authorization of clinical trials and marketing.

Other matters of interest discussed includedreverse transcriptase activity in avian cells,cytokines, reference preparations for evaluatinghepatitis B, C and HIV diagnostic kits and on thestandardization of gene amplification methods forthe virological safety testing of blood products. TheCommittee recognized the great importance of thelast two activities in ensuring the quality and safetyof blood and blood derivatives. The possibleimplications of WHO’s biological standardizationactivities on international trade as a result of theentry into force of World Trade Organizationagreements were also considered.

Reference

1. World Health Organization. Biological standardizationand control. WHO/BLG/97.1 WHO, Geneva, 1997.

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Irinotecan associated mortalityJapan — At least 94 patients are suspected tohave died from side-effects of the anticancer drug,irinotecan, either during clinical trials or followingmarketing in April 1994. Topotecin® (Daiichi) hasbeen administered to some 3100 individuals and,of these, 24 patients (0.8%) have died fromsuspected side-effects. Campto® (Yakult) has beenadministered to 2330 individuals of whom 15(0.65%) have also died because of suspected side-effects including a sudden drop in the white bloodcell count. Neutropenia is known to be associatedwith many types of cancer chemotherapy.

The Ministry of Health and Welfare will circulate anadverse drug reaction warning to physicians andmedical institutions in the near future.

Reference: Communication to WHO from Ministry ofHealth and Welfare, Japan, dated 24 July 1997.

HIV protease inhibitorsassociated with diabetesUnited States of America — The Food and DrugAdministration has warned physicians that proteaseinhibitors used to treat HIV infection may contributeto increases in blood sugar and even diabetes inHIV patients and recommends close monitoring ofpatient glucose levels.

The Agency has received reports of 83 cases ofnew or exacerbated diabetes mellitus and hyper-glycaemia in HIV-infected patients taking saquina-vir, indinavir, ritonavir or nelfinavir. Of the 83patients, 27 were reported to need hospitalization,including six life-threatening cases. Five casesresulted in ketoacidosis, a serious diabetes-relatedcondition that is characterized by a fruity mouthodour, nausea, vomiting, dehydration, weight loss,confusion and, if untreated, coma or death.

The FDA emphasizes that HIV patients on proteaseinhibitor therapy should be informed of the warningsigns of hyperglycaemia and diabetes, which areincreased thirst and hunger, unexpected weightloss, increased urination, fatigue, and dry, itchy

skin. The symptoms in reported cases occurred, onaverage, approximately 76 days from commence-ment of protease inhibitor therapy, but in somecases as early as four days. None the less, theFDA points out that the benefit of these drugs topatients suffering from HIV infection far outweighsthe various risks.

Reference: FDA Talk Paper, T 7-23, June 1997.

Valvular heart disease associatedwith fenfluramine and phentermineUnited States of America — The Food and DrugAdministration has alerted physicians to reports ofvalvular heart disease in women treated for obesitywith a combination of fenfluramine and phenter-mine. The drugs were approved individually morethan 20 years ago for single-drug, short-termobesity therapy. Recently, however, they have beenwidely used “off-label” in combination, for long-termmanagement of obesity (1).

The FDA has received reports of 33 cases of un-usual abnormalities of the mitral, aortic, and tri-cuspid heart valves in women between 30 and 72years of age with no previous cardiac disease whohave been taking fenfluramine and phentermine forbetween one and 28 months.

The valve damage was characterized by a glisten-ing white macroscopic appearance and microscopicendothelial fibrons were seen. The damage may berelated to high circulating serotonin concentrationssince both fenfluramine and phentermine raiseserotonin concentrations (2). As of July 1997,surgical intervention to replace a damaged valvehad been required in six patients (3).

A study carried out on valvular disease in womenwill be published in the New England Journal ofMedicine later this year.

References

1. HHS news, P97–20, July 1997.

2. Ault, A. FDA issues warning on diet drug combination.Lancet, 350: 189 (1997).

3. SCRIP Number 2250, 18 July 1997.

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Withdrawal of antidiarrhoealpaediatric productFrance — The Medicines Agency has takenrestrictive action against two antidiarrhoealproducts, a paediatric formulation containingtilbroquinol (IntetrixP®, Beaufour) and acombination product containing tilbroquinol andtiliquinol (Intetrix®, Beaufour) because of potentialhepatotoxicity.

The approved indications were acute diarrhoea ofinfectious origin without invasive phenomena, andintestinal amoebiasis. The product may also beused for treatment of dysenteric amoebiaisis incombination with a tissue amoebicide, or as mono-therapy in healthy carriers contaminated with intra-luminal amoebae. Eight cases of asymptomaticincreased liver transaminases were reportedamong 12 healthy volunteers enrolled in a clinicalstudy of Intetrix®, and 10 subsequent cases of liverdisorder were identified by the national pharmaco-vigilance system.

Although no cases were reported for the paediatricformulation (1), the manufacturer has suspendedsales of IntetrixP® and batches have been recalled.The therapeutic indications of Intetrix® are nowrestricted to the treatment of intestinal amoebiasisin adults.

The manufacturer has informed WHO that bothproducts have been marketed in various countriesthroughout the world (2).

References

1. Agence du Médicament, Infofax- Pharmacovigilance,4th July 1997.

2. Dear Doctor letter from Beaufour Laboratories andcommunication to WHO of 30 July 1997.

Dangerous products promotedon the InternetUnited States of America — The Food and DrugAdministration has issued a warning to consumersconcerning unapproved products offered for sale onthe Internet which could cause significant healthrisks. The products in question are an abortion kitand a self-sterilization kit.

The abortion kit provides a combination of drugswhich are not approved by the FDA to terminatepregnancy. These drugs, without a physician'ssupervision, could cause heavy vaginal bleeding

and even death. Birth defects in the fetus could alsooccur if the product failed and pregnancy wascarried to term. The sterilization kit containsquinacrine hydrochloride (INN: mepacrine) whichcan cause a pregnancy to become ectopic orabnormal, or cause permanent damage to awoman's re-productive organs. Despite thesedangers, the kits are promoted as "scientific andwithout risk".

Reference: FDA Talk Paper, T97–26 June 1997.

Health risks of herbal productscontaining ephedrineCanada and United States of America — TheCanadian Health Department warns consumers notto take dietary supplements containing ephedrineunless the product label carries a drug identificationnumber (DIN), since close to 20 deaths reported inthe United States have been linked to preparationscontaining this herb or its active constituent (1). In1996, the United States Food and Drug Administra-tion had issued a similar warning following reportsthat ephedrine supplements were being taken toreduce weight, increase energy to enhance body-building and — in large doses — as a euphoric.

A review has now been made of more than 800reports of adverse effects received by the FDA (2),which include high blood pressure, irregularities inheartbeat, insomnia, nervousness, tremors, head-aches, seizures, heart attacks, stroke and evendeath. Most events occurred in otherwise healthyindividuals using the products for weight control andincreased energy and obtaining them from non-approved outlets including fitness centres.

It is proposed that the amount of ephedrine alka-loids in these products should be controlled andmarketing prohibited of products containing morethan 8 mg of ephedrine alkaloids in the amountingested in a 6-hour period or 24 mg in the totaldaily intake. It will also require warning labels andinstructions to consumers not to use the product formore than 7 consecutive days.

Ephedrine alkaloids are amfetamine-like com-pounds with potentially powerful stimulant effectson the nervous system and heart and certainindividuals should avoid their use. In supplements,they are usually derived from a herb known as mahuang, Chinese ephedra, ephedra sinica, epitoninor ephedrine. Other botanical sources include Sidacordifolia.

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WHO Drug Information Vol. 11, No. 3, 1997 Regulatory Matters

References:

1. Health Canada. Health alert. http://www.hc-sc.gc.ca/main/hc/web/datapcb/communc/home/news/97_38e.htm.

2. HHS News, P97–15, June 1997.

Photoallergic and phototoxicreactions associated with fibratesGermany — The Federal Institute of Drugs andMedical Devices has decided to alter the packageinserts and information for health professionals onproducts containing fenofibrate, gemfibrozil, clofi-bric acid, clofibrate, etofylline clofibrate, etofibrateand bezafibrate. If users of these products areexposed to real or artificial sunlight, the skin maybecome reddened and itchy, and blisters or nodulesmay appear. This adverse effect may occur at anytime — even after complication-free use of manymonths duration.

Contraindications now include known hyper-sensitivity, skin reactions following exposure tosolar radiation, and concomitant administration withanother product containing a substance of thefibrate group. In the case of fenofibrate, concomit-ant use of ketoprofen is also contraindicated.

Reference: Communication from the Federal Institute ofDrugs and Medical Devices to WHO dated 4 July 1997.

Restriction on sale of high-dosevitamin B6 productsUnited Kingdom — Following reports of peripheralneuropathy linked with administration of daily dosesof 50 mg of vitamin B6, a safety review has beencarried out by the Committee on Toxicity ofChemicals in Food, Consumer Products and theEnvironment.

A recommendation has subsequently been madeby the Committee on Safety of Medicines that

products containing 50 mg daily dose of vitamin B6should be available on prescription only, productswith a daily dose of between 11 and 49 mg shouldbe sold under the supervision of a pharmacist, andproducts under 10 mg may continue on generalsale. The Committee adds that dietary intake isusually sufficient to satisfy the vitamin B6 require-ments of normal healthy individuals, although someUnited Kingdom therapists and specializedpractitioners recommend high doses for a numberof conditions, including premenstrual syndrome.

Reference: The Pharmaceutical Journal, 259: 46 (1997).

First-year safety reports with triplecomponent pertussis vaccineSweden — The Medical Products Agency hasanalysed adverse reaction reports for the first yearof use (1996) of a combined pertussis vaccine(Infanrix®, SmithKline Beecham). The vaccinecontains pertussis toxin, filamentous haemag-glutinin and pertactin.

Of the 89 reports received, 52 were of a generalnature, including 25 cases of fever and 18 skinreactions. Other reactions included prolongedcrying episodes, restlessness, apparent pain, fever,cramps and 2 cases of muscle hypotonia.

Additionally, there were 18 cases of hypotonichyporesponsive episodes (HHEs) which usuallyoccurred on the first day following vaccination.When this happened, the children became sudden-ly pale, loose, unresponsive and impossible tocommunicate with, often for hours. The mechanismbehind this reaction is unkown but seems to beharmless, although it was an unpleasantexperience for the families concerned. The Agencyhas stated that it did not expect this vaccine tocause HHE.

Reference: Info från Läkemedelsverket, Number 4. 1997.

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Essential Drugs

Antiprotozoal drugs

Drugs used in amoebiasisAmoebic dysentery, caused by Entamoeba histo-lytica, occurs when protozoan parasites invade thewall of the large intestine. Trophozoites may alsoinvade the appendix and terminal ileum, or mayreach the liver and produce an amoebic liverabscess. Extension of hepatic lesions may reachthe right chest, the peritoneum and the pericar-dium. Less commonly, the lesion extends throughthe skin, producing a sinus and cutaneous lesion.Rarely, E. histolytica trophozoites cause brainabscesses. Pregnant women and individuals whoare malnourished or immunocompromised are mostvulnerable.

The incidence of amoebiasis falls as sanitarymeasures are introduced. Chlorination of waterdoes not destroy amoebic cysts but adequatefiltration will remove them. A weak solution of iodineis a potent cysticide.

Luminal amoebicides are active primarily againstorganisms in the colon, and systemic amoebicidesare active against organisms responsible for in-vasive disease. In non-endemic areas, symptom-less carriers should be treated with a luminalamoebicide, which will reduce the risk of trans-mission and protect the patient from invasiveamoebiasis. Diloxanide furoate is most widely used,but other compounds, including clefamide, etofa-mide and teclozan, are also effective.

All patients with invasive amoebiasis require treat-ment with a systemically active compound followedby a luminal amoebicide in order to eliminate any

surviving organisms in the colon. Combined pre-parations are useful. The pathology and clinicalexpression of amoebiasis vary from region to regionand drug regimens should consequently be devisedon the basis of local experience.

The availability of metronidazole and several other5-nitroimidazoles, including ornidazole, tinidazoleand secnidazole, has made the management ofinvasive amoebiasis simpler and safer. Parenteralformulations of metronidazole, ornidazole andtinidazole are available for patients too ill to takedrugs by mouth.

In severe cases of amoebic dysentery, tetracyclinegiven in combination with a systemic amoebicidelessens the risk of overinfection, intestinalperforation and peritonitis. Hepatic abscessesshould be lanced by needle aspiration if severehepatic pain and tenderness indicate that rupture isimminent.

DILOXANIDELuminal amoebicideTablet: 500 mg of diloxanide furoate

Uses: Treatment of asymptomatic carriers in non-endemic areas. Eradication of residual amoebae inthe colonic lumen following treatment of invasivedisease with other drugs.

Dosage: Adults: 500 mg 3 times daily for 10 days.Children: 20 mg/kg daily in 3 divided doses for 10days. Treatment is regarded as successful if stoolsremain free of E. histolytica for one month. Severalspecimens should be taken in evaluating theresponse to treatment.

WHO Model Formulary

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 section related to anthelminthicsshould be addressed to: Drug Selection and Information (DSI), Division of Drug Management& Policies, World Health Organization, 1211 Geneva 27, Switzerland.

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Precautions: In pregnancy, treatment is bestdeferred until after the first trimester.

Adverse effects: Mild gastrointestinal symptoms,particularly flatulence, may be troublesome.Pruritus and urticaria can also occur.

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

Drugs used in giardiasisGiardia intestinalis is a flagellated protozoan para-site which frequently coexists with E. histolyticaand is usually transmitted in drinking-water whichcontains cysts. These can be removed by waterfiltration. Many carriers are symptomless, but otherslose weight and complain of diarrhoea or gastro-intestinal discomfort. Extensive infections result inintestinal malabsorption and impaired growth inchildren. Severe symptoms are more likely to occurin patients who are malnourished, hypochlorhydricor immunocompromised.

Treatment with tinidazole in a single dose or withanother 5-nitroimidazole such as metronidazole ishighly effective and should be offered when practi-cable to all infected patients. Family and institu-tional contacts should also be treated. Largerepidemics are difficult to eradicate because of thehigh proportion of symptomless carriers andbecause excreted cysts can survive for long periodsoutside the human host.

METRONIDAZOLEAntiprotozoal agentTablet: 200 – 500 mgInjection: 500 mg in 100-ml vialOral suspension: 200 mg (as benzoate)/5ml

Uses: Treatment of invasive amoebiasis andgiardiasis. Treatment of asymptomatic carriersin non-endemic areas if no luminal amoebicide isavailable, although it is less effective.

Dosage: Metronidazole should be administeredwith or immediately after food. Various dosageregimens are used, and definitive recommendationsshould be based on local experience.

Invasive amoebiasisAdults and children: 30 mg/kg daily in 3 oral divideddoses after meals for 8 –10 days, or intravenously

in 3 divided injections daily until the patient is ableto take oral formulations. The patient shouldsubsequently receive a luminal amoebicide toeliminate surviving organisms in the colon.

GiardiasisAdults: 2 g once daily for 3 days.Children: 15 mg/kg daily in divided doses for 5–10days.

Contraindications: Known hypersensitivity; firsttrimester pregnancy; chronic alcohol dependence.

Precautions: Peripheral neuropathy, ataxia orother signs of central nervous system dysfunctionwarrant prompt discontinuation.

Adverse effects: Commonly, mild symptoms ofheadache, gastrointestinal irritation and a persistentmetallic taste. Less frequently, drowsiness, rashes,and brownish-red darkening of urine may occur.Rarely, stomatitis and candidiasis, reversibleleukopenia, and sensory peripheral neuropathyoccur. Disulfiram-like effects such as abdominalpain, vomiting, flushing and headache may occur ifalcohol is consumed.


Drugs used in leishmaniasisProtozoa of the Leishmania spp are responsible forseveral clinically distinctive diseases characterizedby chronic inflammatory infiltration, focal necrosisand fibrosis. In some, the lesions are localized atthe point of inoculation but in others the parasitebecomes widely disseminated. The parasite istransmitted from animals by sandflies.

Leishmania species differ in their sensitivity tochemotherapy. Visceral leishmaniasis, caused byparasites of the Leishmania donovani complex, isusually responsive initially to the pentavalentantimonial compounds, meglumine antimoniate orsodium stibogluconate. Both dosage and durationof treatment need to be adjusted according to theclinical response. Patients are considered to beclinically cured when no parasites are detected insplenic or bone marrow aspirates. However,biopsies should be carried out again after 3 and 12months since relapse is frequent. Antimonialscombined with allopurinol, pentamidine andamphotericin B have been used with success in

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patients in relapse who have become unrespons-ive to antimonials alone.

Cutaneous leishmaniasis, caused by L. major, L.tropica, L. mexicana and L. peruviana, is respons-ive to intralesional injections of antimonial com-pounds. Mild lesions can often be left to healspontaneously. However, it is preferable to treatL. tropica infections with a view to reducingtransmission since humans seem to be the onlyhost. When the lesion is inflamed or ulcerated orwhen obstruction of lymphatic drainage or des-truction of cartilage creates a risk of serious dis-figurement or disability, antimonials should beadministered systematically as well as locally.Infections due to L. braziliensis, and the lesscommon L. panamensis, respond to antimonialtreatment. L. aethiopica is less responsive atconventional doses and the sores should be left toheal spontaneously if there is no evidence ofcutaneous involvement. L. guyanensis infectionsshould be treated with pentamidine.

Mucocutaneous leishmaniasis can cause per-manent disfiguring lesions, and L. braziliensisinfections, in particular, are associated with theadded risk of espundia. The latter usually respondsto antimonials and, when relapses occur, moreextended courses of treatment are often success-ful. Patients who still fail to respond should receiveamphotericin B or pentamidine, although neithertreatment is highly satisfactory.

Because of resistance to antimonials, L. aethiopicainfections should be treated with pentamidine fromthe outset until complete healing occurs. Emer-gency use of corticosteroids may be needed tocontrol pharyngeal or tracheal oedema produced bysevere inflammation resulting from antigensliberated from dead parasites during the earlyphase of treatment. Antibiotics may also be neededto treat secondary infections, and plastic surgeryoffers the only means of ameliorating disfiguringscars. Diffuse cutaneous leishmaniasis is usuallytreated with antimonial compounds, but relapsesmust be expected and repeated courses of penta-midine may be needed until clinical immunitybecomes established.

Safe use in pregnancy of antimonial compounds,pentamidine or amphotericin B has not beenestablished and they should be used only when thebenefits to the mother outweigh the risks to thefetus. However, in visceral leishmaniasis, which ispotentially fatal, treatment should always be givenwithout delay.

MEGLUMINE ANTIMONIATE &SODIUM STIBOGLUCONATEAntiprotozoal agentInjection: equivalent of 85 mg/ml meglumineantimoniate or 100 mg/ml sodium stiboglu-conate of antimony (Sb5+) in 5-ml ampoule

Uses:Visceral leishmaniasis; cutaneous leishmaniasis(except for L. aethiopica infections, which areunresponsive); diffuse cutaneous leishmaniasis dueto L. amazonensis; cutaneous and mucocutaneousleishmaniasis due to L. braziliensis.

Dosage: Intramuscular doses are expressed interms of the equivalent amount of pentavalentantimony (Sb5+). All doses, which are weightrelated, are suitable for both adults and children.

Visceral leishmaniasisInjection of 20 mg of Sb5+/kg i.m. daily for a mini-mum of 20 days. Treatment should be continueduntil no parasites are detected in consecutivesplenic aspirates taken at 14-day intervals.

Patients who relapse following the first course oftreatment should be retreated immediately usingthe same daily dosage.

Cutaneous leishmaniasis except L. aethiopica.Local therapy: Injection of 1–3 ml into the base ofthe lesion, repeated once or twice if no response isapparent, at intervals of 1 to 2 days.

Systemic therapy: Injection of 10–20 mg Sb5+/kgi.m. daily until a few days after clinical cure and slit-skin smears are negative. Relapse is unusual.

L. braziliensis therapy: Injection of 20 mg Sb5+/kgi.m. daily until lesion is healed and for at least 4weeks. Relapse is usually associated withinadequate dosage or interrupted treatment. Shouldrelapse occur following a full course of treatment,pentamidine should be used.

Mucocutaneous leishmaniasis (L. braziliensis):Injection of 20 mg Sb5+/kg daily i.m. until slit-skinsmears are negative and for at least 4 weeks. In theevent of toxicity or inadequate response, 10–15 mgSb5+/kg should be administered every 12 hours forthe same period. Patients who relapse should beretreated for at least twice as long. Those who areunresponsive should receive amphotericin B orpentamidine.

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Diffuse cutaneous leishmaniasis (L. amazonensis):Injection of 20 mg Sb 5+/kg daily i.m. for severalmonths after clinical improvement occurs. Relapsemust be expected until immunity develops.

Contraindications: Severe kidney, heart or liverdisorders.

Precautions: Provision of a protein-rich dietthroughout treatment is essential and, wherepossible, iron and other specific deficienciesshould be corrected beforehand. When possible,monitor throughout the electrocardiogram, renaland hepatic functions and reduce dosage in case ofabnormalities.

Safe use in pregnancy has not been established.However, in visceral leishmaniasis, which ispotentially fatal, treatment should always be givenwithout delay.

Adverse effects: Reversible dose-dependentelectrocardiographic changes; hepatic and renalfunction impairment; occasionally, headache,malaise, dyspnoea, skin rashes, facial oedema andabdominal pain.

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

PENTAMIDINEAntiprotozoal agentPowder for injection: 200 mg, 300 mg ofpentamidine isetionate in vial

Uses: In patients who are unresponsive to or in-tolerant of antimony compounds, in cutaneousleishmaniasis, diffuse cutaneous leishmaniasisand mucocutaneous leishmaniasis due toL. aethiopica and L. braziliensis unresponsive toantimony compounds; cutaneous leishmaniasisdue to L. guyanensis.

Dosage: Deep intramuscular injection is preferred.Intravenous infusions must be delivered over aperiod of not less than 60 minutes to avert the riskof cardiovascular collapse. All doses, which areweight related, are suitable for both adults andchildren.

Visceral leishmaniasis: Injection of 4 mg/kg threetimes a week for 5 to 25 weeks, or longer, until noparasites are detected in two consecutive splenicaspirates taken 14 days apart.

Cutaneous leishmaniasis (L. aethiopica and L.guyanensis): Injection of 3–4 mg/kg once ortwice a week until the lesion is no longer visible.Relapse is unusual.

Diffuse cutaneous leishmaniasis (L. aethiopica):Injection of 3–4 mg/kg once a week, continued forat least 4 months after parasites are no longerdetectable in slit-skin smears. Relapse frequentlyoccurs during the first few months before immunityis established.

Mucocutaneous leishmaniasis (L. braziliensisand L aethiopica): Injection of 4 mg/kg 3 times aweek for 5 to 25 weeks, or longer, until the lesion isno longer visible.

Contraindications: Known hypersensitivity andsevere renal impairment.

Safe use in pregnancy has not been established.However, in visceral leishmaniasis, which ispotentially fatal, treatment should always be givenwithout delay.

Precautions: Because of the risk of hypotensionand syncope, all patients should remain supine andunder observation for at least 30 minutes after eachinjection. When possible, monitor blood pressure,full blood count and serum creatinine at regularintervals throughout treatment and blood glucosedaily. In immunodeficient patients, interrupt ordiscontinue treatment if acute deterioration of bonemarrow, renal or pancreatic function occurs.

Adverse effects: Frequently, completely rever-sible mild nephrotoxicity, acute hypotension andsyncope may occur after rapid i.v. injection.Pancreatic damage resulting initially in hypo-glycaemia and finally in insulin insufficiency maylead to permanent insulin-dependent diabetes.

Other effects include hypocalcaemia, gastro-intestinal irritation, confusion, hallucinations,cardiac dysrhythmias, local induration andoccasionally, sterile abscess. Rarely, thrombo-cytopenia, leukopenia, abnormal hepatic functiontests, and Stevens–Johnson syndrome have beenreported.


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AMPHOTERICIN BAntiprotozoal agentPowder for injection: 50 mg in vial

Uses: Visceral and mucocutaneous leishmaniasisunresponsive to pentavalent antimony compounds.

Dosage: Adults: A starting dose of 5–10 mg isincremented by 5 to 10 mg daily to the maximum of0.5–1 mg/kg. This is then administered on alter-nate days. A total cumulative dose of 1–3 g isusually required.

Contraindications: Known hypersensitivity.

Safe use in pregnancy has not been establishedand amphotericin B should be used only when thebenefits to the mother outweigh the risks to thefetus.

Precautions: Close medical supervision is requiredthroughout treatment. Closely monitor renalfunction, serum potassium levels and blood count.

Adverse effects: Drug infusion may cause ana-phylaxis. Frequently, chills, fever, and vomitingoccur. Occasionally, flushing, muscle and jointpains, headache and anorexia are particularlymarked in the first days of treatment, and partiallyreversible deterioration of renal function, as well asprogressive normochromic anaemia indicative ofbone-marrow depression have been reported. Lesscommonly, selective leukopenia and thrombo-cytopenia, nerve palsies, impaired vision, tinnitusand difficult micturition also occur.


Drugs used in trypanosomiasisAfrican trypanosomiasis, or sleeping sickness, is aprotozoan infection transmitted by Glossina spp(tsetse flies). Two subspecies of Trypanosomabrucei — gambiense and rhodesiense — producedistinctive clinical forms of the disease. Early-stageinfection due to T. b. rhodesiense is characterizedby a transient indurated weal or chancre. Invasionof lymphatics and blood vessels occurs a fewdays later, causing regional or generalized lymph-adenopathy and widespread systemic dissemina-tion. Intermittent fevers accompanied by malaise,headaches, joint pains, pruritus, skin rashes andoedema are followed by normochromic or hypo-

chromic anaemia, and a pancarditis ultimatelyresulting in dysrhythmias and heart failure. Othersigns of organic involvement are common. In men,endocrine involvement can cause impotence and,in women, menstruation disorders, sterility, abortionand premature delivery, as well as stillbirth orperinatal death. Signs of meningo-encephalitisdevelop within a few weeks and early symptomsinclude insomnia, neurological disorders andmental changes. Apathy and somnolencesupervene and untreated patients ultimately diefrom malnutrition, intercurrent infection ordeepening coma. Symptoms of African trypano-somiasis caused by T.b. gambiense are similar, buttake several months or even years to develop.

Treatment of early-stage infections of T. b.rhodesiense with suramin sodium and T.b.gambiense with pentamidine can be curative ifstarted before the central nervous system hasbecome involved. In areas where pentamidineresistance occurs, suramin sodium may be used forT.b. gambiense infection.

Eflornithine has been shown to be both effectiveand considerably less toxic than melarsoprol inpatients with meningoencephalopathy resultingfrom T. b. gambiense trypanosomiasis. Eflornithinealone is ineffective in T. b. rhodesiense infections.

MELARSOPROLAntiprotozoal agentInjection: 3.6% solution in propylene glycol

Uses: Confirmed cases of T.b. gambiense or T.b.rhodesiense infection with meningoencephaliticinvolvement.

Dosage: Several treatment regimens for adults andchildren are currently used in the absence of clearevidence that one is better than another. They eachcomprise three or four series of daily injections withintervening periods of 7 to 10 days and are set outin the table on page 150.

Contraindications: Pregnancy.

Precautions: Hospitalization and close medicalsupervision are required throughout treatment.Episodes of reactive encephalopathy may requiresuspension of treatment. Intercurrent infectionssuch as pneumonia and malaria should betreated before melarsoprol is administered. Wherepossible, malnutrition should be corrected with aprotein-rich diet.

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Adverse effects: Serious complications such asreactive encephalopathy characterized by head-ache, tremor, slurring of speech, convulsions andultimately coma. Frequent severe adverse effectsinclude myocardial damage, albuminuria andhypertension. Less commonly, hypersensitivityreactions, agranulocytosis, or dose-related renaland hepatic dysfunction can occur during laterphases of treatment. Less serious adverse effectsinclude hyperthermia, urticaria, headache,diarrhoea and vomiting.


PENTAMIDINEAntiprotozoal agentPowder for injection: 200 mg of pentamidineisetionate in vial

Uses: T.b. gambiense infections with a view toobtaining a radical cure in the haemolymphaticstage of African trypanosomiasis or clearing theblood and lymph of trypanosomes prior to treatmentwith melarsoprol.

Dosage: The powder for injection should be recon-stituted with “water for injection”.

Adults and children:For early disease: 4 mg/kg. in each of a total of7–10 intramuscular injections, administered at arate of one per day or one every other day. For latedisease: see table on page 150.

Contraindications: Known hypersensitivity; severerenal impairment; T. b. rhodesiense trypano-somiasis, since primary resistance to pentamidinehas been observed.

Precautions: Cerebrospinal fluid should always beexamined before treatment since pentamidine is notlikely to be effective if the leukocyte count is greaterthan 5 cells/mm, the total protein content is greaterthan 37 mg/100 ml, or if trypanosomes can bedetected in centrifuged deposits. Use in pregnancycan induce abortion. However, pentamidine shouldnot be withheld during pregnancy even if there isevidence of meningoencephalitic involvement sincemelarsoprol should not be used.

Because of the risk of hypotension and syncope allpatients should remain supine and under observa-tion for at least 30 minutes after each injection.

When possible, monitor blood pressure, full bloodcount and serum creatinine at regular intervalsthroughout treatment and blood glucose daily. Inimmunodeficient patients, interrupt or discontinuetreatment if acute deterioration of bone marrow,renal or pancreatic function occurs.

Adverse effects: Frequently, completely re-versible mild nephrotoxicity, acute hypotension andsyncope after rapid intravenous injection, pan-creatic damage resulting initially in hypoglycaemiaand finally in insulin insufficiency which may lead topermanent insulin-dependent diabetes. Othereffects include hypocalcaemia, gastrointestinaltroubles, confusion, hallucinations, cardiacdysrhythmias, local induration and, occasionally,sterile abscess. Rarely, thrombocytopenia, leuko-penia, abnormal hepatic function tests, andStevens–Johnson syndrome have been reported.


SURAMIN SODIUMAntiprotozoal agentPowder for injection: 1 g in vial

Uses: T. b. gambiense and T. b. rhodesiensetrypanosomiasis with a view to obtaining aradical cure in the haemolymphatic stage of thedisease or clearing the blood and lymph oftrypanosomes prior to treatment with melarsoprol.

Dosage: Doses for both adults and children inmg/kg for radical cure (A) and for administrationbefore melarsoprol treatment (B) are shown in thetable below:

Day 1 3 5 11 17 23 30

Treatment A 5 10 20 20 20 20 20 B 5 10 20

All doses should be administered by slow intra-venous injection of a 10% w/v solution in “water forinjection” to be used within 30 minutes of pre-paration. The first injection should be given withparticular caution.

Contraindications: Previous anaphylactic reac-tions or sensitivity to suramin; pregnancy (seeprecautions page 150–151); children less than 10

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years old; elderly or infirm patients with impairedliver or renal function; total blindness — unlessrequired for relief from intensely itchy lesions.

Precautions: Suramin is extremely toxic andshould always be given under medical supervisionin a hospital. A satisfactory food and fluid intake

should be maintained throughout treatment. Urinesamples should be taken before and during treat-ment to detect the presence of albumin. Moderatealbuminuria indicates that the dose should bereduced but heavy albuminuria with the passage ofcasts indicates the need for immediate discontinu-ation of treatment.

Treatment schedule for African trypanosomiasiswith meningoencephalitic involvement.

Day Drug Dose (mg/kg) For T. b. rhodesiense infection, as used in Kenya and Zambia

1 suramin 5.003 suramin 10.005 suramin 20.007 melarsoprol 0.368 melarsoprol 0.729 melarsoprol 1.10

16 melarsoprol 1.4017 melarsoprol 1.8018 melarsoprol 2.2025 melarsoprol 2.9026 melarsoprol 3.6027 melarsoprol 3.6034 melarsoprol 3.6035 melarsoprol 3.6036 melarsoprol 3.60

For T.b rhodesiense infection, as used in Uganda and the United Republic of Tanzania1 suramin 5.003 suramin 10.005 melarsoprol 1.806 melarsoprol 2.207 melarsoprol 2.56

14 melarsoprol 2.5615 melarsoprol 2.9016 melarsoprol 3.2623 melarsoprol 3.6024 melarsoprol 3.6025 melarsoprol 3.60

For T.b gambiense infection, as used in Cote d’ Ivoire1 pentamidine i.m. 4.002 pentamidine i.m. 4.004 melarsoprol 1.205 melarsoprol 2.406 melarsoprol 3.60

17 melarsoprol 1.2018 melarsoprol 2.4019 melarsoprol 3.6020 melarsoprol 3.6030 melarsoprol 1.2031 melarsoprol 2.4032 melarsoprol 3.6033 melarsoprol 3.60

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Suramin may be given to pregnant women withT. b. rhodesiense trypanosomiasis even if there isevidence of meningoencephalitic involvement,since melarsoprol must not be given beforedelivery.

Adverse effects: Direct toxic effects requireimmediate withdrawal. Rarely, potentially fatal lossof consciousness may occur during the firstinjection. Heavy albuminuria, stomal ulceration,exfoliative dermatitis, severe diarrhoea, prolongedhigh fever and prostration may occur. Lesser, butcommon, symptoms include tiredness, anorexia,malaise, polyuria.


EFLORNITHINEAntiprotozoal agentInjection: 200 mg of eflornithine hydrochloride/ml solution in 100-ml ampoule

Uses: T. b. gambiense trypanosomiasis in both theearly and the late stages.

Dosage:Adults and children: A dose of 100 mg/kg should beadministered, by infusion over a period of 45minutes, every 6 hours for at least 14 days.

Contraindications: Pregnancy and lactation.

Precautions: Hospitalization with close supervisionrequired throughout treatment. Blood and lymphnode aspirates required daily until trypanosomenegative for two consecutive days. Thereafter,weekly aspirate examination throughout treatment.Cerebrospinal fluid examination for determination ofleukocytes, total protein content and trypanosomesrequired after a complete course of treatment, andthereafter at 1, 3, 6, 12 and 24 months.

Parasitological evidence of relapse requires afurther course of therapy.

Adverse effects: Most commonly reported effectsare diarrhoea, anaemia, leukopenia, thrombo-cytopenia, convulsions and impaired hearing. Lesscommonly reported effects, which are reversible ondrug withdrawal, are vomiting, anorexia, alopecia,abdominal pain, headache, facial oedema, eosino-philia and dizziness.


Drugs used in AmericantrypanosomiasisAmerican trypanosomiasis (Chagas disease) iscaused by the protozoan parasite Trypanosomacruzi. The acute febrile phase of the diseasefrequently passes unrecognized. Occasionally,however, infection follows a fulminating courseterminating in a fatal myocarditis and meningo-encephalitis. In about half of the surviving cases,and after a latent interval ranging from 10 to over20 years, chronic myopathic degeneration results indysrhythmias, cardiac enlargement and, lessfrequently, oesophageal and colonic dilatation. Atthis stage, only symptomatic treatment is of benefit.At present, the only therapeutic agents of value arebenznidazole and nifurtimox. Both suppress para-sitaemia and are efficacious during the early stagesof infection. Safe use of both drugs in pregnancyhas not been established and treatment should bedeferred until after the first trimester. Treatmentshould be instituted immediately to avoid the risk ofcongenital transmission. Studies are in progress todetermine whether benznidazole and nifurtimoxhave any influence when used for later manifesta-tions of the disease. Symptomatic treatment maybe necessary in advanced cases.

BENZNIDAZOLEAntiprotozoal agentScored tablet: 100 mg

Uses: Acute American trypanosomiasis (Chagasdisease).

Dosage: Adults: 5 –7 mg /kg orally in two divideddoses daily for 60 days.

Children (up to 12 years): 10 mg/kg orally in twodivided doses daily for 60 days.

Contraindications: Alcohol; first trimesterpregnancy.

Precautions: Patients with hepatic, renal orhaematological insufficiency should be kept underclose medical supervision. The blood count,especially leukocytes, should be monitoredthroughout treatment.

Essential Drugs

152


Adverse effects: Frequently, mild rashes andnausea may occur. Treatment must be discon-tinued in the case of fever, purpura or dose-relatedparaesthesia or symptoms of peripheral poly-neuritis. More serious adverse effects includeleukopenia and, rarely, agranulocytosis orexfoliative dermatitis.


NIFURTIMOXAntiprotozoal agentTablet: 30 mg, 120 mg, 250 mg

Uses: Acute American trypanosomiasis (Chagasdisease).

Dosage:Adults: 8–10 mg/kg orally in three divided dailydoses for 90 days.

Children: 15 –30 mg /kg orally in four divided dailydoses for 90 days.

Contraindications: First trimester pregnancy.

Precautions: Gastrointestinal irritation (reducedwith simultaneous use of aluminium hydroxide).Alcohol avoidance to reduce incidence and severityof adverse effects. History of convulsions (closemedical supervision). Reduction of daily doses ifweight loss, neurological disturbances or othermanifestations of intolerance occur.

Adverse effects: Dose-related reversible effectsfrequently occur and include anorexia, nausea,vomiting, gastric pain, insomnia, head-ache,vertigo, excitability, myalgia, arthralgia andconvulsions. Seizures may be symptomaticallycontrolled with anticonvulsants. Discontinuation oftreatment may be necessary in the case ofperipheral polyneuritis.


Essential Drugs

153


ATC/DDD Classification (temporary)

The following temporary classifications were agreed at a meeting of the International Working Groupon ATC/DDD Classification which took place from 29 to 30 April 1997 in Geneva. Comments on, orobjections to, the classification should be forwarded to the WHO Collaborating Centre for DrugStatistics Methodology, Sven Oftedals Vei 10, 0518, Oslo, Norway (telephone: 00 47 22 16 9810, fax:0047 22 16 9818) before 15 November 1997. Provided there have been no objections, theclassification will come into force on 1 January 1998. A final list of classifications will be publishedsubsequently in this journal.

ATC Level INN/common name ATC code

New ATC levels:

Peripherally acting antiobesity products A08A BDrugs used in erectile dysfunction G04B EDrugs used in benign prostatic hypertrophy G04C

Alpha-adrenoceptor blocking agents G04C ATestosterone-5-alpha reductase inhibitors G04C BOther drugs used in benign prostatic hypertrophy G04C X

Medical gases V03A N

ATC code changes:previous ATC new ATC

alfuzosin G04B X02 G04C A01alprostadil G04B X05 G04B E01dacarbazine L01X X13 L01A X04finasteride G04B X04 G04C B01papaverine A03A D01 G04B E02* (formulations for intracavernous use)papaverine, comb. A03A D51 G04B E52* (in combination with phentolamine)pygeum africanum G04B X07 G04C X01serenoa repens G04B X09 G04C X02tamsulosin G04B X08 G04C A02yohimbin V03A X01 G04B E04

New ATC 5th level codes:atorvastatin C10A A05capsaicin N01B X04dodecafluoropentane V08D A03dolasetron A04A A04donepezil N07A A05ferric acetyl transferrin B03A B08

* additional information

154


New ATC 5th level codes (continued)fexofenadine R06A X26fluoride, combinations A12C D51gamolenic acid, combinations D11A X52hydroxocobalamin V03A B33imiquimod D06B B10lactobacillus fermentum G01A X14lysine B05X B03mepartricin G04B X12montelukast R03D C03orlistat A08A B01nelfinavir J05A E04phospholipids, microspheres of V08D A04proguanil, combinations P01B B51propentofylline N06B C02rimexolone S01B A13saruplase B01A D08technetium(99mTc)votumumab V09I A04temozolomide L01A X03zolmitriptan N02C C03

Change of name:previous: air-filled microspheres of

human albumin V08D A01new: albumin, human, microspheres of V08D A01

New DDDs:

INN/common name DDD Unit Route of ATC code administration

dirithromycin 0,5 g O J01F A13fexofenadine 120 mg O R06A X26ibutilide 1 mg P C01B D05letrozole 2,5 mg O L02B G04miglitol 0,3 g O A10B F02nicotine 60 mg Inhal N07B A01olanzapine 10 mg O N05A H03ropinirole 6 mg O N04B C04sertindole 16 mg O N05A E03sumatriptan 25 mg R N02C C01valsartan 80 mg O C09C A03

* diclofenac combinations (correspond 0.1 g O,P,R M01A B55 to the DDD for diclofenac)

* additional information

ATC Level INN/common name ATC code

ATC/DDD Classification (temporary)

155


Recent Publications and Documents

Drugs for the elderlyMany elderly people often have concomitantillnesses and this can lead to the prescription ofseveral different medicines at the same time. Whilemany of these drugs help improve the survival andquality of life of elderly people, it is estimated thatas many as one-fifth of patients entering a geriatricward of a general hospital have symptomsattributable to effects from prescribed drugs.

The aim of Drugs for the elderly is to promote druguse that is efficacious and safe. Presented in theform of a pocket-size book, it is a convenient guideto possible side-effects of those drugs most oftenused in treating the elderly. For doctors, it consti-tutes a source of essential facts for safe prescrib-ing. For pharmacists and nurses, it provides a guideon what the patient needs to know, and is a quickreference to the many differences in the treatmentof young and old. It also points to alternativetreatments which are equally effective or safer.

The most effective way to ensure the appropriateuse of prescription drugs is through the training ofhealth personnel, and this book will beindispensable for medical, pharmacy and nursingschools around the world.

Drugs for the elderly: second edition. WHO RegionalPublications, European Series, Number 71.ISBN 92 890 1335 4 Price: Sw.fr. 32.-.

Rapid examination methods againstcounterfeit and substandard drugsThe provision of safe and effective pharmaceuticalproducts of good quality is vitally important forhealth care services, for use in the diagnosis,treatment or prevention of disease. Unfortunately,the expansion of international trade has led to theinfiltration of counterfeit and substandard drugs intomany markets.

This manual describes rapid analytical methods forthe detection of counterfeit and substandard drugs.It also gives easy-to-follow directions on how to

identify abnormalities in external packaging, outerappearance and contents of fake products, andhow to inspect for tampering. These rapidexamination methods are also complemented byinstructions on the application of organolepticinspection and thin layer chromatography. It isemphasized that any enforcement action involvingcounterfeit or substandard products should only beundertaken after a complete official laboratoryanalysis in accordance with national legalprovisions in vigour.

Rapid examination methods against counterfeit andsubstandard drugs. Available from the Japan InternationalCorporation of Welfare Services (JICWELS), ShinjukuTakasago Bldg. 10F, 16-5 Tomihisa-cho Shinjuku-ku,Tokyo 162, Japan. Fax number: 03 3225 6590.

Countering counterfeitingCounterfeiting is one of the fastest growing eco-nomic crimes worldwide. It threatens the developedand developing world alike, undermining traderelations, scaring off vital new investment andendangering public health and safety. Legitimatemanufacturers who invest heavily in the researchand development of a product can suffer deva-stating losses and this leads to discouragement offurther research spending, and the consequentslowing of technological innovation.

Countering counterfeiting: a guide to protecting andenforcing intellectual property rights provides anoverview of how owners of intellectual propertyrights may defend themselves against counter-feiting. It describes the nature, scale and impact ofproduct counterfeiting and outlines strategies for itsprevention. Where companies have become thevictims of counterfeiters, information is given onpotential action.

Countering counterfeiting: a guide to protecting andenforcing intellectual property rights. Available from theCounterfeiting Intelligence Bureau, International Chamberof Commerce, Maritime House, 1 Linton Road, Barking,Essex IG1 8HG, United Kingdom. Fax number: 44 149532902. e-mail: [email protected]

156


Malaria: a manual for communityhealth workersCommunity health workers can help in many waysto treat malaria and prevent new cases. Thismanual concentrates on activities that are within thecompetence of such health workers and feasibleand affordable at the community level. Informationis provided on the disease and its transmission, andon treatment schedules for different age groups,including advice in the event of treatment failure.

The manual will be particularly useful in trainingcourses, or as a support to health education in thecommunity. Practical rules for organizing anti-malaria work and community action to reduce theincidence of malaria are set out in two annexes.

Malaria: a manual for community health workers. WHO,Geneva, 1996. ISBN 92 4 154491 0. Price Sw.fr. 16.-(developing countries Sw.fr. 11.20.-).

Guidelines for the management ofdrug-resistant tuberculosisAbout one-third of the world's population is infectedby Mycobacterium tuberculosis and, in 1995, there

were nine million new cases of tuberculosis withthree million deaths.

Effective tuberculosis control can be implementedusing inexpensive, simple and largely standardizedtechniques, coupled with the managerial skills toimplement them on a large intervention scale. Since1992, the WHO Global Tuberculosis Programmehas developed a strategy which has been success-ful in meeting the challenge of large-scale tuber-culosis control.

One major obstacle to the successful implemen-tation of treatment campaigns is the existence ofmultidrug-resistant tuberculosis and the need touse second-line drugs. Once a country has decidedthat it has a clear need for these drugs, they shouldbe provided by a specialized unit working in closeconnection with a laboratory able to carry outcultures and reliable susceptibility tests ofM. tuberculosis. The present handbook gives clearadvice on this important issue.

Guidelines for the management of drug-resistanttuberculosis. Unpublished document WHO/TB/96.210(Rev.1) 1997. Price Sw.fr. 15.- (developing countriesSw.fr. 10.50).

Recent Publications and Documents

WHO Drug Information, Vol. 11, No. 3, 1997 RECOMMENDED INN: List 38

International Nonproprietary Names for Pharmaceutical Substances (INN)

RECOMMENDED International Nonproprietary Names (Rec. INN): List 38

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

Dénominations communes internationales des Substances pharmaceutiques (DCI)

Dénominations communes internationales RECOMMENDÉES (DCI Rec): Liste 38

Il est notifié que, conformément aux dispositions du paragraphe 7 de la Procédure à suivre en vue du choix de Dénominations communes internationales recommandées pour les Substances pharmaceutiques [Actes off. Org. mond. Santé, 1955, 60, 3 (résolution EB15.R7); 1969,173,10 (résolution EB43.R9)] les dénominations ci-dessous sont mises à l'étude par l'Organisation mondiale de la Santé en tant que dénominations communes internationales proposées. L'inclusion d'une dénomination dans les listes de DCI proposées n'implique aucune recommandation en vue de l'utilisation de la substance correspondante en médecine ou en pharmacie. On trouvera d'autres listes de Dénominations communes internationales proposées (1-73) et recommandées (1-35) dans la Liste récapitulative No. 9, 1996.

Denominaciones Comunes Internacionales para las Sustancias Farmacéuticas (DCI)

Denominaciones Comunes Internacionales RECOMENDADAS (DCI Rea): Lista 38

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

157

RECOMMENDED INN: List 38 WHO Drug Information, Vol. 11, No. 3, 1997

MODIFICATION

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

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

MODIFICATION

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

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

MODIFICACION

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

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

158


Latin, English, French, Spanish: Recommended INN

DCI Recommandée

DCI Recomendada

Chemical name or description; Molecular formula; Graphic formula

Nom chimique ou description; Formule brute; Formule développée

Nombre químico o descripción; Fórmula empírica; Fórmula desarrollada

abacavirum

abacavir

abacavir

abacavir

(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol

[(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]cyclopent-2-ényl]méthanol

(1S,4R)-4-[2-amino-6-(ciclopropilamino)-9H-purin-9-il]-2-ciclopenteno-1-metanol

C 1 4 H 1 6 N 6 O

almotriptanum almotriptan

almotriptan

almotriptán

1-[[[3-[2-(dimethylamino)ethyl]indol-5-yl]methyl]sulfonyI]pyrrolidine

1-[[[3-[2-(diméthylamino)éthyl]-1H-indol-5-y]]méthyl]sulfonyl]pyrrolidine

1-[[[3-[2-(dimetilamino)etil]indol-5-il]metil]sulfonil]pirrolidina

C17H25N3O2S

159


amlintidum amlintide

amlintide

amlintida

L-lysyl-L-cysteinyl-L-asparaginyl-L-threonyl-L-alanyl-L-threonyl-L-cysteinyl-L-alanyl-L-threonyl-L-glutaminyl-L-arginyl-L-leucyl-L-alanyl-L-asparaginyl-L-phenylalanyl-L-leucyl-L-valyl-L-histidyl-L-seryl-L-seryl-L-asparaginyl-L-asparaginyl-L-phenylalanylglycyl-L-alanyl-L-isoleucyl-L-leucyl-L-seryl-L-seryl-L-threonyl-L-asparaginyl-L-valylglycyl-L-seryl-L-asparaginyl-L-threonyl-L-tyrosinamide, cyclic(2 7)-disulfide

(2 7)-disufure cyclique de L-lysyl-L-cystéinyl-L-asparaginyl-L-thréonyl-L-alanyl-L-thréonyl-L-cystéinyl-L-alanyl-L-thréonyl-L-glutaminyl-L-arginyl-L-leucyl-L-alanyl-L-asparaginyl-L-phénylalanyl-L-leucyl-L-valyl-L-histidyl-L-séryl-L-séryl-L-asparagi-nyl-L-asparaginyl-L-phénylalanyl-glycyl-L-alanyl-L-isoleucyl-L-leucyl-L-séryl-L-séryl-L-thréonyl-L-asparaginyl-L-valyl-glycyl-L-séryl-L-asparaginyl-L-thréonyl-L-tyrosinamide

(2 7)-disulfuro cíclico de L-lisil-L-cisteinil-L-asparaginil-L-treonil-L-alanil-L-treonil-L-cisteinil-L-alanil-L-treonil-L-glutaminil-L-arginil-L-Ieucil-L-alanil-L-asparaginil-L-fenilalanil-L-leucil-L-valil-L-histidil-L-seril-L-seril-L-asparaginil-L-asparaginil-L-fenilalanilglicil-L-alanil-L-isoleucil-L-leucil-L-seril-L-seril-L-treonil-L-asparaginil-L-valilglicil-L-seril-L-asparaginil-L-treonil-L-tirosinamida

C165H261N51O55S2

avitriptanum avitriptan 3-[3-[4-(5-methoxy-4-pyrimidinyl)-1-piperazinyl]propyl]-N-methylindole-

5-methanesulfonamide

avitriptan

avitriptán

[3-[3-[4-(5-méthoxypyrimidin-4-yl)pipérazin-1-yl]propyl]-1H-indol-5-yl]-N-méthylméthanesulfonamide

3-[3-[4-(5-metoxi-4-pirimidinil)-1-piperazinil]propil]-N-metilindol-5-metanosulfonamida

C22H30N6O3S

160


bamaquimastum

bamaquimast

bamaquimast

bamaquimast

3-(3-hydroxypropyl)-1-propyl-2(1H)-quinoxalinone methylcarbamate (ester)

méthylcarbamate de 3-(3-oxo-4-propyl-3,4-dihydroquínoxalin-2-yl)propyle

metilcarbamató(éster) de 3-(3-hidroxipropil)-1-propiI-2(1H)-quinoxalinona

C16H21N3O3

basiliximabum basiliximab

basiliximab

basiliximab

immunoglobulin G 1 (human-mouse monoclonal CHI621 heavy chain anti-human interleukin 2 receptor), disulfide with human-mouse monoclonal CHI621 light chain, dimer

immunoglobuline G 1 (chaîne lourde de l'anticorps monoclonal chimérique homme-souris CHI621 dirigé contre le récepteur humain de l'interleukine 2), dimère du disulfure avec la chaîne légère de l'anticorps monoclonal chimérique homme-souris CHI621

inmunoglobulina G 1 (cadena pesada del anticuerpo monoclonal quimérico hombre-ratón CHI621 dirigido contra el receptor humano de la interleuquina 2), dimero del disulfuro con la cadena ligera del anticuerpo monoclonal quimérico hombre-ratón CHI621

betadexum betadex bétadex betadex

β-cyclodextrin β-cyciodextrine β-ciclodextrina

C 4 2 H 7 0 O 3 5

161


bimoclomolum bimoclomol

bimoclomol

bimoclomol

(±)-N-(2-hydroxy-3-piperidinopropoxy)nicotinimidoyl chloride

chlorure de N-[(2RS)-2-hydroxy-3-(pipéridin-1-yl)propoxy]pyndin-3-carboximidoyle

cloruro de (±)-N-(2-hidroxi-3-piperidinopropoxi)nicotinimidoil

C14H20CIN3O2

and enantiomer et l'énantiomère y enantiómero

blonanserinum blonanserin

blonansérine

blonanserina

2-(4-ethyl-1-piperazinyl)-4-(p-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclo= octa[b)]pyridine

2-(4-éthylpipérazin-1-yl)-4-(4-fluorophényl)-5,6,7,8,9,10-hexahydrocyclo= octa[b]pyridine

2-(4-etil-1-piperazinil)-4-(p-fluorofenil)-5,6,7,8,9,10-hexahidrociclo= octa[b]piridina

C23H30FN3

brasofensinum brasofensine

brasofensine

brasofensina

3β-(3,4-dichlorophenyl)-1αH,5αH-tropane-2α-carboxaldehyde (E)-(O-methyloxime)

(1R,2R,3S,5S)-3-(3,4-dichlorophényl)-8-méthyl-a-azabicyclo[3.2.1]octane-2-carbaldéhyde (E)-O-méthyloxime

3β-(3,4-diclorofenil)-1αH,5αH-tropano-2α-carboxaldehído (E)-(O-metiloxima)

C16H20CI2N2O

162

WHO Drug Information, Vol. 11, No. 3,1997 RECOMMENDED INN: List 38

brinzolamidum brinzolamide

brinzolamide

brinzolamida

(R)-4-(ethylamino)-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide

(4R-4-(éthylamino)-2-(3-méthoxypropyl)-3,4-dihydro-2H-thiéno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1 -dioxyde

(R)-4-(etilamino)-3,4-dihidro-2-(3-metoxipropil)-2H-tieno[3,2-e]-1,2-tiazina-6-sulfonarnida 1,1 -dióxido

C 1 2 H 2 1 N 3 O 5 S 3

cevimelinum

cevimeline

céviméline

cevimelina

(±)-cis-2-methylspiro[1,3-oxathiolane-5,3'-quinuclidine]

(3RS,2'RS)-2'-méthylspiro[1-azabicyclo[2.2.2]octane-3,5'-[1,3]oxathiolane]

(±)-cis-2-metilespiro[1,3-oxatiolano-5,3'-quinuclidina]

C10H17NOS


cizolirtinum

cizolirtine

cizolirtine

cizolirtina

(±)-5-[α-[2-(dimethylamino)ethoxy]benzyl]-1-metriylpyrazole

N,N-diméthyl-2-[(RS)-(1-méthyl-1H-pyrazol-5-yl)phénylméthoxy]éthanamine

(±)-5-[α-[2-(dimetilamino)etoxi]bencil]-1-metilpirazol

C15H21N3O


1 6 3


dalcotidinum

dalcotidine

dalcotidine

dalcotidina

1-ethyl-3-[3-[(α-piperidino-m-tolyl)oxy]propyl]urea

1-éthyl-3-[3-[3-[(pipéridin-1-yl)méthyl]phénoxy]propyl]urée

1-etil-3-[3-[(α-piperidino-m-tolil)oxi]propil]urea

C18H29N3O2

daniplestimum daniplestim

daniplestim

daniplestim

14-L-alanine-18-L-isoleucine-25-L-histidine-29-L-arginine-32-L-asparagine-37-L-proline-42-L-serine-45-L-methionine-51-L-arginine-55-L-threonine-59-L-leucine-62-L-valine-67-L-histidine-69-L-glutamic acid-73-glycine-76-L-alanine-79-L-arginine-a2-L-glutamine-a7-L-serine-93-L-serine-98-L-isoleucine-101-L-alanine-105-L-glutamine-109-L-glutamic acid-116-L-valine-120-L-glutamine-123-L-glutamic acid-14-125-interleukin 3 (human clone D11 reduced)

[14-L-alanine-18-L-isoleucine-25-L-histidine-29-L-arginine-32-L-asparagine-37-L-proline-42-L-sérine-45-L-méthionine-51-L-arginine-55-L-thréonine-59-L-leucine-62-L-valine-67-L-histidine-69-acideL-glutamique-73-glycine-76-L-alanine-79-L-arginine-82-L-glutamine-87-L-sérine-93-L-sérine-98-L-isoleucine-101-L-alanine-105-L-glutamine-109-acide L-glutamique-116-L-valine-120-L-glutamine-123-acide L-glutamique]-14-125-interleukin 3 (clone humain D11 précurseur de la partie protéique réduite)

[14-L-alanina-1B-L-isoleucina-25-L-histidina-29-L-arginina-32-L-asparagina-37-L-prolina-42-L-serina-45-L-metionina-51-L-arginina-55-L-treonina-59-L-leucine-62-L-valina-67-L-histidina-69-ácido L-glutámico-73-glicina-76-L-alanina-79-L-arginina-82-L-glutamina-87-L-serina-93-L-serina-98-L-isoleucina-101-L-alanina-105-L-glutamina-109-ácido L-glutámico-116-L-valina-120-L-glutamina-123-ácido L-glutámico]-14-125-interleuquina 3 (clon humano D11 precursor de la fracción proteica reducida)

C564H909N161O166S5

dexefaroxanum

dexefaroxan

dexéfaroxan

dexefaroxán

(+)-(R)-2-(2-ethyl-2,3-dihydro-2-benzofuranyl)-2-imidazoline

(+)-2-[(2R)-2-éthyl-2,3-dihydrobenzofuran-2-yl]-4,5-dihydro-1H-imidazole

(+)-(R)-2-(2-etil-2,3-dihidro-2-benzofuranil)-2-imidazolina

164


C13H16N2O

elacridarum

elacridar

élacridar

elacridar

4'-[2-(3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolyl)ethyl]-5-methoxy-9-oxo-4-acridancarboxanilide

N-[4-[2-(6,7-diméthoxy-3,4-dihydroisoquinoléin-2(1H)-yl)éthyl]phényl]-5-rnéthoxy-9-oxo-9,10-dthydroacridine-4-carboxamide

4'-[2-(3,4-dihidro-6,7-dimetoxi-2(1H)-isoquinolil}etil]-5-metoxi-9-oxo-4-acridancarboxanilida

C34H33N3O5

eldacimibum

eldacimibe

eldacimibe

eldacimiba

cyclic isopropylidene[(3,5-di-tert-butyl-4-hydroxyanilirio)[hexyl= (p-neopentylbenzyl)amino]methylene]malonate

5-[[[3,5-bis(1,1-diméthyléthyl)-4-hydroxyphényl]amino][[4-(2,2-diméthyl-propyl)benzyl]hexylamino]méthylène]-2,2-diméthyl-1,3-dioxane-4,6-dione

[(3,5-di-terc-butil-4-hidroxtanilino)[hexil(p-neopentilbencil)amino]= metileno]malonato cíclico de isopropilideno

C39H58N2O5

165


eperezolidum

eperezolid

épérézolide

eperezolida

N-[[(S)-3-[3-fluoro-4-(4-glycoloyl-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acelamide

N-[[(5S)-3-[3-fluoro-4-[4-(2-hydroxyacétyl)pipérazin-1-yl]phényl]-2-oxooxazolidin-5-yl]méthyl]acétamide

N-[[(S)-3-[3-fluoro-4-(4-glicoloil-1-piperazinil)fenil]-2-oxo-5-oxazolldinil]metil]acetamida

C18H23FN4O5

esatenololum

esatenolol

ésaténolol

esatenolol

2-[p-[(2S)-2-hydroxy-3-(isopropylamino)propoxy]phenyl]acetamide

2-[4-[(2S)-2-hydroxy-3-[(1-méthyléthyl)amino]propoxy]phényl]acétamide

2-[p-[(2S)-2-hidroxi-3-(isopropilamino)propoxi]fenil]acetamida

C14H22N2O3

faralimomabum faralimomab

faralimomab

faralimomab

immunoglobulin G 1 (mouse monoclonal 64G12 γ1 -chain anti-human interferon receptor), disulfide with mouse monoclonal 64G12 light chain, dimer

immunoglobuline G 1 (chaîne γ1 de l'anticorps monoclonal de souris (64G12) dirigé contre le récepteur humain des interférons de type I), dimère du disulfure avec la chaîne légère de l'anticorps monoclonal de souris 64G12

inmunoglobulina G 1 (cadena γ1 del anticuerpo monoclonal de ratón (64G12) dirigido contra el receptor humano de los interferones de tipo I), dimero del disulfuro con la cadena ligera del anticuerpo monoclonal de ratón 64G12

166


gacyclidinum

gacyclidine

gacyclidine

gaciclidina

1 -[cis-2-methyl-1 -(2-thienyl)cyclohexyl]piperidine

1 -[(1 RS,2SR)-2-méthyl-1 -(thiophén-2-yl)cyclohexyl]pipéridine

1-[cis-2-metil-1-(2-tienil)ciclohexil]piperidina

C16H25NS


ganaxolonum

ganaxolone

ganaxolone

ganaxolona

3α-hydroxy-3-methyl-5α-pregnan-20-one

3α-hydroxy-3-méthyl-5α-prégnan-20-one

3α-hidroxi-3-metil-5α-pregnan-20-ona

C22H36O2

hemoglobinum crosfumarilum hemoglobin crosfumaril

hémoglobine crosfumaril

hemoglobina crosfumarilo

hemoglobin A0 (human α2β2 tetrameric subunit), α-chain 99,99'-diamide with fumaric acid

99,99'-diamide de la chaîne a de l'hémoglobine A0 (sous-unité tétramérique α2β2 humaine) avec l'acide fumarique

99,99'-diamida de la cadena a de la hemoglobina A0 ( subunidad tetramérica α2β2 humana), con el ácido fumárico

167


îndisetronum

indisetron

indisétron

indisetron

N-(3,9-dimethyl-endo-3,9-diazabicyclo[3 3.1]non-7-yl)-1H-indazole-3-carboxamide

N-[(1R,5S,7s)-3,9-diméthyl-3,9-diazabicyclo[3.3.1]non-7-yl]-1H-indazole-3-carboxamide

N-(3,9-dimeti[-endo-3,9-diazabiciclo[3.3.1]non-7-il)-1H-indazol-3-carboxamida

C17H23N5O

insulinum aspartum

insulin aspart

insuline asparte

insulina asparta

2BB-L-aspartic acid-insulin (human)

[28B-acide L-aspartique]insuline humaine

28B-L-ácido aspártico-insulina(humana)

C 2 5 6 H 3 8 1 N 6 5 O 7 9 S 6

insulinum glarginum

insulin glargine

insuline glargine

insulina glargina

21A-glycine-30Ba-L-arginine-30Bb-L-arginineinsulin (human)

[21A-glycine]30aB-L-arginine-30bB-L-arginine-insuline humaine

21A-glicina-30Ba-L-arginina-30Bb-L-argininainsulina (humana)

C267H404N72O78S6

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iometopanum (123l) iometopane (123l)

íométopane (123l)

iometopano (123I)

methyl 3β-(p-[123l]iodophenyl)-1αH,5αH-tropane-2β-carboxylate

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

3β-(p-[123l]iodofenil)-1αH,5αH-tropano-2β-carboxilato de metilo

C 1 6 H 2 01 2 3 INO 2

israpafantum

israpafant

israpafant

israpafant

(±)-4-(o-chlorophenyl)-2-(p-isobutylphenethyl)-6,9-dimethyl-6/+thieno[3,2-^-s-triazolo[4,3-a][1,4]diazepine

(6RS)-4-(2-chlorophényl)-6,9-diméthyl-2-[2-[4-(2-rnéthylpropyl)phényl]éthyl]-6H-thiéno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazépine

(±)-4-(o-chlorofenil)-2-(p-isobutilfenetil)-6,9-dimetil-6H-tieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepina

C28H29CIN4S

and enantiomer et énantiomère y enantiómero

keliximabum keliximab

kéliximab

keliximab

immunoglobulin G 1 (human-Macaca monoclonal CE9.1 γ1-chain anti-human antigen CD 4), disulfide with human-Macaca monoclonal CE9 1 κ-chain, dimer

immunoglobuline G 1 (chaîne γ1 de l'anticorps monoclonal chimérique homme-macaque CE9 1 dirigé contre l'antigène CD 4 humain), dimère du disulfure avec la chaîne κ de l'anticorps monoclonal chimérique homme-macaque CE9.1

inmunoglobulina G 1 (cadena γ1 del anticuerpo monoclonal quimérico hombre-macaco CE9.1 dirigido contra el antigeno CD4 humano), dimero del disufuro con la cadena Κ del anticuerpo monoclonal dimérico hombre-macaco CE9.1

169


lanoteplasum

lanoteplase

lanotéplase

lanoteplasa

N-[N 2-(N-glycyl-L-alanyl)-L-arginyl]-117-L-glutamine-245-L-methionine-(1-5)-(87-527)-plasminogen activator (human tissue-type protein moiety)

N-[N2-(N-glycyl-L-alanyl)-L-arginyl]-[117-L-glutamine-245-L-méthionine]- (1-5)-(87-527)- activateur du plasminogène (type tissulaire humain, partie protéique)

N-[N 2-(N-glicil-L-alanil)-L-arginil]-[117-L-glutamina-245-L-metionina]-(1 -5)-(87-527)-activador del plasminógeno (tipo tisular humano, fracción proteica)

C2194H3323N633O666S29

* binding sites of sugar chain * sites de fixation de la chaîne osidique * lugares de union de la cadena osidica

lasinavirum lasinavir

lasinavir

tert-butyl [(αS)-α-[(1 S,3R)-1-hydraxy-3-[[(1 S)-1-[(2-methoxyethyl)carbamoyl]-2-methylpropyl]carbamoyl]-4-(2,3,4-trimethoxyphenyl)butyl]phenethyl]= carbamate

[(1S,2S,4R)-1-benzyl-2-hydroxy-5-[[(1S)-1-[(2-méthoxyéthyl)carbamoyl]-2-méthylpropyl]amino]-5-oxo-4-(2,3,4-triméthoxybenzyl)pentyl]carbamate de 1,1-dimethyléthyle

lasinavir [(αS)-α-[(1 S,3R)-1 -hidroxi-3-[[(1 S)-1 -[(2-metoxietil)-carbamoil]-2-metilpropil]carbamoil]-4-(2,3,4-trimetoxifenil)butil]fenetil]carbamato de terc-butilo

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C3 5H5 3N3O9

ledoxantronum

ledoxantrone

ledoxantrone

ledoxantrona

5-[(2-aminoethyl)amino]-2-[2-(diethylamino)ethyl]-2H-[1]benzothiopyrano= [4,3,2- cd]indazol-8-ol

5-[(2-am¡noéthyl)amino]-2-[2-(diéthylamino)éthyl]-2H-[1]benzothiopyrano= 4,3,2-cd]indazol-8-ol

5-[(2-aminoetil)amino]-2-[2-(dietilamino)etil]-2H-[1]benzotiopirano= [4,3,2-cd]indazol-8-ol

C21H27N5OS

linezolidum linezolid

linézolide

linezolid

N-[[(S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl]methyl]acetamide

N-[[(5S)-3-[3-fluoro-4-(morpholin-4-yí)phényl]-2-oxooxazolidin-5-yl]méthyl]acétamide

N-[[(S)-3-(3-fluoro-4-morfolinofenil)-2-oxo-5-oxazolidinil]metil]acetamida

C16H20FN3O4

171


lintuzumabum lintuzumab

lintuzumab

lintuzumab

immunoglobulin G 1 (human-mouse monoclonal HuM195γ1 -chain anti-human antigen CD 33), disulfide with human monoclonal HuM195 κ-chain, dimer

immunoglobulineG 1 (chaîne légère γ1 de l'anticorps monoclonal de souris humanisé HuM195 dirigé contre l'antigène CD 33 humain), dimère du disulfure avec la chaîne Κ de l'anticorps monoclonal humain HuM195

inmunoglobulina G 1 (cadena ligera γ1 del anticuerpo monoclonal de ratón humanizado HuM195 dirigido contra el antigeno CD 33 humano), dimero del disulfuro con la cadena Κ del anticuerpo monoclonal humano Hu195

metesindum metesind

métésind

metesind

4-[[α-[(2-aminobenz[cd]|indol-6-yl)methylamino]-p-tolyl]sulfonyl]morpholine

4-[[4-[[(2-aminobenzo[co]indol-6-yl)(méthyl)amino]méthyl]phényl]= sulfonyl]morpholine

4-[[α-[(2-aminobenz[cd](indol-6-il)metilamino]-p-tolil]sulfonil]morfolina

C23H24N4O3S

milfasartanum milfasartan

miIfasartan

milfasartán

methyl 2-[[4-butyl-2-methyl-6-oxo-5-[p-(o-1 H- tetrazol-5-yIphenyl)benzyi]-1 (6H)-pyrimidinyl]methyl]-3-thiophenecarboxylate

2-[[4-butyl-2-méthyl-6-oxo-5-[4-[2-(1H-tétrazol-5-yl)phényl]bénzyl]pynmidin-1 (6H)-yl]méthyl]thiophène-3-carboxylate de méthyle

2-[[4-butil-2-metil-6-oxo-5-[p-(o-1H-tetrazol-5-ilfenil)bencil]-1 (6H)-pirimidinil]metil]-3-tiofenocarboxilato de metilo

C30H30N6O3S

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minalrestatum

minalrestat

minalrestat

minalrestat

(±)-2-(4-bromo-2-fluorobenzyl)-6-fluorospiro[isoquinoline-4(1H),3-pyrrolidine]-1,2',3,5'(2H)-tetrone

(3'RS)-2-(4-bromo-2-fluorobenzyl)-6-fluorospiro[isoquino]éine-4(1H), 3'-pyrrolidine]-1,2',3,5'(2H)-tétrone

(±)-2-(4-bromo-2-fluorobencil)-6-fluoroespiro[isoquinolina-4(1H), 3'-pirrolidin]-1,2',3,5'(2H)-tetrona

C19H11BrF2N2O4


nagrest ipenum

nagrestipen

nagrestipen

nagrestipen

26-L-alaninelymphokine MiP 1 α (human clone pAT464 macrophage inflammatory)

[26-L-alanine]lymphokine MiP 1 a (clone pAT464 de macrophage inflammatoire humain)

[26-L-alanina]linfoquina MiP 1α (clon pAT464 de macrófago inflamatorio humano)

C338H516N88O108S4

nelfinavirum nelfinavir

nelfinavir

nelfinavir

(3S,4aS,βaS)-N-tert-butyl-2-[(2R,3R)-3-(3,2-cresotamido)-2-hydroxy-4-(phenylthio)butyl]decahydro-3-isoquinolinecarboxamíde

{3S,4aS,8aS)-N-(1,1-d¡méthyléthyl)-2-[(2R,3R)-2-hydroxy-3-[(3-hydroxy-2-méthylbenzoyl)amino]-4-(phénylsulfanyl)butyl]décahydroisoquinoléine-3-carboxamide

(3S,4aS,BaS)-N-terc-butil-2-[(2R,3R)-3-(3,2-cresotamido)-2-h¡droxi-4-feniltio)butil]decahidro-3-isoquinolinacarboxamida

173


C32H45N3O4S

nerelimomabum nerelimomab

nérélimomab

nerelimomab

immunoglobulin G 1 (mouse monoclonal BAYX1351 γ1 -chain anti-human tumor necrosis factor a), disulfide with mouse monoclonal BAYX1351 light chain, dimer

immunogiobuline G 1 (chaîne γ1 de l'anticorps monoclonal de souris BAYX1351 dirigé contre le facteur de nécrose tumorale α humain), dimère du disulfure avec la chaîne légère de l'anticorps monoclonal de souris BAYX1351

inmunoglobulina G 1 (cadena ligera mouse monoclonal BAYX1351 γ1-chain anti-human tumor necrosis factor α), disulfide with mouse monoclonal BAYX1351 light chain, dimer

omiloxetinum

omiloxetine

omiloxétine

omiloxetino

4'-fluoro-2-[trans-4-(p-fluorophenyl)-3-[[3,4-(methylenedioxy)= phenoxy]methyl]piperidino]acetophenone

2-[{3RS,4SR)-3-[(1,3-benzodioxol-5-yloxy)méthyl]-4-(4-fluorophényl)= pipéridin-1 -yl]-1 -(4-fluorophényl)éthanone

4'-fluoro-2-[trans-4-(p-fluorofenil)-3-[[3,4-(metilenodioxi)= fenoxi]metil]piperidino]acetofenona

C27H25F2NO4


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opratonii iodidum

opratonium iodide

iodure d'opratonium

ioduro de opratonio

trimethyl[3-(undecenamido}propyl]ammonium iodide

iodure de N,N,N-triméthyl-3-(undéc-10-énoylamino)propan-1-aminiurn

ioduro de trimetil[3-(undecenamido)propil]amonio

C17H35IN2O

oprelvekinum

oprelvekin

oprelvékine

oprelvekina

2-178-interleukin 11 (human clone pXM/IL-11 )

2-178-interleukine 11 (clone humain pXM/IL-11 )

2-178-interleuquina 11 (clon humano pXM/IL-11)

C854H1411N253O235S2

osutidinum

osutidine

osutidine

osutidina

GPPPGPPRVS PDPRASLDST VLLTRSLLAD TRQLAAQLR

KFPADGDHNL DSLPTLAMSA GALGALQLPG VLTRLRADL

SYLRHVQWLR RAGGSSLKTL EPELGTLQAR LDRLLRRLQ

LMSRLALPQP PPDPPAPPLA PPSSAWGGIR AAHAILGGL

LTLDWAVRGL LLLKTRL

(±)-N-[(E)-[(p,β-dihydroxyphenethyl)amino][[2-[[5-[(methylamino)= methyl]furfuryl]thio]ethyl]amino]methylene]methanesulfonamide

(E)-1-[(2RS)-2-hydroxy-2-(4-hydroxyphényl)éthyl]-3-[2-[[[5-[(méthylamino)= méthyl]-2-furyl]méthyl]sulfanyl]éthyl]-2-(méthylsulfonyl)guanidine

(±)-N-[(E)-[(p,β-dihidroxifenetil)amino][[2-[[5-[(metilamino)= metil]furfuril]tio]etil]amino]metileno]metanosulfonamida

C13H28N4O5S2


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pelubiprofenum

pelubiprofen

pélubiprofène

pelubiprofeno

(±)-p-[[(E)-2-oxocyclohexylidene]methyl]hydratropic acid

acide (2RS)-2-[4-[(E)-(2-oxocyclohexylidène)méthyl]phényl]propanoïque

ácido (±)-p-[[(E)-2-oxociclohexiliden]metil]hidratrópico

C16H18O3


pumaprazolum pumaprazole

pumaprazale

pumaprazol

methyl 2-[[(2,3-d¡methylimidazo[1,2-a]pyridin-8-yl)amino]methyl]-3-methylcarbanilate

2-[[(2,3-diméthylimidazo[1,2-a]pyridin-8-yl)amino]méthyl]-3-méthylphényl]carbamate de méthyle

2-[[(2,3-dimetilimidazo[1,2-a]pirídin-8-il)amino]metil]-3-metilcarbanilato de metilo

C19H22N4O2

quilostigminum

quilostigmine

quilostigmine

quilostigmina

(3aS,8aR)-1,2,3,3a,8,8a-hexahydro-1,3a,a-trimethylpyrrolo[2,3-b]indol-5-yl 3,4-dihydro-2(1H)-isoquinolinecarboxylate

3,4-dihydroisoquinoléine-2(1 H)-carboxylate de (3aS,8aR)-1,3a,8-triméthyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yle

3,4-dihidro-2(1 H)-isaquinolinacarboxilato de (3aS,8aR)-1,2,3,3a,8,8a-hexahidro-1,3a,8-(rimetilpirrolo[2,3-D]indol-5-ilo

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retigabinum

retigabine

rétigabine

retigabina

ethyl 2-amino-4-[(p-fluorobenzyl)amino]carbanilate

[2-amino-4-[(4-fluorobenzyl)amino]phényl]carbamate d'éthyIe

2-amino-4-[(p-fluorobencil)amino]carbanilato de etilo

C16H18FN3O2

sabcomelinum

sabcomeline

sabcoméline

sabcomelina

(R)-3-quinuclidineglyoxylonitrile(Z)-(O)-methyloxime

(Z)-2-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-(méthoxyimino)acétonitrile

(R)-3-quinuclidinaglioxilonitrilo(Z)-(O)-metiloxima

C10H15N3O

scopinastum

scopinast

scopinast

escopinast

7-[3-[4-[bis(p-fluorophenyl)hydroxymethyl]piperidino]propoxy]-6-methoxycoumarin

7-[3-[4-[bis(4-fluorophényl)hydroxyméthyl]pipéridin-1-yl]propoxy]-6-méthoxy-2H-chromén-2-one

7-[3-[4-[bis(p-flluorofenil)hidroximetil]piperidino]propox]-6-metoxicumarina

C31H31F2NO5

177


soretolldum

soretolide

sorétolide

soretolida

2,6-dimethyl-N-(5-methyl-3-isoxazolyl)benzamide

2,6-diméthyl-N-(5-méthylisoxazol-3-yl)benzamide

2,6-dimetil-N-(5-metil-3-isoxazolil)benzamida

C13H14N2O2

tasonerminum

tasonermin

tasonermine

tasonermina

1 -157-tumor necrosis factor alfa-1 a (human)

1 -157-facteur de nécrose tumorale humain alfa-1 a

1-157-factor de necrosis tumoral alfa-1a (humano)

C 7 7 8 H 1 2 2 5 N 2 1 5 O 2 3 1 S 2

technetium (99mTc)nofetumomabum merpentanum technetium (99mTc) nofetumomab merpentan

technétium (99mTc) nofétumomab merpentan

tecnecio (99mTc) nofetumomab merpentán

immunoglobulin G 2b (mouse monoclonal NR-LU-10 Fab fragment anti-human tumor), disulfide with mouse monoclonal NR-LU-10 κ-chain, [N,N'-[(2-formylethyl)ethylene]bis[2-mercaptoacetamidato](4-)N,N',S,S']oxo= [99mTc]technetate(1-) conjugate

immunoglobuline G 2b (fragment Fab de l'anticorps monoclonal de souris NR-LU-10 dirigé contre une tumeur humaine), disulfure avec la chaîne Κ de l'anticorps monoclonal de souris NR-LU-10 conjuguée avec l'oxo-[[N,N'-[1-(3-oxopropyl)éthane-1,2-diyl]bis[2-sulfanylacétamidato]](4-)-N,N',S,S']= [99mTc]technétate(1-)

inmunoglobulina G 2b (fragmento Fab del anticuerpo monoclonal de ratón NR-LU-10 dirigido contra un tumor humano), disulfuro con la cadena K del anticuerpo monoclonal de ratón NR-LU-10 conjugado con el oxo-[[N,N'-[1-(3-oxopropil)etano-1,2-diil]bis[2-sulfanilacetamidato]](4-)-N,N',S,S']= [99mTc]tecnetato(1-)

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temiverinum temiverine

témivérine

temiverina

4-(diethylamino)-1,1-dimethyl-2-butynyl(±)-α-phenylcyclohexaneglycolate

(2RS)-2-cyclohexyl-2-hydroxy-2-phénylacétate de 4-(diéthylamino)-1,1-diméthylbut-2-ynyle

(±)-α-fenilciclohexanoglicolato de 4-(dietilamino)-1,1-dimetil-2-butinilo

C24H35NO3


t icolubantum ticolubant

ticolubant

ticolubant

(E)-6-[[(2,6-dichlorophenyl)thio]methyl]-3-(phenethyloxy)-2-pyfidineacrylic acid

acide (E)-3-[6-[[(2,6-dichlorophényl)sulfanyl]méthyl]-3-(2-phényléthoxy)= pyridin-2-yl]prop-2-énoique

ácido (E)-6-[[(2,6-diclorofenil)tio]metil]-3-(fenetiloxi)-2-piridinacrílico

C23H19CI2NO3S

v a l s p o d a r u m valspodar

valspodar

valspodar

cyclo[[(2S,4R,6E)-4-methyl-2-(methylamino)-3-oxo-6-octenoyl]-L-valyl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl]

cyclo[L-alanyl-D-alanyl-N-méthyl-L-leucyl-N-méthyl-L-leucyl-N-méthyl-L-valyl-[(2S,4R,6E)-4-méthyl-2-(méthylamino)-3-oxooct-6-énoyl]-L-valyl-N-méthylglycyl-N-mé(hyl-L-leucyl-L-valyl-N-méthyl-L-leucyl]

ciclo[[(2S,4R,6E)-4-metil-2-(metilamino)-3-oxo-6-octenoil]-L-valil-N-metilgtici]-N-metil-L-leucil-L-valil-N-metil-L-leucil-L-alanil-D-alanil-N-metil-L-leucil-N-metil-L-leucil-N-metil-L-valil]

C63H111N11O12

179


vedaclidinum

vedaclidine (S)-3-[4-(butylthio)-1,2,5-thiadiazol-3-yl]quinuclidine

védaclidine (3S)-3-[4-(butylsulfanyl)-1,2,5-thiadiazol-3-yl]-1-azabicyclo[2.2.2]octane

vedaclidina (S)-3-[4-(butiltio)-1,2,5-tiadiazol-3-il]quinuclidina

C13H21N3S2

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AMENDMENTS TO PREVIOUS LISTS

Recommended International Nonproprietary Names (Rec. INN): List 30

(WHO Drug Information, Vol. 4, No. 3,1990)

p. 13 saruplasum replace the definition by the following:

saruplase prourokinase (enzyme-activating) (human clone pUK4/pUK18), non-

glycosylated


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

p. 6 nasaruplasum replace the definition by the following

nasaruplase prourokinase (enzyme-activating) (human clone pA3/pD2/pF1 protein

moiety), glycosylated


Dénominations communes internationales recommendées(DCI Rec) : Liste 36

Denominaciones Comunes Internacionales recomendadas(DCI Rec.): Lista 36

(WHO Drug Information, Vol. 10, No. 3, 1996)

p.150 levormeloxifenum

levormeloxifene replace the chemical name by the following:

(-)-1-[2-[4-((3R,4R)-7-methoxy-2.2-dimethyl-3-phenyl-4-chromanyl)phenoxy]=

ethyl]pyrrolidine

levormeloxifeno sustituyase el nombre químico por lo siguiente:

(-)-1-[2-[4-[(3R,4R)-7-metoxi-2,2-dimetil-3-fenil-4-cromanil)fenoxi]=

etil]pirrolidina

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MODIFICATIONS APPORTÉES AUX LISTES ANTÉRIEURES

Dénominations communes internationales recommendées (DCI Rec): Liste 30 (Informations pharmaceutiques OMS, Vol. 4, No.3, 1990)

p. 14 saruplasum remplacer la description par: saruplase pro-urokinase (activateur d'enzyme) (fraction protéique issue du clone humain

pUK47/pUK18), non-glycosylée

Dénominations communes internationales recommendées (DCI Rec): Liste 33 (Informations pharmaceutiques OMS, Vol. 7, No.3, 1993)

p 6 nasaruplasum remplacer la description par:

nasaruplase pro-urokinase (activateur d'enzyme) (fraction protéique issue du clone humain

pA3/pD2/pF1), glycosylée

Pour toutes modifications apportées aux Dénominations communes internationales recommendées (DCI Rec): Listes 34-37 voir page 181, séction AMENDMENTS TO PREVIOUS LISTS.

MODIFICACIONES A LAS LISTAS ANTERIORES

Denominaciones Comunes Internacionales Recomendadas (DCI Rec): Lista 30 (información Farmacéutica, OMS, Vol. 4, No. 3, 1990)

p. 13 saruplasum sustituyase la descripción por la siguiente:

saruplasa prouroquinasa (activador de enzima) (fracción proteica procedente del clon

humano pUK4/pUK18), no glucosilada

Denominaciones Comunes Internacionales Recomendadas (DCI Rec): Lista 33 (información Farmacéutica, OMS, Vol. 7, No. 3, 1993)

p 6 nasaruplasum sustituyase la descripción por la siguiente:

nasaruplasa prouroquinasa (activador de enzima) (fracción proteica procedente del clon

humano pA3/pD2/pF1), glucosilada

Para cualquier modificación de las Denominaciones Comunes Internacionales Recomendadas (DCI Rec):

Listas 34-37 vease página 181, sección AMENDMENTS TO PREVIOUS LISTS.

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

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

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

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

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