information · 2 world health organization who drug information vol 20, no. 1, 2006. prudent use of...

W H O DRUG

INFORMATION V O L U M E 20• N U M B E R 1 • 2 0 0 6

R E C O M M E N D E D I N N L I S T 55 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

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WHO Drug Information Vol 20, No. 1, 2006

Contents

World Health Organization

Counterfeit medicinesCombating counterfeit medicines 3Declaration of Rome 4

Biological medicinesSupply of life-saving antisera: a growing

need for concern 5Latest developments in biological

standardization 6Biological substances: International

Standards and reference reagents 7

Safety and Efficacy IssuesSuicidality risk associated with atomoxetine 9Drug interaction between capecitabine

and warfarin 9Fluoroquinolone antibiotics and interaction

with warfarin 9Clozapine: revised safety information 10Hepatitis B reactivation and anti-TNFα

therapy 10Clinical trials of gatifloxacin: shorter

tuberculosis treatment regimen? 11Update on safety of oseltamivir 11Paroxetine: possible risk of teratogenicity 12Safety update on use of promethazine

in children 12Rosiglitazone and diabetic macular oedema 12Topical immunomodulators: carcinogenic

potential? 13Telithromycin: serious liver toxicity 14Deaths with galantamine in mild cognitive

impairment studies 14Fluoroquinolone antibiotics and tendon

disorders 15Ergot derivatives and fibrotic recreations 15Immune globulin: possible intravascular

haemolysis 16Aprotinin injection: renal toxicity and

ischaemic events 16Benzocaine sprays and methaemo-

globinaemia 16Quetiapine and urinary disorders 17

Hydroxyurea and risk of cutaneous vasculitictoxicities 17

Proton pump inhibitors and reducedtestosterone levels 17

Colchicine and toxicity 17Topical corticosteroids and skin damage 18Pegaptanib sodium injection and hyper-

sensitivity reactions 18

Access to MedicinesEuropean Union initiative to evaluate medicines

for developing countries 19Article 58 procedure allows scientific

assistance to non-Member countries 19Production and export of generic medicines

under the TRIPS Agreement 22

Regulatory Action and NewsNew requirements for prescribing information 26Paediatric hepatitis A vaccine approval

extended 26Electronic individual case safety reports:

testing has begun 26First biosimilar medicinal product approval 27Tenecteplase withdrawn for commercial

reasons 27Immune globulin approved for primary

immune deficiency disease 27Cetuximab approved for head and neck

cancer 28Selegiline patch for depression 28Ketamine now a classified drug 28

Recent Publications,Information and EventsThe importance of independent drug bulletins 29Patient-centred healthcare and safety 29Boletìn Farmacos: medicines information for

Spanish readers 30Antiretroviral programmes in low resource

settings 30Developing countries and paediatric drug

information 31

WHO Drug Information

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WHO Drug Information Vol 20, No. 1, 2006World Health Organization

Prudent use of antibiotics 31International Network for Rational Use

of Drugs now online 31Rational medicines management course for

diseases of poverty 31

General InformationRevised WHO treatment recommendations

for malaria 33Quality assurance: latest guidance 34WHO clinical trial registry initiative: update 35

WHO Drug Information

e-mail table of contents

and subscriptions

available at:

http://www.who.int/druginformation

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Recommended InternationalNonproprietary Names: List 55

Contents (continued)

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Combating counterfeit medicines

Strengthening global cooperationthrough IMPACT

Since 1992, the World Health Organization(WHO) has been calling for action against thegrowing epidemic of counterfeit medicines. In abid to accelerate the war on fake drugs, WHO ispushing for stronger global cooperation, politicalcommitment and creative solutions. During aconference it recently organized in Rome, Italy,WHO has called on stakeholders to find globalsolutions to this health threat.

The conference was attended by 160 participantsrepresenting 57 national drug regulatory authori-ties, 7 international organizations, 12 internationalassociations of patients, health professionals,pharmaceutical manufacturers and organizationsincluding the International Narcotics ControlBoard, Organization for Economic Cooperation

and Development, World Customs Organization,International Pharmaceutical Federation, Interna-tional Federation of Pharmaceutical Manufactur-ers and Associations, World Medical Association,International Council of Nurses, and the Interna-tional Federation of Pharmaceutical Wholesalers.

It was constructive in providing a consensus onmany issues. Two major outputs of the eventinvolved the Declaration of Rome (see page 4)and creation of a global task force (IMPACT)based in WHO. The task force will focus oncreating partnerships and improved cooperationamong all major interested parties in the areas oflegislation and law enforcement, trade, riskcommunication and innovative solutions, includingnew technologies for the detection of counterfeitsand technology transfer to developing countries.Further information is available at http://www.who.int/medicines/counterfeit.

Counterfeit Medicines

Counterfeit medicines are part of a broader phenomenon of substandard pharmaceuticals. Theyare deliberately and fraudulently mislabelled with respect to identity and/or source. Counterfeitingcan involve both branded and generic products and may include products with the correct ingredi-ents but fake packaging, with the wrong ingredients, without active ingredients or with insufficientactive ingredients. The regular use of substandard or counterfeit medicines by the population canlead to therapeutic failure or drug resistance; and in some cases it can lead to death.

Until recently, the most frequently counterfeited medicines in wealthy countries were new, expen-sive lifestyle medicines. In developing countries the most counterfeited medicines have been thoseused to treat life-threatening conditions such as malaria, tuberculosis and HIV/AIDS. As the phe-nomenon develops, more and more medicines are counterfeited, including anticancer drugs andthose in high demand such as antivirals. Although it is difficult to obtain precise figures, estimatesput counterfeits at more than 10% of the global medicines market. They are present in all regionsbut developing countries bear the brunt of the problem. An estimated 25% of the medicines con-sumed in developing countries are believed to be counterfeit. In some countries, the figure isthought to be as high as 50%. In industrialized countries, Internet-based sales remain a majorsource of counterfeit medicines and are a threat to those seeking cheaper, stigmatized or unau-thorized treatments.

Where there is a lack of regulation and enforcement, the quality, safety and efficacy of both im-ported and locally manufactured medicines cannot be guaranteed. Trade in counterfeit products ismore prevalent in countries with weak drug regulatory control and enforcement, scarcity and/orerratic supply of basic medicines, unregulated markets and unaffordable prices. However, as coun-terfeiting methods become more sophisticated, counterfeits are found to be increasingly present inbetter-controlled markets.

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WHO International Conference on Combating Counterfeit Medicines

DECLARATION OF ROME1. Counterfeiting medicines, including the entire range of activities from manufacturing to providing

them to patients, is a vile and serious criminal offence that puts human lives at risk and under-mines the credibility of health systems.

2. Because of its direct impact on health, counterfeiting medicines should be combated andpunished accordingly.

3. Combating counterfeit medicines requires the coordinated effort of all the different public andprivate stakeholders that are affected and are competent for addressing the different aspects ofthe problem.

4. Counterfeiting medicines is widespread and has escalated to such an extent that effectivecoordination and cooperation at the international level are necessary for regional and nationalstrategies to be more effective.

5. National, regional and international strategies aimed at combating counterfeit medicines shouldbe based on:

• Political will, adequate legal framework, and implementation commensurate to the impactof this type of counterfeiting on public health and providing the necessary tools for acoordinated and effective law enforcement.

• Intersectoral coordination based on written procedures, clearly defined roles, adequateresources, and effective administrative and operational tools.

• Creating an awareness about the severity of the problem among all stakeholders andproviding information to all levels of the health system and the public.

• Development of technical competence and skills in all required areas.

• Appropriate mechanisms for ensuring vigilance and input from healthcare professionalsand the public.

6. WHO should lead the establishment of an International Medical Products Anti-CounterfeitingTask force (IMPACT) of governmental, nongovernmental and international institutions aimed at:

• Raising awareness among international organizations and other stakeholders at theinternational level in order to improve cooperation in combating counterfeit medicines,taking into account its global dimensions.

• Raising awareness among national authorities and decision-makers and calling foreffective legislative measures in order to combat counterfeit medicines.

• Establishing effective exchange of information and providing assistance on specific issuesthat concern combating counterfeit medicines.

• Developing technical and administrative tools to support the establishment or strengthen-ing of international, regional and national strategies.

• Encouraging coordination among different anti-counterfeiting initiatives.

IMPACT shall function on the basis of existing structures/institutions and will in the long termexplore further mechanisms, including an international convention, for strengthening internationalaction against counterfeit medicines.

Counterfeit Medicines

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Biological Medicines

Supply of life-saving antisera:a growing need for concernAntisera represent the only therapy for thetreatment of envenomation and are essential, incombination with vaccination, for post-exposurerabies treatment. Antisera are produced by thefractionation of plasma obtained from horsesimmunized against the infectious agent or itstoxin. No alternative specific therapeutic treatmentis available to treat these diseases. Now, produc-tion of effective equine-derived antisera indeveloped countries is being halted beforeaffected countries have developed the capacity tomanufacture enough quality products themselves.As a result, the world is now at imminent risk oflacking effective treatment for rabies and enveno-mation due to snake or scorpion bites.

Rabies is the tenth most common cause of deathdue to infections in humans. Although onehundred percent fatal, it is none the less apreventable disease if post-exposure treatmentwith antisera is readily available. An estimated 3to 4 million people would need to receive equinerabies antisera each year after being exposed toanimals suspected of carrying rabies. Almost halfof those requiring the antisera and those dying ofrabies are children less than 15 years of age.More than 99% of all human deaths from rabiesoccur in Africa, Asia and South America. Six to 8million vials of equine rabies antisera is requiredto cover these needs.

There are close to 5 million snake bites each yearin Africa, Asia, and South America; 50 to 75%necessitating treatment by equine antivenoms toavoid deaths, amputation, or severe neurologicaldisorders. Unfortunately, equine antivenoms arelargely unavailable. Over 2.5 millions vials ofantivenoms would be needed to treat envenoma-tion worldwide. Deaths or disability resulting fromthese accidents and diseases could be avoided ifa sufficient supply of antisera of controlled andassessed quality could be ensured, the logisticsof distribution improved, and education on clinicaluse provided.

The shortage of antisera has become a verycritical health issue at global level. Most manufac-turers in the developed world have abandonedproduction due to reduced clinical needs inindustrialized countries. Most remaining produc-ers are located in developing countries, where theapplication of quality and safety standards needsto be improved. The decreasing number ofproducers and the fragility of the productionsystems in developing countries dramaticallyjeopardize the availability of antisera in Asia,Africa, the Middle East, and South America.

In October 2005, the WHO Expert Committee forBiological Standardization (ECBS) recognized theextent of the problem and endorsed, as a priority,the role that WHO must play in supporting andstrengthening world capacity to ensure long-termand sufficient supply of safe antisera. TheInteragency Pharmaceutical Coordination Group,meeting in November 2005, also endorsed WHOaction.

Prequalification of antiseraWHO is proposing to strengthen existing localproduction of antisera by building the technicalcapacity and expertise of regulatory authoritiesand also to develop a prequalification system forthese products that will ensure quality andfacilitate the procurement of antisera productsthrough procurement schemes. The WHO projectwould inherently facilitate transfer of technologiesto developing countries. WHO proposes to takethe following action to guarantee the productioncapacity of antisera and improve the supply ofsafe products:

• Define a global standard for the production,quality control, and regulation of equine-derivedantisera to be used as a guidance by localregulatory authorities and manufacturers.

• Conduct educational workshops at regional levelto help in the implementation of quality andsafety requirements for antisera productionfollowing the principles of good manufacturingpractices (GMP).

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WHO Drug Information Vol 20, No. 1, 2006Biological Medicines

• Train regulators, pharmaceutical inspectors andlocal manufacturers on the critical parameters ofthe production of antisera and GMP implemen-tation.

• Facilitate transfer of technology to developingcountries.

• In the framework of the WHO prequalificationproject, initiate prequalification of antiseraproducers.

References

1. Burnouf, Th., Griffiths, E., Padilla, A. et al. Assess-ment of the viral safety of antivenoms fractionated fromequine plasma. Biologicals, 32: 115–128 (2004).

2. Theakston, R.D., Warrell, D.A,, Griffiths, E. Report ofWHO workshop on the standardization and control ofantivenoms. Toxicon, 41(5): 541–557 (2003).

3. European Medicines Agency. Note for Guidance onProduction and Quality Control of AnimalImmunoglobulins and Immunosera for Human Use.EMEA (2002).

4. Chippaux, J. P. Snake-bites: appraisal of the globalsituation. WHO Bulletin, 76(5): 515–524 (1998).

5. World Health Organization. http://www.who.int/biologicals

Latest developments inbiological standardizationWHO’s biological standardization programmeprovides, promotes and implements global normsand standards for biological medicines, andstrives to provide the most relevant products forthe improvement of global health.

The WHO Expert Committee on BiologicalStandardization (ECBS) was set up to develop,establish and promote technical standards toassure the quality, safety and efficacy of vaccines,biological therapeutics, blood products andselected in vitro diagnostic devices (IVDs). This isone of the longest standing WHO Committeesand has been operating since 1947. Among itsactivities, the WHO biological reference prepara-tions are important tools that allow the compara-bility of data worldwide in diverse fields of medicalpractice.

The latest meeting of the ECBS was convened inGeneva from 24 to 28 October 2005. Expertswere invited from Belgium, Brazil, France,

Germany, Japan, Russian Federation, UnitedKingdom, and United States of America. Otherparticipants and observers represented theCouncil of Europe, European Department for theQuality of Medicines, France; European Pharma-copoeia Commission, France; DevelopingCountry Vaccine Manufacturer’s Network, SerumInstitute of India; European Diagnostic Manufac-turers Association, Germany; Eye Bank Associa-tion of America, USA; International Association ofBiologicals, Switzerland; International Federationof Clinical Chemistry and Laboratory Medicine,Canada; International Federation of Pharmaceuti-cal Manufacturers Associations, Switzerland;GlaxoSmithKline Biologicals, Belgium; Interna-tional Society of Blood Transfusion/EuropeanPlasma Fractionation Association, Netherlands;International Society on Thrombosis and Hae-mostasis, United Kingdom; Plasma ProteinTherapeutics Association, Belgium; and theUnited States Pharmacopeia.

Current issues of regulatory concernThe means for preventing and controlling mostchronic diseases are well established, and includebiotechnological interventions. The number ofapproved innovative biotherapeutic products isexpected to increase substantially over thecoming years (e.g. some 500 monoclonal anti-body-based products are currently in the pipelinein the European Union and USA alone). Inaddition, the imminent patent expiration of manybiotechnology products will result in a substantialincrease in “follow-on” or “biosimiliar” products

WHO is receiving requests from countries foradvice on appropriate regulatory oversight forbiological therapeutics, since the potential forsuccess of therapeutic biological products used intreatment of a wide variety of chronic diseases isbeing tempered by concerns over quality, safetyand availability of such products. Inappropriateassay methods or poor potency determinationscan lead to life or death clinical problems; andadverse drug reactions — for example, unwantedantibody development in some individuals —could occur with a variety of products. Increasedrisks of infections have been seen with blockersof tumour necrosis factor α and the potential forsubstandard and counterfeit biotech productsrepresents an important matter of concern.

The Committee proposed that WHO shouldorganize a meeting of interested parties to reviewthese issues in depth and help WHO developconsensus on the global needs, priorities andpotential role for global standardization in the area

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of biotherapeutics for the major chronic diseases.The Committee also recommended that WHOshould facilitate the strengthening of technicalcapacity in national regulatory authorities forbiological therapeutics and also collate informa-tion on substandard or counterfeit biologicalmedicines for chronic diseases.

Documents that were considered and approvedby the Committee during its meeting included:

• Guidelines For Assuring The Quality AndNonclinical Safety Evaluation Of DNA Vaccines.

• Recommendations For Inactivated RabiesVaccine for Human Use Produced In CellSubstrates And Embryonated Eggs.

• Guidelines to assure the quality, safety andefficacy of live attenuated rotavirus vaccines(oral).

• Recommendations for the production. controland regulation of human plasma forfractionation.

• WHO biosafety risk assessment and guidelinesfor the production and quality control of humaninfluenza pandemic vaccines.

• Recommendations for whole cell pertussisVaccine.

• Biological Substances: International Standardsand reference reagents.

• Recommendations and guidelines for biologicalsubstances used in medicine and other docu-ments.

Reference: World Health Organization. http://www.who.int/biologicals


Biological substances: International standards and reference reagents

Preparation Activity Status

Antigens and related substances

Haemophilus influenza type b 4.933 ± 0.267 mg/ampoule of First International Standardcapsular polysaccharide polyribosyl ribitol phosphate

(PRP)

Blood products and related substances

Prothrombin Mutation No assigned activity First International GeneticG20210A Reference Panel

Folate in human serum 12.1 nmol/l of folate per ampoule First International Standard

Vitamin B12 in human serum 480 pg/mL of vitamin B12 Second Internationalper ampoule Standard

Coagulation factor V, plasma, 0.74 International Units of First Internationalhuman Factor V:C per ampoule Standard

Coagulation factor XI, plasma, 0.86 International Units First Internationalhuman per ampoule Standard

Thromboplastin, rabbit, plain International Sensitivity Index Third International(ISI) value of 1.15 Standard

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Antisera

Anti-dengue virus types 1,2, 3 100 units per serotype First WHO referenceand 4 serum per ampoule reagent

Anti-Human platelet antigen-1a 100 International Units First International Standardper ampoule

Anti-A blood grouping minimum No assigned activity; however First International Standardpotency reagent a 1 in 8 dilution should define the

recommended minimum potencyspecification for anti-A bloodgrouping reagents

Anti-B blood grouping minimum No assigned activity; however a First International Standardpotency reagent 1 in 4 dilution should define the

recommended minimum potencyspecification for anti-B bloodgrouping reagents

Cytokines, growth factors and endocrinological substances

Vascular endothelial growth 13000 units per ampoule First WHO referencefactor, human reagent

Keratinocyte growth factor, 4000 units per ampoule First WHO referencehuman reagent

Karatinocyte growth factor, 9000 units per ampoule First WHO reference(24–163), human reagent

Diagnostic reagents

HIV–1 RNA 5.56log10 International Second InternationalUnits per vial Standard

These substances are held and distributed by the International Laboratory for Biological Stand-ards, National Institute for Biological Standards and Control, Potters Bar, Herts., EN6 3QG,England.


Preparation Activity Status

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Safety and Efficacy Issues

Suicidality risk associatedwith atomoxetine

Singapore — Atomoxetine (Strattera®) a nor-epinephrine re-uptake inhibitor, is licensed for thetreatment of attention deficit hyperactivity disorderin children 6 years of age and older, in adoles-cents and adults. It was registered in Singapore inApril 2005.

The manufacturer has alerted healthcare profes-sionals to an increased risk of suicidal thinking inchildren and adolescents associated with the useof atomoxetine. This new finding emerges as partof a larger evaluation of psychiatric drugs andsuicidality following the US Food and DrugAdministration’s request to manufacturers toconduct a review of their database and clinicaltrials.

Physicians are advised to carefully monitorpatients on atomoxetine for possible clinicalworsening, as well as agitation, irritability, suicidalthinking or behaviours, and unusual changes inbehaviour, especially during the initial few monthsof therapy or when the dose is increased ordecreased. Patients, their families and caregiversshould be informed of this risk.

Reference: Health Sciences Agency, Product SafetyAlert, 12 December 2005 on http://www.hsa.gov.sg/cda/safetyalerts

Drug interaction betweencapecitabine and warfarin

Singapore — Capecitabine (Xeloda®) is acytostatic agent indicated for metastatic breastcancer when used as an adjunct to docetaxel,and for metastatic colorectal cancer. The co-administration of capecitabine and warfarin maypredispose a patient to an increased risk ofbleeding. The probable mechanism for theinteraction is the down-regulation of CYP 2C9isoenzyme by which warfarin is principallymetabolised (1).

Postmarketing reports have revealed clinicallysignificant increases in prothrombin time (PT) andthe international normalized ratio (INR) in patients

who were stabilized on anticoagulants whencapecitabine therapy was initiated. These eventsoccurred within several days to several monthsafter concurrent therapy (1).

Patients being prescribed warfarin and capecitab-ine concurrently should be closely and regularlymonitored for alterations in the PT or INR; thedose of warfarin should be retitrated if necessary.

References

1. Klasco RK (Ed): DRUGDEX® System (electronicversion). Thomson Micromedex, Greenwood Village,Colorado, USA. Available at: http://www.thomsonhc.com(cited: 09/06/2005).

2. Product Info Xeloda®, 15/06/2005.

3. Health Sciences Agency, Product Safety Informationon http://www.hsa.gov.sg/cda/safetyalerts

Fluoroquinolone antibioticsand interaction with warfarin

Australia — The potential interaction betweenwarfarin and fluoroquinolones (ciprofloxacin,norfloxacin, moxifloxacin, gatifloxacin) wasreported in a 1993 review (1). The AustralianAdverse Drug Reactions Committee (ADRAC)has received 20 reports of this interaction,implicating ciprofloxacin (9 reports), norfloxacin(11) and moxifloxacin (1). One of the reportsinvolves both ciprofloxacin and norfloxacin. Asyet, no reports have been received with gati-floxacin, which has had little use.

Health Canada has reported 57 cases of thisinteraction up to January 2004 (2). Gatifloxacinwas also implicated in the Canadian series. In 16of the 57 cases the patient was hospitalized andfour patients aged 70–90 years with complexmedical conditions died.

Although significant pharmacokinetic interactionshave not been demonstrated in interactionstudies, the product information for each of thefluoroquinolones and for warfarin warn that anincreased effect of warfarin is possible, and thatthe INR should be closely monitored when a

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WHO Drug Information Vol 20, No. 1, 2006Safety and Efficacy Issues

fluoroquinolone and warfarin are administeredconcomitantly.

Possible mechanisms of this interaction includedecreased warfarin cytochrome P450-mediatedmetabolism, and reduction in gut flora thatproduce vitamin K.

ADRAC advises health professionals to considerthe possibility of this interaction and monitor theINR when fluoroquinolones and warfarin are usedconcomitantly.

Extracted from Australian Adverse Drug Reac-tions Bulletin, Volume 25, Number 1, February2006.

References

1. Marchbanks, C.R. Drug-drug interactions withfluoroquinolones. Pharmacotherapy, 1993;13: 23S–28S.

2. Morawiecka, I. Fluoroquinolones and warfarin:suspected interactions. Canadian Adv ReactionNewsletter, 2004;14: 1–2.

Clozapine: revised monitoringfrequency

United States of America — After reviewingrecommendations provided by the Psycho-pharmacological Drugs Advisory Committee(PDAC) of June 2003 regarding the white bloodcell monitoring schedule required for all clozapineusers, the Food and Drug Administration (FDA)concluded that the current monitoring scheduleshould be modified. The changes to monitoringfrequency have resulted in revisions to the boxedwarning concerning.

• The absolute neutrophil count (ANC) to bedetermined and reported along with each WBCcount.

• New parameters for initiation of clozapinetreatment.

• Initiation of monthly monitoring schedule afterone year (six months weekly, six months everytwo weeks) of WBC counts and ANCs in thenormal range (WBC t 3500/mm3 and ANC t2000/mm3).

• Addition of cautionary language to prescribersdescribing the increased risk of agranulocytosisin patients who are rechallenged with clozapine

following recovery from an initial episode ofmoderate leukopenia(3000/mm3 > WBC t 2000/mm3 and/or 1500/mm3 >ANC t 1000/mm3).After recovering from such an episode, thesepatients are now required to undergo weeklymonitoring for 12 months if they are re-chal-lenged.

References

1. Revised prescribing information is available at http://www.clozaril.com/index.jsp.

2. http://www.fda.gov/medwatch.

Hepatitis B reactivationand anti-TNFααααα products

Canada — The manufacturers of anti-TNFαproducts, in consultation with Health Canada,have updated safety information regarding anti-TNFα therapy. There are three such productsauthorized for sale in Canada, and a summary ofthese products and their general indicationsfollows:

INN Indication(s)

etanercept Rheumatoid arthritisJuvenile rheumatoid arthritisPsoriatic arthritisAnchylosing spondylitisChronic plaque psoriasis

adalimumab Rheumatoid arthritis

infliximab Rheumatoid arthritisCrohn diseaseAnchylosing spondylitis

Hepatitis B virus (HBV) reactivation has beenreported very rarely in patients with chronichepatitis B infection receiving anti-TNFα agents.

Patients at risk should be evaluated for priorevidence of HBV infection before initiating anti-TNFα therapy. Those identified as chronic HBVcarriers (i.e. surface antigen positive) should bemonitored for signs and symptoms of active HBVinfection throughout the course of therapy and forseveral months following discontinuation. Reacti-vation of HBV is not unique to anti-TNFα agentsand has been reported with other immunosup-pressive drugs.

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WHO Drug Information Vol 20, No. 1, 2006 Safety and Efficacy Issues

Very rare cases of HBV reactivation associatedwith anti-TNFa therapy have been reportedcumulatively, with one report originating fromCanada. Clinically-active HBV infections occurredfollowing a latency period ranging from 3 weeks to20 months after initiation of therapy. In themajority of cases, patients were also beingtreated with other immunosuppressive drugs,including methotrexate, azathioprine, and/orcorticosteroids. Hence, establishing a directcausal relationship to anti-TNFa agents is con-founded by the presence of these other medica-tions.

Where outcome information was provided, mostpatients were reported to have improved afterantiviral treatment and/or discontinuation of theanti-TNFα agent. However, fatal outcomes havealso occurred in reported cases.

Reference: Health Canada alert, 13 January 2006 athttp://www.hc-sc

Clinical trials of gatifloxacin: shortertuberculosis treatment regimen?

World Health Organization — Clinical results ona new combination treatment that could dramati-cally shorten the length of tuberculosis (TB)treatment were recently presented at the 45thAnnual Interscience Conference on AntimicrobialAgents and Chemotherapy, in Washington, D.C.

The phase II trial results of a gatifloxacin-contain-ing regimen have demonstrated good potential.The regimen is significantly more potent than thecurrently recommended six-month regimen ofisoniazid, rifampicin, pyrazinamide and ethambu-tol, and suggests that when gatifloxacin is usedinstead of ethambutol, the standard six-monthregimen may be shortened to four months. This isthe most advanced shorter TB treatment regimenpresently in development, and could be availableto the public by the end of 2009 if positive resultscontinue.

The phase II trial was conducted by the SouthAfrican Medical Research Council in patients withnewly diagnosed pulmonary tuberculosis with andwithout HIV co-infection. It was designed tomeasure the anti-tuberculosis activity of thetreatment in the first two months of therapy whencompared to standard WHO recommendedtreatment and two other similar regimens whichcontained either ofloxacin or moxifloxacin.

Treatment with either the gatifloxacin or moxi-floxacin containing regimen was shown to besignificantly more active than either the standardregimen or the ofloxacin containing regimen aftertwo months of treatment. A multicentre Phase IIIclinical trial is planned to definitely assesswhether the four-month gatifloxacin containingregimen is equivalent to the current standard six-month short course regimen. Study sites are inBenin, Guinea, Kenya, Senegal and South Africa.The clinical trial sites are the result of an ECfunded Consortium of ten European and Africaninstitutions (OFLOTUB) that are in the process offinalizing the terms of a proposed collaborationwith WHO to develop a new short-course treat-ment regimen.

Research is planned to continue as part of aninternational collaboration which is being devel-oped between the World Health Organization-based Special Programme for Research andTraining in Tropical Diseases (TDR), the Euro-pean Commission (EU), the OFLOTUB Consor-tium that is coordinated by the French Institut deRecherche pour le Développement (IRD), andLupin Pharmaceuticals Ltd.

Reference: WHO Special Programme for Research andTraining in Tropical Diseases (TDR). WHO PressRelease, 16 December 2005. http://www.who.int

Update on safety of oseltamivir

European Union — A potential influenza pan-demic remains currently of high public interestand the European Medicines Agency (EMEA) hasprovided the following update on oseltamivir(Tamiflu®).

Oseltamivir is an antiviral approved in the Euro-pean Union for the treatment of influenza inchildren between 1 and 13 years ofage and for the prevention and treatment ofinfluenza in adolescents over 13 years and adults.Two cases of alleged suicide associated withtreatment of influenza (involving a 17-year-old boyin February 2004 and a 14-year-old boy inFebruary 2005) were reported to EMEA. In bothcases the adolescents exhibited abnormal/disturbed behaviour which led to their deaths. Sofar, no causal relationship has been identifiedbetween the use of oseltamivir and psychiatricsymptoms (such as hallucination and abnormalbehaviour). EMEA stresses that the assessmentof psychiatric events during oseltamivir treatmentis difficult because:

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• Other medicines are often taken at the sametime as oseltamivir.

• Patients with influenza and a high fever canshow psychiatric symptoms. This is particularlyrelevant for children and elderly patients.

All adverse reactions are monitored and assessedby the Committee for Medicinal Products forHuman Use (CHMP) on a continuous basis.The CHMP, at its meeting of 14–17 November2005, decided to request the Marketing Authoriza-tion Holder of Tamiflu® to provide a cumulativesafety review of all available data on seriouspsychiatric disorders, including all case reportswith a fatal outcome where oseltamivir wasinvolved. The EMEA will make a statement on theoutcome

Reference: Press release. EMEA/385013/2005.London, 17 November 2005 http://www.emea.eu.int

Paroxetine: possible riskof teratogenicity

Singapore — The manufacturer of paroxetinehas notified healthcare professionals of prelimi-nary findings of a retrospective epidemiologicalstudy which showed a 2-fold increase in the riskof congenital malformations in infants born tomothers who took paroxetine during the firsttrimester compared to other antidepressants.Paroxetine (Seroxat®) is indicated for the treat-ment of depression, obsessive-compulsivedisorder, panic disorder, social anxiety disorder,generalized anxiety disorder and post-traumaticstress disorder. Seroxat CR® is approved for thetreatment of major depressive disorder. Thecompany has updated the package inserts of bothSeroxat® and Seroxat CR® to reflect this riskunder the Pregnancy subsection.

Physicians are advised to carefully weigh thepotential risks and benefits of using paroxetinetherapy in women during pregnancy and todiscuss the risks and benefits as well as treat-ment alternatives with their patients. Paroxetineshould be used during pregnancy only if thepotential benefit outweighs the possible risk to thefoetus.

References

1. HSA Product Safety Alert, 12 December 2005. http://www.hsa.gov.sg/cda/safetyalerts

2. GSK Clinical Trial Register; http://ctr.gsk.co.uk/Summary/paroxetine/epip083.pdf

3. Ministry of Health, Singapore. MOH Clinical PracticeGuidelines 3/2004: Depression. http://www.moh.gov.sg

Restrictions on useof promethazine in children

Singapore — The Health Sciences Authority(HSA) and its Pharmacovigilance AdvisoryCommittee (PVAC) have recently reviewed thesafety profile of promethazine in children followingaction taken by the US Food and Drug Adminis-tration (FDA) to contraindicate the use of promet-hazine hydrochloride preparations (e.g.Phenergan®) in children younger than 2 yearsold.

From a review of the risks versus benefits ofpromethazine, it was concluded that the risk ofserious adverse drug reactions outweighs thepotential benefits of the drug in young children. Toreflect this safety concern, HSA is currentlyworking with pharmaceutical companies toinclude the following information in the affectedpackage inserts/patient information leaflets:

• Promethazine is contraindicated in children lessthan 6 months old;

• It is not recommended for use in children lessthan 2 years old;

• Caution should be exercised when used inchildren 2 years of age and older.

Although there have been no local reports of fatalADRs associated with promethazine, HSA isaware of cases of apnoea occurring in very youngchildren. In view of the unpredictable nature of theadverse events and their serious outcomes,healthcare professionals should exercise cautionwhen prescribing promethazine to young children.

Reference: HSA Product Safety Alert. 12 December2005 http://www.hsa.gov.sg/cda/safetyalerts

Rosiglitazone and diabeticmacular oedema

United States of America — The Food and DrugAdministration (FDA) and the manufacturer ofproducts containing rosiglitazone (Avandia®,Avandamet®, and Avandaryl™) have received

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very rare postmarketing reports of new onset andworsening diabetic macular oedema. In themajority of these cases, the patients also reportedconcurrent peripheral oedema. In some cases,the macular oedema resolved or improvedfollowing discontinuation of therapy and in onecase resolved after dose reduction.

Macular oedema typically occurs in associationwith diabetic retinopathy, although it is morelikely to occur as retinopathy progresses. Riskfactors for macular oedema include duration ofdiabetes, presence of retinopathy, hypertension,and poor glycaemic control. Symptomssuggestive of macular oedema include blurred ordistorted vision, decreased colour sensitivity,and decreased dark adaptation.

Reference: Communication from GlaxoSmithKlineavailable at: http://www.fda.gov/medwatch. December2005.

Topical immunomodulators :carcinogenic potential?

Singapore — Pimecrolimus cream (Elidel®) andtacrolimus ointment (Protopic®) are topicalimmunomodulators granted local marketingapproval in January 2003 and March 2004respectively.

Elidel® (1%) is licensed for short-term andintermittent long-term treatment of mild to moder-ate atopic dermatitis in non-immunocompromisedpatients who are 2 years and older in whom theuse of alternative, conventional therapies isdeemed inadvisable because of potential risks, orin the treatment of patients who are not ad-equately responsive to or intolerant of conven-tional therapies.

Protopic® (0.1%; 0.03%) is licensed for thetreatment of moderate to severe atopic dermatitisin adults (0.1%) and children aged 2 years andabove (0.03%) who are not adequately respon-sive to or are intolerant of conventional therapies.

Topical immunomodulators are increasingly beingused in the US as first-line therapy in atopicdermatitis because they are perceived to be saferthan steroid preparations. This perception byphysicians and patients has been attributed toaggressive promotion of the drugs in the USmarket.

Prompted by concern over the increasing use ofthese products especially in very young children

and findings of carcinogenicity in some of theanimal studies as well as postmarketing reports ofmalignancies, the US Food and Drug Administra-tion (FDA) issued a public advisory in March2005.

HSA’s assessmentThe HSA Pharmacovigilance Advisory Committee(PVAC) have reviewed the following safetyinformation.

(i) Animal studiesCarcinogenicity findings were not uniformlydetected in all animal studies. Although someanimal studies revealed no carcinogenic potential,others demonstrated some signals. For studieswith positive findings, the data showed that therisk of cancer increased with increasing dose andduration of treatment. It was noted that in generalthe doses used in these animal studies werehigher than the maximum recommended humandose (MRHD). For example, lymphoma formationin mice was reported with dermal application oftacrolimus and pimecrolimus dissolved in ethanol,at 26 times and 47 times MRHD, respectively.

(ii) Postmarketing reportsAs of December 2004, the US FDA reported thatit received 10 and 20 cases of postmarketingreports of malignancy-related events (e.g.lymphoma) with pimecrolimus and tacrolimus,respectively. For many of these cases, thecausality could not be established due to thepresence of other confounding factors. To-date,HSA has not received any reports of malignancyassociated with pimecrolimus or tacrolimus.

RecommendationsHSA and its PVAC advise physicians to weigh therisks and benefits of the drugs for individualpatients and to take into consideration thefollowing:

• Pimecrolimus and tacrolimus are approved forshort-term and intermittent treatment of atopicdermatitis in patients unresponsive to, orintolerant of other treatments

• They are not approved for use in childrenyounger than 2 years old. The long term effectof these drugs on the developing immunesystem is not known

• They should not be used continuously for aprolonged period of time as their long-termsafety has yet to be determined.

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• Patients who are immunocompromised shouldnot be prescribed pimecrolimus or tacrolimus.

References

1. FDA Paediatric Advisory Committee Meeting. http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4089b2.htm

2. FDA Talk Paper on Elidel® and Protopic®. http://www.fda.gov/bbs/topics/ANSWERS/2005/ANS01343.html

3. HSA Product Safety Alert. 12 December 2005.http://www.hsa.gov.sg/cda/safetyalerts

Telithromycin: serious liver toxicity

United States of America — An article reportingthree patients who experienced serious livertoxicity following administration of telithromycin(Ketek®) has recently been published. The caseshave also been reported to the Food and DrugAdministration (FDA).

FDA is continuing its investigation of this issue,and is providing the following recommendations tohealthcare providers and patients:

• Healthcare providers should monitor patientstaking telithromycin for signs or symptoms ofliver problems. Telithromycin should be stoppedin patients who develop signs or symptoms ofliver problems.

• Patients who have been prescribed telithromycinand are not experiencing side effects such asjaundice should continue taking their medicineas prescribed unless otherwise directed by theirhealthcare provider.

• Patients who notice any yellowing of their eyesor skin or other problems like blurry visionshould contact their healthcare provider immedi-ately.

• As with all antibiotics, telithromycin should onlybe used for infections caused by a susceptiblemicroorganism. Telithromycin is not effective intreating viral infections, so a patient with a viralinfection should not receive telithromycin sincethey would be exposed to the risk of side effectswithout any benefit.

A case review of the reports shows seriousadverse events following administration oftelithromycin. All three patients developedjaundice and abnormal liver function. One patient

recovered, one required a transplant, and onedied. When the livers of the latter two patientswere examined in the laboratory, they showedmassive tissue death. These two patients hadreported some alcohol use. All three patients hadpreviously been healthy and were not using otherprescription drugs. The FDA is also aware thatthese patients were all treated by physicians inthe same geographic area. The significance ofthis observation is not clear at the present time.

In pre-marketing clinical studies, including a largesafety trial and data from other countries, theoccurrence of liver problems was infrequent andusually reversible. Based on the pre-marketingclinical data, it appeared that the risk of liver injurywith telithromycin was similar to that of othermarketed antibiotics. Nonetheless, the productlabel advises doctors about the potential for liver-related adverse events associated with the use oftelithromycin.

Telithromycin is an antibiotic of the ketolide class.It was the first antibiotic of this class to be ap-proved by the FDA in April, 2004 for the treatmentof respiratory infections in adults caused byseveral types of susceptible microorganismsincluding Streptococcus pneumoniae andHaemophilus influenzae.

Reference.

1. FDA Public Health Advisory. 20 January 2006. http://www.fda.gov/medwatch/

2. Clay, K.D., Hanson, J.S., Pope, S.D. Brief communi-cation: severe hepatotoxicity of telithromycim: threecase reports and literature review. Annals of InternalMedicine (on-line edition), January 20, 2006, http://www.acponline.org

Deaths with galantamine in mildcognitive impairment studies

Australia — Galantamine (Reminyl®), donepezil(Aricept®) and rivastigmine (Exelon®) areapproved for the treatment of mild to moderatelysevere Alzheimer dementia. Cardiac arrhythmiaswith these cholinesterase inhibitors have beenreported (1).

Galantamine has also been investigated inpatients with mild cognitive impairment, anindication which is not approved in Australia. Intwo placebo controlled trials, there was a highermortality with galantamine than placebo, andgalantamine was not effective (2). The deaths

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were due to various causes which could beexpected in an elderly population.

The precautions’ section of the Australian ProductInformation for Reminyl® has been updated,along with further advice to use with caution inpatients with cardiovascular and pulmonaryconditions, particularly immediately after myocar-dial infarction and with new onset atrial fibrillation,second or third degree heart block, unstableangina and pneumonia.

It is recommended that galantamine should onlybe used for the approved indication of mild tomoderately severe Alzheimer dementia. Thesafety and efficacy in other indications have notbeen established and the risks may outweighbenefits.

Extracted from the Australian Adverse DrugReactions Bulletin, Volume 25, Number 1,February 2006.

References

1. Australian Adverse Drug Reactions Committee(ADRAC). Cholinesterase Inhibitors and CardiacArrhythmias. Australian Adverse Drug ReactionsBulletin, 2004; 23:5.

2. http://www. clinicalstudyresults.org/drugdetails/

Fluoroquinolone antibioticsand tendon disorders

Australia — Since the beginning of 2005, theAustralian Adverse Drug Reactions Committee(ADRAC) has received 16 cases of tendondisorders, predominantly Achilles tendinitis.Eleven of these cases have involved thefluoroquinolones ciprofloxacin, norfloxacin, andgatifloxacin.

ADRAC reminds prescribers that there is anincreased risk of tendinitis or even tendon rupturewith all fluoroquinolones (1). Of the 213 cases oftendinitis or tendon rupture reported to ADRAC,over 80% have involved fluoroquinolones. Inaddition to fluoroquinolone use, increasing ageand concomitant corticosteroid use are estab-lished risk factors.

Patients should be advised to be alert for pain ordiscomfort in the Achilles tendon or calf and toinform their doctors and cease taking the medi-cine if this occurs.


Reference

1. Australian Adverse Drug Reactions Committee(ADRAC). Fluoroquinolones and tendon disorders.Australian Adverse Drug Reactions Bulletin, 2002; 21:15

Ergot derivativesand fibrotic reactions

Australia — Ergot derivatives are now the mostcommonly used dopamine agonists in the treat-ment of Parkinson disease in Australia.

Important potential adverse reactions associatedwith ergot derivatives such as cabergoline,bromocriptine and pergolide are fibrotic complica-tions, including pericarditis and retroperitoneal orpleural fibrosis. From marketing in 1997 toDecember 2005, the Australian Adverse DrugReactions Committee (ADRAC) has received 86reports of suspected adverse reactions in asso-ciation with cabergoline. Of these, 15 havedescribed pleural or pulmonary fibrosis/effusion orpneumonitis. Time to onset varied but apart fromone report which indicated a few days, the onsettime was from 1 month to over 3 years.

Most of the reports described either pleuralfibrosis or pleural effusion or both and this wasdemonstrated by biopsy or chest X-ray in overhalf of the cases. Eight of the patients hadrecovered, two were improving but the remainingfive had not recovered at the time the report wassubmitted.

As cabergoline has a long half-life (65 hours),recovery may be slow or the fibrotic changes mayprogress after drug withdrawal (1).

There have been no reports of fibrotic complica-tions in association with low-dose cabergoline(Dostinex®) for the treatment of lactation suppres-sion and hyperprolactinaemia. All ergot deriva-tives can induce fibrotic changes.

Prescribers should be aware of the possibility offibrotic changes associated with long-termadministration of ergot derivatives such ascabergoline, bromocriptine and pergolide, andshould instruct the patient to report dyspnoea orcough.

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Reference

1. Frans E, Dom R, Demedts M. Pleuropulmonarychanges during treatment of Parkinson’s disease with along-acting ergot derivative, cabergoline. Eur Respir J1992; 5: 263-265.

Immune globulin: possibleintravascular haemolysis

United States of America — The Food and DrugAdministration (FDA) has requested the manufac-turer of an immune globulin product (WinRho®SDF) to address two safety concerns and alertpatients to the early signs and symptoms ofintravascular haemolysis. Symptoms include backpain, shaking chills, fever, discoloured urine,decreased urine output, sudden weight gain, fluidretention/oedema, and/or shortness of breath.Rare, but severe and sometimes fatal, intravascu-lar haemolysis and its potentially serious compli-cations, including disseminated intravascularcoagulation have been observed. Analysis ofthese events indicates that the aetiology iscomplex and the potential associations are notclearly understood.

Important safety information on potentialinterference with blood glucose.Healthcare professionals are also alerted to thepotential for falsely elevated glucose readingswhen using certain blood glucose testing systemsthat are not glucose-specific in patients who havereceived maltose-containing parenteral products.

Reference: Communication from Cangene Corporation,Baxter Healthcare Corporation on https://www.accessdata.fda.gov/scripts/medwatch/

Aprotinin injection: renal toxicityand ischaemic events

United States of America — Recently publishedarticles (1, 2) have associated aprotinin injectionwith serious renal toxicity and ischaemic events(myocardial infarction and stroke) in patientsundergoing coronary artery bypass graftingsurgery (CABG) or undergoing cardiac surgerywith cardiopulmonary bypass. The Food and DrugAdministration (FDA) is evaluating these studiesto determine if labelling changes or other actionsare warranted.

In the meantime, the following recommendationshave been issued to healthcare providers andpatients:

Physicians who use aprotinin injection shouldcarefully monitor patients for the occurrence oftoxicity, particularly to the kidneys, heart, orcentral nervous system and promptly reportadverse event information.

Physicians should consider limiting aprotinininjection use to those situations where the clinicalbenefit of reduced blood loss is essential tomedical management of the patient and out-weighs the potential risks.

Reference: FDA Public Health Advisory, 26 January2006. http://www.fda.go

Benzocaine sprays andmethaemoglobinaemia

United States of America — Benzocaine spraysare used in medical practice for locally numbingmucous membranes of the mouth and throat forminor surgical procedures or when a tube mustbe inserted into the stomach or airways. Theiruse is known to be occasionally associated withmethemoglobinemia. On February 8, 2006, theVeterans Health Administration (VA) announcedthe decision to stop using benzocaine sprays forthese purposes.

The Food and Drug Administration (FDA) is awareof the reported adverse events and is reviewingall available safety data, but at this time is notplanning action to remove the drugs from themarket. Up until now, the FDA has concluded thatthe number of reported adverse events with thesesprays has been low and, when properly used,these products can help make important proce-dures less uncomfortable for patients.

Benzocaine sprays used in the mouth and throatcan result in potentially dangerous levels ofmethemoglobinemia. Patients who have breathingproblems such as asthma, bronchitis, or emphy-sema, patients with heart disease, and patientswho smoke are at greater risk for complicationsrelated to methemoglobinemia and may becandidates for other forms of therapy.

Patients who may have greater tendency forelevated levels of methemoglobinemia, such asall children less than 4 months of age and olderpatients with certain inborn defects (such as

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glucose-6-phosphodiesterase deficiency, haemo-globin-M disease, NADH-methaemoglobinreductase (diaphorase 1) deficiency, and pyru-vate-kinase deficiency may benefit from productswith different active ingredients such as lidocaine.

Patients who receive benzocaine sprays shouldbe given the minimum amount needed, to reducethe risks associated with methemoglobinemia.Patients who receive benzocaine sprays shouldbe carefully observed for signs of methaemoglobi-naemia including pale, gray or blue coloured skin,headache, light-headedness, shortness of breath,anxiety, fatigue and tachycardia.

Reference: FDA Public Health Advisory. 10 February2006. http://www.fda.gov

Quetiapine and urinary disorders

Netherlands — Four reports of urinary retentionand three reports of urinary incontinence associ-ated with the use of quetiapine were received bythe Pharmacovigilance Centre, Lareb, prior to midJune 2005. The time to urinary incontinence onsetranged from four weeks to four months, the timeto urinary retention onset ranged from three daysto six months, and most patients recovered fromthe disorders. According to Lareb, urinary inconti-nence and urinary retention were disproportion-ately associated with the use of quetiapine inreports in both the WHO and Lareb databases.

Reference: Lareb, August 2005. http://www.lareb.nl

Hydroxyurea and risk ofcutaneous vasculitic toxicities

Canada — Postmarketing case reports ofcutaneous vasculitic toxicities, including vasculiticulcerations and gangrene, have been receivedconcerning patients with myeloproliferativedisorders during therapy with hydroxyurea(Hydrea®). In response, Health Canada isrevising the product monograph to include thefollowing statements:

Cutaneous vasculitic toxicities, including vasculiticulcerations and gangrene, have occurred inpatients with myeloproliferative disorders duringtherapy with hydroxyurea. These vasculitictoxicities were reported most often in patients witha history of, or currently receiving, interferontherapy. Hydroxyurea should be discontinued ifcutaneous vasculitic ulcerations develop andalternative cytoreductive agents should beinitiated as indicated.

To minimize the risk of exposure, imperviousgloves should be worn. This includes handlingactivities in clinical settings, pharmacies, store-rooms, and home healthcare settings, includingduring unpacking and inspections, transport withina facility, and dose preparation and administra-tion.

Reference: Bristol-Myers Squibb Canada 1 March2006. http://www.hc-sc.ca

Proton pump inhibitors andreduced testosterone levels

Netherlands — Prior to 30 June 2005, thePharmacovigilance Centre, Lareb, received 28reports of gynaecomastia associated with the useof proton pump inhibitors (PPIs), includingomeprazole, lansoprazole, pantoprazole,esomeprazole and rabeprazole; in most reportsthere was a latency period of several weeks tomonths from start of treatment, and all reportswere in men. In addition, Lareb has also receivedseveral reports of impotence, erectile dysfunctionand decreased libido that may also be associatedwith reduced testosterone levels. According toLareb, most of the gynaecomastia reports wereassociated with the use of omeprazole, andaccording to reports in the WHO database therewas also a disproportionate association withgynaecomastia and the use of PPIs, suggestingthat gynaecomastia may be a class effect.

Reference: Internet document. Lareb, August 2005.http://www.lareb.nl

Colchicine and toxicity

New Zealand — The Medicines and MedicalDevices Safety Authority, Medsafe, has revisedthe dosage advice for colchicine following reportsof dose-related serious adverse effects. Thisadvice coincides with the introduction of acolchicine 0.5 mg tablet (Colgout®).

Medsafe also advises that:

• colchicine is now limited to second-line treat-ment for acute gout, when nonsteroidal anti-inflammatory drugs (NSAIDs) are contraindi-cated, lack efficacy or have unacceptableadverse drug effects;

• the dosing interval has increased from two-threehourly to six hourly, the maximum daily colchi-cine dose is 2.5 mg in the first 24 hours and the

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maximum cumulative dose should not exceed 6mg over four days;

• other treatments should be considered in elderlypatients and, if using colchicine, prescribersshould observe a maximum cumulative dose of3 mg over four days;

• colchicine is contraindicated in severe renal orhepatic impairment, and concomitant renal andhepatic disease, and doses should be reducedin patients with less severe impairment or whoweigh < 50 kg;

• at least three days must elapse betweencolchicine courses.

Patients should be warned that the initial symp-toms of colchicine-associated toxicity includenausea, vomiting and diarrhoea, and usuallyoccur approximately 12 hours after ingestion; iftoxicity does occur, patients should discontinuecolchicine immediately and seek medical advice.

Reference: Prescriber Update, 26(2), December 2005.http://www.medsafe.govt.nz

Topical corticosteroidsand skin damage

New Zealand — The Centre for Adverse Reac-tions Monitoring has received 14 reports of facialskin damage associated with the use of potenttopical corticosteroids. The reports includedtelangiectasia, abnormal pigmentation, rosacea,perioral dermatitis, skin atrophy and striae, andwere primarily associated with mometasone

(Elocon®), although all topical corticosteroidsused on the face carry a risk of facial skin dam-age. Prescribers and patients are reminded thatthe use of topical corticosteroids on the faceshould not exceed two weeks and prescribers areadvised to give clear instructions to patients aboutwhere, and how often to apply the medication.

Reference: Prescriber Update, 26(2), December 2005.http://www.medsafe.govt.nz

Pegaptanib sodium injection andhypersensitivity reactions

Canada — Health Canada has issued safetyinformation for pegaptanib sodium injection(Macugen®), following postmarketing reports ofhypersensitivity reactions including anaphylaxis/anaphylactoid reactions. Ophthalmologists shouldbe aware of the potential for hypersensitivityreactions and should monitor their patientsaccordingly. Appropriate procedures should befollowed to treat anaphylaxis/anaphylactoidreactions if necessary.

Macugen® is indicated for the treatment ofsubfoveal choroidal neovascularization secondaryto age-related macular degeneration, and isadministered once every six weeks by intravitre-ous injection. Since the aseptic injection prepara-tion procedure consists of various components(e.g., anaesthesia, broad-spectrum microbicide,or possibly latex gloves), a direct relationship hasnot been established .

Reference: http://www.hc-sc.ca and http://www.pfizer.ca

Spontaneous monitoring systems are useful in detecting signals of relatively rare, serious and unex-pected adverse drug reactions. A signal is defined as "reported information on a possible causal rela-tionship between an adverse event and a drug, the relationship being unknown or incompletely docu-mented previously. Usually, more than a single report is required to generate a signal, depending uponthe seriousness of the event and the quality of the information". All signals must be validated before anyregulatory decision can be made.

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Access to Medicines

Article 58 procedure allows scientificassistance to non-Member countries

Many developing countries with limited regulatorycapacity rely on prior assessment of a medicinalproduct by a developed country as an indicator formarketing suitability. However, many productsneeded by developing countries may have no mar-keting authorization in a developed country. Thismay happen for those diseases that have no, orlow, prevalence in developed countries and whichare not economically viable. In an effort to facilitateaccess to these often life-saving medicines, the Eu-ropean Commission included in its proposal forRegulation (EC) No 726/2004 (1) an article estab-lishing a mechanism whereby:

“The Agency [EMEA ] may give a scientific opin-ion, in the context of cooperation with the WorldHealth Organization, for the evaluation of cer-tain medicinal products for human use intendedexclusively for markets outside the Community.For this purpose, an application shall be sub-mitted to the Agency in accordance with the pro-visions of Article 6. The Committee for Medici-nal Products for Human Use [CHMP] may, afterconsulting the World Health Organization, drawup a scientific opinion in accordance with Arti-cles 6 to 9. The provisions of Article 10 [Com-mission Decision granting a marketing authori-zation] shall not apply”.

This mechanism is now formalized as Article 58 ofRegulation (EC) No 726/2004, which was adoptedon 31 March 2004. Part of the Regulation,including Article 58, entered into force on 20 May

The European Medicines Agency (EMEA) is a decentralized body of the European Union located inLondon, United Kingdom. Its main responsibility is the protection and promotion of public and ani-mal health through the evaluation and supervision of medicines for human and veterinary use.EMEA coordinates the evaluation and supervision of medicinal products throughout the EuropeanUnion and brings together the scientific resources of Member States of the European EconomicArea (EEA) in a network of 42 national competent authorities. A network of some 3500 Europeanexperts supports the scientific work of EMEA and its committees. EMEA cooperates closely withinternational partners, reinforcing the EU contribution to global harmonization.

EMEA began activities in 1995, when the European system for authorizing medicinal products wasintroduced, providing for a centralized and mutual recognition procedure. EMEA is primarily in-volved in the centralized procedure. Where this procedure is used, companies submit one singlemarketing authorization application to EMEA. A single evaluation is carried out through the Com-mittee for Medicinal Products for Human Use (CHMP) or the Committee for Medicinal Products forVeterinary Use (CVMP). If the relevant Committee concludes that quality, safety and efficacy of themedicinal product is sufficiently proven, it adopts a positive opinion. This is sent to the Commissionto be transformed into a single market authorization valid for the whole of the European Union.

The Committee for Medicinal Products for Human Use (CHMP) is a scientific body that is part ofEMEA and consists of representatives from all the EU Member States plus Iceland, Liechtensteinand Norway. The CHMP meets monthly and is responsible for drawing up the opinion of EMEA onany matter concerning the admissibility of the files submitted in accordance with the centralizedprocedure, the granting, variation, suspension or revocation of an authorization to place a medici-nal product for human use on the market, and pharmacovigilance.

European Union initiative to evaluatemedicines for developing countries

Article prepared by Dr Antoon Gijsens, Pre-Authoriza-tion Unit of Medicines for Human Use, EuropeanMedicines Agency (EMEA), London.

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WHO Drug Information Vol 20, No. 1, 2006Access to Medicines

2004. Article 58 thus responds to the need toprotect public health and to give scientific assist-ance to non-member countries in the context ofcooperation with WHO, whilst at the same timeallowing rapid access to those countries forimportant medicinal products.

For the implementation of Article 58, the EMEAdeveloped, in cooperation with WHO, a procedure(2) with the objective of delivering a CHMPscientific opinion of equal standing to theopinions provided for medicinal products intendedto be marketed in the EU. In order to achieve thisobjective, the procedure mirrors the EU central-ized evaluation procedure in line with the legisla-tion.

Eligibility for the procedureIn order to have access to the Article 58 proce-dure, eligibility of the medicinal product needs tobe confirmed. After having consulted WHO,EMEA will inform the applicant whether theproduct is eligible. To be eligible, the medicinalproduct for human use intended exclusively formarkets outside the Community should beintended to prevent or treat diseases of majorpublic health interest. A non-exhaustive list ofsuch products includes

• vaccines used, or of possible use, in the WHOExpanded Programme on Immunization (EPI);

• vaccines for protection against a WHO publichealth priority disease;

• vaccines that are part of a WHO managedstockpile for emergency response; and

• medicinal products for WHO target diseasessuch as HIV/AIDS, malaria, tuberculosis,lymphatic filariasis (elephantiasis), trachoma,leishmaniasis, schistosomiasis, African trypano-somiasis (sleeping sickness), onchocerciasis(river blindness), dengue fever, Chagas dis-ease, leprosy.

Scientific adviceWhen developing a medicinal product, pharma-ceutical companies are often confronted withcritical choices on how to demonstrate the quality,safety and efficacy of the product. In order toconfirm whether CHMP agrees with certainapproaches in the development of a medicinalproduct, applicants are encouraged to apply forscientific advice, whether it is in the initial devel-opment, before an application for a CHMP

scientific opinion or in the post-opinion phase. Inthe request for scientific advice, applicants canask questions or seek CHMP agreement withregard to quality, safety or efficacy related aspectsin the development of their medicinal product. Thescientific advice procedure is the result of theinput of coordinators preparing assessmentreports, experts and the different CHMP WorkingParties providing comments, the Scientific AdviceWorking Group where the assessment reportsand comments are discussed and a commonposition is adopted and forwarded to CHMP forformal adoption. The standard scientific adviceprocedure takes 70 days.

Application for a CHMP scientific opinionThe evaluation procedure for applications for aCHMP scientific opinion mirrors the procedure forapplications for a medicinal product intended tobe marketed in the EU. The same data require-ments and evaluation standards will be adheredto, taking into account possible adjustments asappropriate (e.g. stability). The evaluation proce-dure will be an EMEA/WHO partnership, withinput from WHO experts as needed. In addition,observers from WHO and observers from authori-ties of developing countries (recommended byWHO) may attend CHMP plenary discussions onproducts under the CHMP scientific opinionprocedure in cooperation with WHO. All expertsand observers involved will be bound by theEMEA rules on public declaration of interest andconfidentiality undertaking.

Where CHMP considers it necessary in order tocomplete its evaluation of the application, CHMPmay require the applicant to undergo a goodmanufacturing practices (GMP), good clinicalpractices (GCP) or good laboratory practices(GLP) inspection with regard to the medicinalproduct concerned.

A CHMP scientific opinion is given within 210days, excluding clock stops during which theapplicant prepares the responses to questionsadopted by CHMP. Taking account of the fullscientific debate within CHMP and the conclu-sions reached, the final assessment report isprepared, which, once adopted by CHMP,becomes the CHMP assessment report and isappended to the CHMP scientific opinion. TheCHMP assessment report contains the conclu-sions on the quality, safety and efficacy of themedicinal product and will take into accountappropriate benefit/risk scenarios on the popula-tions and conditions of use as documented withinclinical data supplied by the applicant.

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WHO Drug Information Vol 20, No. 1, 2006 Access to Medicines

The CHMP assessment report of the medicinalproduct and the reasons for the favourable CHMPscientific opinion will be made available on theEMEA website (http://www.emea.eu.int), afterconsulting the applicant on deletion of anyinformation of a commercially confidential nature.This document is called the European PublicAssessment Report (EPAR) on a scientific opinionin cooperation with WHO.

CertificationBefore issuing a marketing authorization to amedicinal product, some countries require acertificate that the product has a valid marketingauthorization in a country or region with recog-nised regulatory capacity. The current WHOCertification Scheme (http://who.int/medicines)accommodates the issuing of Certificates of aMedicinal Product (CMPs) for products havingreceived a positive CHMP scientific opinion incooperation with WHO. EMEA will issue theseCMPs upon request from the Opinion Holder, inthe same way as it does for medicinal productsthat have a marketing authorisation in the EU.

CHMP scientific opinions reflecting thecurrent status of the medicinal productCountries relying on CMPs as part of theirprocess to issue a marketing authorization,rightfully expect that the CMPs are based onCHMP Opinions that truly reflect the currentstatus of the medicinal product. Therefore, theOpinion Holder shall be held responsible toupdate the CHMP scientific opinion through post-opinion follow-up, variations and extensionapplications, before implementing any changes, inanalogy to medicinal products authorized in theEuropean Union. Updates to the CHMP scientificopinion will be reflected in updates to the EPAR.

PharmacovigilanceTogether with the countries where productsevaluated via this procedure have received amarketing authorization, the EMEA endeavours toreview any new relevant data to ensure continuedsafe and effective use.

Therefore, the Opinion Holder will have to ensurethat all serious adverse reactions to a medicinalproduct are recorded and reported promptly to the

competent authorities of the countries where theproduct is marketed and to the EMEA.In addition, detailed records of all suspectedadverse reactions will have to be submitted forevaluation to the EMEA, immediately uponrequest or periodically in the form of a periodicsafety update report. Any other informationrelevant to the evaluation of the risks and benefitsof a medicinal product should also be submitted,particularly information concerning post-authoriza-tion safety studies.

CHMP can perform a benefit/risk review at anytime. In some cases and taking into account thepharmacovigilance reporting received, CHMPcan, after having consulted WHO, revise itsopinion based on the reassessment of the benefit/risk profile of the product. Such revisions will bereflected in updates to the EPAR.The EMEA will collaborate with WHO and mayexchange any information related to the pharma-covigilance of medicinal products evaluated underthis procedure.

Recognition of CHMP scientific opinionsin cooperation with WHOTo inform drug regulatory authorities worldwide,this article will be complemented with presenta-tions at international fora such as the InternationalConference of Drug Regulatory Authorities(ICDRA) and the Drug Information Association(DIA). The websites of EMEA and WHO will alsofeature Questions & Answers sections, address-ing frequent questions from both pharmaceuticalindustry and drug regulatory authorities world-wide.

References

1. Regulation (EC) No 726/2004 of the EuropeanParliament and of the Council of 31 March 2004 layingdown Community procedures for the authorisation andsupervision of medicinal products for human andveterinary use and establishing a European MedicinesAgency, OJ L 136, 30.4.2004, p. 1-33.

2. Guideline on procedural aspects regarding a CHMPscientific opinion in the context of cooperation with theWorld Health Organization (WHO) for the evaluation ofmedicinal products intended exclusively for marketsoutside the Community (EMEA/CHMP/5579/04). http://www.emea.eu.int/pdfs/human/regaffair/557904en.pdf

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At the WTO Ministerial Conference in Doha, November 2001, WTO Members adopted the Minis-terial Declaration on the TRIPS Agreement and Public Health (the Doha Declaration). The DohaDeclaration confirmed, amongst others, the right of WTO Members to use safeguard measures,such as compulsory licensing and parallel imports, to protect public health and promote access tomedicines.

However, WTO Members failed to resolve a key issue at Doha: how countries which have insuffi-cient or no manufacturing capacity in the pharmaceutical sector can effectively exercise the right touse compulsory licensing? The TRIPS Agreement permits the grant of compulsory licences forlocal production of generic versions of patented medicines in the interest of facilitating access toaffordable medicines. But countries with insufficient or no manufacturing capacity cannot takeadvantage of this measure.

One option for these countries is to grant a compulsory licence to enable the import of genericmedicines produced by foreign manufacturers. The problem is that where generic versions ofpatented drugs are produced under a compulsory licence, the TRIPS Agreement (Article 31f) re-quires that such production shall be predominantly for the supply of the domestic market. This hasraised concerns that exporting countries may have difficulties exporting sufficient quantities tomeet the needs of those countries with insufficient or no manufacturing capacity. The Doha Decla-ration highlighted this problem in Paragraph 6 and WTO Members were instructed to find an expe-ditious solution.

On 30 August 2003, the WTO General Council established, as an interim measure, a system topermit the export of pharmaceutical products manufactured under compulsory licence. This sys-tem was finally adopted on 6 December 2005 as an amendment (subject to ratification) to theTRIPS Agreement.

Production and export of generic medicinesunder the TRIPS Agreement

Can the system work?Whilst the proposed amendment has been hailedby some as an important breakthrough in thedebate on patents and access to medicines, thisoptimism may be a little premature. No countryhas yet to make use of the system even though itwas adopted in 2003. Since the final 2005amendment will essentially incorporate the samesystem (and the same conditions), the workabilityof the system remains to be proven.

The system permits countries wishing to importgeneric medicines to do so from a foreign pro-ducer. Whilst least-developed countries areautomatically eligible, developing countries haveto establish either that they have no manufactur-ing capacity or the current capacity is insufficientto meet their needs. Countries make the determi-nation themselves; and the WHO guide onimplementing the Decision observes that this is amatter of self-assessment that is not challenge-able by other Members. The system requires theimporting country to notify the TRIPS Council.Where the needed medicine is patent protected in

the importing country, the government will have togrant a compulsory licence for the import of thegeneric version of the medicine. Where no patentis in force, the importing country has to providenotification of its intention to use the system.

Whilst much has been made about the amend-ment allowing least-developed countries to importgeneric medicines, the most significant aspect ofthe system is the ability of generic-producingcountries to export generic medicines without thequantitative restrictions. The generic manufac-turer has to obtain a compulsory licence toproduce and export, which will only permit theproduction and export of the quantity required bythe importing country. The compulsory licence willalso require the manufacturer to make theproducts clearly identifiable through labelling ormarking, and notify the TRIPS Council of thequantities supplied to the importing countries andthe distinguishing features of product. But willgeneric manufacturers be willing and able toproduce and export the needed medicines underthe system?

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How to make it workIn order to ensure that countries can makeeffective use of the system adopted in thedecision on Paragraph 6 and the amendment, itwill be important for national laws to be reviewedand amended where necessary, in order to putthe system into effect. A list of required changesto national laws is set out on page 24. Theworkability of the system will depend, in largepart, on how the demand-and-supply chain canbe linked up. On the demand side, importingcountries must be able to indicate their needs.Procurement agencies in these countries must beable to forecast and quantify needed medicines,so that this information can be notified to theTRIPS Council.

This notification will be the trigger for necessarymeasures to be taken on the supply side. Withoutthis indication of demand, it is difficult to see howgeneric manufacturers will be moved to offer theirproducts for export. In Canada, India and China— where national legislation has been amendedto permit the production and export of genericmedicines under compulsory licence — the lawgenerally requires some indication from animporting country of its intention to permit theimport of products manufactured under compul-sory licences, before the compulsory licence maybe granted.

Pooled procurementGeneric manufacturers will have to respond bymaking the necessary applications for compulsorylicences. They will have to evaluate the economicfeasibility of applying for a compulsory licence. Ithas been said that the system is a “drug-by-drug,

country-by-country, case-by-case system”, so thatmanufacturers will be forced to produce limitedquantities under each compulsory licence.However, it should be possible for a number ofthe purchasing countries to coordinate theirorders in order for the manufacturers to use asingle compulsory licence for production andexport to more than one country. This method ofpooled procurement should be explored in orderto take advantage of the significant cost and otherefficiency savings that can accrue. But it requiresa degree of cooperation between participants andshared purchasing needs.

Exporting country governments will have torespond by enabling the granting of compulsorylicences for production and export by their genericmanufacturers. This may involve amendments topatent legislation. The initiative taken by Canada,India and most recently, by China, to provide forthe granting of compulsory licences under thesystem is welcome; given that the concentrationof generic manufacturers is in these countries.Governments should demonstrate their good faithby enacting simple and speedy procedures for thegranting of compulsory licences without unneces-sary requirements that may delay the grant of thelicences, or restrictions on the types of pharma-ceutical products or diseases.

Importing country governments may have totake the necessary first step by notifying theirintention to use the system. Where the product ispatent protected in the importing country, acompulsory licence or government use authoriza-tion will be required. Where no patent exists, orwhere a least-developed country has opted not togrant or enforce pharmaceutical patents until

Access to Medicines

TRIPS AmendmentTheTRIPS Amendment agreed on 6 December 2005 essentially converts the interim system adoptedon 30 August 2003 into a new Article of the TRIPS Agreement —Article 31bis. It is agreed that thisamendment will come into force when it is ratified by two-thirds of WTO Members by 1 December2007. It can be expected that the amendment will come into force on or before this date.

The first component of the system is the lifting of the requirement that pharmaceutical productsmanufactured under a compulsory licence shall be “predominantly for the supply of the domesticmarket”. The second is elimination of the need to pay remuneration to the patent holder in theimporting country if remuneration has already been paid to the patent holder in the exporting country.This prevents double remuneration to the patent holder.

Other components of the system include: definition of products covered under the system; criteria foreligibility of Members to import or export; measures to prevent re-exportation (or anti-diversion meas-ures); and requirements to notify the WTO when use is made of the system. WHO has published aguide on how to implement the system.

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Changes required in national laws for effective implementation of the system

1. National laws should allow export of pharmaceutical products produced under compulsorylicence to another country, for example, by explicitly stating that the supply of an export market isa possible ground for a compulsory licence.

2. To be able to make the best use of the system as an importer, national laws should explicitlypermit compulsory licences for import and also include specific provisions for government use orpublic, non-commercial use of patents.

3. Where a compulsory licence is granted to enable import of pharmaceutical products producedabroad under the system, payment of remuneration or royalties to the patent holder should bewaived, i.e. payment of remuneration or royalties is waived in the importing country.

4. In granting a compulsory licence, prior negotiations for a voluntary license with the patentholder may be required. If so, a defined time limit, preferably short, should be set for such nego-tiations so that where the negotiations are unsuccessful within that period of time the issuing of acompulsory licence can proceed).

5. Where a compulsory licence is granted on grounds of national emergency, other circumstancesof extreme urgency, public non-commercial use/government use, or to remedy anticompetitivebehaviour, the requirement for prior negotiation with the patent holder may be waived.

6. A compulsory licence may be granted for the lifetime of the patent.

7. There should be a definition of “pharmaceutical products” for which the system be used, andthis definition should be a broad one. Countries should consider explicitly including diagnostics,vaccines and medical devices used for treatment, within the definition.

8. National laws should not limit the implementation of the Decision to a restricted list of productsor diseases;

9. Least-developed countries may wish to make necessary changes to their legislation in order tomake use of Paragraph 7 of the Doha Declaration, which allows them to defer the implementationand enforcement of pharmaceutical patents until at least 2016.

10. Any litigation or appeal by the patent holder should not suspend the implementation of acompulsory license (CL).

2016, a notification to the TRIPS Council ofintention to use the system would be sufficient.

What may also be needed is an intermediary tolink up the various actors in the demand andsupply chain. In this regard, the United Nationsagencies such as WHO, UNAIDS and UNICEF,and the Global Fund for the Fight Against AIDS,TB and Malaria may have an important role toplay. These agencies are well-placed to assistcountries in forecasting demand for medicines,identifying the potential suppliers of qualityassured medicines and have as part of theirmandate the public health objective of access tomedicines.

Making it happenIt is now time for governments and internationalorganizations to make a concerted effort to

implement the system. There are several goodreasons to put the system to the test.

One reason for not using the Paragraph 6Decision was that developing countries did nothave sufficient assurance that the interim waiversystem was “permanent” enough. Where changesto national law were required, governments werereluctant to take such action if more changesseemed imminent. With an amendment that issubstantially the same as the Paragraph 6Decision, this should no longer be a concern.

Secondly, the post–2005 environment shouldprovide another impetus for countries to test thesystem. As all new medicines come under therequirement for the 20-year patent protection in allbut the least-developed countries, genericsuppliers, including those in India, will not be able

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to reproduce patented medicines, without compul-sory licensing. This is already the case of medi-cines such as second-line HIV treatments.

Global efforts, such as WHO’s 3 by 5 Strategymay have helped to put more people on treat-ment, but it has also increased the need — asresistance inevitably develops — for a switch tosecond-line or third-line treatments. The genericcompetition that resulted in the price plunge forfirst-line antiretrovirals (ARV) does not yet existfor the second-line medicines. Current prices ofthe typical second-line treatments can be 6 to 12times higher than those of the older first-linemedicines. Governments and internationalorganizations will have to develop alternativestrategies to ensure the future sustainability ofARV treatment, particularly in low-income coun-tries. Compulsory licensing to permit imports (andlocal production) of generic second-line ARVs isan obvious option to introduce market competitionand reduce prices.

Third, the seemingly imminent avian flu pandemicdemonstrates that it is neither easy nor possibleto predict the future need for medicines, or thequantities in which they may be required. In theevent of another public health emergency orpandemic, countries will want to ensure theirability to obtain the necessary treatments insufficient quantities, at affordable prices. Theglobal debate about access to oseltamivir and theability of countries to fill national stockpiles haveraised questions about the need to ensuremultiple suppliers to guarantee availability andaffordability.

The amendment proposing this solution isexpected to come into force 1 December 2007.WTO Members have set this deadline to have theamendment ratified by the required two-thirds ofthe membership. It would appear that this systemwill be the permanent solution to the Paragraph 6problem. WTO Members have been congratu-

Access to Medicines

lated for their unprecedented decision to amendthe TRIPS Agreement, which demonstrates theirwillingness and flexibility to take concrete steps toimprove intellectual property rules to ensure theprimacy of health.

References

1. World Health Organization. Implementation of theWTO General Council Decision on Paragraph 6 of theDoha Declaration on the TRIPS Agreement and PublicHealth (2004). Health Economics and Drugs. EDMSeries No. 16.

2. Médicins Sans Frontières. Untangling the web ofprice reductions: A pricing guide for the purchase ofARVs for developing countries. (2005) http://www.accessmed-msf.org/index.asp

3. Sources and prices of selected medicines anddiagnostics for people living with HIV/AIDS at: http://www.who.int/medicines/

4. World Health Organization. Implementation of theWTO General Council Decision on Paragraph 6 of theDoha Declaration on the TRIPS Agreement and PublicHealth, at: http://www.who.int/medicines/

5. World Health Organization. Statement on the TRIPSAmendment for the WTO Ministerial Conference inHong Kong, 13–18 December 2005 at: http://www.who.int/medicines/areas/policy/WHO_Statement_Hong_Kong.pdf

6. Will the TRIPS Amendment on compulsory licensingwork? Bridges Monthly Review, 10(1): 22 (2006) at:http://www.ictsd.org

7. World Health Organization. Determining the patentstaus of essential medicines in developing countries.(2004). Health Economics and Drugs. EDM Series No.17

8. World Health Organization. Remuneration guidelinesfor non-voluntary use of a patent on medical technolo-gies. (2005). Health Economics and Drugs. EDM SeriesNo. 18

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Regulatory Action and News

New requirements forprescribing information

United States of America — The Food and DrugAdministration (FDA) is issuing final regulationsamending the content and format of prescribinginformation for human drug and biological prod-ucts. The final rule revises the current regulationsto require that the prescribing information of newand recently approved products includes high-lights of the prescribing information and a table ofcontents for the full prescribing information.Requirements on the Content and Format ofLabelling for Human Prescription Drug andBiological Products, come into effect on 30 June2006.

The goal is to provide more informative andaccessible prescribing information, resulting in abetter risk communication and management tool.These revisions will make it easier for healthcareprofessionals to access, read, and use prescrib-ing information, and will enhance the safe andeffective use of prescription drug products.

Reference: FDA News, P06-08. 18 January 2006. http://www.fda.gov/cder/regulatory/physLabel/default.htm

Paediatric hepatitis A vaccineapproval extended

United States of America — The Food and DrugAdministration (FDA) has approved an applicationto allow use of the paediatric/adolescent formula-tion of hepatitis A vaccine, inactivated (Havrix®)for persons 1—18 years of age. Previously,paediatric use of hepatitis A vaccine was ap-proved for use in persons aged 2—18 years.

The formulation, dosage, and schedule for Havrixhave not been changed. Each 0.5-mL dose ofpaediatric/adolescent the vaccine contains 720enzyme-linked immunosorbent assay units offormalin-inactivated hepatitis A viral antigenadsorbed onto aluminium hydroxide. The formula-tion contains 0.5% 2–phenoxyethanol as apreservative.

The primary vaccination schedule is unchangedand consists of 2 doses, administered on a 0, 6—12–month schedule. Hepatitis A vaccine iscontraindicated in persons with known hypersen-sitivity to any component of the vaccine.

References

1. Notice to Readers: FDA Approval of Havrix (HepatitisA Vaccine, Inactivated) for Persons Aged 1-18. MMWR:posted on line 12/22/2005

2. CDC. Prevention of hepatitis A through active orpassive immunization: recommendations of the AdvisoryCommittee on Immunization Practices (ACIP). Morbidityand Mortality Weekly Report, No. 48, (RR-12) 1999.

Electronic individual case safetyreports: testing has begun

United Kingdom — The Medicines andHealthcare Products Regulatory Agency (MHRA)is preparing the introduction of mandatoryelectronic transmission of an individual casesafety report (ICSR) between marketing authori-zation holders (MAHs) and the MHRA.

All MAHs will be required to successfully testelectronic transmission with the MHRA prior toswitching from paper to electronic reporting.Testing will be conducted within a dedicatedtesting environment at the MHRA. Paper reportingof real reports in fulfilment of reporting obligationsshould continue in parallel during the testingperiod. Once testing has been completed to thesatisfaction of the MHRA and the MAH, paperreporting can stop and electronic reporting of realreports can begin. It is not intended to have atransition period of parallel paper and electronicreporting of real reports.

If an MAH has already successfully testedelectronic reporting with the EMEA Eudra-Vigilance system or intends to submit reports viathe EMEA EVWEB tool, then it is envisaged that atruncated testing process can be followed.Registering requests should be sent [email protected]

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WHO Drug Information Vol 20, No. 1, 2006 Regulatory Action and News

Until testing is completed, paper reporting shouldcontinue in line with reporting obligations.

Reference: http://www.mhra.gov.uk

First biosimilar medicinalproduct approval

European Union — The European MedicinesAgency (EMEA) has adopted the first positiveopinion for a similar biological medicinal product.The product, Omnitrope®, contains somatropin, arecombinant-DNA growth hormone. It is intendedfor the treatment of growth disturbance andgrowth hormone deficiency in children and adults.

EMEA’s scientific committee, the Committee forMedicinal Products for Human Use (CHMP)considered that, in accordance with EuropeanUnion requirements, Omnitrope® has beenshown by studies demonstrating comparablequality, safety and efficacy to be similar to areference medicinal product already authorized inthe EU, namely Genotropin®.

The European Commission and EuropeanMedicines Agency have worked actively over anumber of years to put in place a legal andregulatory framework for similar biologicalmedicinal products. The first guidelines on quality,nonclinical and clinical issues were adopted bythe CHMP in December 2003. A general regula-tory guideline on similar biological medicinalproducts was adopted in September 2005.Further guidelines, including guidance on specificclasses of products, are planned for adoptionduring the first quarter of 2006. A conference washeld in Paris in December 2005 as part of thepublic consultation process.

Reference: European Medicines Agency adopts firstpositive opinion for a similar biological medicinalproduct. EMEA/31797/2006. Press release, 27 January2006 http://www.emea.eu.int

Tenecteplase withdrawn forcommercial reasons

European Union — Tenecteplase is not mar-keted anywhere in the European Union. On 28June 2005, the manufacturer notified the Euro-pean Commission of its decision to withdraw theCommunity Marketing Authorization forTenecteplase Boehringer Ingelheim Pharma KG®for commercial reasons. There is still one Com-

munity Marketing Authorization valid throughoutthe European Union for medicinal productscontaining tenecteplase, namely Metalyse®.

On 9 August 2005, the European Commissionissued a decision to withdraw the MarketingAuthorization for Tenecteplase BoehringerIngelheim Pharma KG®. Consequently, theEuropean Public Assessment Report has beenremoved from the EMEA website.

Reference: European Medicines Agency. Publicstatement on tenecteplase Noehringer IngelheimPharma. Withdrawal of the marketing authorization inthe European Union. CHMP/343408/2005. London, 1December 2005. http://www.emea.eu.int

Immune globulin approved forprimary immune deficiency disease

United States of America — The Food and DrugAdministration has approved the first immuneglobulin product for subcutaneous injection for theprevention of serious infections in patients withprimary immune deficiency diseases (PIDD).Vivaglobin®, manufactured from human plasmacollected at US licensed plasma centres, providesnew delivery options for PIDD patients. It is givenunder the skin (subcutaneously) on a weeklybasis using an infusion pump, which meanspatients can self-administer the product at home.Some patients develop problems that makechronic intravenous administration of neededmedicines difficult.

PIDD are inherited disorders that affect anestimated 50 000 people in the United States.These patients require regular treatment withimmune globulin in order to fight off or preventpotentially serious or life-threatening infections.Other immune globulin products are administeredeither intravenously or intramuscularly. In clinicalstudies, the most common side effect is mild ormoderate injection site reaction such as swelling,redness and itching.

As for all immune globulin preparations, plasma istested and found to be nonreactive for HIV andhepatitis viruses prior to its use, and the manufac-turing process includes steps that further reducethe risk of transmission of viruses.

Reference. FDA Approves First Immune Globulin forSubcutaneous Use.. FDA Talk Paper, P06-03, 9 January2006. http://www.fda.gov

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WHO Drug Information Vol 20, No. 1, 2006Regulatory Action and News

Cetuximab approvedfor head and neck cancer

United States of America —The Food and DrugAdministration (FDA) has announced approval ofcetuximab (Erbitux®) for use in combination withradiation therapy to treat patients with squamouscell cancer of the head and neck (SCCHN) thatcan not be removed by surgery (unresectableSCCHN). This is the first drug approved for headand neck cancer that has shown a survival benefitin this population. Cetuximab was also approvedfor monotherapy to treat patients whose head andneck cancer has metastasized despite the use ofstandard chemotherapy.

Cetuximab received a priority review and approvalwas based on a study that showed it prolongedsurvival by 20 months compared to treatment withradiation alone. Approval of monotherapy wasbased on evidence of tumor shrinkage in 13percent of patients, lasting on average of 6months.

Commonly reported side effects of cetuximabwere infusion reactions (fever, chills), skin rash,fatigue/malaise, nausea. The common sideeffects associated with radiation such as soremouth, trouble swallowing, and radiation skinchanges were similar in frequency in patientsreceiving cetuximab plus radiation and thosereceiving radiation alone.

Reference: FDA News, P06-34. 1 March 2006.

Selegiline patch for depression

United States of America — The Food and DrugAdministration has approved the first transdermalpatch (Emsam®) for use in treating major depres-sion. The once a day patch works by deliveringthe monoamine oxidase inhibitor (MAOI)selegiline. At its lowest strength, the patch can beused without the dietary restrictions that areneeded for all oral MAO inhibitors that areapproved for treating major depression.

MAO inhibitors usually require specific dietaryrestrictions because when combined with certainfoods they can cause hypertensive crisis whichcan lead to a stroke and death.

The only common side effect of Emsam® de-tected in placebo-controlled trials was a mild skinreaction where the patch is placed. There may bemild redness at the site when a patch is removed.If the redness does not go away within severalhours after removing the patch or if irritation oritching continues, patients are advised to contacttheir doctor. Another side effect that was seenless commonly was light-headedness related to adrop in blood pressure. Like all approved antide-pressants, this product carries a warning ofincreased suicidality in children and adolescents.

Although the effects of heat on the patch are notknown, the drug labelling advises health careprofessionals and patients about the possibleeffects of direct heat applied to the Emsam®patch. Direct heat may result in an increasedamount of the drug absorbed from the patch.Patients should avoid exposing the patch toheating pads, electric blankets, heat lamps,saunas, hot tubs, or prolonged sunlight.

Reference: FDA News, P06-31, 28 February 2006.

Ketamine now a classified drug

United Kingdom — As of 1 January 2006,Ketamine has become a controlled drug in theUnited Kingdom. This step has been takenbecause of its increasing misuse within thecountry. It is now a Class C drug, in Schedule 4part 1, under the United Kingdom Misuse ofDrugs Act, which places it alongsidebenzodiazepines, such as diazepam, etc.

Reference: News & Updates. National electronicLibrary for Medicines, 3 January 2006. http://www.nelm.nhs.uk

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Recent Publications,Information and EventsThe importance ofindependent drug bulletins

Using medicines safely and effectively requiresthat information is available to prescribersand others who give advice about medicines.Providing information in an impartial, objectiveand accessible way is a challenge and oneeffective approach is the local production of adrug bulletin.

In collaboration with the International Society ofDrug Bulletins (ISDB), the World Health Organiza-tion (WHO) has published a comprehansivemanual entitled Starting or Strengthening a DrugBulletin. Bulletins provide reliable comparativeinformation on drugs and therapeutics and can bea key means of improving health. Impartial, clear,reliable and up-to-date advice and informationabout treatments is invaluable and bulletins havean added advantage if the information is deliveredin a local context by local experts. By strengthen-ing the provision of advice at local level, themanual will benefit health workers, patients andcommunity members alike.

In recent years the concept of the empoweredpatient and the informed community has grown.This development has been mirrored by drugbulletins, which initially focused on prescribersand pharmacists but have since broadened toproducing materials for patients and consumers.

Reference: World Health Organization, InternationalSociety of Drug Bulletins, European Community.Starting or Strengthening a Drug Bulletin. A PracticalManual. WHO/PSM/PAR/2005.1 (2005). http://www.who.int/medicnes

Patient-centred healthcareand safety

The International Alliance of Patients’ Organiza-tions (IAPO) organized the second GlobalPatients Congress in Barcelona, Spain from 22–24 February 2006. The congress brought togetherover 120 patient leaders from around the world,together with global health professional associa-tions and the World Health Organization (WHO).

The aim was to develop strategies to bringpatients to the centre of healthcare systems. Over150 participants attended from more than 25countries.

A key event was the launch of IAPO’s Declarationon Patient-Centred Healthcare as the first globallyaccepted definition developed by and represent-ing the global patients movement. The Declara-tion contains five principles which, if followed, willresult in patient-centred healthcare:

• Respect.

• Choice and empowerment.

• Patient involvement in health policy.

• Access and support.

• Information.

IAPO is calling for the support and collaborationof policy-makers, health professionals, serviceproviders, and health-related industries to en-dorse and commit to these five principles andmake them the core of their policies and practice.

A second policy focus responds to the globalproblem of patient safety. The World HealthOrganization estimates that in developed coun-tries, up to one in every 10 hospital patientsexperiences an adverse event. In developingcountries, over 50% of medical equipment isfaulty (1). An international panel of policy-makers,patient advocates, industry and health profes-sional representatives considered the globalchallenges to improving patient safety. The paneldiscussion raised awareness of patient safetyissues such as medical errors, the importance ofcommunication and information to patients, andhow risks and benefits of medicines are consid-ered.

IAPO is particularly concerned about the specificpatient safety issues related to counterfeitmedicines and supported the proposal to estab-lish an International Medical Products Anti-Counterfeiting Taskforce (IMPACT) during the

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WHO Drug Information Vol 20, No. 1, 2006Recent Publications, Information and Events

recent WHO International Conference on Com-bating Counterfeit Drugs held in Rome (see page4).

IAPO is a global alliance representing patients ofall nationalities across all disease areas andpromoting patient-centred healthcare worldwide.Members are patient organizations working at thelocal, national, regional and international levels torepresent and support patients, their families andcarers. Through its membership, IAPO representsnearly 370 million patients worldwide.

References

1. WHO World Alliance for Patient Safety. A Year ofLiving less Dangerously. Progress Report 2005. http://www.who.int

2. International Alliance of Patients Organizations.Together we can. Press release, 28 February 2006.http://www.patientsorganizations.org

Boletín Fármacos: medicinesinformation in Spanish

In April 1997, during the First internationalconference on improving use of medicines, anetwork was created entitled Researchers andpromoters of the appropriate use of medicines inLatin America (RUAMAL). Publication of anelectronic bulletin in Spanish was considered thebest way to facilitate communication and, in1998,the first issue of Boletín Fármacos was published.

The main objective is to collect information onappropriate use of medicines. The staff of theBoletín Fármacos is composed of physicians,pharmacists, and social scientists. It has anAdvisory Council and Editorial Board made up ofexperts in the field.

The content includes research articles and briefs,news about drug policies and regulations, phar-maceutical industries, intellectual property rightand trade agreements, ethics and law, drug pricesand access, safety and adverse drug reactions,drug interactions, recommended therapies, anddispensation and pharmacy. A section includesabstracts of articles on the above issues pub-lished in the leading journals in the field.

Boletín Fármacos is pleased to receive researchpapers, news and articles on any topic related tothe use and promotion of drugs, drug policies,ethics and drugs, controversial drugs, recom-mended practices and questioned practices for

the use and promotion of drugs. It also publishesnews about conferences and workshops that aregoing to be held or have been held on the appro-priate use of drugs.

There are three sections on its website :

• Presentaciòn: where the main goals are set .

• Boletín Fármacos: containing all the bulletinspublished so far (with acess in html, Word, PDFor Zip).

• Otras paginas de interès: with hundreds of linksclassified by topics.

Reference: Boletín Fármacos is available on http://www.boltinfamacos.org

Antiretroviral programmesin low resource settings

The promise of improved funding through interna-tional initiatives has meant that HIV infection istreatable in developing and transitional countries.Resources such as antiretroviral medicines (ARV)and diagnostics are increasingly becomingavailable. Notwithstanding this progres, rapidscale-up of HIV treatment programmes has notbeen as fast as expected, in part, due to manage-ment issues such as difficulties with pharmaceuti-cal supply systems and logistics, insufficienthuman resources and problems of compliance.

The WHO Collaborationg Centre for Pharmaceuti-cal Policy at Boston University will be organizing atraining seminar from 7–18 August 2006 for policymakers, ARV program managers, and nongovern-mental organization officials responsible fornational and local programmes. Social scientists,pharmacists, and other public health professionalsinterested in ARV management and adherenceare also welcome.

The seminar will cover:

• Drug management issues, evidence-basedselection of medications, quantification, procure-ment, pricing, quality assurance, pre-qualifica-tion of suppliers and monitoring and evaluation.

• Approaches to improve adherence to AIDS andother chronic diseases.

The format will be highly interactive with presenta-tions by international experts followed by facili-tated group exercises and discussion. Case

31


studies and guided readings will be provided andsubstantial preparation is required for eachsession.

Reference: WHO Collaborationg Centre for Pharma-ceutical Policy, Boston University. Sarah Petty [email protected]

Developing countries andpaediatric drug information

The British National Formulary has published aBritish National Formulary for Children (BNFC)which is available online. The website is accessi-ble free of charge for certain countries. (To findout which countries can access BNFC see http://www.who.int/hinari/eligibility/en/).

Paediatricians often use medicines in childrenwith serious or complicated conditions that havebeen developed and tested only in adults. TheBNFC fills an important gap as there is often noinformation on off-label or unlicensed pediatricuse of medicines from manufacturers if themedicine was licensed to be used only in adults ina country.

Reference: BNFC website http://bnfc.org/bnfc/

Prudent use of antibiotics

The Alliance for the Prudent Use of Antibiotics(APUA) Newsletter has been published quarterlysince 1982. The Newsletter contains expertinformation on antibiotic use and resistance forhealthcare practitioners, researchers and policymakers. It is distributed to several thousandindividuals, including members, organizations andlbraries worldwide. Newsletters up to year 2005are available as a PDF at http://www.tufts.edu/med/apua/Newsletter/

Reference: Alliance for the Prudent Use of Antibiotics(APUA). http://www.apua.org

International Network for RationalUse of Drugs now online

The International Network for Rational Use ofDrugs (INRUD) was established in 1989 todesign, test, and disseminate effective strategiesand to improve the way drugs are prescribed,dispensed and used, with particular emphasis onresource poor countries.

The network now comprises 23 groups, 18 fromAfrica, Asia and Latin America, and other groupsfrom the World Health Organization, HarvardMedical School, the Karolinski Institute in Swe-den, the University of Newcastle in Australia, andManagement Sciences for Health in the UnitedStates.

A key responsibility for any health programme ororganization is to ensure that high-quality essen-tial drugs are available, affordable, and usedrationally. For both health systems and individu-als, pharmaceuticals represent a major expendi-ture. Misuse of scarce resources, makes a difficultsituation even worse. INRUD’s mission is toidentify the best ways of improving the use ofmedicines and to disseminate these findings.

The International Network for the Rational Use ofDrugs (INRUD) is pleased to announce posting ofthe first web only edition of the INRUD News isnow posted on the INRUD website.

Reference: http://www.inrud.org.

Rational medicines managementcourse for diseases of poverty

Health is an intrinsic human right as well as acentral input to poverty reduction and socioeco-nomic development. Cost-effective interventionsincluding medicines for controlling major diseasesexist, but a lack of money for health and a rangeof system constraints hamper efforts to expandhealth services to the poor.

Medicines have led to improvements in healthworldwide. Yet the main diseases of poverty suchas HIV/AIDS, malaria and tuberculosis continue toclaim innumerable lives in the developing world.Medicines are an essential and cost-effective toolof health care and an important element of healthsystems. The number and type of medicines onthe world market is constantly increasing, whilefinancial resources for health care services ingeneral remain limited or decrease. Today, formillions of people worldwide essential medicinesremain unavailable and unaffordable.

The sixth international training course on rationalmedicine management for HIV, tuberculosis andmalaria will take place from 28 August to 9September 2006 in Ifakara, Tanzania. Theobjectives of the course are to enable healthprofessionals to understand and apply the

Recent Publications, Information and Events

32


concepts and principles of essential medicinesand rational medicine management witha focus on the diseases of poverty HIV/Aids,malaria and tuberculosis, to recognise the needfor a national and international medicine policyenvironment, to improve knowledge and skills andto gain practical field experience for rationalmedicine management within different healthsystem contexts.

The target group is health professionals andmanagers with experience (at least two years)in the health sector and in the pharmaceuticalsector.

Reference: Swiss Tropical Institute at http://http://www.sti.ch or [email protected]

Recent Publications, Information and Events

33


General Information

Revised WHO treatmentrecommendations for malaria

Global malaria control is being threatened on anunprecedented scale by rapidly growing resist-ance of Plasmodium falciparum to conventionalmonotherapies such as chloroquine, sulfadoxine-pyrimethamine (SP) and amodiaquine. Multidrug-resistant falciparum malaria is widely prevalent inSouth-East Asia and South America and nowAfrica, the continent with highest burden ofmalaria, is also being seriously affected.

In response to this situation, WHO recommendsthat treatment policies for falciparum malaria in allcountries experiencing resistance to mono-therapies should be combination therapies,preferably those containing an artemisininderivative.

The therapeutic options currently recommendedby WHO are:

• artemether/lumefantrine

• artesunate plus amodiaquine

• artesunate plus sulfadoxine/pyrimethamine (inareas where SP efficacy remains high)

• amodiaquine plus sulfadoxine/pyrimethamine, inareas where efficacy of both amodiaquine andsulfadoxine/pyrimethamine remains high (mainlylimited to West Africa).

• artesunate plus mefloquine, an additionalrecommended combination treatment which isreserved for areas of low transmission.

Expanding access to artemisinincombination therapyOver the last three years around 20 countries(seven in Africa) have updated their treatmentpolicies to include artemisinin combinationtherapy (ACT) as first or second-line treatment ofmalaria.

The single non-artemisinin-based combinationtherapy (amodiaquine plus SP), listed above

among WHO recommended options is reservedfor countries which, for whatever reason, areunable to move into ACT. However, the limitationsof this option should be noted:

• The number of countries where efficacy is highof both amodiaquine and SP is limited andmainly restricted to West Africa.

• As both amodiaquine and SP are currently inwide usage as monotherapies it is unlikely thatthe adoption of this combination therapy willsignificantly delay the spread of resistance toeither drug. Therefore, the adoption of combina-tion therapy with amodiaquine plus SP is likelyto be a short-term solution.

• Even in areas where the efficacy of both amodi-aquine and SP remain high, their combined usewill compromise the useful therapeutic life ofboth, and thus endanger their potential use aspartner drugs for artesunate in ACT.

• There is currently no replacement for SP as adrug for Intermittent Preventive Treatment (IPT)in pregnancy. Rather than compromise itstherapeutic life by using it as a component of acombination therapy, SP should be reserved forIPT.

• As the process of drug policy change andimplementation is resource and time intensive(experience shows it to take from one to threeyears), all efforts for improving access totreatment should be directed towards imple-menting the most effective and durable treat-ment policy.

One of the principal reasons for countries wishingto adopt non artemisinin-based combinations istheir lower price. However, multiple financialmechanisms are now available in countries, andinternational support is being mobilized to helpcountries adopt ACT, and an increasing number ofcountries are now replacing ineffectivemonotherapies.

To facilitate access to ACT, WHO will continue toinspect manufacturers of artemisinin derivativesas part of the WHO prequalification project,

34

WHO Drug Information Vol 20, No. 1, 2006General Information

negotiate price agreements with manufacturers,engage in international procurement, and set upsystems of pharmacovigilance. A service formalaria medicines and supplies has been estab-lished by WHO and RBM partners to facilitateaccess to ACT within a larger facility for improvingaccess to medicines and supplies for HIV-AIDS,TB and Malaria.

Consistent with WHO recommendations, malariaendemic countries which are experiencingresistance to currently used antimalarial drugmonotherapies (chloroquine, sulphadoxine/pyrimethamine or amodiaquine) should changetreatment policies to the highly effective artemisi-nin-based combination treatments (ACT).

References

1 World Health Organization. The Use of AntimalarialDrugs. Report of a WHO Informal Consultation. WHOunpublished report. WHO/CDS/RBM/2001.33.

2 World Health Organization. Antimalarial Drug Combi-nation Therapy, Report of a WHO Technical Consulta-tion. WHO unpublished report . WHO/CDS/RBM/2001.35.

3. World Health Organization. New malaria treatmentguidelines issued by WHO. News Release, WHO/2, 19January 2006.

Quality assurance: latest guidance

The purpose of the WHO Expert Committee onSpecifications for Pharmaceutical Preparations isto provide guidance to WHO and Member Statesconcerning the quality of medicines. Within thisbroad mandate, it focuses on good manufacturingpractices and provides regulatory guidance textsfor interrelated activities on bioequivalence,prequalification, stability testing, fixed-dosecombinations, and counterfeit and substandardmedicines. Guidelines, specifications and interna-tional nomenclature developed under the aegis ofthis Expert Committee serve all Member States.

During its most recent meeting in Geneva from24 to 28 October 2005, the Expert Committeemade recommendations in various specific workareas related to quality assurance. Quality controlissues discussed target essential medicines andthose used in the treatment of large populationsfor which no international quality requirementsmay be available. The following new standardsand guidelines were approved.

1. ICRS, List of available International ChemicalReference Substances.

2. Supplementary guidelines on GMP for heating,ventilation and air-conditioning systems.

3. Good manufacturing practices: supplementaryguidelines on GMP for the manufacture ofherbal medicines.

4. Good manufacturing practices: Validation.

5. Good distribution practices (GDP) for pharma-ceutical products.

6. Model Quality Assurance System for Assess-ment of Procurement Agencies.

7. Guidelines on registration requirements toestablish interchangeability of multisource(generic) pharmaceutical products.

8. Proposal to waive in-vivo bioequivalencerequirements for the WHO model List ofEssential Medicines, immediate release, soliddosage forms.

9. Guidelines for organizations performing in vivobioequivalence studies.

10. International Pharmacopoeia monographs on:

abacavir sulfate, efavirenz, lamivudine, stavu-dine, zidovudine, nelfinavir mesilate tablets,nelfinavir mesilate oral powder, and saquinavirmesilate capsules

fixed-dose antituberculosis medicines in theirfinished dosage forms: rifampicin tablets,rifampicin capsules, rifampicin + isoniazidtablets, rifampicin + isoniazid + pyrazinamide +ethambutol HCl tablets, isoniazid + ethambutolHCl tablets, and rifampicin + isoniazid +pyrazinamide tablets.

In addition, the following revisions were adoped.

• WHO Guidelines for stability testing of pharma-ceutical products containing well establisheddrug substances in conventional dosage formsAnnex 5, WHO Technical Report Series 863,1996, and Update, WHO Technical ReportSeries 908, 2003. http://www.who.int/medicines

35


• List of comparator products included in theGuidance on the selection of comparatorpharmaceutical products for equivalenceassessment of interchangeable multisource(generic) products. Annex 11, WHO TechnicalReport Series No. 902, 2002, and Annex 11,WHO Technical Report Series No. 902, 2002.http://www.who.int/medicines/areas/quality_safety/quality_assurance/regulatory_standards/en/index.html) to bepublished on the web in order to ease its regularupdates, and

• Several test methods currently published in thepublication entitled “Quality control methods formedicinal plant materials”, in collaboration withTRM.

Reference: World Health Organization. http://www.who.int/medicines

WHO clinical trial registryinitiative: update

As previously reported (1), a registry platform hasbeen set up within WHO to link registers into acomprehensive network and provide harmoniza-tion and information for the initiative. The Scien-tific Advisory Group (SAG) is composed ofinternational experts who represent key stake-holders involved in clinical trials and advises onthe principles and substantive standards for trialregistration. The Group met for the first time inGeneva, Switzerland on 17 and 18 November2005 where participants agreed to key elementsof global trial registration policies:

• Registration of all interventional trials is ascientific, ethical, and moral responsibility.

• At a minimum, the 20 item Data Set is requiredfor trial registration (See table below). (1).

• Full disclosure of all 20 items at the time ofregistration is critical on scientific grounds and isin the public interest.

The SAG also supported the general structureand composition of an international network ofregisters, and confirmed the importance ofdetecting multiply-registered trials.

The first meeting of the International AdvisoryBoard (IAB) took place at Imperial College,London, UK on 6 February 2006. The panel ofexperts endorsed the strategic plan of the Regis-try Platform and provided a strong vote of sup-port, in particular for the key milestones whichincludes the launch of a network of qualified trialregisters, a unique identification number fortracking trials (Universal Trial Reference Numberor UTRN), and a one-stop search portal that willdirect users to trial information contained inindividual registers worldwide. The IAB alsoendorsed the Registry Platform’s two-tieredapproach to the proposed network of Primary andAssociate Registers.

WHO Network of Member RegistersWHO will establish a coordinated, internationalnetwork of trial registers that will serve globalhealth needs through a web-based platform.Acceptable registers will be approved based oncriteria that are being finalized. The WHO has noplans to administer its own trial register.

The composition of the register network has beenfinalized. It will consist of two types of registers:

• A relatively small number of national, regional, orinternational Primary Registers, which accept alltrials, perform deduplication of entries withintheir own register, and provide data directly tothe WHO;

General Information

1. Primary Register and Trial ID number2. Date of Registration in Primary Register3. Secondary ID number(s)4. Source(s) of Monetary or Material Support5. Primary Sponsor6. Secondary Sponsor(s)7. Contact for Public Queries8. Contact for Scientific Queries9. Public Title10. Scientific Title

11. Countries of Recruitment12. Health Condition(s) or Problem(s) Studied13. Intervention(s)14. Key Inclusion and Exclusion Criteria15. Study Type16. Date of First Enrollment17. Target Sample Size18. Recruitment Status19. Primary Outcome(s)20. Key Secondary Outcomes

20 item Data Set

36


• A larger number of Associate Registers, whichsend their registration data to designatedPrimary Registers. They can be either broadly-based or restricted in scope, such as a specificdisease, company, or institution.

In collaboration with its six regional offices andthrough other mechanisms, WHO is facilitatingthe coordination of regional approaches to trialregistration worldwide (5).

The Registry Platform Newsletter website isavailable at: www.who.int/ictrpis and e-mail copiescan be requested through: [email protected] the word “Subscribe” or “Unsubscribe” in thesubject line.

General Information

References

1. WHO Drug Information, 19(2): 126–129 (2005)

2. World Health Organization. SAG meeting report:http://www.who.int/ictrp/SAG_Report.pdf

3. The minutes of the International Advisory Board (IAB)meeting are available online at: http://www.who.int/ictrp/IAB_report.pdf.

4. Trial Registration Data Set Detailed explanation ofeach item is available at: http://www.who.int/ictrp/data_set/en/index1.html

5. http://www.who.int/ictrp/registration/member_reg/en/index1.html

WHO Network of Member Registers

WHO Drug Information, Vol. 20, No. 1, 2006 Recommended INN: List 55

37

International Nonproprietary Names for Pharmaceutical Substances (INN)

RECOMMENDED International Nonproprietary Names: List 55 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 (1–91) and Recommended (1–52) International Nonproprietary Names can be found in Cumulative List No. 11, 2004 (available in CD-ROM only).

Dénominations communes internationales des Substances pharmaceutiques (DCI)

Dénominations communes internationales RECOMMANDÉES: Liste 55 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 choisies par l’Organisation mondiale de la Santé en tant que dénominations communes internationales recommandées. L’inclusion d’une dénomination dans les listes de DCI recommandées 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 (1–91) et recommandées (1–52) dans la Liste récapitulative No. 11, 2004 (disponible sur CD-ROM seulement).

Denominaciones Comunes Internacionales para las Sustancias Farmacéuticas (DCI) Denominaciones Comunes Internacionales RECOMENDADAS: Lista 55 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 (1–91) y Recomendadas (1–52) se encuentran reunidas en Cumulative List No. 11, 2004 (disponible sólo en CD-ROM).

Recommended INN: List 55 WHO Drug Information, Vol. 20, No. 1, 2006

38

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 molecular; Fórmula desarrollada

apixabanum apixaban 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-

4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

apixaban 1-(4-méthoxyphényl)-7-oxo-6-[4-(2-oxopipéridin-1-yl)phényl]- 4,5,6,7-tétrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

apixabán 1-(4-metoxifenil)-7-oxo-6-[4-(2-oxopiperidin-1-il)fenil]- 4,5,6,7-tetrahidro-1H-pirazolo[3,4-c]piridina-3-carboxamida

C25H25N5O4

N

NN

N

ONH2

OCH3

O

O

apratastatum apratastat (2S)-N-hydroxy-4-({4-[(4-hydroxybut-2-yn-1-yl)oxy]phenyl]}sulfonyl)-

2,2-dimethylthiomorpholine-3-carboxamide

apratastat (2S)-N-hydroxy-4-[[4-[(4-hydroxybut-2-ynyl)oxy]phényl]sulfonyl]- 2,2-diméthylthiomorpholine-3-carboxamide

apratastat (2S)-N-hidroxi-4-({4-[(4-hidroxibut-2-in-1-il)oxi]fenil]}sulfonil)- 2,2-dimetiltiomorfolina-3-carboxamida

C17H22N2O6S2

S

NNH

HO

S

O

OOO

H3CCH3

H

OH


39

arasertaconazolum arasertaconazole 1-{(2R)-2-[(7-chloro-1-benzothiophen-3-yl)methoxy]-

2-(2,4-dichlorophenyl)ethyl}-1H-imidazole

arasertaconazole (-)-1-[(2R)-2-[(7-chloro-1-benzothiophén-3-yl)méthoxy]- 2-(2,4-dichlorophényl)éthyl]-1H-imidazole

arasertaconazol 1-{(2R)-2-[(7-cloro-1-benzotiofen-3-il)metoxi]-2-(2,4-diclorofenil)etil}-1H-imidazol

C20H15Cl3N2OS

N

N

O

HCl

Cl

S

Cl

bapineuzumabum bapineuzumab immunoglobulin G1, anti-(human β-amyloid) (human-mouse

monoclonal heavy chain), disulfide with human-mouse monoclonal light chain, dimer

bapineuzumab immunoglobuline G1, anti-(protéine β-amyloïde humaine), dimère du disulfure entre la chaîne lourde et la chaîne légère de l’anticorps monoclonal de souris humanisé

bapineuzumab inmunoglobulina G1, anti-(proteína β-amiloide humana), dímero del disulfuro entre la cadena pesada y la cadena ligera del anticuerpo monoclonal humanizado de ratón

C6466H10018N1734O2026S44

brivaracetamum brivaracetam (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide

brivaracétam (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide

brivaracetam (2S)-2-[(4R)-2-oxo-4-propilpirrolidin-1-il]butanamida

C11H20N2O2

NNH2

O

O

H

H3CH

CH3


40

caricotamidum caricotamide 1-(2-amino-2-oxoethyl)-1,4-dihydropyridine-3-carboxamide

caricotamide 1-(2-amino-2-oxoéthyl)-1,4-dihydropyridine-3-carboxamide

caricotamida 1-(2-amino-2-oxoetil)-1,4-dihdropiridina-3-carboxamida

C8H11N3O2

N NH2

O

H2N

O

catumaxomabum catumaxomab immunoglobulin G2a, anti-(human antigen 17-1A) (mouse

monoclonal Ho-3/TP-A-01/TPBs01 heavy chain), disulfide with mouse monoclonal Ho-3/TP-A-01/TPBs01 light chain, disulfide with immunoglobulin G2b anti-(human CD3 (antigen)) (rat monoclonal 26/II/6-1.2/TPBs01 heavy chain), bidisulfide with rat monoclonal 26/II/6-1.2/TPBs01 light chain

catumaxomab hétérodimère entre l’immunoglobuline G2a, anti-(molécule d’adhésion des cellules épithéliales (Ep-CAM) humaine), disulfure entre la chaîne lourde et la chaîne légère de l’anticorps monoclonal de souris Ho-3/TP-A-01/TPBs01 (monomère) et l’immunoglobuline G2b, anti-(antigène CD3 humain), disulfure entre la chaîne lourde et la chaîne légère de l’anticorps monoclonal de rat 26/II/6-1.2/TPBs01 (monomère)

catumaxomab heterodímero entre la inmunoglobulina G2a, anti-(molécula de adhesión de las células epiteliales (Ep-CAM) humana), disulfuro entre la cadena pesada y la cadena ligera del anticuerpo monoclonal de ratón Ho-3/TP-A-01/TPBs01 (monómero) y la inmunoglobulina G2b, anti-(antígeno CD3 humano), disulfuro entre la cadena pesada y la cadena ligera del anticuerpo monoclonal de rata 26/II/6-1.2/TPBs01 (monómero)

dapiclerminum dapiclermin [17-alanine,63-arginine]ciliary neurotrophic factor-(2-185)-peptide

(human)

dapiclermine [17-alanine,63-arginine]facteur neurotrophique ciliaire humain- (2-185)-peptide

dapiclermina [17-alanina ,63-arginina]factor neurotrófico ciliar humano-(2-185)-péptido

C945H1482N266O278S3

PHRRDLASRSTDRWSELTEA

TLLLQVAAFA

IWLARKIRSDERLQENLQAYLTALTESYVK

RTFHVLLARLHQGLNKNINL

LEDQQVHFTP

AFTEHSPLTDSADGMPVAS

TEGDFHQAIHLFEKKLWGLKYQIEELMILL EYKIPRNEAD GMPINVGDGG

VLQELSQWTV RSIHDLRFIS SHQTG


41

dexlansoprazolum dexlansoprazole (+)-2-[(R)-{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}=

sulfinyl]-1H-benzamidazole

dexlansoprazole (+)-2-[(R)-[[3-méthyl-4-(2,2,2-trifluoroéthoxy)pyridin-2-yl]méthyl]= sulfinyl]-1H-benzimidazole

dexlansoprazol (+)-2-[(R)-[[3-metil-4-(2,2,2-trifluoroetoxi)piridin-2-il]metil]sulfinil]- 1H-benzoimidazol

C16H14F3N3O2S

N

NH

S

NO

CH3

O CF3

dianiclinum dianicline (5aS,8S,10aR)-6,7,9,10-tetrahydro-5aH,11H-8,10a-

methanopyrido[2',3':5,6]pyrano[2,3-d]azepine

dianicline (-)-(5aS,10aR)-6,7,9,10-tétrahydro-5aH,11H-8,10a-méthanopyrido[2',3':5,6]pyrano[2,3-d]azépine

dianiclina (5aS,8S,10aR)-6,7,9,10-tetrahidro-5aH,11H-8,10a-metanopirido[2',3':5,6]pirano[2,3-d]azepina

C13H16N2O

N

ON

H

ecallantidum ecallantide [Glu20,Ala21,Arg36,Ala38,His39,Pro40,Trp42]tissue factor pathway

inhibitor (human)-(20-79)-peptide (modified on reactive bond region Kunitz inhibitor 1 domain containing fragment)

écallantide [Glu20,Ala21,Arg36,Ala38,His39,Pro40,Trp42]inhibiteur de la voie du facteur tissulaire humain-(20-79)-peptide (fragment du TFPI contenant le domaine de type Kunitz 1modifié au niveau de sa boucle réactive)

ecalantida [Glu20,Ala21,Arg36,Ala38,His39,Pro40,Trp42]inhibidor de la vía del factor tisular humano-(20-79)-péptido (fragmento del TFPI que contiene el dominio de tipo Kunitz 1 modificado en su región reactiva)

C305H442N88O91S8

DDGPCRAAHP

ECKKMCTRDRWFFNIFTRQ CEEFIYGGCE GNQNRFESLE

E AMHSFCAFKA


42

ertumaxomabum ertumaxomab immunoglobulin G2a, anti-(human neu (receptor)) (mouse

monoclonal 2502A/TP-A-02/TPBs03 heavy chain), disulfide with mouse monoclonal 2502A/TP-A-02/TPBs03 light chain, disulfide with immunoglobulin G2b anti-(human CD3 (antigen)) (rat monoclonal 26/II/6-1.2/TPBs03 heavy chain), bidisulfide with rat monoclonal 26/II/6-1.2/TPBs03 light chain

ertumaxomab hétérodimère entre l’immunoglobuline G2a, anti-(récepteur erbB-2 tyrosine protéine kinase (HER2, NEU) humain), disulfure entre la chaîne lourde et la chaîne légère de l’anticorps monoclonal de souris 2502A/TP-A-02/TPBs03 (monomère) et l’immunoglobuline G2b, anti-(antigène CD3 humain), disulfure entre la chaîne lourde et la chaîne légère de l’anticorps monoclonal de rat 26/II/6-1.2/TPBs03 (monomère)

ertumaxomab heterodímero entre la inmunoglobulina G2a, anti-(receptor erbB-2 tirosina proteína kinasa (HER2, NEU) humano), disulfuro entre la cadena pesada y la cadena ligera del anticuerpo monoclonal de ratón 2502A/TP-A-02/TPBs03 (monómero) y la inmunoglobulina G2b, anti-(antígeno CD3 humano), disulfuro entre la cadena pesada y la cadena ligera del anticuerpo monoclonal de rata 26/II/6-1.2/TPBs03 (monómero)

esmirtazapinum esmirtazapine (14bS)-2-methyl-1,2,3,4,10,14b-hexahydropyrazino[2,1-a]pyrido=

[2,3-c][2]benzazepine

esmirtazapine (+)-(14bS)-2-méthyl-1,2,3,4,10,14b-hexahydropyrazino= [2,1-a]pyrido[2,3-c][2]benzazépine

esmirtazapina (14bS)-2-metil-1,2,3,4,10,14b-hexahidropirazino[2,1-a]pirido= [2,3-c][2]benzazepina

C17H19N3

N

N

N

HCH3

fosfluridinum tidoxilum fosfluridine tidoxil 5-fluorouridine 5'-[(2RS)-2-(decyloxy)-3-(dodecylsulfanyl)propyl

hydrogen phosphate]

fosfluridine tidoxil hydrogénophosphate de (2RS)-2-(décyloxy)-3-(dodécylsulfanyl)= propyle et de [(2R,3S,4R,5R)-5-(5-fluoro-2,4-dioxo- 3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxytétrahydrofuran- 2-yl]méthyle

fosfluridina tidoxilo 5-fluorouridina 5'-[(2RS)-2-(deciloxi)-3-(dodecilsulfanil)propil hidrógeno fosfato]


43

C34H62FN2O10PS

HN

NO

O

O

OH

O

F

POS

HOH3C

O OHand epimer at C*et l'épimère en C*y el epímero al C*

*

OH

CH3

isproniclinum ispronicline (2S,4E)-N-methyl-5-{5-[(propan-2-yl)oxy]pyridin-3-yl}pent-4-en-

2-amine

ispronicline (2S,4E)-N-méthyl-5-[5-(1-méthyléthoxy)pyridin-3-yl]pent-4-én- 2-amine

isproniclina (2S,4E)-N-metil-5-{5-[(propan-2-il)oxi]piridin-3-il}pent-4-en-2-amina

C14H22N2O

N

NH

H3CO CH3

CH3CH3H

istaroximum istaroxime 3-[(2-aminoethoxy)imino]-5α-androstan-6,17-dione

istaroxime 3-[(2-aminoéthoxy)imino]-5α-androstane-6,17-dione

istaroxima 3-[(2-aminoetoxi)imino]-5α-androstano-6,17-diona

C21H32N2O3

CH3

CH3

H

HH

O

NO

H2NO

H

lecozotanum lecozotan 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-

1-yl]propyl}-N-(pyridin-2-yl)benzamide

lécozotan (+)-4-cyano-N-[(2R)-2-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)pipérazin-1-yl]propyl]-N-(pyridin-2-yl)benzamide

lecozotán 4-ciano-N-{(2R)-2-[4-(2,3-dihidro-1,4-benzodioxin-5-il)piperazin- 1-il]propil}-N-(piridin-2-il)benzamida


44

C28H29N5O3

N

NC

O

N

N

O

O

NH CH3

levolansoprazolum levolansoprazole (-)-2-[(S)-{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}=

sulfinyl]-1H-benzamidazole

lévolansoprazole (-)-2-[(S)-[[3-méthyl-4-(2,2,2-trifluoroéthoxy)pyridin-2-yl]méthyl]= sulfinyl]-1H-benzimidazole

levolansoprazol (-)-2-[(S)-{[3-metil-4-(2,2,2-trifluoroetoxi)piridin-2-il]metil}sulfinil]- 1H-benzoimidazol

C16H14F3N3O2S

N

NH

S

NO

CH3

O CF3

manitimusum manitimus (2Z)-2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]hept-2-en-

6-ynamide

manitimus (2Z)-2-cyano-3-hydroxy-N-[4-(trifluorométhyl)phényl]hept-2-én- 6-ynamide

manitimús (2Z)-2-ciano-3-hidroxi-N-[4-(trifluorometil)fenil]hept-2-en-6-inamida

C15H11F3N2O2

HN

CF3O

CN

OH

HC


45

mapatumumabum mapatumumab immunoglobulin G1, anti-(human cytokine receptor DR4 (death

receptor 4))(human monoclonal TRM-1 heavy chain), disulfide with human monoclonal TRM-1 λ-chain, dimer

mapatumumab immunoglobuline G1, anti-(élément 10A humain dans la « superfamille » du récepteur du facteur de nécrose tumorale (récepteur DR4)), dimère du disulfure entre la chaîne lourde et la chaîne λ de l’anticorps monoclonal humain TRM-1

mapatumumab inmunoglobulina G1, anti-(elemento 10A humano de la « superfamilia » del receptor del factor de necrosis tumoral (receptor DR4)), dímero del disulfuro entre la cadena pesada y la cadena λ del anticuerpo monoclonal humano TRM-1

C6748H10408N1800O2092S52

nebicaponum nebicapone 1-(3,4-dihydroxy-5-nitrophenyl)-2-phenylethan-1-one

nébicapone 1-(3,4-dihydroxy-5-nitrophényl)-2-phényléthanone

nebicapone 1-(3,4-dihidroxi-5-nitrofenil)-2-feniletan-1-ona

C14H11NO5

OH

HO

O2N

O

nerispirdinum nerispirdine N-(3-fluoropyridin-4-yl)-3-methyl-N-propyl-1H-indol-1-amine

nérispirdine N-(3-fluoropyridin-4-yl)-3-méthyl-N-propyl-1H-indol-1-amine

nerispirdina N-(3-fluoroparidin-4-il)-3-metil-N-propil-1H-indol-1-amina

C17H18FN3

N

NCH3

N

CH3

F


46

ofatumumabum ofatumumab immunoglobulin G1, anti-(human CD20 (antigen))(human

monoclonal HuMax-CD20 heavy chain), disulfide with human monoclonal HuMax-CD20 κ-chain, dimer

ofatumumab immunoglobuline G1, anti-(antigène CD20 humain), dimère du disulfure entre la chaîne lourde et la chaîne κ de l’anticorps monoclonal humain HuMax-CD20

ofatumumab inmunoglobulina G1, anti-(antígeno CD20 humano), dímero del disulfuro entre la cadena pesada y la cadena κ del anticuerpo monoclonal humano HuMax-CD20

C6480H10022N1742O2020S44

olmesartanum olmesartan 4-(2-hydroxypropan-2-yl)-2-propyl-1-{[2'-(1H-tetrazol-5-yl)biphenyl-

4-yl]methyl}-1H-imidazole-5-carboxylic acid

olmésartan acide 4-(1-hydroxy-1-méthyléthyl)-2-propyl-1-[[2'-(1H-tétrazol-5-yl)= biphényl-4-yl]méthyl]-1H-imidazole-5-carboxylique

olmesartán ácido 4-(2-hidroxipropan-2-il)-2-propil-1-{[2'-(1H-tetrazol-5-il)bifenil- 4-il]metil}-1H-imidazol-5-carboxílico

C24H26N6O3

N

NNHN

NN

CH3

CO2H

H3C

OHH3C

padoporfinum padoporfin {hydrogen 3-[(22R,7R,8R,17S,18S)-12-acetyl-7-ethyl-

22-(methoxycarbonyl)-3,8,13,17-tetramethyl-21-oxo-21,22,7,8,17,18-hexahydrocyclopenta[at]porphorin-18-yl]propanoato-κ4N21,N22,N23,N24}palladium

padoporfine (SP-4-2)-[hydrogéno-3-[(22R,7R,8R,17S,18S)-12-acétyl-7-éthyl- 22-(méthoxycarbonyl)-3,8,13,17-tétraméthyl-21-oxo-21,22,7,8,17,18-hexahydrocyclopenta[at]porphyrin-18-yl]propanoato-κN21,κN22,κN23,κN24]palladium

padoporfina (SP-4-2)-[hidrógeno-3-[(22R,7R,8R,17S,18S)-12-acetil-7-etil- 22-(metoxicarbonil)-3,8,13,17-tetrametil-21-oxo-21,22,7,8,17,18-hexahidrociclopenta[at]porfirin-18-il]propanoato-κN21,κN22,κN23,κN24]paladio


47

C35H36N4O6Pd

Pd

N

NN

N

H3CH3C

H

O

H

H3C

H

CH3H

H

CH3

O

O CH3

CO2H

O

CH3

pagibaximabum pagibaximab immunoglobulin G1, anti-(Staphylococcus epidermidis lipoteichoic

acid)(human-mouse monoclonal heavy chain), disulfide with human-mouse monoclonal κ-chain, dimer

pagibaximab immunoglobuline G1, anti-(acide lipotéichoïque Staphylococcus epidermis), dimère du disulfure entre la chaîne lourde et la chaîne κ de l’anticorps monoclonal chimérique homme-souris

pagibaximab inmunoglobulina G1, anti-(ácido lipoteicoico de Staphylococcus epidermis), dímero del disulfuro entre la cadena pesada y la cadena κ del anticuerpo monoclonal quimérico hombre-ratón

C6462H9996N1728O2028S54

palirodenum paliroden 1-[2-(biphenyl-4-yl)ethyl]-4-[3-(trifluoromethyl)phenyl]-

1,2,3,6-tetrahydropyridine

palirodène 1-[2-(biphényl-4-yl)éthyl]-4-[3-(trifluorométhyl)phényl]- 1,2,3,6-tétrahydropyridine

palirodeno 1-[2-(bifenil-4-il)etil]-4-[3-(trifluorometil)fenil]-1,2,3,6-tetrahidropiridina

C26H24F3N

N

CF3

peforelinum peforelin 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-histidyl-L-α−asparagyl-

L-tryptophyl-L-lysyl-L-prolylglycinamide

péforéline 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-séryl-L-histidyl-L-α-aspartyl- L-tryptophyl-L-lysyl-L-prolylglycinamide

peforelina 5-oxo-L-prolil-L-histidil-L-triptofil-L-seril-L-histidil-L-α-asparagil- L-triptofil-L-lisil-L-prolilglicinamida


48

C59H74N18O14

NH

His Trp Ser His Asp Trp Lys ProOH

O

Gly NH2

plerixaforum plerixafor 1,1'-(1,4-phenylenebismethylene)bis(1,4,8,11-

tetraazacyclotetradecane)

plérixafor 1,1'-(1,4-phénylènebisméthylène)bis(1,4,8,11-tétraazacyclotétradécane)

plerixafor 1,1'-(1,4-fenilenobismetileno)bis(1,4,8,11-tetraazaciclotetradecano)

C28H54N8

N

HN

NH

NHN

NH

HN

HN

plitidepsinum plitidepsin 3,6-anhydro(N-{(2S,4S)-4-[(3S,4R,5S)-3-hydroxy-

4-{[N-(2-oxopropanoyl)-L-prolyl-N-methyl-D-leucyl-L-threonyl]amino}-5-methylheptanoyloxy]-2,5-dimethyl-3-oxohexanoyl}-L-leucyl-L-prolyl-N,O-dimethyl-L-tyrosine)

plitidepsine (-)-(3S,6R,7S,10R,11S,15S,17S,20S,25aS)-11-hydroxy- 3-(4-méthoxybenzyl)-2,6,17-triméthyl-15-(1-méthyléthyl)- 7-[[(2R)-4-méthyl-2-[méthyl[[(2S)-1-(2-oxopropanoyl)pyrrolidin- 2-yl]carbonyl]amino]pentanoyl]amino]-10-[(1S)-1-méthylpropyl]- 20-(2-méthylpropyl)tétradécahydro-15H-pyrrolo[2,1-f]= [1,15,4,7,10,20]dioxatétrazacyclotricosine-1,4,8,13,16,18,21(17H)-heptone

plitidepsina 3,6-anhidro(N-{(2S,4S)-4-[(3S,4R,5S)-3-hidroxi- 4-{[N-(2-oxopropanoil)-L-prolil-N-metil-D-leucil-L-treonil]amino}- 5-metilheptanoiloxi]-2,5-dimetil-3-oxohexanoil}-L-leucil-L-prolil- N,O-dimetil-L-tirosina)


49

C57H87N7O15

O

N

CH3

HN

O

O

HN

O

N

CH3

O

O

HO H

H

H3CO

HH3C

O

H

HN

CH3

HHO

H3CCH3

H

H

CH3

HH3C

CH3

N

O

O

HH3C

CH3

O

H

N

HOH3C

O

H3C

pradefovirum pradefovir (2R,4S)-2-{[2-(6-amino-9H-purin-9-yl)ethoxy]methyl}-

4-(3-chlorophenyl)-1,3,2λ5-dioxaphosphinan-2-one

pradéfovir (2R,4S)-2-[[2-(6-amino-9H-purin-9-yl)éthoxy]méthyl]- 4-(3-chlorophényl)-1,3,2λ5-dioxaphosphinan-2-one

pradefovir (2R,4S)-2-{[2-(6-amino-9H-purin-9-il)etoxi]metil}-4-(3-clorofenil)-1,3,2λ5-dioxafosfinan-2-ona

C17H19ClN5O4P

N

N N

N

NH2

OP

O

O

H

O

Cl

radequinilum radequinil 5-(3-methoxyphenyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)-

1,6-naphthyridin-2(1H)-one

radéquinil 5-(3-méthoxyphényl)-3-(5-méthyl-1,2,4-oxadiazol-3-yl)- 1,6-naphtyridin-2(1H)-one

radequinilo 5-(3-metoxifenil)-3-(5-metil-1,2,4-oxadiazol-3-il)-1,6-naftiridin- 2(1H)-ona

C18H14N4O3

N

HN O

OCH3

N O

NCH3


50

rimacalibum rimacalib N-{3-[(1S)-1-(2-fluorobiphenyl-4-yl)ethyl]-1,2-oxazol-5-yl}morpholine-

4-carboximidamide

rimacalib (+)-N-[3-[(1S)-1-(2-fluorobiphényl-4-yl)éthyl]isoxazol-5-yl]morpholine-4-carboximidamide

rimacalib N-{3-[(1S)-1-(2-fluorobifenil-4-il)etil]-1,2-oxazol-5-il}morfolina- 4-carboximidamida

C22H23FN4O2

NO

NH

N

O

F

NH

H CH3

rivaniclinum rivanicline (3E)-N-methyl-4-(pyridin-3-yl)but-3-en-1-amine

rivanicline (3E)-N-méthyl-4-(pyridin-3-yl)but-3-én-1-amine

rivaniclina ácido (3E)-N-metil-4-(piridin-3-il)but-3-en-1-amina

C10H14N2

N

NH

H3C

rivenprostum rivenprost methyl 4-({2-[(1R,2R,3R)-3-hydroxy-2-{(1E,3S)-3-hydroxy-

4-[3-(methoxymethyl)phenyl]but-1-en-1-yl}-5-oxocyclopentyl]0 ethyl}sulfanyl)butanoate

rivenprost 4-[[2-[(1R,2R,3R)-3-hydroxy-2-[(1E,3S)-3-hydroxy- 4-[3-(méthoxyméthyl)phényl]but-1-ényl]-5-oxocyclopentyl]= éthyl]sulfanyl]butanoate de méthyle

rivenprost 4-({2-[(1R,2R,3R)-3-hidroxi-2-{(1E,3S)-3-hidroxi-4-[3-(metoximetil)= fenil]but-1-en-1-il}-5-oxociclopentil]etil}sulfanil)butanoato de metilo

C24H34O6S

S

OCH3

HOH

O

H OHH

OH

OCH3


51

satavaptanum satavaptan N-tert-butyl-4-({cis-5'-ethoxy-4-[2-(morpholin-4-yl)ethoxy)]-2'-oxo-

1',2'-dihydrospiro[cyclohexane-1:3'-indole]-1'-yl}sulfonyl)- 3-methoxybenzamide

satavaptan N-(1,1-diméthyléthyl)-4-[[cis-5'-éthoxy-4-[2-(morpholin-4-yl)éthoxy]-2'-oxospiro[cyclohexane-1,3'-[3H]indol]-1'(2'H)-yl]sulfonyl]- 3-méthoxybenzamide

satavaptán N-terc-butil-4-({cis--5'-etoxi-4-[2-(morfolin-4-il)etoxi)]-2'-oxo- 1',2'-dihidrospiro[ciclohexano-1:3'-indol]-1'-il}sulfonil)- 3-metoxibenzamida

C33H45N3O8S

N

S OO

O

O

ON

H

OCH3NH

CH3

H3CH3C

O

H3C

O

seletracetamum seletracetam (2S)-2-[(4S)-4-(2,2-difluoroethenyl)-2-oxopyrrolidin-1-yl]butanamide

sélétracétam (2S)-2-[(4S)-4-(2,2-difluoroéthényl)-2-oxopyrrolidin-1-yl]butanamide

seletracetam (2S)-2-[(4S)-4-(2,2-difluoroetenil)-2-oxopirrolidin-1-il]butanamida

C10H14F2N2O2

NNH2

O

O

H

F

F

H

CH3

sipoglitazarum sipoglitazar 3-(3-ethoxy-1-{4-[(2-phenyl-1,3-thiazol-4-yl)methoxy]benzyl}-

1H-pyrazol-4-yl)propanoic acid

sipoglitazar acide 3-[3-éthoxy-1-[4-[(2-phénylthiazol-4-yl)méthoxy]benzyl]- 1H-pyrazol-4-yl]propanoïque

sipoglitazar ácido 3-(3-etoxi-1-{4-[(2-fenil-1,3-tiazol-4-il)metoxi]bencil}-1H-pirazol-4-il)propanoico

C25H25N3O4S

N

S

O

NN

O

CO2H

CH3


52

sunitinibum sunitinib N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-

3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide

sunitinib N-[2-(diéthylamino)éthyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidène)méthyl]-2,4-diméthyl-1H-pyrrole-3-carboxamide

sunitinib N-[2-(dietilamino)etil]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihidro-3H-indol- 3-ilideno)metil]-2,4-dimetil-1H-pirrol-3-carboxamida

C22H27FN4O2

NHNH

N

NH

F

OH3C

CH3OH3C

H3C

surinabantum surinabant 5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-N-(piperidin-1-yl)-

1H-pyrazole-3-carboxamide

surinabant 5-(4-bromophényl)-1-(2,4-dichlorophényl)-4-éthyl-N-(pipéridin-1-yl)-1H-pyrazole-3-carboxamide

surinabant 5-(4-bromofenil)-1-(2,4-diclorofenil)-4-etil-N-(piperidin-1-il)- 1H-pirazol-3-carboxamida

C23H23BrCl2N4O

NN N

H

N

O

Br

Cl

Cl

CH3

tasidotinum tasidotin N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-N-(tert-butyl)-

L-prolinamide

tasidotine N,N-diméthyl-L-valyl-L-valyl-N-méthyl-L-valyl-L-prolyl- N-(1,1-diméthyléthyl)-L-prolinamide

tasidotina N,N-dimetil-L-valil-L-valil-N-metil-L-valil-L-prolil-N-(terc-butil)- L-prolinamida

C32H58N6O5

NNH

O CH3

CH3

CH3O H

N

O

N

CH3H3C

CH3

O

NH

H3C CH3

N

O

CH3H3C

H3C

CH3 HH

H H


53

tasquinimodum tasquinimod 4-hydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-[4-(trifluoromethyl)=

phenyl]-1,2-dihydroquinoline-3-carboxamide

tasquinimod 4-hydroxy-5-méthoxy-N,1-diméthyl-2-oxo-N-[4-(trifluorométhyl)= phényl]-1,2-dihydroquinoléine-3-carboxamide

tasquinimod 4-hidroxi- N,1-dimetil 5-metoxi-N-[4-(trifluorometil)fenil]-2-oxo- 1,2-dihidroquinolina-3-carboxamida

C20H17F3N2O4

N

CH3

O

OHOCH3

N

O

CH3

CF3

terutrobanum terutroban 3-[(6R)-6-(4-chlorobenzenesulfonamido)-2-methyl-5,6,7,8-

tetrahydronaphthalen-1-yl]propanoic acid

térutroban acide 3-[(6R)-6-[[(4-chlorophényl)sulfonyl]amino]-2-méthyl-5,6,7,8-tétrahydronaphtalén-1-yl]propanoïque

terutrobán ácido 3-[(6R)-6-(4-clorobencenosulfonamido)-2-metil-5,6,7,8-tetrahidronaftalen-1-il]propanoico

C20H22ClNO4S

CH3

CO2H

HN

S

Cl

O O

H

tesetaxelum tesetaxel 2'-[(dimethylamino)methyl]-1-hydroxy-5β,20-epoxy-

9α,10α-dihydro[1,3]dioxolo[4',5':9,10]tax-11-ene-2α,4,13α-triyl 4-acetate 2-benzoate 13-{(2R,3S)-3-[(tert-butoxycarbonyl)amino]- 3-(3-fluoropyridin-2-yl)-2-hydroxypropanoate}

tésétaxel (-)-2a-acétate, 3-benzoate et 6-[(2R,3S)-3-[[(1,1-diméthyléthoxy)= carbonyl]amino]-3-(3-fluoropyridin-2-yl)-2-hydroxypropanoate] de (2aS,2bR,3S,4S,6S,8aR,10S,11aS,11bR,13aR)-10-[(diméthylamino)méthyl]-4-hydroxy-7,11b,14,14-tétraméthyl-3,4,5,6,8a,11a,11b,12,13,13a-décahydro-4,8-méthano- 2H-oxéto[3'',2'':3',4']benzo[1',2':3,4]cyclodéca[1,2-d][1,3]dioxol-2a,3,6(2bH)-triyle

tesetaxel 2'-[(dimetilamino)metil]-1-hidroxi-5β,20-epoxi- 9α,10α-dihidro[1,3]dioxolo[4',5':9,10]tax-11-eno-2α,4,13α-triil 4-acetato 2-benzoato 13-{(2R,3S)-3-[(terc-butoxicarbonil)amino]- 3-(3-fluoropiridin-2-il)-2-hidroxipropanoato}


54

C46H60FN3O13

O

H

O

CH3

O

HH

O CH3

H NH

H3C

CH3

CH3

OHH

O

H O

O

OO

CH3

H3C

H3C

HO

N

F

OO

H NCH3

CH3

HH

tretazicarum tretazicar 5-(aziridin-1-yl)-2,4-dinitrobenzamide

trétazicar 5-(aziridin-1-yl)-2,4-dinitrobenzamide

tretazicar 5-(aziridin-1-il)-2,4-dinitrobenzamida

C9H8N4O5

NH2

O

NO2O2N

N

udenafilum udenafil 3-(1-methyl-7-oxo-3-propyl-4,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-

5-yl)-N-{2-[(2RS)-1-methylpyrrolidin-2-yl]ethyl}- 4-propoxybenzenesulfonamide

udénafil 3-(1-méthyl-7-oxo-3-propyl-4,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-[(2RS)-1-méthylpyrrolidin-2-yl]éthyl]- 4-propoxybenzènesulfonamide

udenafilo 3-(1-metil-7-oxo-3-propil-4,7-dihidro-1H-pirazolo[4,3-d]pirimidin-5-il)-N-{2-[(2RS)-1-metilpirrolidin-2-il]etil}-4-propoxibencenosulfonamida

C25H36N6O4S

N

NH

NN

SNH

OO

O CH3

CH3OCH3

N H

CH3

and enantiomeret énantiomèrey enantiómero


55

valategrastum valategrast 2-(diethylamino)ethyl N-(2-chloro-6-methylbenzoyl)-

4-(2,6-dichlorobenzamido)-L-phenylalaninate

valatégrast (2S)-2-[(2-chloro-6-méthylbenzoyl)amino]-3-[4-[(2,6-dichlorobenzoyl)amino]phényl]propanoate de 2-(diéthylamino)éthyle

valategrast 2-(dietilamino)etil N-(2-cloro-6-metilbenzoil)- 4-(2,6-diclorobenzamido)-L-fenilalaninato

C30H32Cl3N3O4

NH

O

ON CH3

CH3

OCH3

Cl

HN

Cl

ClO

H

valopicitabinum valopicitabine 3'-O-(L-valyl)-2'-C-methylcytidine

valopicitabine 4-amino-1-[3-O-[(2S)-2-amino-3-méthylbutanoyl]-2-C-méthyl-

β-D-ribofuranosyl]pyrimidin-2(1H)-one

valopicitabina 3'-O-(L-valil)-2'-C-metilcitidina

C15H24N4O6

N

NO

NH2

O

O

HO

H3C

OH

O

H3C

CH3

NH2H

volociximabum volociximab immunoglobulin G4, anti-(human α5β1 integrin)(human-mouse clone

p200-M heavy chain), disulfide with human-mouse clone p200-M κ-chain, dimer

volociximab immunoglobuline G4, anti-(intégrine α5β1 humaine), dimère du disulfure entre la chaîne lourde et la chaîne κ de l’anticorps monoclonal chimérique homme-souris p200-M

volociximab inmunoglobulina G4, anti-(integrina α5β1 humana), dímero del disulfuro entre la cadena pesada y la cadena κ del anticuerpo monoclonal quimérico hombre-ratón p200-M

C6434H9942N1706O2040S52


56

yttrium (90Y) tacatuzumabum tetraxetanum yttrium (90Y) tacatuzumab tetraxetan immunoglobulin G1, anti-(human α-fetoprotein) (human-mouse

monoclonal hAFP-31 γ1-chain), disulfide with human-mouse monoclonal hAFP-31 κ-chain, dimer, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid conjugate, yttrium-90Y chelate

yttrium (90Y) tacatuzumab tétraxétan chélate d'yttrium (90Y) d'immunoglobuline G1, anti-(α-fétoprotéine humaine) ; dimère du disulfure entre la chaîne γ1 et la chaîne κ de l'anticorps monoclonal de souris humanisé hAFP-31 liée à l'acide 2,2',2'',2'''-(1,4,7,10-tétraazacyclododécane-1,4,7,10-tétryl)= tétraacétique par une fonction amide

ytrio (90Y) tacatuzumab tetraxetán quelato d'ytrio (90Y) de la inmunoglobulina G1, anti-(α-fetoproteína humana) ; dímero del disulfuro entre la cadena γ1 y la cadena κ del anticuerpo monoclonal de ratón humanizado hAFP-31 vinculada al ácido 2,2',2'',2'''-(1,4,7,10-tetraazaciclododecano-1,4,7,10-tetril)= tetraacetico por una función amida

C6470H9971N1712O2007S4290Y

NN

NN

CO2-

CO2-

-O2C

90Y3+

O

NHIg

zabofloxacinum zabofloxacin 1-cyclopropyl-6-fluoro-7-[8-(methoxyimino)-2,6-diazaspiro[3.4]octan-

6-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid

zabofloxacine acide 1-cyclopropyl-6-fluoro-7-[8-(méthoxyimino)-2,6-diazaspiro= [3.4]oct-6-yl]-4-oxo-1,4-dihydro-1,8-naphtyridine-3-carboxylique

zabofloxacino ácido 1-ciclopropil-6-fluoro-7-[8-(metoxiimino)-2,6-diazaespiro= [3.4]octan-6-il]-4-oxo-1,4-dihidro-1,8-naftiridina-3-carboxílico

C19H20FN5O4

NN

CO2H

O

N

F

HN

NH3CO


57

zalutumumabum zalutumumab immunoglobulin G1, anti-(human epidermal growth factor

receptor)(human monoclonal 2F8 heavy chain), disulfide with human monoclonal 2F8 κ-chain, dimer

zalutumumab immunoglobuline G1, anti-(récepteur du facteur de croissance épidermal humain), dimère du disulfure entre la chaîne lourde et la chaîne κ de l’anticorps monoclonal humain 2F8

zalutumumab inmunoglobulina G1, anti-(receptor del factor de crecimiento epidérmico humano), dímero del disulfuro entre la cadena pesada y la cadena κ del anticuerpo monoclonal humano 2F8

C6512H10074N1734O2032S46


58

AMENDMENTS TO PREVIOUS LISTS

MODIFICATIONS APPORTÉES AUX LISTES ANTÉRIEURES MODIFICACIONES A LAS LISTAS ANTERIORES

Recommended International Nonproprietary Names (Rec. INN): List 30 Dénominations communes internationales recommandées (DCI Rec.): Liste 30 Denominaciones Comunes Internacionales Recomendadas (DCI Rec.): Lista 30 (WHO Drug Information, Vol. 4, No. 3, 1990) p. 2 artesunatum artesunate insert the following graphic formula:

artésunate insérer la formule graphique suivante:

artesunato insertáse la fórmula desarollada por la siguiente:

O

O

O

O CH3

HH3C

H

H

HO

H

CO2H

O

HCH3

Recommended International Nonproprietary Names (Rec. INN): List 43 Dénominations communes internationales recommandées (DCI Rec.): Liste 43 Denominaciones Comunes Internacionales Recomendadas (DCI Rec.): Lista 43 (WHO Drug Information, Vol. 14, No. 1, 2000) p. 70 suprimase insértese tezosentano tezosentán

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 proposed INN lists only.

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