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WHO Drug Information Vol. 24, No. 1, 2010

Prequalification of MedicinesProgrammeWHO Prequalification of Medicines

Programme: facts and figuresfor 2009 3

Regulatory HarmonizationUpdating medicines regulatory systems

in sub-Saharan African countries 6

International NonproprietaryNamesThe glycosylation pattern of epoetins 21

Safety and Efficacy IssuesDidanosine: serious liver disorder 25Bortezomib: updated safety information 25Deferasirox: renal events and gastro-

intestinal haemorrhage 25Sirolimus: drug monitoring assay

comparison 26Mycophenolate: pure red cell aplasia 26Fosamprenavir: myocardial infarction

and dyslipidaemia 27Exenatide: altered kidney function 27Drospirenone in oral contraceptives 28Glucose test strips 28HIV drug combination: safety review

of clinical trial data 28Sibutramine: ongoing safety review 29Becaplermin: contraindication in

patients with cancer 29ACSOM — advisory committee

on safety of medicines 29

Regulatory ScopeTobacco product regulation 30

Regulatory Action and NewsInfluenza vaccines: 2010–2011 northern

hemisphere 33European Medicines Agency: new

organizational structure andvisual identity 33

Risk management systems formedicinal products 34

Orciprenaline sulphate: registrationcancelled 35

Peramivir IV: emergency useauthorization 35

Carisbamate: withdrawal of marketingauthorization application 35

Benfluorex withdrawal 35Ethyl eicosapent: withdrawal of

marketing authorization application 36Olanzapine approved in adolescents 36Lisuride: withdrawal of marketing

authorization application 36Velaglucerase alfa approved for

Gaucher disease 37Pneumococcal 13-valent conjugate

vaccine approved 37Monoclonal antibody products approved

for chronic lymphocytic leukaemia 37Rosuvastatin: new indication approved 38Influenza A/H1N1: collection-to-

detection assay 38

Recent Publications,Information and EventsTSE tissue infectivity distribution

update 39Restricted availability of opioids for

cancer patients 39Transparency and the public pharma-

ceutical sector 40

Recommended InternationalNonproprietary Names List 63 41

WHO Drug Information

World Health Organization

Contents

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Announcement

The 14th International Conference of Drug

Regulatory Authorities (ICDRA) will be hosted by

the Health Sciences Authority, Singapore, in

collaboration with the World Health Organization

The ICDRA will take place in Singapore

from 30 November to 3 December 2010

Updated information is available at:http://www.icdra2010.sg

http://www.who.int/medicines/icdra

World Health Organization

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Prequalification of medicinessuccess in 2009In 2009, a record 44 medicinal productswere prequalified of which 39 are generic.By the end of 2009, the WHO list ofprequalified medicines totalled 237products manufactured in 16 countries.WHO prequalification “firsts” includedthree reproductive health products as wellas generic lopinavir/ritonavir, genericoseltamivir, generic tenofovir, cipro-floxacin infusion, generic ceftriaxone andgeneric abacavir oral solution.

Three medicines quality control laborato-ries (QCLs) were also prequalified: one inKenya and two in Singapore. At the endof 2009, a total of 11 QCLs had beenprequalified and a further 29 were work-ing towards becoming prequalified.

Updated invitations for expressions ofinterest to manufacturers to submitproduct dossiers for prequalification were

issued for antimalarial medicines, anti-tuberculosis medicines, HIV/AIDS-relatedmedicinal products, influenza-specificantiviral medicines and medicinal prod-ucts and reproductive health products.The updated invitations incorporateadditional products and/or take intoaccount revisions made to WHO treat-ment guidelines.

Assessment activitiesThe pace of dossier submission andassessment from previous years wasmaintained. Eighty-four dossiers weresubmitted for evaluation and 53 dossierswere accepted for evaluation. Sevendossier assessment sessions were heldin Copenhagen, during which 898 as-sessment reports were produced: 528 forHIV/AIDS-related products; 197 forantituberculosis medicines; 110 forantimalarial medicines; 28 for influenza-specific antiviral medicines and 35 forreproductive health products. The Copen-

The WHO Prequalification of Medicines Programme was launched in 2001 in part-nership with UNAIDS, UNICEF and the UN Population Fund, with support from theWorld Bank. Its focus is on tackling the quality problems commonly associated withmedicines for treating HIV/AIDS, malaria and tuberculosis. In 2006, the Programmealso laid the groundwork for prequalifying medicines and commodities for reproduc-tive health. This was in response to the fact that, in many developing countries, theneed for family planning and reproductive health services remains urgent.

Evaluation of medicines by the Programme includes assessment of data and infor-mation on safety, efficacy and quality. In addition, inspections are performed to as-certain compliance with good manufacturing practices. Inspection activities expandedin 2003 to include manufacturers of selected active pharmaceutical ingredients and,in 2004, to include clinical sites and contract research organizations. These are alsoinspected to verify compliance with good laboratory practices and good clinical prac-tices.

WHO Prequalification of Medicines Programme:facts and figures for 2009

Prequalification of MedicinesProgramme

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hagen sessions include a training compo-nent for assessors from developingcountries and are enabling a growingnumber of these to acquire stringentregulatory expertise. The Copenhagensessions also incorporate consultationsbetween assessors and applicants so thatthe latter can discuss technical issuesrelating to their dossiers. The consulta-tions benefit from the presence of a rangeof assessors with considerable experi-ence. Applicants pay their own costs toattend consultations and must be commit-ted to the prequalification process.

Problems continue to be seen regardingantituberculosis products: the number ofrelated dossiers continues to be low andtheir quality is often poor. The Program-me has therefore initiated a study toreview dossier deficiencies for theseproducts and determine which deficien-cies are most commonly observed ateach evaluation stage. (Study results willbe published and guidance on how toavoid deficiencies developed.) Addition-ally, members of the Programme teamand the WHO China country officeworked to secure funding from the Bill &Melinda Gates Foundation for a project toprovide technical support on qualityissues to manufacturers of fixed-dosecombination antituberculosis products. Itis hoped that this will lead to increaseddossier submissions for these products.

InspectionsProgramme inspectors carried out 50inspections in seven countries: 27 offinished pharmaceutical product manufac-turing sites; seven of active pharmaceuti-cal ingredient (API) manufacturing sites;ten of contract research organizations(CROs) and six of pharmaceutical QCLs.The majority of inspections were carriedout in India, followed by China.

A number of manufacturers were con-tacted in late 2009 and requested tosubmit their inspection reports fromstringent regulatory authorities together

with a report of corrective action they hadimplemented following these inspections.The Prequalification of Medicines Pro-gramme is investigating the possibility ofconducting a “desk review” of thesedocuments and of any relevant qualityreview reports prepared by the manufac-turers. Such review would be in lieu of anon-site inspection by WHO subject tospecified conditions. The aim is to avoidduplication of site inspections and tooptimize use of inspection resources. Inthe event, only two cases were found inwhich the inspection reports and correc-tive actions were considered to meet therequirements set by the inspection teamfor allowing postponement of an on-siteinspection by WHO. An amendment tothe WHO procedure for prequalification ofpharmaceutical products is now beingconsidered to make provision for this newprocess.

Advice and assistanceWHO assessors continued to providescientific advice to manufacturers during2009. This included review of bioequiva-lence study protocols and responding ona daily basis to specific questions relatingto quality, efficacy and safety. Newguidance was issued on Submission ofDocumentation for Prequalification ofMultisource (generic) Finished Pharma-ceutical Products approved by StringentRegulatory Authorities, and an alternativeprocedure for accepting second-line TBproduct dossiers for assessment.

The Programme organized ten technicalmissions to pharmaceutical manufactur-ers and QCLs in seven different coun-tries. Missions focused principally ongood manufacturing practice but also ondossier preparation and quality systemsin QCLs. It also organized 12 trainingworkshops and co-organized or sup-ported a further five workshops for nearly800 participants. Workshops ranged fromintroductory workshops on WHO Pre-qualification and how to meet require-ments, assessment of multisource inter-

Prequalification of Medicines Programme

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changeable medicines, and to the plan-ning, implementation and assessment ofstability studies.

Testing of medicines qualityThe pilot phase of an activity to sampleand monitor the quality of paediatric andsecond-line antiretrovirals and sulfa-methoxazole-trimethoprim for treatingHIV/AIDS was completed. Nearly 400medicines samples produced by 24manufacturers were collected, mostlyfrom treatment centres. Only threesamples failed quality testing and none ofthe failures were life-threatening forpatients. The results underscore that,provided procurement and distributionpractices are sound, medicines prequali-fied by the Programme can be viewedwith confidence by health workers andpatients alike.

The quality of antimalarial medicines wassurveyed in six African countries forartemisinin-based combination therapyand sulfadoxine-pyrimethamine oraldosage forms. Over 900 medicinessamples were collected from all levels ofthe distribution chain and informal marketand were screened using “minilabs” incooperation with the relevant nationalmedicines regulatory authority. Thereaf-ter, 306 samples were fully tested in thelaboratory: 74 samples were non-compli-ant and demonstrated a range of qualityproblems, including absence of the API intwo samples. A quality survey was alsoinitiated in Armenia, Azerbaijan, Belarus,Kazakhstan, Ukraine and Uzbekistan. Itfocuses on antituberculosis medicinescontaining rifampicin, isoniazid, kanamy-cin and ofloxacin. Testing is ongoing forthe 291 samples collected.

Norms and standards relevant to WHOprequalification activitiesThe 44th meeting of the WHO ExpertCommittee on Specifications for Pharma-ceutical Preparations adopted sevenmonographs for HIV and related condi-tions, five monographs for antimalarial

medicines, six monographs for antituber-culosis medicines and one monograph foran influenza-specific antiviral medicine.The Committee also adopted: an updateof good practices for quality controllaboratories; a guideline for the prepara-tion of a CRO master file; a guideline onrequalification of prequalification dossiers;various updates and revisions of goodmanufacturing practice texts; and anupdate of good distribution practices forpharmaceutical products. Each of thesenorms and standards is of direct rel-evance to the Programme’s activities.

Improving Prequalification of Medi-cines Programme servicesA business plan for the Prequalification ofMedicines Programme was completed inAugust 2009. It analyses the currentmandate and functions, maps perform-ance, estimates resources required forcoming years and makes recommenda-tions on how the Programme can improveorganization and management. The planprojects an economic return on invest-ment of 170:1 for the Programme for theperiod 2009–2013. The projection isbased on: projected availability of globalfunding for procuring medicines fortreating HIV/AIDS, TB and malaria;projected prequalification of 105 addi-tional medicines (around 90% of whichwill be generic medicines); and projectedestimated impact on additional volume ofmedicines that can be purchased as aresult of increased competition amonggenerics.

Survey of manufacturersIn late 2009, work started on develop-ment of a first survey of manufacturers.The aim is to obtain feedback on theservices provided by the Programme andto analyse where and how improvementsto those services might be made.

Further information on the WHO Prequalifica-tion of Medicines Programme, including thefull list of medicines prequalified by WHO canbe found at: http://www.who.int/prequal

Prequalification of Medicines Programme

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Regulatory Harmonization

An effective medicines regulatory system ensures that all pharmaceutical productson the market are safe, effective and consistently meet approved quality standards(1). The World Health Organization (WHO) works with its Member States in assess-ing national regulatory systems to identify gaps, develop strategies for improvementand support countries in their commitment to build national regulatory capacity.

The WHO report, Assessment of medicines regulatory systems in sub-SaharanAfrican countries (2), synthesizes the findings of rapid assessments performed overthe last eight years of national medicines regulatory authorities (NMRAs) in 26African countries: Angola, Benin, Botswana, Burkina Faso, Burundi, Cameroon, Chad,Democratic Republic of Congo, Cote d’Ivoire, Djibouti, Ethiopia, Gabon, Ghana,Kenya, Malawi, Mali, Mozambique, Niger, Nigeria, Rwanda, Senegal, South Africa,Sudan, United Republic of Tanzania, Uganda, Zambia. Although the emphasis ofthe missions was on capacity-building rather than a standardized comparison ofindicators, the findings give a useful insight into the regulatory situation in Africa andpotential areas for collaboration. The report sheds light on the urgent need for regu-latory capacity strenghtening in African countries and proposes action for sustain-able progress. A summary of the report is set out on the following pages.

Updating medicines regulatory systemsin sub-Saharan African countries

Medicines regulation indeveloping countriesMedicines are essential to health careand should be available to the inhabitantsof every country. Medicines regulationaims to ensure that medicines circulatingin national markets and internationalcommerce are safe, effective and of goodquality, are accompanied by completeand correct product information, and aremanufactured, stored, distributed andused in accordance with good practices.

Affordable products are now availablewith the potential to dramatically reducemorbidity and mortality in resource-constrained countries. Although Africancountries import most of their pharmaceu-ticals, the African Union has recentlystarted to promote local manufacture ofmedicines in Africa.

Globalization of commerce and themerging of pharmaceutical companieshas led to an increasing breakdown ofnational boundaries in medicines supply.Substandard and counterfeit pharmaceu-tical products are now reported from allparts of the world (3). The problem isgreatest in developing countries, whichhave insufficient funds for medicinesprocurement, and even fewer resourcesto enforce quality standards and protectthe medicines supply chain.

Norms and standards for medicinesquality are becoming more sophisticatedand make the assessment of new chemi-cal entities especially challenging. WHOcontinues to develop international normsand standards to serve as guidance fornational regulatory systems. In practicehowever, medicine quality standards aresubject primarily to the requirements in

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force in the country of destination (4).Regulating the increasingly complexchannels of medicines supply requiresconstant vigilance, adaptation and con-siderable organizational capacity andresources.

Aim of the WHO reportAssessments of medicines regulatorysystems in sub-Saharan African countriespresents assessments of regulatorysystems conducted in 26 sub-SaharanAfrican countries over the past eightyears. It identifies regulatory gaps andsuggests priority activities to strengthenregulatory capacity.

At the request of each country, nationalmedicines regulatory authority (NMRA)assessments were carried out between2002 and 2009 by teams composed ofWHO experts, staff from NMRAs and/orexternal consultants. Written terms ofreference and an agenda for the visitswere agreed beforehand with the regula-tory authority being assessed. Theduration of the visits varied depending onthe complexity of the country’s regulatoryfunctions, most visits took approximatelythree to five working days.

Data were collected by interviewingpersonnel, reviewing documents (manu-als, records, reports, files), analysing dataand/or observing activities. Findings wererecorded on a comprehensive datacollection tool developed by WHO (5)which has since been complemented by adetailed guidance document (6). A draftreport was submitted to the regulatoryauthority after the visit together with adrafted proposal for a plan of action. Themain aim of the visits, and the design ofthe tool itself, were geared towardsidentifying priorities for strengtheningregulatory capacity. They were notintended to provide comparable indicatorsof regulatory capacity over time.

The strengths and weaknesses identifiedby the country reports are a reflection of

their technical judgement of the authorstogether with the views expressed byrelevant national regulatory officials.

Country profilesThe 26 countries included in the reportrepresented 88% of the population ofsub-Saharan Africa in 2007. Key eco-nomic and health-related data are alsosummarized in the report (2).

Pharmaceutical sector data contained incountry reports indicated that Africancountries generally had:

• Limited pharmaceutical productioncapacity, while most depended mainlyon imports.

• Some pharmaceutical manufacturingactivity catering mainly for domestic andregional demand. However there weresome exporting countries.

• A diverse distribution chain, with varioustypes of unauthorized outlets suggest-ing the presence of an informal market.

In virtually all countries included in thereport, limited public funds were availablefor law enforcement in general and formedicines regulation in particular. Addi-tionally, there were indications of thepresence of parallel, unregulated medi-cines markets, posing a serious risk toindividual and public health.

Nevertheless, differences did exist in theefficiency of the measures implementedamong countries. This illustrates theimpact of political commitment and levelof resources allocated to medicinesregulation.

Regulatory frameworkLegislationWritten laws, Acts or Statutes enacted byParliament give the NMRA the power tocontrol medicines. Regulations preparedunder the authority of an Act providedirections on how regulatory functions are


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to be carried out. Guidelines are alsoneeded to interpret legislation and adviseon how to comply with a regulation. Theway in which these legal and explanatorytexts are drafted affects the efficiency ofmedicines regulation.

The legal framework should allow effec-tive implementation and provide ad-equate powers to the NMRA. Legislationshould cover all products for whichmedicinal claims are made as well asrelated manufacture and trade activities inthe public and private sectors. Countriesshould update their medicines legislationand regulations regularly to reflect na-tional realities and to address new phar-maceutical issues as they arise (1).

Key findings

• In most countries, legislation hadevolved over many years. In only threecountries had a medicines regulationAct been adopted later than 2000.

• Successive regulations and decreeshad created a complex legal frameworkwith overlaps and grey areas.

• Regulations for specific regulatoryfunctions were missing in some coun-tries, especially where the NMRA wasundergoing transformation.

Regulatory scopeIn the last few decades, expansion ofregulatory scope has been considered inmany countries (7). A medicine has beendefined as “Any substance or pharmaceu-tical product for human or veterinary usethat is intended to modify or explorephysiological systems or pathologicalstates for the benefit of the recipient” (8).In addition to conventional medicines forhuman use, this definition also includesbiological medicines (including vaccinesand blood products), veterinary medi-cines, and traditional and herbal medi-cines, although the latter category ischallenging to define and to regulate (9).

All types of medicines should be regu-lated by the NMRA. At the same time,implementation of medicines regulationshould not be compromised by other,non-regulatory activities exerted by theNMRA.

Key findings

• Seventeen of 26 NMRAs (65%) had themandate to control veterinary medi-cines. In four countries veterinarymedicines were controlled by anotherMinistry, such as the Ministry of Agricul-ture or Livestock.

• Eighteen of 26 NMRAs (69%) had somepolicy or provisions to deal with tradi-tional or herbal medicines. While elevenof these registered traditional or herbalmedicines, another two were about tostart doing so.

• NMRAs in eleven countries (42%)regulated a wide scope of products,which included foods, poisons, pesti-cides, bottled water, cosmetics and/oranimal food supplements.

• In seven countries, the NMRA wasinvolved in designing and implementingnational medicines strategies, imple-menting legislation or coordinatingpublic sector medicines supply; in onecase a clearly distinguished unit was incharge of policy issues.

Organizational formsOne central authority should be account-able for the overall effectiveness ofmedicines regulation. It should havegovernment backed legal power toacquire and use resources, recruit anddismiss staff, and make independentdecisions. The choice of a specific organi-zational form will have an impact on theautonomy, visibility and accountability ofan NMRA and would affect efficiency inmedicines control.


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Key findings

Historically, most NMRAs in Africa startedlife as departments under the Ministry ofHealth. Organizations of this type havelittle autonomy. They cannot recruit theirown staff, nor can they offer adequatesalaries to attract and retain qualifiedexperts. With the maturation of regulatorysystems, some countries are movingaway from this model and are establish-ing their NMRAs as autonomous bodiesor as centralized parastatal agencies withtheir own management structures.

• Seventeen of 26 authorities (65%) weredepartments of the Ministry of Health,with very little or no autonomy to man-age their own funds and human re-sources.

• Seven NMRAs (27%) were in transitionor not formally constituted at the time ofthe visit.

Regulatory functionsNMRA responsibilities should cover allmedicines regulatory functions andshould be performed in a balancedfashion.

If functions are distributed betweendifferent authorities, either horizontally(e.g., ministry of health, ministry ofagriculture) or vertically (federal, state/regional and local governments), acentral coordinating body should beaccountable for all aspects of medicinesregulation in the country (1).

Key findings

• Four of the 26 NMRAs (15%) carried outfunctions of marketing authorization,licensing, inspection, quality control andpharmacovigilance together under oneumbrella.

• Seventeen NMRAs (65%) had access toa functional national regulatory qualitycontrol laboratory, while seven of these

laboratories were part of the NMRA. Inone of the remaining countries, therewas an NMRA laboratory which hadceased to function.

• Most countries had fragmented regula-tory systems. Gaps and overlaps ofresponsibilities were common, espe-cially in licensing (involving the Ministryof Public Health or Ministry of Trade)and inspection (involving pharmaceuti-cal councils, regional authorities orpublic health inspectorates).

• Decentralization and cooperationbetween authorities was problematic;12 reports highlighted the lack ofcommunication at operational level.

• In many cases, regulatory functionswere not operational and in some casesauthorities were not legally delegated.

Structure and managementFundingSustainable funding for NMRAs should bederived from various sources:

• Fees, which contribute significantly tooperational costs without being too highto discourage applications.

• Public funding, to ensure a certainindependence from the parties thatMNRAs are mandated to regulate.

• Donations to supplement limited publicfunds.

NMRAs should have the autonomy toretain and use the fees collected forservices provided for their own purposes.

Key findings

• Most NMRAs derived their funding frommore than one source, although theproportions varied from one country toanother.


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• Fees were commonly charged for initialmarketing authorization, renewal andretention. More rarely, fees werecharged for importation of medicines,inspection, analysis of samples andregistering persons and premises.

• Generally, the fees were lower than thecost of services rendered, and were notretained or redistributed in full.

• Nine NMRAs depend on governmentfunding, with all fees paid directly to thetreasury and not redistributed. FourNMRAs also receive donor funding.Funds allocated by the states were notalways released on time.

• None of the NMRAs assessed hadadequate and sustainable funding tocover operations.

Human resource managementPersonnel engaged in medicines regula-tion should be individuals of integrity andbe appropriately trained and qualified.

Human resource development pro-grammes should be made available toenable staff to keep up with develop-ments in pharmaceutical science andtechnology.

Key findings

In general, human resource managementwas virtually non-existent. This was thecase especially where an NMRA was notgiven importance by the Ministry ofHealth. As a result, lack of qualified staffaffected critical regulatory functions whilespecific shortcomings included thefollowing.

• Only two of the 26 NMRAs (8%) had ahuman resource development plan,which was however not specific to thetasks of the NMRA. Specific trainingneeds and difficult access to sources ofcurrent information were noted in mostcountries.

• Job descriptions for key personnel weredescribed as absent in five countries,and as unclear or outdated in four. Fourreports mentioned the absence of anorganigram.

• In some authorities, responsibilitieswere not assigned appropriately. OneNMRA director was at the same timethe director of the national laboratory,resulting in an unmanageable workload.Three others were simultaneously incharge of public sector medicinessupply or tenders, creating a potentialconflict of interest.

• Four reports mentioned the absence ofa legal adviser on the NMRA’s payroll.

Quality management systemsNMRAs perform critical and sensitivefunctions such as handling and assessingmarketing application dossiers containingconfidential information, inspectingfacilities and handling site master files.A quality management system (QMS)should ensure that the operations of anNMRA are carried out to defined, uniformstandards, and that each step of theregulatory process is identified anddocumented.

Key findings

• Four NMRAs (15%) were in the processof implementing a QMS and had ele-ments of the system in place, two otherswere drafting a system.

• None of the NMRAs had implemented acomprehensive QMS.

Impartiality and transparencyMedicines regulation is a public policythat regulates private sector activities inorder to attain the promotion of publichealth. Conflicting interests thereforeneed to be recognized and managedappropriately.


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To provide credible regulatory services,NMRAs must have specific measures inplace to avoid conflict of interest indecision-making, to ensure confidentiality,to make their rules and decisions trans-parent, and to consult with stakeholders.

Key findings

• Nine of the 26 NMRAs had a dedicatedweb site. Five of these were in need ofupdating, one was not functioningcorrectly at the time of the visit. As atNovember 2009, seven additional siteswere identified (10).

• Consultation with stakeholders tookplace in most countries, although ittended to be limited to specific issues orgroups.

• Current information was not alwayspublicly available: lists of approvedproducts or establishments were oftenmissing and/or outdated. Little informa-tion was made public on decision-making.

• Twenty-three of 26 NMRAs (88%) hadno written declaration of interest orconfidentiality agreements in place,although some had general rules ofconduct such as a code for civil serv-ants. In the three countries which didhave a specific written system, this didnot apply to all technical staff involved.

Medicines registrationA core regulatory function is the authori-zation of medicines based on a scientificassessment of their safety, efficacy andquality.

To assess applications for marketingauthorization, NMRAs need:

1. Legislation giving the NMRA the powerto grant, renew, vary, suspend andwithdraw marketing authorizations.

2. Guidelines for applicants setting outthe conditions, content and format ofapplications, and the detailed technicalrequirements against which dossiers willbe assessed, based on internationalguidelines (11–13).

3. Standard operating procedures (SOPs)to assess submissions, and standardformats to communicate and publish theoutcomes.

4. Involvement of an advisory committeeand expert assessors in adequate num-bers with specific, current expertise.

5. Logistics for management, securestorage, retrieval and exchange of datawith other regulatory departments, as wellas access to current scientific and techni-cal information.

6. Mechanisms to consider decisionsfrom more stringent NMRAs.

Key findings

• Some evaluation of technical docu-ments was performed in 19 of 26countries (73%) to varying degrees ofstringency, at least for generic medi-cines.

• The technical standard of evaluationswas generally not in line with WHOstandards. For example, in at least fourcountries, guidelines did not exist. Atleast three NMRAs did not require themanufacturer to have GMP certification.At least six NMRAs did not assesssummaries of product characteristics(SPC).

• The capacity to assess applications fornew innovator products was almostnon-existent.

• NMRAs in seven countries conductedonly an administrative review of docu-ments, or no review at all at the time ofthe assessment.


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Legal basis and regulations

• Eighteen of 26 NMRAs (69%) operatedwithin a legal basis which empoweredthem to assess applications for market-ing authorization, with regulations thatbriefly outlined the requirements orlisted the components of dossiers to besubmitted for different types of products.

• Provisions for renewal of marketingauthorizations were in place, usuallyevery five years.

• Seven countries had provisions whichexempted wide ranges of products(such as public sector imports or dona-tions) from registration or from specificrequirements irrespective of quality risk.For example, in one country, all oralsolid-dose anti-infectives were exemptfrom in vivo bioequivalence studies.

GuidelinesSome countries had guidelines whichdescribed the required content of submis-sions and gave brief instructions, but didnot give sufficient guidance on technicalissues such as bioequivalence andstability. Others described the administra-tive steps and others provided onlychecklists. A specific format for submis-sions was not required in any of thecountries.

• Only three NMRAs (12%) provideddetailed technical guidelines (but not inline with WHO Guidelines).

Procedures for assessmentWritten SOPs for dossier assessmentwere either absent or they described onlyadministrative steps such as checking thecompleteness of dossiers, payment offees or inclusion of samples, or werechecklists outlining elements of theassessment methodology.

• Adequate SOPs for dossier assessmentwere in place in only three countries.

Timeframes for assessment of applica-tions ranged from three months to fiveyears, depending on the complexity ofassessments and available resources.Fast-track mechanisms existed for certainproduct types. Two reports mentioned theshort preparation and meeting timesavailable for committee members to maketheir decisions, meaning that they maynot be able to read all documents andcarry out any real assessment.

• Although overall assessment timeframes were long, little time was avail-able for an in-depth thorough assess-ment by experts due to schedulingdifficulties and backlogs.

Expert assessorsMost NMRAs had formal advisory com-mittees. However, not all committeeswere operational, bringing assessment toa halt in two countries. Eleven countriesused external experts, two of themexclusively. Appointment of committeemembers and experts was not necessar-ily based on specific regulatory expertise,and provisions for confidentiality anddeclaration of interest were lacking inmost countries.

• Twenty-four of 26 country reports (92%)mentioned the shortage of adequatelyqualified assessors as an obstacle totimely dossier evaluation.

Logistics

• Only four NMRAs (15%) had appropri-ate archiving space to store confidentialdata securely.

• Only six of 26 countries (23%) hadcoherent, networked computerizedsystems designed for medicines regis-tration. Nine (35%) had only manualsystems.

The latter shortcoming affected transpar-ency and information-sharing with other


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departments. Lists of registered productswere not readily available, which made itdifficult to verify the registration status ofmedicines circulating in the market andthose being imported. The countrieswhich did publish a list did not include theapproved summary of product character-istics (SPC) needed to verify packageinserts, information for health profession-als and advertising claims.

Recognition of decisionsmade by other NMRAsCertificates of pharmaceutical products(CPPs) issued under the provisions of theWHO Certification Scheme on the Qualityof Pharmaceutical Products Moving inInternational Commerce (14) werecommonly requested as part of applica-tions, but usually without considering thecapacity of the issuing regulatory author-ity to certify that the data on the certifi-cates was correct. Conversely, one reportfrom an exporting country mentioned thatthe NMRA “issues CPP without ascertain-ing that all prerequisites as specified byWHO are fulfilled”.

• Only two NMRAs (8%) explicitly reliedon other regulatory bodies/organizationswhich they considered stringent, includ-ing the WHO Prequalification Pro-gramme (15).

The lack of mechanisms and proceduresthat would enable NMRAs to benefit fromthe scientific assessments and inspec-tions carried out by other well resourcedand established regulators is a majorcause of concern, as most of the authori-ties in the region have limited humanresources and scientific expertise. (SeeFigure 1.)

Licensing of pharmaceuticalestablishmentsHealth budgets in African countries arelow and a high percentage of health costsare paid out of pocket. There are manytypes of medicines outlets not managedby a pharmacist. Concerns about theparallel medicines market were voiced inmost country reports, such as this typicalstatement: “The illicit medicines markethas become a real plague in the country.All therapeutic classes can be found,including psychotropic medicines, andthere is no national strategy to combatthis situation.”

A mandatory system of licensing manu-facturers, wholesalers/distributors andretailers is essential to ensure thatmedicines conform to acceptable stand-ards of quality, safety and efficacy untilthey reach the end user. Licensing mustbe complemented by inspections andmarket surveillance.


Figure 1. Resources for medicines registration

Nu

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f N

MR

As

25

20

25

20

5

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Legal basis Guidelines SOPs for Assessors Secure IT system outline (tech. detail) assessment filing space

Adequate Existing but inadequate Not existing No information or not applicable

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NMRAs should ensure that all premisesand practices used to manufacture, store,distribute and supply pharmaceuticalproducts to patients comply with currentguidelines on good manufacturing prac-tice (GMP), good distribution practice(GDP) and good pharmacy practice(GPP).

Key findings

• All countries except one had systems inplace to license pharmaceutical estab-lishments.

• Authorities other than the NMRA wereinvolved in licensing in 16 countries(62%), resulting in overlaps, grey areasand gaps in the control of pharmaceuti-cal activities.

• Decentralization of licensing, involvingregional authorities, was not organizedefficiently. Lack of coordination wascommonly highlighted; lax control oflicensing by local authorities wasmentioned specifically in three countryreports.

• Licences or renewals were grantedwithout inspection in some instances.

• In practice, good practices requirementswere poorly enforced. In one countryonly one of many established manufac-turers was licensed.

Import and export controlWith the rapid introduction of high-technology medicines into import, exportand distribution networks (including e-commerce), the safety, quality andefficacy of medicines on the market arematters of considerable concern.

Setting in place a registration systemshould not be considered as the onlymechanism to guarantee the quality ofproducts on the market. It should becomplemented by other control measuressuch as the authorization of each act of

importation of pharmaceutical productson the basis of the product’s registrationstatus.

Products for export should be subject tothe same standards as those for domesticconsumption.

Key findings

• Control of imported products was weak.In at least eight countries (31%) therewas no efficient system to verify themarketing authorization status andexemptions for imported products.

• Cooperation with police and customswas consistently described as problem-atic.

• Control of exports was not stringent.One report mentioned manufacturers’illegal practice of issuing “free salecertificates”, which leaves all control tothe receiving country.

InspectionsInspections conducted on pharmaceuticalfacilities should enable medicines regula-tory authorities to monitor whether phar-maceutical activities are carried out inaccordance with approved standards andguidelines. The efficiency of inspectionshas a direct impact on the extent to whichmedicines control is enforced.

A legal basis must be in place for inspec-tions and enforcement. Planning ofroutine inspections should be imple-mented to regularly check compliancewith relevant good practices in place.

A quality management system (16)should ensure that inspections areplanned, conducted, documented andfollowed up in a consistent way, based onrisk assessment.

Sufficient qualified inspectors and logisticresources must be available to cover thearea to be regulated.


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Key findings

• A legal basis empowering the relevantauthority to perform inspections was inplace in 17 countries.

• GMP was not required in at least ninecountries. In at least two countrieswhere GMP was required, none of theestablished manufacturers had GMPcertification.

• Only five of 26 countries (20%) hadpublished GMP guidelines meetingWHO standards (two had national texts,and another three used the WHO text).Only one country had adequate GDPguidelines.

• SOPs for inspection, if any, were mostlyin checklist format and were not com-prehensive.

• No NMRA had a comprehensive qualitymanagement and planning system forinspections in place.

• Shortages of qualified inspectors were auniversal problem. The need for specifictraining of inspectors in current GMPwas commonly highlighted.

• Potential conflicts of interest werenoted. Inspectors could be pharmacytechnical directors or supervisors in atleast three countries. Pharmacists fromprivate retail and manufacturing facilitieswere used as inspectors in another.

• Inadequate logistic resources, espe-cially means of transport and communi-cation, were a major constraint. Theeffectiveness of inspections sufferedfrom these constraints. (See figure 2.)

Quality controlQuality control (QC) aims to verify thatproducts comply with the specifications ofthe marketing authorization. QC testing ofpre-marketing samples can be useful tosome extent, although applicants maytake measures to ensure that theirregistration samples will not fail. However,the same quality standards may not bemet by each batch of product put on themarket. QC testing of post-marketingsamples thus acts as a deterrent againstnegligent or fraudulent manufacturing andtrading practices.

NMRAs should have access to a qualitycontrol laboratory with adequate capacityto undertake quality surveillance.


Figure 2. Resources for inspections

25

20

25

20

5

0

Nu

mb

er o

f N

MR

As

Adequate Existing but inadequate Not existing No information or not applicable

Legal basis Published Standard Quality Inspectors Logistics GMP text Operating Management

Procedures System

16


QC facilities should have sufficientqualified personnel and the necessaryequipment and materials, and mustoperate according to established stand-ards. A quality management system, suchas ISO 17025 (17), provides a frameworkfor QC laboratories to operate accordingto defined procedures and standards.WHO’s good practices for national phar-maceutical control laboratories (18) andguidance on good laboratory practice (19)provides detailed advice on organiza-tional and technical issues.

If dossiers are assessed and samplestested, good collaboration betweenassessors and laboratory staff needs tobe in place.

Key findings

• A QMS was in place at five (29%) of the17 functioning regulatory laboratories;three others had partial systems whichwere lacking essential elements andwere not fully operational.

• Satisfactory staffing and equipmentwere in place in the majority of cases,but six laboratories were housed ininadequate buildings.

Ten reports mentioned QC testing for pre-marketing applications. However, thelaboratories were not always given therelevant dossiers, manufacturer’s refer-ence materials and validated methods.

Market surveillance

Product quality monitoringSubstandard pharmaceuticals maycirculate on the market if good practicesin manufacturing, distribution and storageare not adhered to.

In addition, counterfeiting — the produc-tion and distribution of medicines that aredeliberately and fraudulently mislabelledwith respect to identity and/or source —is becoming an increasing problem. Itrequires a coordinated response from

different sectors both at country level andinternationally (20). In both cases, thedeficient products pose a risk for indi-vidual and public health.

A risk-based system of inspections andsampling should be in place to monitorthe quality of pharmaceutical products onthe market. Manufacturers should beobliged to report complaints and qualityproblems to the NMRA. An effective recallprocedure to remove defective productsfrom the market should be in place.

The NMRA should coordinate an anti-counterfeiting programme with all con-cerned parties, including industry, cus-toms, police and any other stakeholdersinvolved in trade or distribution of phar-maceuticals.

Key findings

• Fourteen of 26 NMRAs (54%) lacked aquality monitoring programme alto-gether; seven had the capacity to testsamples in case of complaints or in theframework of specific programmes, andonly five (19%) had a systematic ap-proach.

• Twenty of 26 NMRAs (77%) lacked awritten procedure to organize an effec-tive recall; of the existing six proceduresthree needed clarification. Five reportsnoted the lack of batch traceabilityneeded to recall products. This findingis consistent with the general absenceof published GDP guidelines.

• Anti-counterfeiting measures includedinspections and surveillance in fivecountries and awareness programmesin three. No country had a specific,comprehensive programme in place atthe time of the visits.

PharmacovigilancePre-marketing clinical trials are usuallyconducted on a small number of volun-teers. Not all adverse reactions can be


17


anticipated from these studies. NMRAsshould implement a system to monitoradverse events. For this to be effective,there must be a high probability foradverse events to be identified andreported, reports must be reviewed andvalidated by experts, results must be fedback, and appropriate regulatory actionmust be taken.

Key findings

• Eight of 26 countries collected reportson adverse events, with three of theprogrammes being sufficiently estab-lished to contribute a sizeable numberof results. Seven of the eight countrieswere members of the WHO Programmefor International Drug Monitoring (seehttp://www.who-umc.org/).

• Where it existed, pharmacovigilancewas generally not well integrated withother regulatory activities. Also, clinicalsurveillance measures implemented byspecific national or NGO treatmentprogrammes were not organized orenvisaged.

Medicine promotion and advertising,provision of drug informationInformation propagated through promo-tion and advertising can significantlyinfluence the way in which medicines areprescribed by health professionals andused by consumers. Inaccurate andmisleading information therefore poses ahealth risk.

NMRAs should control promotion andadvertising to ensure that any claimsmade correspond to the approved sum-mary of product characteristics (SPC).They should also provide independentinformation on medicines to the publicand health professionals.

Key findings

• Most countries had some legal provi-sions for the control of medicinespromotion. Seven of 26 countries (27%)

controlled pharmaceutical promotion tovarying extents.

• In 19 countries (73%) there was nocontrol of promotion and advertising inpractice, meaning that even if theregulations were in place, they were notimplemented.

• At least 13 NMRAs did not provide anyindependent medicines information tothe public.

Oversight of clinical trialsClinical trials are an essential componentof pharmaceutical research and develop-ment. They serve to establish the safetyand efficacy of new medicines, and todevelop new treatment uses of wellknown medicines. Clinical trials alsoinclude in vivo bioequivalence studiescarried out with generic medicines toestablish their therapeutic interchange-ability with originator products. In all thesetypes of studies the ethical rights and thesafety of trial subjects must be protected,and the methodology must be designedin such a way as to arrive at useful,scientifically valid results.

NMRAs should control clinical trials jointlywith external bodies such as national orinstitutional ethics committees. Trialsshould conform with ethical principles formedical research involving human sub-jects and the Declaration of Helsinki (21).Guidelines by the Council of InternationalOrganization of Medical Sciences(CIOMS) provide valuable additionalinformation on research ethics.

WHO guidelines for GCP (22) and GLP(19) should be followed. GMP of investi-gational products should be verified.Other more specific guidelines on clinicalresearch may apply.

Trials should be monitored for compliancewith all applicable guidelines. Investiga-tors should be required to report on theoutcomes promptly, including any seriousadverse events encountered.


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Key findings

• In 18 of 26 countries (69%) clinical trialswere controlled to some extent, mostlywith regard to ethical review.

• Where ethics committees were involved,NMRAs retained little or no control dueto lack of capacity, unclear assignmentof responsibilities or non-representationin the relevant committees.

• Adherence to GLP and GCP was not arequirement in 22 countries (85%);detailed GCP guidelines were found inonly two countries (8%).

• Eight reports mentioned the absence ofimport controls and GMP requirementsfor investigational products.

• Only four country reports mentioned thatinspections of clinical trials were beingconducted.

ConclusionsThe countries included in this report hadlegal provisions for the most essentialneeds of medicines control. However,their regulatory systems presented someweaknesses. Generally, the legal frame-work had evolved over time, resulting in afragmentation of responsibilities with gapsand grey areas and a multitude of provi-sions which were difficult to implement.

Many NMRAs were allowed little powerand autonomy, and were unable tooversee the full range of regulatoryfunctions, with few having systems foraccountability or managerial commitment.Lack of sustainable funding restrictedoperations to a great extent. Virtually allNMRAs suffered from staff shortages. Forthe most part, assessors and inspectorswere unable to satisfactorily attain thelevel of scientific and technical expertiseneeded to fully implement regulatorytasks. Many regulatory requirements andprocesses were not in line with recom-mended WHO standards.

As a result of these drawbacks, medi-cines regulation was not being carried outto the fullest extent. The findings confirmthe results of a 2004 questionnaire surveyconducted by WHO in 38 African MemberStates, which found that 90% of countrieswere in a situation which did not allowthem to adequately carry out regulatoryfunctions (23).

Despite the universally scarce resourcesand the health workforce crisis experi-enced throughout sub-Saharan Africa,marked differences were noted in therelative efficiency of medicines controlamong countries, showing that politicalcommitment at national level can make adifference.

On the positive side, many countries weregreatly committed to improving theirmedicines regulatory capacity: reviews ofsystems were invited and regulatoryrestructuring is being adapted. However,in many cases, the transformation proc-ess has created new administrativehurdles for effective decision-making,management and release of funding.

The follow-up assessments conducted infour countries showed progress in spe-cific areas. However, for a sound, well-resourced national medicines regulatorysystem to operate within the difficultconditions imposed by African markets,commitment must be long term.

The way forward should be towardseffective implementation of medicinescontrol in practice. Political will andsubstantial human and financial re-sources will be needed for this purpose.Countries will need to take concertedaction if they are to expand access tomedicines of assured quality and safetyfor their populations. It was felt that thefollowing approaches would be the mostuseful in building regulatory capacity inAfrica.


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WHO should:

• Encourage African countries to provideNMRAs with adequate organizationalstructure, sufficient autonomy andsustainable resources to enable them tocarry out operations.

• Encourage and assist African countriesto regularly assess their own regulatorysystems in a standardized way. TheWHO assessment tool and the accom-panying guidance have been developedfor this purpose.

Countries should:

• Consider mechanisms to share theoutcomes of regulatory assessmentsamong NMRAs.

• Work towards effective implementationof all essential regulatory functionsunder the umbrella of an NMRA net-work.

• Continuously harmonize, adapt andupdate the legal framework for medi-cines regulation based on internationallyrecognized norms, standards and bestpractices.

• Provide specific, relevant training forassessors, inspectors and other techni-cal staff, in line with current technicalrequirements and good practices.

References

1. World Health Organization. Effectivemedicines regulation: ensuring safety, efficacyand quality. WHO Policy Perspective onMedicines No. 7. Geneva: WHO, 2003. http://apps.who.int/medicinedocs/pdf/s4921e/s4921e.pdf

2. World Health Organization. Assessment ofmedicines regulatory systems in sub-SaharanAfrican countries (under preparation) http://www.who.int/medicines

3. Caudron JM, Ford N, Henkens M et al.Substandard Medicines in resource-poorsettings: a problem that can no longer beignored. Trop Med Int Health. 2008;13(8):1062–72. http://www.msf.org.za/docs/ScientificDocsTMIH2008_Vol13_ sub-standards.pdf

4. US Pharmacopeia Drug Quality andInformation Program. Matrix of Drug QualityReports in USAID-assisted Countries. July1st, 2008. Available at www.uspdqi.org

5. World Health Organization. Data collectiontool for assessment of regulatory authorities.http://www.who.int/medicines/areas/quality_safety/regulation_legislation/assess-ment/en/index.html

6. World Health Organization. PracticalGuidance for Conducting a Review (based onthe WHO Data Collection Tool for the Reviewof Drug Regulatory Systems). RegulatorySupport Series, No.12. 2007. http://www.who.int/medicines/

7. World Health Organization. RatanawijitrasinS, Wondemagegnehu E. Effective drugregulation: A multicountry study. Geneva:2002. http://www.who.int/medicines

8. World Health Organization. Guidelines forregistration of fixed-dose combination medici-nal products. Annex 5. In: Technical ReportSeries, No. 929, 2005. http://whqlibdoc.who.int/trs/WHO_TRS_ 929_eng.pdf

9. World Health Organization. National policyon traditional medicine and regulation ofherbal medicines. Report of a WHO globalsurvey. 2005. http://apps.who.int/medicinedocs/collect/medicinedocs/pdf/

10. World Health Organization. List of Globallyidentified Websites of Medicines RegulatoryAuthorities (2009). http://www.who. int/entity/medicines/areas/quality_safety/regulation_legislation/ListMRAWebsites.pdf

11. World Health Organization. Marketingauthorization of pharmaceutical products withspecial reference to multisource (generic)products: A manual for drug regulatory


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authorities. Regulatory Support Series, No. 5.WHO/DMP/RGS/98.5 (1999) http://www.who.int/prequal/info_general/documents/

12. World Health Organization. Multisource(generic) pharmaceutical products: guidelineson registration requirements to establishinterchangeability. Annex 7. In: TechnicalReport Series, No. 937, 2006. http://whqlibdoc.who.int/trs/WHO_TRS_ 937_eng.pdf

13. World Health Organization. Guidelines fororganizations performing in vivo bioequiva-lence studies. Annex 9. In: Technical ReportSeries, No. 937, 2006. http://whqlibdoc.who.int/trs/WHO_TRS_937_ eng.pdf

14. World Health Organization. Guidelines forimplementation of the WHO certificationscheme on the quality of pharmaceuticalproducts moving in international commerce.Annex 10. In: Technical Report Series, No.863, 1996. Current version of the guidelineavailable at http://www.who.int/medicines/areas/quality_safety/regulation_legislation/certification/en/

15. World Health Organization. Procedure forprequalification of pharmaceutical products.Annex 3. In: Technical Report Series, No. 953,2009. http://www.who.int/medicines/publica-tions/pharmprep/pdf_trs953.pdf#page=164

16. World Health Organization. Qualitysystems requirements for national goodmanufacturing practice inspectorates. Annex8. In: Technical Report Series, No. 902, 2002.http://apps.who.int/prequal/info_general/documents/TRS902/WHO_TRS_902-Annex8.pdf

17. International Organization for Standardiza-tion. General requirements for the compe-tence of testing and calibration laboratories.ISO/IEC 17025:2005. 2005.

18. UNDP/World Bank/WHO Special Pro-gramme for Research and Training in TropicalDiseases (TDR). Handbook. Good laboratorypractice (GLP). Quality practices for regulatednon-clinical research and development (2001)at http://www.who.int/tdr/svc/publications/

19.World Health Organization. Good practicesfor national pharmaceutical control laborato-ries. Annex 3. In: Technical Report Series, No.902, 2002. http://apps.who.int/prequal/info_general/documents/TRS902/WHO_TRS_902-Annex 3.pdf

20. World Health Organization. Fact sheet oncounterfeiting. Key facts. July 2009. http://www.who.int/medicines/services/counterfeit/CfeitsFactSheetJuly09.pdf

21. World Medical Association. DeclarationOf Helsinki — Ethical Principles for MedicalResearch Involving Human Subjects,(amended by the 59th WMA General Assem-bly, Seoul, October 2008). http://www.wma.net/en/30publications/10policies/b3/index.html

22. World Health Organization. Guidelines forgood clinical practice (GCP) for trials onpharmaceutical products. Annex 3. In: Techni-cal Report Series, No. 850, 1995. http://www.who.int/medicinedocs/collect/medicinedocs/pdf/whozip13e/whozip13e.pdf

23. Organisation mondiale de la Santé,Comité Régional de l’Afrique. Cinquante-sixième session, Addis-Abéba, Ethiopie, 28août–1er septembre 2006. Autorités deréglementation pharmaceutique: situationactuelle et perspectives. Rapport du Directeurrégional. http://www.afro.who.int/rc56/docu-ments/french/afr_rc56_11_ autorites_reglement_ pharmaceutique.pdf


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The glycosylation patternof epoetinsThe human gene for erythropoietin wascloned in the early 1980s and recom-binant production processes were set upby several companies shortly thereafter.Commencing in 1989, these processeshave led to the introduction of two thera-peutic compounds onto the market,epoetin alfa and epoetin beta. Both ofthese recombinant versions of humanerythropoietin are manufactured inengineered Chinese Hamster Ovary(CHO) cells.

In parallel with epoetin alfa and epoetinbeta development, two other versions ofepoetins have been developed. One wasproduced in Baby Hamster Kidney (BHK)cells and another in C127 (mouse epithe-lial) cells. The BHK product received theInternational Nonproprietary Name (INN)epoetin omega and the C127 productepoetin gamma. Neither of these twoproducts reached the market in theEuropean Union, North America or Japanfor intellectual property reasons. Epoetinomega, developed by Elanex, has beenmanufactured in several developingcountries and used in Latin America, Indiaand other countries for many years underdifferent trade names (Epomax®; Hemo-max®, etc.).

Further development involved the use ofa human fibroblast cell line (HT1082)producing erythropoietin by activating theendogenous erythropoietin gene. Thisproduct, under the INN epoetin delta, was

well characterized, clinically tested,approved and distributed under the brandname Dynepo® in the European Union.Almost at the same time as Dynepo®appeared on the market, the first biosimi-lar epoetin products were introduced: aproduct developed by Sandoz wasmarketed under three brands (Binocrit®;Epoetin alfa®; Abseamed®) and a prod-uct developed by Stada/Hospira mar-keted under two brands (Silapo®;Retacrit®). Common to all biosimilarepoetins so far is the claim of similarity toepoetin alfa and production in CHO cells.The INN they use is rather epoetin alfa(Sandoz products) or epoetin zeta (Stada/Hospira products). A further epoetinproduced in CHO cells has recently beenapproved in the European Union as a denovo development: epoetin theta fromRatiopharm (Biopoin®; Ratioepo®;Eporatio®).*

In conclusion, the majority of products onthe market in the European Union, NorthAmerica and parts of Asia are derivedfrom CHO cells, while BHK derivedproducts are available widely in develop-ing countries. However, the C127 productnever reached the market, and the onlyproduct based on a human cell system(Dynepo®) has been withdrawn from theEuropean Union market.

GlycosylationGlycosylation is an inherent feature of theparticular cell line used for manufacturingerythropoietin and will depend on theenzymatic machinery of the cell and thegrowth conditions used for cultivating thecells. CHO cells in general show glyco-

Prepared by Dr Anton Haselbeck, Head ofNew Technologies, Roche Pharma Research,Germany. (This article does not necessarilyrepresent the views of WHO)

* Development of modified versions of erythro-poietin, such as darbepoetin or mircera, willnot be covered in this summary.

International NonproprietaryNames

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sylation capabilities similar to human cellswith some slight differences. The aminoacid sequence encoded in the gene andinserted into the production cell linedictates the position (the exact aminoacid) where a carbohydrate chain can beattached. The location within the se-quence and, more importantly, within thethree-dimensional structure of the proteininfluences the nature of the final carbo-hydrate structure.

In general there are two ways carbo-hydrates can be attached to proteins,either N-glycosidically on asparagine(Asn) residues or O-glycosidically onserine (Ser) or threonine (Thr) residues.Erythropoietin contains three asparagineresidues in a sequence motif sufficient forN-glycosylation and one serine used forO-glycosylation. The four sites are glyco-sylated in human erythropoietin as wellas in all recombinant epoetin products onthe market. This leads to approximately15 major carbohydrate structures (glyco-forms) present in all epoetins in some-what different quantitative distribution.

For secretory proteins like erythropoietin,the glycosylation process starts with aninitial attachment of a precursor carbohy-drate structure to the growing polypeptidechain. This carbohydrate structure will befurther modified during the secretionprocess of the glycoprotein from theendoplasmic reticulum through the Golgiapparatus and finally through secretoryvesicles to the outside of the cell. Thisprocess of modifying the carbohydratechains involving numerous enzymes fromthe host cell during secretion is the mainreason for the heterogeneity obtained inthe final carbohydrate structures.

All CHO production cells, albeit devel-oped independently, generally produceglycosylation patterns which consist of anumber of CHO-typical structures withquantitative differences in the distributionof the individual structures. The glyco-sylation pattern of erythropoietin obtained

from BHK cells, another rodent cell lineused, basically shows the same structuralelements as CHO, whereas other celllines, like the human line HT1081, mayshow certain differences.

Nevertheless, all cells will produce agreat variety of glycoprotein moleculeswith different carbohydrate structureswhich in the course of manufacturing willbe further refined by selecting a subset ofthese molecules as the therapeutic entity.This process will further influence theactual carbohydrate heterogeneity of aglycoprotein drug. Thus, the process willfinally define the end product.

Carbohydrate structuresof epoetinsCHO-derived products (epoetin alfa,beta, theta, zeta)Three N-linked carbohydrate structuresare predominantly of the tetra-antennarycomplex type. Characteristic for CHOglycosylation is a high degree of complexstructures with LacNAc repeats (GlcNAc-Gal); there is a tendency to have smallercomplex type structures (e.g., bi-anten-nary and tri-antennary on Asn 24, where-as Asn38 and Asn83 almost exclusivelycarry tetra-antennary structures withvariable numbers of LacNAc repeats.

Minor structures, like high-mannose-typeswith phosphate groups can also be foundif sophisticated analytical tools areapplied, as well as hybrid-type structures.

Sialic acids (mainly NeuAc) are boundexclusively α2–3 to galactose as CHOcells lack the enzyme for the formation ofα2–6 linkages found on human glycopro-teins. A small percentage (approximately1%) of the sialic acid appears as N-glycolyl-neuraminic acid (NeuGc).

There are quantitative differences in theglycosylation patterns of epoetin alfa,beta and zeta reflecting the actual CHOproduction clone and unique production

International Nonproprietary Names

23


process used. The glycosylation profile ofepoetin theta has not been released yet.The O-linked carbohydrate is smaller andconsists of 2 to 4 sugars bound to Serine-126. (See Figures 1 and 2 below).

As an example, statements from theEuropean Public Assessment Reports(EPAR) of two biosimilar epoetins devel-oped using epoetin alfa (Eprex®) as thereference product describing carbohy-drate similarities and differences highlightthe issue of using glycosylation patternsas a discriminator for different epoetins:

Binocrit® (epoetin alfa)“Differences were observed at the glyco-sylation level. Phosphorylated highmannose type structures in HX575 weredetected at higher levels than in Eprex/Erypo®”.

Silapo® (epoetin zeta)“With respect to the glycan moieties, theoverall range of structures was found tobe comparable. Even upon sub-fractionation of glycans of both products a

very similar profile with respect toantennarity and sialylation was revealed.However, the amount of glycoformswithout an O-glycan chain was slightlyhigher for epoetin zeta as compared toepoetin alfa. On the other hand, theamounts of undesired variants of sialicacid, N-glycolyl neuraminic acid and O-acetyl neuraminic acid were higherin the reference product as compared toepoetin zeta”.

BHK derived product (epoetin omega)Nimtz et al (1) reported a significantamount (2 to 4 %) of phosphorylatedhigh-mannose type structures on the Asn-24 glycosylation site, otherwise a verysimilar carbohydrate pattern, as seen inerythropoietin from CHO cells, wasobserved. Since phosphorylated high-mannose structures are also found inerythropoietins from CHO cells (althoughin somewhat lower amounts) this featuredoes not qualitatively differentiate BHK-derived erythropoietin from CHO-derivederythropoietin.

Figure 1. Main N-linked carbohydrate structures of erythropoietin(terminal sialic acids omitted)

Figure 2. Main O-linked carbohydratestructures of erythropoietin

Codes

Mannose(Man)

N-acetylglucosamine (GlcNAc)

Galactose (Gal)

Fucose(Fuc)

N-acteylneuraminic acid (NeuAc)


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HT1081 derived product (epoetin delta)Llop et al (2) report on the carbohydratepattern of epoetin delta and conclude thatthe pattern is similar to CHO-derivedepoetins with slightly less bi- and tri-antennary structures. Neu5Gc cannot befound in epoetin delta as humans cellscannot synthesize this sialic acid variant.But since it is only a minor component inCHO-derived products it is not suitable asa general analytical feature to distinguishCHO-derived from human-cell derivedproducts.

ConclusionAll epoetins (regardless of INN) exhibit aglycosylation pattern which is quantita-tively different from each other and mainlyreflects the individual production cellclone and the unique production process.Even small differences in the glycosyla-tion pattern may or may not have animpact on clinically relevant parameterslike in vivo elimination time and safety.The complexity of the glycosylationpattern does not allow a prediction basedsolely on analytical data if the comparisoncan only be carried out at final productlevel. The situation is different if smallchanges in the glycosylation pattern canbe followed over time within an estab-

lished production process with all analy-tical and clinical data available to themanufacturer.

Even greater differences in the glycoformpattern have been observed amongvarious epoetin products marketedoutside the European Union, USA, andJapan which were developed independ-ently without adequate proof of similarityto a reference product. These are, never-theless, often marketed using the INNepoetin alfa (3–5).

Since both the cell line and the produc-tion processes define the glycosylationpattern, a unique INN for each independ-ently manufactured epoetin is fully justi-fied.

References

1. FEBS Letters 1995; 365:203–208

2. Analytical Biochemistry 2008; 383:243–254

3. Schellekens, H. European Journal ofHospital Pharmacy 2004; 3:43–47;

4. Park, S.S. et al. Journal of PharmaceuticalSciences 2009; 98:1688–1699

5. Reichel, C. et al. Drug Test Analysis 2009;1:43–50.


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Safety and Efficacy Issues

Didanosine: seriousliver disorderUnited States of America — The Foodand Drug Administration (FDA) is alertinghealthcare professionals to the risk ofnon-cirrhotic portal hypertension inpatients using didanosine (Videx® orVidex EC®). Didanosine is used to treathuman immunodeficiency virus (HIV)infection.

The FDA became aware of cases of non-cirrhotic portal hypertension throughadverse event reports. The FDA believesthe clinical benefits of didanosine forcertain patients with HIV continue tooutweigh its potential risks. The decisionto use this drug, however, must be madeon an individual basis between thetreating physician and the patient. Dida-nosine already has a boxed warning forlactic acidosis and hepatomegaly withsteatosis. Didanosine in combination withother antiretroviral agents as well ashydroxyurea or ribavirin has been associ-ated with the development of liver toxicity.

Reference: MedWatch Alert, 29 January 2010at http://www.fda.gov

Bortezomib: updatedsafety informationUnited States of America — The newlabel for bortezomib (Velcade®) containsimportant updates to the full prescribinginformation including dose adjustmentsfor patients with moderate to severehepatic impairment. Bortezomib is indi-cated for the treatment of patients withmultiple myeloma or mantle cell lym-phoma who have received at least oneprior therapy.

A lower starting dose is recommended inpatients with moderate or severe hepaticimpairment, and those patients should bemonitored closely. Contraindicationsinclude hypersensitivity to bortezomib,boron, or mannitol. Velcade® should beadministered under the supervision of aphysician experienced in the use ofantineoplastic therapy. Complete bloodcounts should be monitored frequentlyduring treatment.

There have been reports of peripheralneuropathy, hypotension congestive heartfailure and new onset of decreased leftventricular ejection fraction, acute diffuseinfiltrative pulmonary disease of unknownetiology, reversible posterior leuko-encephalopathy syndrome, nausea,diarrhoea, constipation, and vomiting,thrombocytopenia and neutropenia,gastrointestinal and intracerebral haemor-rhage, tumour lysis syndrome, cases ofacute liver failure.

Reference: Communication from the TakedaOncology Company at http://www.fda.gov

Deferasirox: renal events andgastrointestinal haemorrhageCanada — Deferasirox (Exjade®) isindicated in the management of chroniciron overload in patients with transfusion-dependent anaemias aged six years orolder. The product is also indicated in themanagement of chronic iron overload inpatients with transfusion-dependentanaemias aged two to five who cannot beadequately treated with desferoxamine.

Therapy with deferasirox should beinitiated and maintained by physiciansexperienced in the treatment of chroniciron overload due to blood transfusions.

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Review of adverse events for patientstreated with deferasirox suggests agreater risk of kidney failure, gastrointesti-nal haemorrhage (potentially fatal) anddeaths in patients with myelodysplasticsyndrome (MDS) and in elderly patientscompared to younger patients with otherchronic anaemias such as α-thalassae-mia and sickle cell disease. Many of theadverse events reported are common toelderly patients and patients with MDS,making it difficult to draw conclusions.

Risk factors for kidney failure include pre-existing compromised renal function, andit is therefore recommended that creati-nine clearance (and/or serum creatinine)be assessed twice before initiatingtherapy. Weekly monitoring of creatinineclearance (and/or serum creatinine) isrecommended in the first month afterinitiation or modification of therapy, andmonthly thereafter.

Gastrointestinal haemorrhage is a knownadverse reaction of deferasirox. Therehave been rare reports of fatal gastroin-testinal haemorrhage, especially inelderly patients who had advancedhaematologic malignancies and/or lowplatelet counts.

In the review of death cases in the MDSpatient population, it was apparent thatapproximately two-thirds of deaths werein patients who had received less than sixmonths of therapy, indicating that patientswith advanced disease and a correspond-ing poor prognosis have been treated.These patients are unlikely to derivebenefit from treatment with deferasirox.

Reference: Communication from NovartisPharmaceuticals Canada Inc. dated 30November 2009 at http://www.hc-sc.gc.ca

Sirolimus: drug monitoringassay comparisonCanada — Different laboratory assaysused to measure sirolimus (Rapamune®)trough concentrations generate results

that are not interchangeable. Healthcareprofessionals should be aware that themethods used to measure sirolimuswhole blood concentration have a directimpact on the values obtained. Improperadjustment to the dose of sirolimus basedon the use of differing assay methods canlead to allograft rejection (if the patient isunderdosed) or toxicity (if the patient isoverdosed).

Therapeutic drug monitoring is recom-mended for patients taking Rapamune®.Adjustments to the targeted range shouldbe made according to the assay beingused to determine the sirolimus troughconcentration. Several immuno-assayshave been developed that allow for rapidturnaround of results. Most immuno-assays have a positive bias of approxi-mately 15–20% relative to the referenceHPLC assay with detection by tandemmass spectrometry due to antibody cross-reactivity with sirolimus metabolites.However, it has recently come to theattention of the manufacturer that one ofthe more commonly used immunoassayplatforms, IMx®, generally yields resultswith a negative bias of approximately10% relative to HPLC/MS/MS.

Reference: Communication from Wyeth(Pfizer) dated 26 November 2009 at http://www.hc-sc.gc.ca and 20 January 2010 athttp://www.hsa.gov.sg/publish/hsaportal/en/health_ products_regulation/safety_ informa-tion/DHCPL.html

Mycophenolate: purered cell aplasiaCanada — The manufacturer of myco-phenolate sodium (Myfortic®) has in-formed healthcare professionals ofreports of pure red cell aplasia (PRCA) inpatients when treated in combination withother immunosuppressive agents.

Mycophenolate sodium, an immuno-suppressive agent, is currently indicatedfor the prophylaxis of organ rejection in


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patients receiving allogeneic renal trans-plants, administered in combination withcyclosporine, and corticosteroids.

PRCA is a type of anaemia that developssecondary to failure of erythropoiesis.PRCA describes a condition in whichRBC precursors in bone marrow arenearly absent, while megakaryocytes andwhite blood cell precursors are usuallypresent at normal levels. PRCA may beidiopathic or occur as a manifestation ofan underlying condition. Approximately5% of all cases of PRCA are drug in-duced. Patients with PRCA may presentwith fatigue, lethargy, and/or abnormalpaleness of the skin (pallor). Anaemia isthe primary clinical concern in PRCA. Thedegree of anaemia can range fromsubclinical to severe. Anaemia in acuteself-limited PRCA is barely noticeable;however, profound anaemia can occur inchronic acquired PRCA and in congenitalPRCA. Patients with severe anaemiahave symptoms and signs of uncompen-sated anaemia and present with weak-ness, tachycardia, and dyspnoea.

As of 31 October 2009, between fiveand ten cases of PRCA out of an esti-mated cumulative worldwide exposure of208 978 patient-years have been re-ported in patients receiving Myfortic® incombination with other immunosuppres-sive agents (such as tacrolimus, cy-closporine, corticosteroids). No cases arefrom Canada.

Reference: Communication from NovartisPharmaceuticals Canada Inc. dated 21December 2009 at http://www.hc-sc.gc.ca

Fosamprenavir: myocardialinfarction and dyslipidaemiaUnited States of America — Fosam-prenavir calcium is indicated in combina-tion with other antiretroviral agents for thetreatment of HIV infection. The manufac-turer of fosamprenavir calcium (Lexiva®)has informed healthcare professionals of

a potential association between fosam-prenavir calcium and myocardial infarc-tion in HIV-infected adults.

Elevations in triglyceride levels arealready described in the prescribinginformation which has now also beenmodified to highlight that increases incholesterol have occurred with treatment.This statement includes a recommenda-tion that triglyceride and cholesteroltesting should be performed prior toinitiating therapy with fosamprenavircalcium tablets and oral suspension andat periodic intervals during therapy.

References

1. Communication from GlaxoSmithKlinedated November 2009 at www.fda.gov/medwatch

2. Lang S, Mary-Krause M, Cotte L et al.Impact of Specific NRTI and PI Exposure onthe Risk of Myocardial Infarction: A Case-Control Study Nested within FHDH ANRSCO4. 16th Conference on Retro-viruses andOpportunistic Infections (CROI 2009) Febru-ary 8 –11, 2009, Montreal, Canada.

3. DAD Study Group. Class of antiretroviraldrugs and the risk of myocardial infarction.N Engl J Med. 2007;356(17): 1723-35.

Exenatide: alteredkidney functionUnited States of America — The Foodand Drug Administration (FDA) hasapproved revisions to the drug label forexenatide (Byetta®) to include informa-tion on post-marketing reports of alteredkidney function, including acute renalfailure and insufficiency.

Exenatide, an incretin-mimetic, is ap-proved as an adjunct to diet and exerciseto improve glycaemic control in adultswith type 2 diabetes mellitus.

From April 2005 through October 2008,the FDA has received 78 cases of altered


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kidney function. Some cases occurred inpatients with pre-existing kidney diseaseor in patients with one or more risk factorsfor developing kidney problems.

Revisions to the drug label include:

• Byetta® should not be used in patientswith severe renal impairment (creatinineclearance <30 ml/min) or end-stagerenal disease.

• Caution should be applied when initiat-ing or increasing doses of Byetta® from5 mcg to 10 mcg in patients with moder-ate renal impairment (creatinine clear-ance 30 to 50 ml/min).

• Patients should be monitored carefullyfor the development of kidney dysfunc-tion and evaluate continued need ifkidney dysfunction is suspected whileusing the product.

Reference: MedWatch Alert, 2 November2009 at http://www.fda.gov

Drospirenone in oralcontraceptivesSaudi Arabia — Recently, the SaudiFood and Drug Authority’s (SFDA) Na-tional Drug and Poison InformationCenter (NDPIC) has received questionsfrom patients and healthcare profession-als about the safety of two combined oralcontraceptive drugs Yasmin® and Yaz®.

Yasmin® is different from other birth-control pills because it contains theprogestin drospirenone. Drospirenonemay increase potassium. Therefore,patients with kidney, liver or adrenaldisease should not take Yasmin®. Otherdrugs may also increase potassium andpatients who are currently on daily, long-term treatment for a chronic conditionshould consult their healthcare providerabout whether Yasmin® is safe for useand, during the first month of use, a bloodtest to check potassium levels should beperformed.

The use of oral contraceptives is associ-ated with increased risk of several seriousconditions including venous and arterialthrombotic and thromboembolic events.The risk of morbidity and mortality in-creases significantly in the presence ofother underlying risk factors such ashypertension, hyperlipidaemias, obesityand diabetes.

Reference: Press Release, Saudi Food andDrug Authority, 1 March 2010 at http://www.sfda.gov.sa/En/Drug/News/697

Glucose test stripsSaudi Arabia — The Saudi Food andDrug Authority’s (SFDA) National Centerfor Medical Devices Reporting has foundthat test strips to measure blood glucoseby the glucose dehydrogenase pyrrolo-quinoline quinone (GDH-PQQ) methodcannot distinguish between glucose andother non-glucose sugars, includingmaltose, xylose, and galactose found incertain drug and biological formulations orresulting from the metabolism of a drug ortherapeutic product. This leads to inaccu-rate readings and possibly inappropriatemedical intervention.

Therefore SFDA has advised healthcareproviders to refer to device labelling toconfirm the used blood sugar measuringmethodology. SFDA advice to the publicis to stop using these strips since thereare other glucose test strip methodologiesnot affected by the presence of non-glucose sugars.

Reference: Press Release, Saudi Food andDrug Authority, 22 December 2009 at http://www.sfda.gov.sa/En/Drug/News/697

HIV drug combination: safetyreview of clinical trial dataUnited States of America — The Foodand Drug Administration (FDA) is review-ing clinical trial data about a potentiallyserious effect on the heart from the use ofthe antiretroviral medications saquinavir


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(Invirase®) in combination with ritonavir(Norvir®). The data suggest that togetherthe two drugs may affect the electricalactivity of the heart.

Saquinavir and ritonavir should not beused in patients already taking medica-tions known to cause QT interval prolon-gation or in patients with a history of QTinterval prolongation.

Reference: FDA Safety Announcement, 23February 2010 at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrug SafetyInformationforPatientsandProviders/ucm201221.htm

Sibutramine: ongoingsafety reviewUnited States of America — The Foodand Drug Administration (FDA) hasnotified healthcare professionals of areview of additional data indicating anincreased risk of heart attack and strokein patients with a history of cardiovasculardisease using sibutramine. Based on theserious nature of the review findings, anew contraindication has been added tothe sibutramine drug label stating thatsibutramine is not to be used in patientswith a history of cardiovascular disease,including:

• History of coronary artery disease;stroke or transient ischemic attack;heart arrhythmias; congestive heartfailure; or peripheral arterial disease.

• Uncontrolled hypertension.

Patients currently using sibutramineshould talk with their healthcare profes-sional to determine if continued use ofsibutramine is appropriate and discussany questions they may have about theirtreatment.

References

1. MedWatch Alert. Meridia® (sibutraminehydrochloride): Follow-Up to an Early Commu-nication about an Ongoing Safety Review,dated 21 January 2010 at http://www.fda.gov

2. MedWatch Alert. Follow-Up to the Novem-ber 2009 Early Communication about anOngoing Safety Review of Sibutramine,Marketed as Meridia®, dated 21 January 2010at http://www.fda.gov

Becaplermin: contraindicationin patients with cancerEuropean Union — Following a reviewof the available data on a possible risk ofcancer in patients using becaplermin(Regranex®), the European MedicinesAgency (EMEA) has concluded that themedicine must not be used in patientswho have any form of cancer. A similarrestriction previously applied, but only forpatients who had a skin cancer close tothe area where the gel was to be applied.

Regranex® is a gel that is used togetherwith other wound care measures to treatlong-term skin ulcers in people withdiabetes.

Reference: Press Release, http://www.emea.europa.eu and http://www.ema.europa.eu/ humandocs/PDFs/EPAR/Regranex/31245209en.pdf

ACSOM — advisory committeeon safety of medicinesAustralia — A new expert advisorycommittee on medicines safety, called theAdvisory Committee on the Safety ofMedicines (ACSOM), has replaced theAdverse Drug Reactions Advisory Com-mittee (ADRAC). This new committeeexists as a statutory committee in its ownright and has broader and enhancedterms of reference compared to ADRAC.A key role of ACSOM will be the provisionof expert advice to the TherapeuticGoods Administration (TGA) about theappropriateness of risk managementplans and risk minimization strategies fornew high-risk medicines.

Reference: Therapeutic Goods Administra-tion, Medicines Safety Update, No.1, 2010 athttp://www.tga.gov.au


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Regulatory Scope

Regulation of tobacco products is endorsed by the WHO Framework Convention onTobacco Control. Regulation serves public health goals by providing an understand-ing of tobacco products and meaningful surveillance of their manufacture, packag-ing, labelling and distribution. Tobacco product regulation includes regulation of thecontents and emissions of tobacco products by testing, measuring and mandatingdisclosure of the results and regulating their packaging and labelling.

Chemical consumer products are usually regulated after a review of the scientificevidence on the hazards presented by the product, the exposure likely to occur, thepatterns of use and the marketing messages of the manufacturer. Many jurisdictionsrequire manufacturers to classify and label products according to their hazardousproperties, to control the hazardous contents or to limit the advertising, promotionand sponsorship of such products. Electronic nicotine delivery systems deliver nico-tine and other substances but do not contain tobacco, and smokeless tobacco isproduced in ‘cottage’ industries or can be modified significantly by the end user. Boththerefore pose a significant challenge to regulation, as they may fall outside thescope of domestic regulatory regimes for tobacco products. Nevertheless, their popu-larity and the fact that they are marketed as alternatives to cigarette smoking indi-cate the need to characterize them, regulate them and ensure that the public isproperly informed of the potential health hazards of these products.

Tobacco product regulation

Electronic nicotine deliverysystemsThe WHO Study Group on TobaccoProduct Regulation (TobReg) reviews thescientific evidence on topics related totobacco product regulation and identifiesthe research needed to fill regulatorygaps in tobacco control. The Study Groupis composed of national and internationalscientific experts on product regulation,treatment of tobacco dependence andlaboratory analysis of tobacco ingredientsand emissions.

At its fifth meeting, the Study Groupaddressed regulation of electronic ciga-rettes, smokeless tobacco toxicants, ‘roll-your-own’ products, products marketedas cessation aids, particles in smoke and

menthol. The meeting followed a WHOpress release in 2008, which assertedthat WHO does not consider electroniccigarettes to be a legitimate tobaccocessation therapy.

The TobReg recommendations addresselectronic nicotine delivery systems(ENDS) designed for nicotine delivery tothe respiratory system. This designationencompasses products that containtobacco-derived substances but in whichtobacco is not necessary for their opera-tion. ENDS are marketed under a varietyof brand names and descriptors, including‘electronic cigarettes’, ‘ecigarro’, ‘electro-smoke’, ‘green cig’ and ‘smartsmoker’.ENDS pose significant public healthissues and raise questions for tobaccocontrol policy and regulation because:

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• Manufacturers have not fully disclosedthe chemicals used in ENDS;

• There are few data on emissions oractual human exposure;

• The health effects have not been stud-ied;

• Marketing and use could underminepublic smoking bans, which are impor-tant tobacco control interventions;

• Products could also undermine smokingcessation efforts by proposing unprovendevices for smoking cessation in theplace of products of proven efficacy.

• ENDS might also undermine the pre-vention of tobacco use because of theirappearance and marketing as safealternatives to tobacco products for non-tobacco users, including children.

ENDS fall into a regulatory gap in mostcountries, escaping regulation as drugs

and avoiding the controls levied ontobacco products. An important regulatoryconsideration is the validity of the market-ing claims made for the products, whichinclude statements that ENDS are smok-ing cessation aids and that they deliversafer nicotine but at variable levelscompared to those in cigarettes.

ENDS are a category of consumerproducts designed to deliver nicotine tothe lungs after one end of a plastic ormetal cylinder is placed in the mouth, likea cigarette or cigar, and inhaled to draw amixture of air and vapours from thedevice into the respiratory system (seefigure 1). They contain electronic vapori-zation systems, a rechargeable batteryand charger, electronic controls andreplaceable cartridges that may containnicotine and other chemicals. Somebrands are claimed to deliver a range ofnicotine concentrations or no nicotine atall, and some are claimed to providesensory experiences similar to thoseobtained with major cigarette brands. The

Figure 1. Prototype e-cigarette devices

Rechargeable battery Vaporizing chamber

Indicator light Replaceable ingredients cartridge tip

Battery Atomizer Inhaler

Electronic circuit Cartridge

Regulatory Scope

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chemicals used to produce the odoursand flavours that simulate those ofcigarettes have not all been identified,although some products claim to include‘menthol’. Some devices have light-emitting diodes, to reproduce the appear-ance of a burning cigarette tip. Thepremise stated by some marketers of theproducts is that ENDS provide nicotinethat would otherwise be obtained bytobacco use.

The United States Food and Drug Admin-istration recently analysed the chemicalsin 18 varieties of ENDS cartridges mar-keted with two different brands and foundsignificant variation in contents anddeliveries. Several contained “detectablelevels of nitrosamines, tobacco-specificcompounds known to cause cancer”. TheAdministration’s testing also revealed thatthe nicotine levels were inconsistent withthe information on the cartridge labelsand that some cartridges that were statednot to contain nicotine actually did.

Delivery of nicotine to the lung raisesconcern about safety and addiction thatgo beyond that related to currentlyapproved nicotine replacement therapy.Concern about the safety of ENDS isassociated with the probable exposure ofthe lung to repeated dosing, perhapshundreds of times a day for manymonths, if these products are used as asmoking cessation aid, or for years, forsmokers who use them as long-term

cigarette substitutes. An added concern isthe safety of the chemical combinations invarious ENDS cartridges, which have notbeen evaluated for either short-term orlong-term safety. It is possible that atsome time in the future ENDS might bedeveloped as smoking cessation aids.However, currently, the evidence isinsufficient to conclude that any of theENDS products is an effective smokingcessation aid.

In summary, claims for the effectivenessof ENDS for smoking cessation and otherhealth effects must be substantiated byrigorous studies of pharmacokinetics,trials of safety and efficacy and reviewand approval by major drug regulatoryauthorities. The types of data and studiesthat would be required include:

• Complete listing of the chemicals usedin ENDS products.

• Listing and reporting of the concentra-tions of chemicals delivered to theconsumer.

• Comparisons of the effect of ENDS onsmoking cessation with that of approvednicotine replacement therapies andplacebo.

• Adverse effects of these products.

Reference: World Health Organization. WHOStudy Group on Tobacco Poduct Regulation.Technical Report Series, No. 955 (2009).

Regulatory Scope

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Influenza vaccines: 2010-2011northern hemisphereWorld Health Organization — Pandemicinfluenza A(H1N1) viruses emerged inMarch 2009 and remain globally predomi-nant, while seasonal influenza A(H1N1),A(H3N2) and B viruses circulated at verylow levels in many countries during theperiod September 2009 to January 2010.

Pandemic A(H1N1) 2009 viruses wereantigenically and genetically similar toA/California/7/2009. Vaccines containingA/California/7/2009 antigen stimulatedanti-HA antibodies of similar titres againstthe vaccine virus and recent pandemicA(H1N1) 2009 viruses.

Very few seasonal influenza A(H1N1)viruses were reported. Of these, themajority were antigenically and geneti-cally similar to the (previous northernhemisphere) vaccine virus A/Brisbane/59/2007.

It is recommended that the followingviruses be used for influenza vaccines inthe 2010–2011 influenza season (north-ern hemisphere):

• an A/California/7/2009 (H1N1)-likevirus;

• an A/Perth/16/2009 (H3N2)-like virus(A/Wisconsin/15/2009 is an A/Perth/16/2009 (H3N2)-like virus and is a 2010southern hemisphere vaccine virus);

• a B/Brisbane/60/2008-like virus.

As in previous years, national or regionalcontrol authorities approve the composi-tion and formulation of vaccines used in

each country. National public healthauthorities are responsible for makingrecommendations regarding the useof the vaccine.

Reference: Recommended viruses forinfluenza vaccines for use in the 2010–2011northern hemisphere influenza season.Weekly Epidemiological Record, 85:10 (2010).

European Medicines Agency:new organizational structureand visual identityEuropean Union — The EuropeanMedicines Agency officially unveiled apackage of changes on 8 December2009 with the launch of a new organiza-tional structure and new visual identity.

Among the highlights of the new organi-zational structure is the integration ofhuman pre- and post-authorizationactivities into one unit, to guaranteeseamless lifecycle-management ofmedicines. The creation of a new unit forpatient health protection further strength-ens the Agency’s focus on safety-monitor-ing of medicines. In addition, a dedicatedgroup for the management of productdata and documentation will improve theefficiency of data management processesthroughout the Agency.

A new public web site for the Agency isnearing the end of development and willbe launched in the coming months. Withthe current website being visited morethan 700 000 times each month, the newsite is being designed with the needs ofthe public in mind, offering improvednavigation and search functionality,providing better access to information onpublic-health issues.

Regulatory Action and News

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Reference: Press Release, EMA/704918/2009, 8 December 2009 at http://www.ema.europa.eu/

Risk management systemsfor medicinal productsAustralia — In April 2009 the Therapeu-tic Goods Administration (TGA) formallyadopted the European Guideline on RiskManagement Systems for MedicinalProducts for Human Use (EMEA/CHMP/96268/2005).

Applications for the registration of certainhigher risk prescription medicines (newchemical entities, applications for paediat-ric use, new dosage forms, new routes ofadministration and significant extensionsof indication) are now required to includea Risk Management Plan as part of theapplication.

The Risk Management Plan is meant todocument not only what is known aboutthe safety of the medicine at that particu-lar point in time (termed the SafetySpecifications), but also potential risksthat require further elucidation and howthe sponsor intends to investigate thoserisks.

Reference: Therapeutic Goods Administra-tion, Medicines Safety Update, No.1, 2010 athttp://www.tga.gov.au

Relative effectivenessassessments: joint actionEuropean Union — The EuropeanMedicines Agency and representativesfrom the European network for HealthTechnology Assessment (EUnetHTA)Joint Action met in London on 11 Febru-ary 2010 for the first of a series of work-shops. This initiates a new collaboration,in which the European Medicines Agencyand EUnetHTA will be considering howthe European Public Assessment Report(EPAR) could make a better contributionto the assessment of relative effective-

ness by health technology assessmentbodies in the EU Member States.

Relative effectiveness assessments areincreasingly used in the European Mem-ber States to help policy makers toidentify the most valuable medicines.

Reference: CHMP assessment templates andguidance at http://www.ema.europa. eu/htms/human/chmptemplates/artemplates.htm

NIH and FDA: fast-trackinnovationsUnited States of America — The Foodand Drug Administration (FDA) and theNational Institutes of Health (NIH) haveunveiled an initiative designed to acceler-ate the process from scientific break-through to the availability of new, innova-tive medical therapies for patients.

The initiative involves two interrelatedscientific disciplines:

• Translational science, the shaping ofbasic scientific discoveries into treat-ments.

• Regulatory science, the developmentand use of new tools, standards andapproaches to more efficiently developproducts and to more effectively evalu-ate product safety, efficacy and quality.

Both disciplines are needed to turn bio-medical discoveries into products thatbenefit people.

As part of the effort, the agencies willestablish a Joint NIH-FDA LeadershipCouncil to spearhead collaborative workon important public health issues. TheJoint Leadership Council will work toensure that regulatory considerationsform an integral component of biomedicalresearch planning, and that the latestscience is integrated into the regulatoryreview process.


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In addition, the NIH and the FDA willjointly issue a Request for Applications,making US$ 6.75 million available overthree years for work in regulatory science.

Reference: FDA – NIH News Release, 24February 2010 at http://www.fda.gov andhttp://.www.nih.gov4.

Orciprenaline sulphate:registration cancelledSaudi Arabia — The Saudi Food andDrug Administration (SFDA) has an-nounced the cancellation of orciprenalinesulphate (Alupent®) registration due to itshazards to the heart and the availability ofmore safe alternative drugs.

Accordingly, the Drug Products andManufacturers’ Registration Committeedecided to cancel registration of thisproduct and recall it from the market.SFDA also asked the manufacturer torecall any available stocks from the localmarket to protect the health of the public.SFDA requests all concerned to use otheralternative drugs.

Reference: Communication dated 15 Febru-ary 2010 at www.sfda.gov.sa/ar/drug

Peramivir IV: emergencyuse authorizationUnited States of America — The Foodand Drug Administration (FDA) hasnotified healthcare professionals that, inresponse to a request from the Centersfor Disease Control and Prevention, it hasissued an emergency use authorization(EUA) for the investigational antiviral drugperamivir in certain adult and paediatricpatients with confirmed or suspected2009 H1N1 influenza infection who areadmitted to a hospital. IV peramivir isauthorized only for hospitalized adult andpaediatric patients for whom therapy withan IV drug is clinically appropriate.

Given that limited safety data are avail-able on peramivir, mandatory reporting

requirements are in place for this unap-proved drug.

Reference: FDA News, 23 October 2009http://www.fda.gov

Carisbamate: withdrawal ofmarketing authorizationapplicationEuropean Union — The manufacturer ofcarisbamate (Comfyde®) has notified theEuropean Medicines Agency () of itsdecision to withdraw its application for acentralized marketing authorization forthe medicine Comfyde®.

This medicine was intended to be usedfor adjunctive treatment of partial onsetseizures with or without secondarygeneralization in patients aged 16 yearsor older.

The decision to withdraw the applicationwas based on feedback from the Commit-tee on Human Medicinal products(CHMP) indicating that the Committee isunlikely to reach a favourable opinionwithout additional efficacy data, which atthis time cannot be provided.

Reference: Press Release, EMA/32401/2010,20 January 2010. http://www.ema.europa. eu/

Benfluorex withdrawalEuropean Union — The EuropeanMedicines Agency has recommended thewithdrawal of all medicines containingbenfluorex in the European Union be-cause their risks, particularly the risk ofheart valve disease, are greater than theirbenefits.

Doctors should stop prescribing ben-fluorex-containing medicines and con-sider alternative treatments. Becauseheart valve disease can develop someyears after treatment, patients who havetaken benfluorex in the past should telltheir doctor so that they can be checked


36


for the signs and symptoms of heart valvedisease.

Benfluorex is approved for use in over-weight patients with diabetes, combinedwith an appropriate diet.

Reference: Press release,EMA/CHMP/815033/2009, 18 December 2009 at http://www.ema.europa.eu/

Ethyl eicosapent: withdrawalof marketing authorizationapplicationEuropean Union — The manufacturer ofethyl eicosapent (Ethyl Eicosapent®),500 mg soft gelatine capsules has noti-fied the European Medicines Agency ofits decision to withdraw its application fora centralized marketing authorization.

Ethyl eicosapent was expected to beused for the long-term stabilization ofsymptoms in patients with Huntingtondisease, a hereditary neurological disor-der of the central nervous system thatcauses progressive degeneration of cellsin the brain.

Withdrawal of the application was basedon preliminary comments which indicatethat the CHMP is unlikely to conclude afavourable opinion without additionalefficacy information.

Reference: Press Release, EMA/796337/2009, 8 December 2009 at http://www.ema.europa.eu/

Olanzapine approved inadolescentsUnited States of America — The Foodand Drug Administration (FDA) hasapproved of the use of oral olanzapine(Zyprexa®) in adolescents (ages 13–17).

Olanzapine is indicated for the treatmentof schizophrenia and acute treatment ofmanic or mixed episodes associated withbipolar I disorder and maintenance

treatment of bipolar I disorder. Whendeciding among the alternative treat-ments available for adolescents, clini-cians should consider the increasedpotential for weight gain and hyperlipidae-mia.

It is recommended that medication thera-py for paediatric schizophrenia andbipolar I disorder be initiated only after athorough diagnostic evaluation has beenperformed and careful considerationgiven to the risks associated with medica-tion treatment. Medication treatment forboth paediatric schizophrenia and bipolarI disorder should be part of a total treat-ment programme that includes psycho-logical, educational and social interven-tions.

The types of adverse events observed inadolescents were similar to those seen inadult patients. However, the magnitudeand frequency of some events weregreater in adolescents than in adults.Compared to patients from adult clinicaltrials, adolescents were likely to gainmore weight and have greater increasesin total cholesterol, triglycerides, LDLcholesterol, prolactin and hepatictransaminase levels, and sedation.

Reference: FDA News, 24 October 2009http://www.fda.gov

Lisuride: withdrawal ofmarketing authorizationapplicationEuropean Union — The manufacturer oflisuride (Nenad®) has notified the Euro-pean Medicines Agency of its decision towithdraw its application for a centralizedmarketing authorization for the Nenad®,2.5 and 5.0 microgram/h transdermalpatch. Nenad® was expected to be usedin adults with moderate-to-severe idi-opathic restless legs syndrome.

Withdrawal of the application was basedon the CHMP’s view that the data pro-


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vided do not allow the Committee toconclude on a positive benefit-risk bal-ance in the claimed indication.

Reference: Press Release, Doc. Ref. EMEA/781919/2009. 3 December 2009 at http://www.ema.europa. eu/

Velaglucerase alfa approvedfor Gaucher diseaseUnited States of America — The Foodand Drug Administration (FDA) has ap-proved velaglucerase alfa for injection(VPRIV) to treat children and adults witha form of the rare genetic disorder,Gaucher disease.

VPRIV provides long-term enzyme re-placement therapy for Type 1 Gaucherdisease, the most common form of thegenetic disorder. It is an alternative toimiglucerase (Cerezyme®), anotherenzyme replacement therapy.

The most common adverse reactions toVPRIV are allergic reactions. Otherobserved adverse reactions with VPRIVare headache, dizziness, abdominal pain,back pain, joint pain, nausea, fatigue/weakness, fever, and prolongation ofactivated partial thromboplastin time, ameasure of clotting time.

Reference: FDA News Release, 26 February2010 at http://www.fda.gov and http://www.ninds.nih.gov/disorders/gauchers/gauchers.htm 2

Pneumococcal 13-valentconjugate vaccine approvedUnited States of America — The Foodand Drug Administration (FDA) hasapproved Prevnar 13®, a pneumococcal13-valent conjugate vaccine for infantsand young children ages 6 weeks through5 years. Prevnar 13® will be the succes-sor to Prevnar®, the pneumococcal 7-valent conjugate vaccine licensed by theFDA in 2000 to prevent invasive pneumo-

coccal disease (IPD) and otitis media.The new vaccine extends the protectionto six additional types of the diseasecausing bacteria.

Prevnar 13® is approved for the preven-tion of invasive disease caused by 13different serotypes of the bacteriumStreptococcus pneumoniae. It also isapproved for the prevention of otitismedia caused by the seven serotypesshared with Prevnar®. The bacterium cancause infections of the blood, middle ear,and the covering of the brain and spinalcord, as well as pneumonia.

Common adverse reactions reported afteradministration of Prevnar 13® were pain,redness and swelling at the injection site,irritability, decreased appetite and fever.

Reference: FDA News Release, 24 February2010 at http://www.fda.gov

Monoclonal antibody productsapproved for chronic lympho-cytic leukaemiaUnited States of America — The Foodand Drug Administration (FDA) hasapproved the monoclonal antibodyrituximab (Rituxan®) to treat certainpatients with chronic lymphocytic leukae-mia (CLL), a slowly progressing bloodand bone marrow cancer.

Rituximab, an anti-cancer drug, is in-tended for patients with CLL who arebeginning chemotherapy for the first timeand for those who have not responded toother cancer drugs for CLL. Rituximab isadministered with two other chemo-therapy drugs, fludarabine and cyclo-phosphamide.

FDA approved ofatumumab (Arzerra®) inOctober 2009 for patients whose canceris no longer being controlled by otherforms of chemotherapy and benda-mustine (Treanda®) in March 2008 for


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patients with CLL who had not receivedprior treatment.

Rituxan® carries a boxed warning forinfusion reactions. A decrease in normalwhite blood cells was also commonlyobserved in patients enrolled in theclinical trials. Other boxed warnings forRituxan® include rashes and sores in theskin and mouth; progressive multifocalleukoencephalopathy (PML); and tumourlysis syndrome.


Rosuvastatin: new indicationapprovedUnited States of America — The Foodand Drug Administration (FDA) hasapproved the cholesterol-lowering medi-cation rosuvastatin (Crestor®) for somepatients who are at increased risk of heartdisease but have not been diagnosed.

The new indication is for reducing thelikelihood of a heart attack or stroke orthe need for a procedure to treat blockedor narrowed arteries in patients who havenever been told they have heart diseasebut are nevertheless at increased risk of acardiac event.

Specifically, this includes men 50 years ofage and older and women 60 years ofage and older who have an elevated

amount of a substance known as highsensitivity C-reactive protein in their bloodand at least one additional traditionalcardiovascular risk factor such as smok-ing, high blood pressure, a family historyof premature heart disease, or lowamounts of high-density lipoprotein orHDL cholesterol.


Influenza A/H1N1: collection-to-detection assayUnited States of America — The manu-facturer of Longhorn Influenza A/H1N1-09Prime RRT-PCR Assay® has beengranted Emergency Use Authorization(EUA) from the Food and Drug Adminis-tration (FDA) for a ready-use assay thatrequires no mixing prior to use.

The device includes PrimeStore®, aclinical collection and transport solutionthat preserves the released nucleic acids,including labile RNA for testing andcontains an internal positive control,providing the first specimen collectionsolution to contain an internal RNAcontrol capable of tracking the degrada-tion of the sample from the point ofcollection.

Reference: Longhorn Vaccines & Diagnostics,New Release, 22 February 2010 at http://www.lhnvd.com


39


TSE tissue infectivitydistribution updateThe data reported in the World HealthOrganization (WHO) Tables on TissueInfectivity Distribution in TransmissibleSpongiform Encephalopathies wereoriginally assembled by an expert groupappointed during a WHO Consultationheld in 2003 and subsequently updatedduring a later Consultation held in 2005.As new information became available,the tables were updated and now reflectthe current status of knowledge aboutinfectivity in body tissues, secretions, andexcretions of humans with sporadic orvariant Creutzfeldt-Jakob disease (CJD);cattle with typical or atypical bovinespongiform encephalopathy (BSE); sheepwith scrapie and, (for the first time), deeror elk with chronic wasting disease(CWD).

It is not the purpose of the document torevise the current WHO Guidelines onTissue Infectivity Distribution in Trans-missible Spongiform Encephalopathiespublished in 2006, which remain valid,but new information on tissue infectivitydistribution is important in the context ofpotential transmission of variant CJDthrough human blood and blood products,as well as through medicinal productsprepared with bovine-derived materials,and may have implications for futurerecommendations.

Since the publication in 2006 of MajorCategories of Infectivity, Annex 1 in theWHO Guidelines on Tissue InfectivityDistribution in Transmissible SpongiformEncephalopathies, some tissues (ovary,uterus, mammary glands/udder, skin,adipose tissue, and heart/pericardium)and body fluids (saliva, milk, urine, and

faeces) in which infectivity had not beendetected, have since been found tocontain infectivity or PrPTSE and there-fore have been moved from the categoryof ‘‘tissues with no detectable infectivity’’ ’’to the category of ‘‘lower-infectivitytissues.’’

The inclusion of infectivity data in CWD inthese Tables was considered importantfor three reasons:

• CWD is continuing its spread to newregions of North America.

• Infectivity has been convincingly dem-onstrated in several bodily secretionsand excretions of infected deer.

• CWD is the only form of animal trans-missible spongiform encephalopathy(TSE) that exists in the wild and, al-though not presently considered to bean important concern for humans, couldpose serious problems of control in thefuture, especially as a potential sourceof infection in other animal species.

Reference: World Health Organization. Tableson Tissue Infectivity Distribution in Transmissi-ble Spongiform Encephalopathies. WHO/EMP/QSM/2010.1 at http://www.who.int/medicines

Restricted availability ofopioids for cancer patientsA report regarding the regulations andrestrictions preventing cancer patientaccess to medication to relieve strongcancer pain has been released by theEuropean Society for Medical Oncology(ESMO) and the European Associationfor Palliative Care (EAPC).

The study, published online in Annals ofOncology, collected data from twenty-one

Recent Publications,Information and Events

40


eastern European countries and twentywestern European countries to evaluatethe availability of official lists of allowedopioid drugs (formulary) for the manage-ment of strong pain, the cost of opioidmedication to patients and the regulatorybarriers that can make it more difficult, ifnot impossible, for cancer patients andtheir doctors to get access to thesemedications in a timely manner.

The study found that in many Europeancountries (particularly in eastern Europe)the balance between enabling cancerpatients to receive the pain relief that theyneed, while, at the same time, preventingprescription drugs being diverted forsubstance abuse in illicit drug markets, isweighted too much in favour of the latter.

References

1. Annals of Oncology, at http://www.oxfordjournals.org/our_journals/annonc/press_releases/freepdf/mdp581.pdf

2. European Society for Medical Oncology, athttp://www.esmo.org

3. Formulary availability and regulatorybarriers to accessibility of opioids for cancerpain in Europe: a report from the ESMO/EAPCOpioid Policy Initiative. Annals of Oncology,21: pp 615-626, 2010 DOI: 10.1093/annonc/mdp581

4. Access to therapeutic opioid medications inEurope by 2011? Fifty years on from theSingle Convention on Narcotic Drugs. Pallia-tive Medicine, 24: pp109-110 DOI: 10.1177/0269216309360103

Transparency and the publicpharmaceutical sectorThe Assessment Tool for MeasuringTransparency in the Public Pharmaceuti-cal Sector represents the first step of athree-phase approach within The WorldHealth Organization’s Good Governancefor Medicines (GGM) Programme started

in late 2004. The goal of the GGMprogramme is to contribute to healthsystems strengthening and preventcorruption by promoting good governancein the pharmaceutical sector.

The purpose of the national assessmentis to provide countries with a comprehen-sive picture of the level of transparencyand potential vulnerability to corruption ofthe following eight functions of the phar-maceutical sector:

• Registration of medicines.

• Control of medicines promotion.

• Inspection of establishments.

• Control of clinical trials.

• Licensing of establishments.

• Selection of essential medicines.

• Procurement of medicines.

• Distribution of medicines.

The methodology probes the perceptionof pharmaceutical policy makers andother stakeholders about transparencyand provides both qualitative and quanti-tative information on the level of transpar-ency present in the eight areas.

The assessment should be viewed as astarting point for investigating weak-nesses and strengths in the nationalmedicine regulatory and supply manage-ment systems. It represents the beginningof a process aimed at bringing long-lasting changes through efforts tostrengthen the national health systems.Twenty-six countries have adopted theGGM and conducted the assessment.

Reference: Assessment Tool for MeasuringTransparency in the Public PharmaceuticalSector. http://www.who.int/medicines/areas/policy/goodgovernance/

Recent Publications, Information and Events

WHO Drug Information, Vol. 24, No. 1, 2010 Recommended INN: List 63

41

International Nonproprietary Names for Pharmaceutical Substances (INN)

RECOMMENDED International Nonproprietary Names: List 63 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); Resolution EB115.R4 (EB115/2005/ERC/1)], 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 (1–101) and Recommended (1–62) International Nonproprietary Names can be found in Cumulative List No. 13, 2009 (available in CD-ROM only).

Dénominations communes internationales des Substances pharmaceutiques (DCI)

Dénominations communes internationales RECOMMANDÉES: Liste 63 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); résolution EB115.R4 (EB115/2005/ERC/1)] 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 (1–101) et recommandées (1–62) dans la Liste récapitulative No. 13, 2009 (disponible sur CD-ROM seulement).

Denominaciones Comunes Internacionales para las Sustancias Farmacéuticas (DCI) Denominaciones Comunes Internacionales RECOMENDADAS: Lista 63 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); Resolución EB115.R4 (EB115/2005/ERC/1)], 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 (1–101) y Recomendadas (1–62) se encuentran reunidas en Cumulative List No. 13, 2009 (disponible sólo en CD-ROM).

Recommended INN: List 63 WHO Drug Information, Vol. 24, No. 1, 2010

42

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

acidum obeticholicum obeticholic acid 6α-ethyl-3α,7α-dihydroxy-5β-cholan-24-oic acid

acide obéticholique acide 6α-éthyl-3α,7α-dihydroxy-5β-cholan-24-oïque

ácido obeticólico ácido 6α-etil-3α,7α-dihidroxi-5β-colan-24-oico

C26H44O4

CH3

CH3 H

H

H

H

H3C

CO2H

H

H

OH

H

HHO

H

CH3

acidum tiomolibdicum tiomolibdic acid dihydrogen(tetrasulfidomolybdate)

acide tiomolibdique tétrasulfidomolybdate d'hydrogène

ácido tiomolíbdico dihidrógeno(tetrasulfuromolibdato)

H2MoS4

HS SHMo

SS

afacifenacinum afacifenacin (4S)-4-phenyl-3-(1-{[3-(trifluoromethoxy)phenyl]methyl}piperidin-

4-yl)-3,4-dihydroquinazolin-2(1H)-one

afacifénacine (4S)-4-phényl-3-(1-{[3-(trifuorométhoxy)phényl]méthyl}pipéridin-4-yl)-3,4-dihydroquinazolin-2(1H)-one

afacifenacina (4S)-4-fenil-3-(1-{[3-(trifluorometoxi)fenil]metil}piperidin-4-il)- 3,4-dihidroquinazolin-2(1H)-ona


43

C27H26F3N3O2

N

HN

H

O

N

OCF3

afegostatum afegostat (3R,4R,5R)-5-(hydroxymethyl)piperidine-3,4-diol

afégostat (3R,4R,5R)-5-(hydroxyméthyl)pipéridine-3,4-diol

afegostat (3R,4R,5R)-5-(hidroximetil)piperidina-3,4-diol

C6H13NO3

NHHO

HO

H

H

OH

H

aganirsenum aganirsen all-P-ambo-thymidylyl-(3′ →5′ )-2′ -deoxy-P-thioadenylyl-(3′ →5′ )-P-

thiothymidylyl-(3′ →5′ )-2′ -deoxy-P-thiocytidylyl-(3′ →5′ )-2′ -deoxy-P-thiocytidylyl-(3′ →5′ )-2′ -deoxy-P-thioguanylyl-(3′ →5′ )-2′ -deoxy-P-thioguanylyl-(3′ →5′ )-2′ -deoxy-P-thioadenylyl-(3′ →5′ )-2′ -deoxy-P-thioguanylyl-(3′ →5′ )-2′ -deoxy-P-thioguanylyl-(3′ →5′ )-2′ -deoxy-P-thioguanylyl-(3′ →5′ )-2′ -deoxy-P-thiocytidylyl-(3′ →5′ )-P-thiothymidylyl-(3′ →5′ )-2′ -deoxy-P-thiocytidylyl-(3′ →5′ )-2′ -deoxy-P-thioguanylyl-(3′ →5′ )-2′ -deoxy-P-thiocytidylyl-(3′ →5′ )-2′ -deoxy-P-thiocytidylyl-(3′ →5′ )-2′ -deoxy-P-thioadenylyl-(3′ →5′ )-P-thiothymidylyl-(3′ →5′ )-2′ -deoxy-P-thioguanylyl-(3′ →5′ )-2′ -deoxy-P-thiocytidylyl-(3′ →5′ )-P-thiothymidylyl-(3′ →5′ )-2′ -deoxy-P-thioguanylyl-(3′ →5′ )-2′ -deoxy-P-thiocytidylyl-(3′ →5′ )-P-thiothymidine

aganirsen tout-P-ambo-P-thiothymidylyl-(3'→5')-2'-déoxy-P-thioadénylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-déoxy-P-thiocytidylyl-(3'→5')-2'-déoxy-P-thiocytidylyl-(3'→5')-2'-déoxy-P-thioguanylyl-(3'→5')-2'-déoxy-P-thioguanylyl-(3'→5')-2'-déoxy-P-thioadénylyl-(3'→5')-2'-déoxy-P-thioguanylyl-(3'→5')-2'-déoxy-P-thioguanylyl-(3'→5')-2'-déoxy-P-thioguanylyl-(3'→5')-2'-déoxy-P-thiocytidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-déoxy-P-thiocytidylyl-(3'→5')-2'-déoxy-P-thioguanylyl-(3'→5')-2'-déoxy-P-thiocytidylyl-(3'→5')-2'-déoxy-P-thiocytidylyl-(3'→5')-2'-déoxy-P-thioadénylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-déoxy-P-thioguanylyl-(3'→5')-2'-déoxy-P-thiocytidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-déoxy-P-thioguanylyl-(3'→5')-2'-déoxy-P-thiocytidylyl-(3'→5')-thymidine


44

aganirsén todo-P-ambo-timidilil-(3'→5')-2'-desoxi-P-tioadenilil-(3'→5')-P-tiotimidilil-(3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')-2'-desoxi-P-tioguanilil-(3'→5')-2'-desoxi-P-tioguanilil-(3'→5')-2'-desoxi-P-tioadenilil-(3'→5')-2'-desoxi-P-tioguanilil-(3'→5')-2'-desoxi-P-tioguanilil-(3'→5')-2'-desoxi-P-tioguanilil-(3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')-P-tiotimidilil-(3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')-2'-desoxi-P-tioguanilil-(3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')-2'-desoxi-P-tioadenilil-(3'→5')-P-tiotimidilil-(3'→5')-2'-desoxi-P-tioguanilil-(3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')-P-tiotimidilil-(3'→5')-2'-desoxi-P-tioguanilil-(3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')-P-tiotimidina

C242H307N91O127P24S24

(3'-5')d(P-thio)(T-A-T-C-C-G-G-A-G-G-G-C-T-C-G-C-C-A-T-G-C-T-G-C-T)

albitiazolii bromidum albitiazolium bromide 3,3′-(dodecan-1,12-diyl)bis[5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-

3-ium] dibromide

bromure d'albitiazolium dibromure de 3,3'-(dodécane-1,12-diyl)bis[5-(2-hydroxyéthyl)- 4-méthyl-1,3-thiazol-3-ium]

bromuro de albitiazolio dibromuro de 3,3′-(dodecan-1,12-diil)bis[5-(2-hidroxietil)-4-metil- 1,3-tiazol-3-io]

C24H42Br2N2O2S2

NS

CH3

N S

H3CBr

BrHO

OH

arhalofenatum arhalofenate 2-(acetamido)ethyl (2R)-2-(4-chlorophenyl)-

2-[3-(trifluoromethyl)phenoxy]acetate

arhalofénate (2R)-2-(4-chlorophényl)-2-[3-(trifluorométhyl)phénoxy]acétate de 2-(acétylamino)éthyle

arhalofenato (2R)-2-(4-clorofenil)-2-[3-(trifluorometil)fenoxi]acetato de 2-(acetamido)etilo

C19H17ClF3NO4

O

O

HN CH3

H

CF3

O

O

Cl


45

atalurenum ataluren 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid

ataluren acide 3-[5-(2-fluorophényl)-1,2,4-oxadiazol-3-yl]benzoïque

atalureno ácido 3-[5-(2-fluorofenil)-1,2,4-oxadiazol-3-il]benzoico

C15H9FN2O3

CO2HN

ON

F

atiratecanum atiratecan (9S)-9-ethyl-10,13-dioxo-1-pentyl-9,10,13,15-tetrahydro-1H,12H-

pyrano[3′′,4′′:6′,7′]indolizino[2′,1′:5,6]pyrido[4,3,2-de]quinazolin-9-yl glycyl-N-methylglycinate

atiratécan glycyl-N-méthylglycinate de (9S)-9-éthyl-10,13-dioxo-1-pentyl-9,10,13,15-tétrahydro-1H,12H-pyrano[3'',4'':6',7']indolizino[2',1':5,6]pyrido[4,3,2-de]quinazolin-9-yle

atiratecán glicil-N-metilglicinato de (9S)-9-etil-10,13-dioxo-1-pentil-9,10,13,15-tetrahidro-1H,12H-pirano[3′′,4′′:6′,7′]indolizino[2′,1′:5,6]pirido[4,3,2-de]quinazolin-9-ilo

C31H34N6O6

ON

N

O

O

N

N

CH3

O

O

NNH2

CH3

CH3

O

bardoxolonum bardoxolone 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid

bardoxolone acide 2-cyano-3,12-dioxooléana-1,9(11)-dién-28-oïque

bardoxolona ácido 2-ciano-3,12-dioxooleana-1,9(11)-dien-28-oico

C31H34N6O6

CH3CH3

CH3

CH3H3C

CH3H3C

O

CO2H

H

NC

O

H

H


46

beclanorsenum beclanorsen all-P-ambo-5-methyl-2'-O,4'-C-methylene-P-thiocytidylyl-(3'→5')-2'-

O,4'-C-methylene -P-thiothymidylyl-(3'→5')-2'-deoxy-P-thiocytidylyl-(3'→5')-2'-deoxy-P-thiocytidylyl-(3'→5')-2'-deoxy-P-thiocytidylyl-(3'→5')-2'-deoxy-P-thioadenylyl-(3'→5')-2'-deoxy-P-thioadenylyl-(3'→5')-2'-deoxy-P-thiocytidylyl-(3'→5')-2'-deoxy-P-thioguanylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-deoxy-P-thioguanylyl-(3'→5')-2'-deoxy-P-thiocytidylyl-(3'→5')-2'-deoxy-P-thioguanylyl-(3'→5')-5-methyl-2'-O,4'-C-methylene-P-thiocytidylyl-(3'→5')-5-methyl-2'-O,4'-C-methylene-P-thiocytidylyl-(3'→5')-2'-deoxyadenosine

béclanorsen tout-P-ambo-5-méthyl-2'-O,4'-C-méthylène-P-thiocytidylyl-(3'→5')-5-méthyl-2'-O,4'-C-méthylène-P-thiouridylyl-(3'→5')-2'-déoxy-P-thiocytidylyl-(3'→5')-2'-déoxy-P-thiocytidylyl-(3'→5')-2'-déoxy-P-thiocytidylyl-(3'→5')-2'-déoxy-P-thioadénylyl-(3'→5')-2'-déoxy-P-thioadénylyl-(3'→5')-2'-déoxy-P-thiocytidylyl-(3'→5')-2'-déoxy-P-thioguanylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-déoxy-P-thioguanylyl-(3'→5')-2'-déoxy-P-thiocytidylyl-(3'→5')-2'-déoxy-P-thioguanylyl-(3'→5')-5-méthyl-2'-O,4'-C-méthylène-P-thiocytidylyl-(3'→5')-5-méthyl-2'-O,4'-C-méthylène-P-thiocytidylyl-(3'→5')-2'-déoxyadénosine

beclanorsén todo-P-ambo-5-metil-2'-O,4'-C-metileno-P-tiocitidilil-(3'→5')-2'-O,4'-C-metileno-P-tiotimidilil-(3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')-2'-desoxi-P-tioadenilil-(3'→5')-2'-desoxi-P-tioadenilil-(3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')-2'-desoxi-P-tioguanilil-(3'→5')-P-tiotimidilil-(3'→5')-2'-desoxi-P-tioguanilil-(3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')-2'-desoxi-P-tioguanilil-(3'→5')-5-metil-2'-O,4'-C-metileno-P-tiocitidilil-(3'→5')-5-metil-2'-O,4'-C-metileno-P-tiocitidilil-(3'→5')-2'-desoxiadenosina

C159H201N58O82P15S15

(3'-5')d(P-thio)(mrC-rT-C-C-C-A-A-C-G-T-G-C-G-mrC-mrC-A) mrC

H2C

O

N

NO NH2

O

HO

OH

CH3

HH2C

O

N

HNO O

O

HO

OH

CH3

rT

H

bixalomerum bixalomer cross linked polymer made of N,N,N',N'-tetrakis(3-

aminopropyl)butane-1,4-diamine N substituted by bivalent substituent groups 2-hydroxypropane-1,2-diyl and 1-(hydroxymethyl)ethylene (x=20, 45≤y≤50)

bixalomère N,N,N',N'-tétrakis(3-aminopropyl)butane-1,4-diamine N substituée par les groupes substituants divalents 2-hydroxypropane-1,2-diyle et 1-(hydroxyméthyl)éthylène pour former un polymère réticulé (x=20, 45≤y≤50)

bixalómero N,N,N',N'-tétrakis(3-aminopropil)butano-1,4-diamina N sustituida por los grupos sustituyentes divalentes 2-hidroxipropano-1,2-diilo y 1-(hidroximetil)etileno para formar un polímero reticulado (x=20, 45≤y≤50)


47

(C16H36N6)x . (C3H6O)y

NH

NN

HN

HN

NH x

CH2

y

CH2

OH H2C

CH

HO

orouo

briakinumabum # briakinumab immunoglobulin G1-lambda, anti-[Homo sapiens interleukin 12 beta

subunit (IL12B, IL-12B, IL12 p40, NKSF2, CMLF p40)], Homo sapiens monoclonal antibody; gamma1 heavy chain (1-445) [Homo sapiens VH (IGHV3-30*02 (99.00%) -(IGHD)-IGHJ3*01) [8.8.8] (1-115) -IGHG1*03 R120>K (116-445)], (218-216')-disulfide with lambda light chain (1'-217') [Homo sapiens V-LAMBDA (IGLV1-44*01 (88.20%) -IGLJ2*01 G120>T) [8.3.12] (1'-111') -IGLC2*01 (112'-217')]; (224-224'':227-227'')-bisdisulfide dimer

briakinumab immunoglobuline G1-lambda, anti-[Homo sapiens interleukine 12 sous-unité bêta (IL12B, IL-12B, IL12 p40, NKSF2, CMLF p40)], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-445) [Homo sapiens VH (IGHV3-30*02 (99.00%) -(IGHD)-IGHJ3*01) [8.8.8] (1-115) -IGHG1*03 R120>K (116-445)], (218-216')-disulfure avec la chaîne légère kappa (1'-217') [Homo sapiens V-LAMBDA (IGLV1-44*01 (88.20%) -IGLJ2*01 G120>T) [8.3.12] (1'-111') -IGLC2*01 (112'-217')]; dimère (224-224'':227-227'')-bisdisulfure

briakinumab inmunoglobulina G1-lambda, anti-[interleukina 12 subunidad beta (IL12B, IL-12B, IL12 p40, NKSF2, CMLF p40) de Homo sapiens], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma1 (1-445) [Homo sapiens VH (IGHV3-30*02 (99.00%) -(IGHD)-IGHJ3*01) [8.8.8] (1-115) -IGHG1*03 R120>K (116-445)], (218-216')-disulfuro con la cadena ligera kappa (1'-217') [Homo sapiens V-LAMBDA (IGLV1-44*01 (88.20%) -IGLJ2*01 G120>T) [8.3.12] (1'-111') -IGLC2*01 (112'-217')]; dímero (224-224'':227-227'')-bisdisulfuro


48

C6376H9874N1722O1992S44

Heavy chain / Chaîne lourde / Cadena pesadaQVQLVESGGG VVQPGRSLRL SCAASGFTFS SYGMHWVRQA PGKGLEWVAF 50IRYDGSNKYY ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCKTHG 100SHDNWGQGTM VTVSSASTKG PSVFPLAPSS KSTSGGTAAL GCLVKDYFPE 150PVTVSWNSGA LTSGVHTFPA VLQSSGLYSL SSVVTVPSSS LGTQTYICNV 200NHKPSNTKVD KKVEPKSCDK THTCPPCPAP ELLGGPSVFL FPPKPKDTLM 250ISRTPEVTCV VVDVSHEDPE VKFNWYVDGV EVHNAKTKPR EEQYNSTYRV 300VSVLTVLHQD WLNGKEYKCK VSNKALPAPI EKTISKAKGQ PREPQVYTLP 350PSREEMTKNQ VSLTCLVKGF YPSDIAVEWE SNGQPENNYK TTPPVLDSDG 400SFFLYSKLTV DKSRWQQGNV FSCSVMHEAL HNHYTQKSLS LSPGK 445

Light chain / Chaîne légère / Cadena ligeraQSVLTQPPSV SGAPGQRVTI SCSGSRSNIG SNTVKWYQQL PGTAPKLLIY 50YNDQRPSGVP DRFSGSKSGT SASLAITGLQ AEDEADYYCQ SYDRYTHPAL 100LFGTGTKVTV LGQPKAAPSV TLFPPSSEEL QANKATLVCL ISDFYPGAVT 150VAWKADSSPV KAGVETTTPS KQSNNKYAAS SYLSLTPEQW KSHRSYSCQV 200THEGSTVEKT VAPTECS 217

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuroIntra-H 22-96 142-198 259-319 365-423 22''-96'' 142''-198'' 259''-319'' 365''-423''Intra-L 22'-89' 139'-198' 22'''-89''' 139'''-198''' Inter-H-L 218-216' 218''-216''' Inter-H-H 224-224'' 227-227''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación295, 295''

budiodaronum budiodarone (2S)-butan-2-yl 2-(3-{4-[2-(diethylamino)ethoxy]-3,5-diiodobenzoyl}-

1-benzofuran-2-yl)acetate

budiodarone 2-(3-{4-[2-(diéthylamino)éthoxy]-3,5-diiodobenzoyl}-1-benzofuran- 2-yl)acétate de (2S)-butan-2-yl

budiodarona 2-(3-{4-[2-(dietilamino)etoxi]-3,5-diiodobenzoil}-1-benzofuran- 2-il)acetato de (2S)-butan-2-ilo

C27H31I2NO5

O

O

O

OI

I

N CH3

CH3

O

H3C

HH3C

burapitantum burapitant 2-(1-{2-[(2R)-4-{2-[3,5-bis(trifluoromethyl)phenyl]acetyl}-

2-(3,4-dichlorophenyl)morpholin-2-yl]ethyl}piperidin-4-yl)- 2-methylpropanamide

burapitant 2-(1-{2-[(2R)-4-{2-[3,5-bis(trifluorométhyl)phényl]acétyl}- 2-(3,4-dichlorophényl)morpholin-2-yl]éthyl}pipéridin-4-yl)- 2-méthylpropanamide

burapitant 2-(1-{2-[(2R)-4-{2-[3,5-bis(trifluorometil)fenil]acetil}- 2-(3,4-diclorofenil)morfolin-2-il]etil}piperidin-4-il)-2-metilpropanamida


49

C31H35Cl2F5N3O3

N

CF3

CF3

O

O

N

H2N

Cl

Cl

CH3H3C

O

danegaptidum danegaptide (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid

danégaptide acide (2S,4R)-1-(2-aminoacétyl)-4-benzamidopyrrolidine-

2-carboxylique

danegaptida ácido (2S,4R)-1-(2-aminoacetil)-4-benzamidopirrolidina-2-carboxílico

C14H17N3O4

N

CO2HHH2N

HNH

O

O

daratumumabum # daratumumab immunoglobulin G1-kappa, anti-[Homo sapiens ADP-ribosyl cyclase

1 (CD38, cyclic ADP-ribose hydrolase 1, cADPr hydrolase 1, T10)], Homo sapiens monoclonal antibody; gamma1 heavy chain (1-452) [Homo sapiens VH (IGHV3-23*01 (94.90%) -(IGHD)-IGHJ4*01) [8.8.15] (1-122) -IGHG1*03 (123-452)], (225-214')-disulfide with kappa light chain (1'-214') [Homo sapiens V-KAPPA (IGKV3-11*01 (100.00%) -IGKJ1*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; (231-231'':234-234'')-bisdisulfide dimer

daratumumab immunoglobuline G1-kappa, anti-[Homo sapiens ADP-ribosyl cyclase 1 (CD38, cyclic ADP-ribose hydrolase 1, cADPr hydrolase 1, T10)], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-452) [Homo sapiens VH (IGHV3-23*01 (94.90%) -(IGHD)-IGHJ4*01) [8.8.15] (1-122) -IGHG1*03 (123-452)], (225-214')-disulfure avec la chaîne légère kappa (1'-214') [Homo sapiens V-KAPPA (IGKV3-11*01 (100.00%) -IGKJ1*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dimère (231-231'':234-23''')-bisdisulfure

daratumumab inmunoglobulina G1-kappa, anti-[ADP-ribosil ciclasa 1 de Homo sapiens (CD38, hidrolasa 1 de ADP ciclico-ribosa, cADPr hidrolasa 1, T10)], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma1 (1-452) [Homo sapiens VH (IGHV3-23*01 (94.90%) -(IGHD)-IGHJ4*01) [8.8.15] (1-122) -IGHG1*03 (123-452)], (225-214')-disulfuro con la cadena ligera kappa (1'-214') [Homo sapiens V-KAPPA (IGKV3-11*01 (100.00%) -IGKJ1*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dímero (231-231'':234-23''')-bisdisulfuro


50

C6466H9996N1724O2010S42

Heavy chain / Chaîne lourde / Cadena pesadaEVQLLESGGG LVQPGGSLRL SCAVSGFTFN SFAMSWVRQA PGKGLEWVSA 50ISGSGGGTYY ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYFCAKDK 100ILWFGEPVFD YWGQGTLVTV SSASTKGPSV FPLAPSSKST SGGTAALGCL 150VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT 200QTYICNVNHK PSNTKVDKRV EPKSCDKTHT CPPCPAPELL GGPSVFLFPP 250KPKDTLMISR TPEVTCVVVD VSHEDPEVKF NWYVDGVEVH NAKTKPREEQ 300YNSTYRVVSV LTVLHQDWLN GKEYKCKVSN KALPAPIEKT ISKAKGQPRE 350PQVYTLPPSR EEMTKNQVSL TCLVKGFYPS DIAVEWESNG QPENNYKTTP 400PVLDSDGSFF LYSKLTVDKS RWQQGNVFSC SVMHEALHNH YTQKSLSLSP 450GK 452

Light chain / Chaîne légère / Cadena ligeraEIVLTQSPAT LSLSPGERAT LSCRASQSVS SYLAWYQQKP GQAPRLLIYD 50ASNRATGIPA RFSGSGSGTD FTLTISSLEP EDFAVYYCQQ RSNWPPTFGQ 100GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200LSSPVTKSFN RGEC 214



davalintidum # davalintide amylin analogue

human islet amyloid polypeptide-(1-7)-peptidyl- [11-L-arginine(K>R),18- L-arginine(K>R)]salmon calcitonin-1 (Oncorhynchus keta)-(8-27)-peptidyl-human islet amyloid polypeptide-(33-37)-peptidamide

davalintide analogue de l'amyline polypeptide amyloïde d'îlots pancréatiques humains-(1-7)-peptidyl-[11-L-arginine(K>R),18-L-arginine(K>R)]calcitonine-1 de saumon (Oncorhynchus keta)-(8-27)-peptidyl-polypeptide amyloïde d'îlots pancréatiques humains-(33-37)-peptidamide

davalintida análogo de la amilina polipéptido amiloide de los islotes pancreáticos humanos-(1-7)-peptidil-[11-L-arginina(K>R),18-L-arginina(K>R)]calcitonina-1 de salmón (Oncorhynchus keta)-(8-27)-peptidil-polipéptido amiloide de los islotes pancreáticos humanos -(33-37)-peptidamida

C152H248N50O49S2

H Lys Cys Asn Thr Ala Thr Cys Val Leu Gly Arg Leu

Ser Gln Glu Leu

Thr

His

Asn

Arg

Thr

Leu

Gly Ser

Gln Thr

Asn

Tyr

Thr

Pro

Tyr

Arg

NH230

10

20

elinogrelum elinogrel N-[(5-chlorothiophen-2-yl)sulfonyl]-N'-{4-[6-fluoro-7-(methylamino)-

2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl]phenyl}urea

élinogrel N-[(5-chlorothiophén-2-yl)sulfonyl]-N'-{4-[6-fluoro-7-(méthylamino)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl]phényl}urée


51

elinogrel N-[(5-clorotiofen-2-il)sulfonil]-N'-{4-[6-fluoro-7-(metilamino)-2,4-dioxo-1,4-dihidroquinazolin-3(2H)-il]fenil}urea

C20H15ClFN5O5S2

NH

NH

S

N

HN

S

F

HN

H3CO

O

O O O

Cl

elisidepsinun elisidepsin 13,8-anhydro{N-[(4S)-4-methylhexanoyl]-D-valyl-L-threonyl-L-valyl-

D-valyl-D-prolyl-L-ornithyl-D-alloisoleucyl-D-allothreonyl- D-alloisoleucyl-D-valyl-L-phenylalanyl-(2Z)-2-aminobut-2-enoyl- L-valine}

élisidepsine 13,8-anhydro{N-[(4S)-4-méthylhexanoyl]-D-valyl-L-thréonyl-L-valyl- D-valyl-D-prolyl-L-ornithyl-D-alloisoleucyl-D-allothréonyl- D-alloisoleucyl-D-valyl-L-phénylalanyl-(2Z)-2-aminobut-2-énoyl- L-valine}

elisidepsina 13,8-anhidro{N-[(4S)-4-metilhexanoil]-D-valil-L-treonil-L-valil-D-valil- D-prolil-L-ornitil-D-aloisoleucil-D-alotreonil-D-aloisoleucil-D-valil- L-fenilalanil-(2Z)-2-aminobut-2-enoil-L-valina}

C75H124N14O16

O

NH

HN

HNHN

NH

O

O

O

HH3CCH3

CH3

H

H

HO

H3CCH3O

H3CH

O

H3C

H3C

H

NH

OHN

CH3O

CH3

H H

H

NH

HO

NO

NHO

H3C

H3C H

NH

HO

CH3

H3C

HN

OCH3HO

NH

O CH3

H

H CH3

H3C

H CH3

H

H2N

H

elpetriginum elpetrigine 3-(2,3,5-trichlorophenyl)pyrazine-2,6-diamine

elpétrigine 3-(2,3,5-trichlorophényl)pyrazine-2,6-diamine

elpetrigina 3-(2,3,5-triclorofenil)pirazina-2,6-diamina


52

C10H7Cl3N4

N

N

ClNH2

NH2

Cl

Cl

enisamii iodidum enisamium iodide 4-(benzylcarbamoyl)-1-methylpyridin-1-ium iodide

iodure d'énisamium iodure de 4-(benzylcarbamoyl)-1-méthylpyridinium

ioduro de enisamio ioduro de 4-(bencilcarbamoil)-1-metilpiridin-1-io

C14H15IN2O

N

NH

O

H3C

I

eptacogum alfa pegolum (activatum) # eptacog alfa pegol (activated) pegylated human coagulation factor VII, activated

blood-coagulation factor VII (EC 3.4.21.21, serum prothrombin conversion accelerator), human factor VII light chain (135-262)-disulfide with human factor VII heavy chain, some sialyl units of the N-linked carbohydrates are mono-O-[a-methylpoly(oxyethylene) hydrogen phosphate] esterified (average value of the ratio factor VII/pegol is close to 1)

eptacog alfa pégol (activé) facteur VII humain de la coagulation pégylé, activé facteur VII de la coagulation sanguine (EC 3.4.21.21, accélérateur de conversion de la prothrombine sérique), (135-262) disulfure entre la chaîne légère et la chaîne lourde du facteur VII humain, quelques unités acide N-acétylneuraminique de la partie N-glycosyl sont estérifiées, mono-O-[a-méthylpoly(oxyéthylène) hydrogénophosphate] (rapport facteur VII/pegol voisin de 1)

eptacog alfa pegol (activado) factor VII de coagulación humano pegilado, activado factor VII de coagulación sanguínea (EC 3.4.21.21, acelerador de conversión de la protrombina de suero), (135-262) disulfuro entre la cadena ligera y la cadena pesada del factor VII humano, algunas unidades acido N-acetilneuraminico de la parte N-glicosilo están esterificadas, mono-O-[a-metilpoli(oxietileno) hidrogenofosfato] (relación factor VII/pegol cercano de 1)


53

C1982H3054N560O618S28

Light chain / Chaîne légère / Cadena ligeraANAFLEELRP GSLERECKEE QCSFEEAREI FKDAERTKLF WISYSDGDQC 50ASSPCQNGGS CKDQLQSYIC FCLPAFEGRN CETHKDDQLI CVNENGGCEQ 100YCSDHTGTKR SCRCHEGYSL LADGVSCTPT VEYPCGKIPI LEKRNASKPQ 150GR 152

Heavy chain / Chaîne lourde / Cadena pesada IVGGKVCP KGECPWQVLL LVNGAQLCGG TLINTIWVVS AAHCFDKIKN 200WRNLIAVLGE HDLSEHDGDE QSRRVAQVII PSTYVPGTTN HDIALLRLHQ 250PVVLTDHVVP LCLPERTFSE RTLAFVRFSL VSGWGQLLDR GATALELMVL 300NVPRLMTQDC LQQSRKVGDS PNITEYMFCA GYSDGSKDSC KGDSGGPHAT 350HYRGTWYLTG IVSWGQGCAT VGHFGVYTRV SQYIEWLQKL MRSEPRPGVL 400LRAPFP 406

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro17-22 50-61 55-70 72-81 91-102 98-112114-127 135-262 159-164 178-194 310-329 340-368

Modified residues / Résidus modifiés / Residuos modificados

E6-7-14-16-19-20-25-26-29-35

4-carboxyGluHO2C

CO2H

CO2H

H NH2

Glycosylation sites (S , N) / Sites de glycosylation (S , N) / Posiciones de glicosilación (S , N)Ser-52 Ser-60 Asn-145 Asn-322

(β-Xyl)n-β-Glc→S-52n = 0-2

α-Fuc→S-60

β-Man→4-β-Gl-N→4-β-Gl-N→NR→3-β-Gal→3-β-Gl-N→2-α-Man→6-

R'→3-β-Gal→3-β-Gl-N→2-α-Man→3-

R = α-Sia, R' = α-Sia or PEG-α-Sia or R' = α-Sia, R = α-Sia or PEG-α-Sia

Fuc = 6-deoxy-L-galactopyranosylGal = D-galactopyranosylGl-N = 2-(acetylamino)-2-deoxy-D-glucopyranosylMan = D-mannopyranosylPEG- = O-[α-methylpoly(oxyethylene) hydrogen phosphate]Sia = 5-N-acetyl-α-neuramin-2-ylXyl = D-xylopyranosyl

etamicastatum etamicastat 5-(2-aminoethyl)-1-[(3R)-6,8-difluoro-3,4-dihydro-2H-chromen-3-yl]-

1,3-dihydro-2H-imidazole-2-thione

étamicastat 5-(2-aminoéthyl)-1-[(3R)-6,8-difluoro-3,4-dihydro-2H-chromen-3-yl]-1,3-dihydro-2H-imidazole-2-thione

etamicastat 5-(2-aminoetil)-1-[(3R)-6,8-difluoro-3,4-dihidro-2H-cromen-3-il]- 1,3-dihidro-2H-imidazol-2-tiona

C14H15F2N3OS

O

NNH

SF

F H

H2N


54

evatanepagum evatanepag 2-{3-[(N-{[4-(tert-butyl)phenyl]methyl}pyridine-

3-sulfonamido)methyl]phenoxy}acetic acid

évatanépag acide 2-{3-[(N-{[4-(tert-butyl)phényl]méthyl}pyridine- 3-sulfonamido)méthyl]phénoxy}acétique

evatanepag ácido 2-{3-[(N-{[4-(terc-butil)fenil]metil}piridina- 3-sulfonamido)metil]fenoxi}acético

C25H28N2O5S

N

S

O CO2H

CH3NH3C CH3

OO

fezakinumabum # fezakinumab immunoglobulin G1-lambda, anti-[Homo sapiens interleukin 22 (IL22,

IL-22, ILTIF, IL-TIF)], Homo sapiens monoclonal antibody; gamma1 heavy chain (1-450) [Homo sapiens VH (IGHV1-2*02 (91.80%) -(IGHD)-IGHJ2*01) [8.8.14] (1-121) -IGHG1*03 CH1 R120>K, CH3 K130>del (122-450)], (224-216')-disulfide with lambda light chain (1'-217') [Homo sapiens V-LAMBDA (IGLV1-40*01 (96.00%) -IGLJ2*01 K123>Q) [9.3.11] (1'-111') -IGLC2*01 (112'-217')]; (230-230'':233-233'')-bisdisulfide dimer

fézakinumab immunoglobuline G1-lambda, anti-[Homo sapiens interleukine 22 (IL22, IL-22, ILTIF, IL-TIF)], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-450) [Homo sapiens VH (IGHV1-2*02 (91.80%) -(IGHD)-IGHJ2*01) [8.8.14] (1-121) -IGHG1*03 CH1 R120>K, CH3 K130>del (122-450)], (224-216')-disulfure avec la chaîne légère lamba (1'-217') [Homo sapiens V-LAMBDA (IGLV1-40*01 (96.00%) -IGLJ2*01 K123>Q) [9.3.11] (1'-111') -IGLC2*01 (112'-217')]; dimère (230-230'':233-233'')-bisdisulfure

fezakinumab inmunoglobulina G1-lambda, anti-[interleukina 22 (IL22, IL-22, ILTIF, IL-TIF) de Homo sapiens], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma1 (1-450) [Homo sapiens VH (IGHV1-2*02 (91.80%) -(IGHD)-IGHJ2*01) [8.8.14] (1-121) -IGHG1*03 CH1 R120>K, CH3 K130>del (122-450)], (224-216')-disulfuro con la cadena ligera lambda (1'-217') [Homo sapiens V-LAMBDA (IGLV1-40*01 (96.00%) -IGLJ2*01 K123>Q) [9.3.11] (1'-111') -IGLC2*01 (112'-217')]; dímero (230-230'':233-233'')-bisdisulfuro


55

C6408H9886N1710O2016S44

Heavy chain / Chaîne lourde / Cadena pesadaQVQLVQSGAE VKKPGASVKV SCKASGYTFT NYYMHWVRQA PGQGLEWVGW 50INPYTGSAFY AQKFRGRVTM TRDTSISTAY MELSRLRSDD TAVYYCAREP 100EKFDSDDSDV WGRGTLVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV 150KDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTQ 200TYICNVNHKP SNTKVDKKVE PKSCDKTHTC PPCPAPELLG GPSVFLFPPK 250PKDTLMISRT PEVTCVVVDV SHEDPEVKFN WYVDGVEVHN AKTKPREEQY 300NSTYRVVSVL TVLHQDWLNG KEYKCKVSNK ALPAPIEKTI SKAKGQPREP 350QVYTLPPSRE EMTKNQVSLT CLVKGFYPSD IAVEWESNGQ PENNYKTTPP 400VLDSDGSFFL YSKLTVDKSR WQQGNVFSCS VMHEALHNHY TQKSLSLSPG 450

Light chain / Chaîne légère / Cadena ligeraQAVLTQPPSV SGAPGQRVTI SCTGSSSNIG AGYGVHWYQQ LPGTAPKLLI 50YGDSNRPSGV PDRFSGSKSG TSASLAITGL QAEDEADYYC QSYDNSLSGY 100VFGGGTQLTV LGQPKAAPSV TLFPPSSEEL QANKATLVCL ISDFYPGAVT 150VAWKADSSPV KAGVETTTPS KQSNNKYAAS SYLSLTPEQW KSHRSYSCQV 200THEGSTVEKT VAPTECS 217



filibuvirum filibuvir (6R)-6-cyclopentyl-6-[2-(2,6-diethylpyridin-4-yl)ethyl]-

3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one

filibuvir (6R)-6-cyclopentyl-6-[2-(2,6-diéthylpyridin-4-yl)éthyl]- 3-[(5,7-diméthyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)méthyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one

filibuvir (6R)-6-ciclopentil-6-[2-(2,6-dietilpiridin-4-il)etil]- 3-[(5,7-dimetil[1,2,4]triazolo[1,5-a]pirimidin-2-il)metil]-4-hidroxi- 5,6-dihidro-2H-piran-2-ona

C29H37N5O3

O O

OH

N

NNN

CH3

H3C

N

H3C

H3C

flutemetamolum (18F) flutemetamol (18F) 2-{3-[18F]fluoro-4-(methylamino)phenyl}-1,3-benzothiazol-6-ol

flutémétamol (18F) 2-[3-[18F]fluoro-4-(méthylamino)phényl]-1,3-benzothiazol-6-ol

flutemetamol (18F) 2-{3-[18F]fluoro-4-(metilamino)fenil}-1,3-benzotiazol-6-ol

C14H11[18F]N2OS

N

SHO

NHCH3

18F


56

fonturacetamum fonturacetam rac-2-[(4R)-2-oxo-4-phenylpyrolidin-1-yl]acetamide

fonturacétam rac-2-[(4R)-2-oxo-4-phénylpyrrolidin-1-yl)acétamide

fonturacetam rac-2-[(4R)-4-fenil-2-oxopirolidin-1-il]acetamid

C12H14N2O2

NNH2

O

Oand enantiomeret énantiomèrey enantiómero

H

fresolimumabum # fresolimumab immunoglobulin G4-kappa, anti-[Homo sapiens transforming growth

factor beta (TGFB or TGFbeta or TGF-beta, including TGF-beta-1 or TGFB1, TGF-beta-2 or TGFB2 or G-TsF and TGF-beta-3 or TGFB3)], Homo sapiens monoclonal antibody; gamma4 heavy chain (1-447) [Homo sapiens VH (IGHV1-69*10 (89.70%) -(IGHD)-IGHJ3*01) [8.8.13] (1-120) -IGHG4*01 (121-447)], (134-215')-disulfide with kappa light chain (1'-215') [Homo sapiens V-KAPPA (IGKV3-20*01 (93.80%) -IGKJ5*01) [7.3.9] (1'-108') -IGKC*01 (109'-215')]; (226-226'':229-229'')-bisdisulfide dimer

frésolimumab immunoglobuline G4-kappa, anti-[Homo sapiens facteur de croissance transformant bêta (TGFB ou TGFbêta ou TGF-bêta, comprenant TGF-bêta1 ou TGFB1, TGF-bêta2 ou TGFB2 ou G-TsF et TGF-bêta3 ou TGFB3)], Homo sapiens anticorps monoclonal; chaîne lourde gamma4 (1-447) [Homo sapiens VH (IGHV1-69*10 (89.70%) -(IGHD)-IGHJ3*01) [8.8.13] (1-120) -IGHG4*01 (121-447)], (134-215')-disulfure avec la chaîne légère kappa (1'-215') [Homo sapiens V-KAPPA (IGKV3-20*01 (93.80%) -IGKJ5*01) [7.3.9] (1'-108') -IGKC*01 (109'-215')]; dimère (226-226'':229-229'')-bisdisulfure

fresolimumab inmunoglobulina G4-kappa, anti-[factor de crecimiento transformador beta de Homo sapiens (TGFB o TGFbeta o TGF-beta, incluye TGF-beta-1 o TGFB1, TGF-beta-2 o TGFB2 o G-TsF y TGF-beta-3 o TGFB3)], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma4 (1-447) [Homo sapiens VH (IGHV1-69*10 (89.70%) -(IGHD)-IGHJ3*01) [8.8.13] (1-120) -IGHG4*01 (121-447)], (134-215')-disulfuro con la cadena ligera kappa (1'-215') [Homo sapiens V-KAPPA (IGKV3-20*01 (93.80%) -IGKJ5*01) [7.3.9] (1'-108') -IGKC*01 (109'-215')]; dímero (226-226'':229-229'')-bisdisulfuro


57

C6392H9926N1698O2026S44

Heavy chain / Chaîne lourde / Cadena pesadaQVQLVQSGAE VKKPGSSVKV SCKASGYTFS SNVISWVRQA PGQGLEWMGG 50VIPIVDIANY AQRFKGRVTI TADESTSTTY MELSSLRSED TAVYYCASTL 100GLVLDAMDYW GQGTLVTVSS ASTKGPSVFP LAPCSRSTSE STAALGCLVK 150DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTKT 200YTCNVDHKPS NTKVDKRVES KYGPPCPSCP APEFLGGPSV FLFPPKPKDT 250LMISRTPEVT CVVVDVSQED PEVQFNWYVD GVEVHNAKTK PREEQFNSTY 300RVVSVLTVLH QDWLNGKEYK CKVSNKGLPS SIEKTISKAK GQPREPQVYT 350LPPSQEEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS 400DGSFFLYSRL TVDKSRWQEG NVFSCSVMHE ALHNHYTQKS LSLSLGK 447

Light chain / Chaîne légère / Cadena ligeraETVLTQSPGT LSLSPGERAT LSCRASQSLG SSYLAWYQQK PGQAPRLLIY 50GASSRAPGIP DRFSGSGSGT DFTLTISRLE PEDFAVYYCQ QYADSPITFG 100QGTRLEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK 150VDNALQSGNS QESVTEQDSK DSTYSLSSTL TLSKADYEKH KVYACEVTHQ 200GLSSPVTKSF NRGEC 215



girentuximabum # girentuximab immunoglobulin G1-kappa, anti-[Homo sapiens carbonic anhydrase

IX (CAIX, CA9, MN, G250)], chimeric monoclonal antibody; gamma1 heavy chain (1-449) [Mus musculus VH (IGHV5-6-2*01 -(IGHD)-IGHJ4*01) [8.8.12] (1-119) -Homo sapiens IGHG1*01 (120-449)], (222-214')-disulfide with kappa light chain (1'-214') [Mus musculus V-KAPPA (IGKV6-13*01 -IGKJ1*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; (228-228'':231-231'')-bisdisulfide dimer

girentuximab immunoglobuline G1-kappa, anti-[Homo sapiens anhydrase carbonique IX (CAIX, CA9, MN, G250)], anticorps monoclonal chimérique; chaîne lourde gamma1 (1-449) [Mus musculus VH (IGHV5-6-2*01 -(IGHD)-IGHJ4*01) [8.8.12] (1-119) -Homo sapiens IGHG1*01 (120-449)], (222-214')-disulfure avec la chaîne légère kappa (1'-214') [Mus musculus V-KAPPA (IGKV6-13*01 -IGKJ1*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dimère (228-228'':231-231'')-bisdisulfure

girentuximab inmunoglobulina G1-kappa, anti-[anhidrasa carbónica IX de Homo sapiens (CAIX, CA9, MN, G250)], anticuerpo monoclonal quimérico; cadena pesada gamma1 (1-449) [Mus musculus VH (IGHV5-6-2*01 -(IGHD)-IGHJ4*01) [8.8.12] (1-119) -Homo sapiens IGHG1*01 (120-449)], (222-214')-disulfuro con la cadena ligera kappa (1'-214') [Mus musculus V-KAPPA (IGKV6-13*01 -IGKJ1*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dímero (228-228'':231-231'')-bisdisulfuro


58

C6460H10006N1718O2018S48

Heavy chain / Chaîne lourde / Cadena pesadaDVKLVESGGG LVKLGGSLKL SCAASGFTFS NYYMSWVRQT PEKRLELVAA 50INSDGGITYY LDTVKGRFTI SRDNAKNTLY LQMSSLKSED TALFYCARHR 100SGYFSMDYWG QGTSVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD 150YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY 200ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK 250DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS 300TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV 350YTLPPSRDEL TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL 400DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK 449

Light chain / Chaîne légère / Cadena ligeraDIVMTQSQRF MSTTVGDRVS ITCKASQNVV SAVAWYQQKP GQSPKLLIYS 50ASNRYTGVPD RFTGSGSGTD FTLTISNMQS EDLADFFCQQ YSNYPWTFGG 100GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200LSSPVTKSFN RGEC 214



gisadenafilum gisadenafil 5-{2-ethoxy-5-[(4-ethylpiperazin-1-yl)sulfonyl]pyridin-3-yl}-3-ethyl-

2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

gisadénafil 5-{2-éthoxy-5-[(4-éthylpipérazin-1-yl)sulfonyl]pyridin-3-yl}-3-éthyl- 2-(2-méthoxyéthyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

gisadenafilo 3-etil-5-{5-[(4-etilpiperazin-1-il)sulfonil]-2-etoxipiridin-3-il}- 2-(2-metoxietil)-2,6-dihidro-7H-pirazolo[4,3-d]pirimidin-7-ona

C23H33N7O5S

HN

N

NN

N

SN

N

OO

O

CH3O CH3

OCH3

H3C

givinostatum givinostat {6-[(diethylamino)methyl]naphthalen-2-yl}methyl

[4-(hydroxycarbamoyl)phenyl]carbamate

givinostat [4-(hydroxycarbamoyl)phényl]carbamate de {6-[(diéthylamino)méthyl]naphtalén-2-yl}méthyle

givinostat [4-(hidroxicarbamoil)fenil]carbamato de {6-[(dietilamino)metil]naftalen-2-il}metilo


59

C24H27N3O4

O NH

NH

OH

O

O

NH3C

H3C

golnerminogenum pradenovecum #

golnerminogene pradenovec a replication deficient human adenovirus 5 viral vector deleted in the E1, E4 and part of the E3 region and expressing a human tumour necrosis factor alpha (TNF-α) gene inserted in the E1 region and under the control of an Egr-1 promoter and the SV40 polyadenylation sequence

golnerminogène pradénovec vecteur viral adénovirus humain 5 sans capacité de réplication, dont les régions E1, E4 et une partie de la région E3 ont été supprimées, et exprimant un gène humain du facteur de nécrose tumorale alpha (TNF-α) inséré dans la région E1 et sous lecontrôle d'un promoteur Egr-1 et la séquence de polyadénylation SV40

golnerminogén pradenovec vector viral adenovirus humano 5 sin capacidad de replicación con deleción de E1, E4 y parte de la región E3 y que expresa un gen humano del factor de necrosis tumoral alfa (TNF-α) insertado en la región E1 y bajo control de un promotor Egr-1 y la secuencia de poliadenilación de SV40

gosogliptinum gosogliptin (3,3-difluoropyrrolidin-1-yl){(2S,4S)-4-[4-(pyrimidin-2-yl)piperazin-

1-yl]pyrrolidin-2-yl}methanone

gosogliptine (3,3-difluoropyrrolidin-1-yl){(2S,4S)-4-[4-(pyrimidin-2-yl)pipérazin- 1-yl]pyrrolidin-2-yl}méthanone

gosogliptina (3,3-difluoropirrolidin-1-il){(2S,4S)-4-[4-(pirimidin-2-il)piperazin- 1-il]pirrolidin-2-il}metanona

C17H24F2N6O

HN

NH

N

O

FF

H

NN

N

imagabalinum imagabalin (3S,5R)-3-amino-5-methyloctanoic acid

imagabaline acide (3S,5R)-3-amino-5-méthyloctanoïque

imagabalina ácido (3S,5R)-3-amino-5-metiloctanoico

C9H19NO2

CO2HH3C

NH2HHH3C


60

imetelstatum imetelstat 3'-amino-3'-deoxy-P-thiothymidylyl-(3'→5')-3'-amino-2',3'-dideoxy-P-

thioadenylyl-(3'→5')-3'-amino-2',3'-dideoxy-P-thioguanylyl-(3'→5')-3'-amino-2',3'-dideoxy-P-thioguanylyl-(3'→5')-3'-amino-2',3'-dideoxy- P-thioguanylyl-(3'→5')-3'-amino-3'-deoxy-P-thiothymidylyl-(3'→5')-3'-amino-3'-deoxy-P-thiothymidylyl-(3'→5')-3'-amino-2',3'-dideoxy- P-thioadenylyl-(3'→5')-3'-amino-2',3'-dideoxy-P-thioguanylyl-(3'→5')-3'-amino-2',3'-dideoxy-P-thioadenylyl-(3'→5')-3'-amino-2',3'-dideoxy-P-thiocytidylyl-(3'→5')-3'-amino-2',3'-dideoxy-P-thioadenylyl-(3'→5')-3'-amino-2',3'-dideoxyadenosine 5'-{O-[2-hydroxy- 3-(hexadecanoylamino)propyl] hydrogen phosphorothioate}

imételstat 5'-{O-[2-hydroxy-3-(hexadécanoylamino)propyl] hydrogénophosphorothioate} de 3'-amino-3'-déoxy-P-thiothymidylyl-(3'→5')-3'-amino-2',3'-didéoxy-P-thioadénylyl-(3'→5')-3'-amino- 2',3'-didéoxy-P-thioguanylyl-(3'→5')-3'-amino-2',3'-didéoxy- P-thioguanylyl-(3'→5')-3'-amino-2',3'-didéoxy-P-thioguanylyl-(3'→5')-3'-amino-3'-déoxy-P-thiothymidylyl-(3'→5')-3'-amino-3'-déoxy- P-thiothymidylyl-(3'→5')-3'-amino-2',3'-didéoxy-P-thioadénylyl-(3'→5')-3'-amino-2',3'-didéoxy-P-thioguanylyl-(3'→5')-3'-amino- 2',3'-didéoxy-P-thioadénylyl-(3'→5')-3'-amino-2',3'-didéoxy- P-thiocytidylyl-(3'→5')-3'-amino-2',3'-didéoxy-P-thioadénylyl-(3'→5')-3'-amino-2',3'-didéoxyadénosine

imetelstat 5'-{O-[2-hidroxi-3-(hexadecanoilamino)propil] hidrógenofosforotioato} de 3'-amino-3'-desoxi-P-tiotimidilil-(3'→5')-3'-amino-2',3'-didesoxi- P-tioadenilil-(3'→5')-3'-amino-2',3'-didesoxi-P-tioguanilil-(3'→5')-3'-amino-2',3'-didesoxi-P-tioguanilil-(3'→5')-3'-amino-2',3'-didesoxi- P-tioguanilil-(3'→5')-3'-amino-3'-desoxi-P-tiotimidilil-(3'→5')-3'-amino-3'-desoxi-P-tiotimidilil-(3'→5')-3'-amino-2',3'-didesoxi-P-tioadenilil-(3'→5')-3'-amino-2',3'-didesoxi-P-tioguanilil-(3'→5')-3'-amino- 2',3'-didesoxi-P-tioadenilil-(3'→5')-3'-amino-2',3'-didesoxi-P-tiocitidilil-(3'→5')-3'-amino-2',3'-didesoxi-P-tioadenilil-(3'→5')-3'-amino- 2',3'-didesoxiadenosina

C148H211N68O53P13S13 (3'-5')d(3'-amino-3'-deoxy-P-thio)( A G G G T T A G A C A A)pT

HO

HN

O H3C

insulinum degludecum insulin degludec N6.B29-[N2-(15-carboxypentadecanoyl)-L-γ-glutamyl]-des-B30-

L-threonine-insulin human

insuline dégludec N6,B29-[N2-(15-carboxypentadécanoyl)-L-γ-glutamyl]-dés-B30- L-thréonine-insuline humaine

insulina degludec N6.B29-[N2-(15-carboxipentadecanoil)-L-γ-glutamil]-des-B30- L-treonina-insulina humana

C274H411N65O81S6

H Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Gln Leu

Glu Asn Tyr Cys Asn OH

H Phe

Leu

Val

Val

Asn

Cys

Gln His Leu Cys

Gly

Gly Ser

Glu

His Leu Val Glu

Arg Gly Phe Phe Tyr Thr Pro Lys

Ala

OH

Leu Tyr

10

20

10

20

O

N6HN

H CO2HO

HO2C


61

intetumumabum # intetumumab immunoglobulin G1-kappa, anti-[Homo sapiens integrin alpha-V

(CD51, ITGAV, subunit of alphaV-beta3 or CD51/CD61 or vitronectin receptor or VNR, subunit of alphaV-beta5)], Homo sapiens monoclonal antibody; gamma1 heavy chain (1-449) [Homo sapiens VH (IGHV3-30*01 (91.80%) -(IGHD)-IGHJ3*02) [8.8.12] (1-119) -IGHG1*01 (120-449)], (222-215')-disulfide with kappa light chain (1'-215') [Homo sapiens V-KAPPA (IGKV3-11*01 (100.00%) -IGKJ3*01) [6.3.10] (1'-108') -IGKC*01 (109'-215')]; (228-228'':231-231'')-bisdisulfide dimer

intétumumab immunoglobuline G1-kappa, anti-[Homo sapiens intégrine alpha-V (CD51, ITGAV, sous-unité de alphaV-bêta3 ou CD51/CD61 ou récepteur de la vitronectine ou VNR, sous-unité de alphaV-bêta5)], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-449) [Homo sapiens VH (IGHV3-30*01 (91.80%) -(IGHD)-IGHJ3*02) [8.8.12] (1-119) -IGHG1*01 (120-449)], (222-215')-disulfure avec la chaîne légère kappa (1'-215') [Homo sapiens V-KAPPA (IGKV3-11*01 (100.00%) -IGKJ3*01) [6.3.10] (1'-108') -IGKC*01 (109'-215')]; dimère (228-228'':231-231'')-bisdisulfure

intetumumab inmunoglobulina G1-kappa, anti-[integrina alfa-V de Homo sapiens (CD51, ITGAV, subunidad de alfaV-beta3 o CD51/CD61 o receptor de la vitronectina o VNR, subunidad de alfaV-beta5)], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma1 (1-449) [Homo sapiens VH (IGHV3-30*01 (91.80%) -(IGHD)-IGHJ3*02) [8.8.12] (1-119) -IGHG1*01 (120-449)], (222-215')-disulfuro con la cadena ligera kappa (1'-215') [Homo sapiens V-KAPPA (IGKV3-11*01 (100.00%) -IGKJ3*01) [6.3.10] (1'-108')-IGKC*01 (109'-215')]; dímero (228-228'':231-231'')-bisdisulfuro

C6468H10008N1744O2006S40

Heavy chain / Chaîne lourde / Cadena pesadaQVQLVESGGG VVQPGRSRRL SCAASGFTFS RYTMHWVRQA PGKGLEWVAV 50ISFDGSNKYY VDSVKGRFTI SRDNSENTLY LQVNILRAED TAVYYCAREA 100RGSYAFDIWG QGTMVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD 150YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY 200ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK 250DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS 300TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV 350YTLPPSRDEL TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL 400DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK 449

Light chain / Chaîne légère / Cadena ligeraEIVLTQSPAT LSLSPGERAT LSCRASQSVS SYLAWYQQKP GQAPRLLIYD 50ASNRATGIPA RFSGSGSGTD FTLTISSLEP EDFAVYYCQQ RSNWPPFTFG 100PGTKVDIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK 150VDNALQSGNS QESVTEQDSK DSTYSLSSTL TLSKADYEKH KVYACEVTHQ 200GLSSPVTKSF NRGEC 215




62

iodum (124I) girentuximabum # iodine (124I) girentuximab immunoglobulin G1-kappa, anti-[Homo sapiens carbonic anhydrase

IX (CAIX, CA9, MN, G250)], chimeric monoclonal antibody radiolabeled with iodine-124; gamma1 heavy chain (1-449) [Mus musculus VH (IGHV5-6-2*01 -(IGHD)-IGHJ4*01) [8.8.12] (1-119) -Homo sapiens IGHG1*01 (120-449)], (222-214')-disulfide with kappa light chain (1'-214') [Mus musculus V-KAPPA (IGKV6-13*01 -IGKJ1*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; (228-228'':231-231'')-bisdisulfide dimer covalently linked to iodine-124

iodine (124I) girentuximab immunoglobuline G1-kappa, anti-[Homo sapiens anhydrase carbonique IX (CAIX, CA9, MN, G250)], anticorps monoclonal chimérique marqué à l'iode 124; chaîne lourde gamma1 (1-449) [Mus musculus VH (IGHV5-6-2*01 -(IGHD)-IGHJ4*01) [8.8.12] (1-119) -Homo sapiens IGHG1*01 (120-449)], (222-214')-disulfure avec la chaîne légère kappa (1'-214') [Mus musculus V-KAPPA (IGKV6-13*01 -IGKJ1*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dimère (228-228'':231-231'')-bisdisulfure lié de façon covalente à de l'iode 124

iodine (124I) girentuximab inmunoglobulina G1-kappa, anti-[anhidrasa carbónica IX de Homo sapiens (CAIX, CA9, MN, G250)], anticuerpo monoclonal quimérico marcado con iodo 124; cadena pesada gamma1 (1-449) [Mus musculus VH (IGHV5-6-2*01 -(IGHD)-IGHJ4*01) [8.8.12] (1-119) -Homo sapiens IGHG1*01 (120-449)], (222-214')-disulfuro con la cadena ligera kappa (1'-214') [Mus musculus V-KAPPA (IGKV6-13*01 -IGKJ1*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dímero (228-228'':231-231'')-bisdisulfuro covalentemente ligado con iodo 124

C6460H(10006-n)124InN1718O2018S48

Heavy chain / Chaîne lourde / Cadena pesada

DVKLVESGGG LVKLGGSLKL SCAASGFTFS NYYMSWVRQT PEKRLELVAA 50INSDGGITYY LDTVKGRFTI SRDNAKNTLY LQMSSLKSED TALFYCARHR 100SGYFSMDYWG QGTSVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD 150YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY 200ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK 250DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS 300TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV 350YTLPPSRDEL TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL 400DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK 449

Light chain / Chaîne légère / Cadena ligeraDIVMTQSQRF MSTTVGDRVS ITCKASQNVV SAVAWYQQKP GQSPKLLIYS 50ASNRYTGVPD RFTGSGSGTD FTLTISNMQS EDLADFFCQQ YSNYPWTFGG 100GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200LSSPVTKSFN RGEC 214




63

isopropylis turofexoras turofexorate isopropyl propan-2-yl 3-(3,4-difluorobenzoyl)-1,1-dimethyl-1,2,3,6-

tetrahydroazepino[4,5-b]indole-5-carboxylate

isopropyl de turofexorate 3-(3,4-difluorobenzoyl)-1,1-diméthyl-1,2,3,6-tétrahydroazépino[4,5-b]indole-5-carboxylate de propan-2-yle

turofexorato de isopropilo 3-(3,4-difluorobenzoil)-1,1-dimetil-1,2,3,6-tetrahidroazepino[4,5-b]indol-5-carboxilato de propan-2-ilo

C25H24F2N2O3

N

O O

O CH3

CH3

NHH3C

CH3F

F

lagociclovirum lagociclovir 2-amino-9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-

1,9-dihydro-6H-purin-6-on

lagociclovir 2-amino-9-(2,3-didéoxy-3-fluoro-β-D-érythro-pentofuranosyl)- 1,9-dihydro-6H-purin-6-one

lagociclovir 2-amino-9-(2,3-didesoxi-3-fluoro-β-D-eritro-pentofuranosil)- 1,9-dihidro-6H-purin-6-ona

C10H12FN5O3

HN

N N

N

H2N

O

O

F

HO

lebrikizumabum # lebrikizumab immunoglobulin G4-kappa, anti-[Homo sapiens interleukin 13 (IL13,

IL-13)], humanized monoclonal antibody; gamma4 heavy chain [humanized VH (Homo sapiens IGHV2-70*01 (82.80%) -(IGHD)-IGHJ6*01) [8.7.12] (1-118) -Homo sapiens IGHG4*01 hinge S10>P (119-445)], (132-218')-disulfide with kappa light chain (1’-218’) [humanized V-KAPPA (Homo sapiens IGKV4-1*01 (79.20%) –IGKJ4*01) [10.3.9] (1'-111') -Homo sapiens IGKC*01 (112'-218')]; (224-224":227-227")-bisdisulfide dimer


64

lébrikizumab immunoglobuline G4-kappa, anti-[Homo sapiens interleukine 13 (IL13, IL-13)], anticorps monoclonal humanisé; chaîne lourde gamma4 [VH humanisé (Homo sapiens IGHV2-70*01 (82.80%) -(IGHD)-IGHJ6*01) [8.7.12] (1-118) -Homo sapiens IGHG4*01 charnière S10>P (119-445)], (132-218')-disulfure avec la chaîne légère kappa (1’-218’) [V-KAPPA humanisé (Homo sapiens IGKV4-1*01 (79.20%) –IGKJ4*01) [10.3.9] (1'-111') -Homo sapiens IGKC*01 (112'-218')]; dimère (224-224":227-227")-bisdisulfure

lebrikizumab inmunoglobulina G4-kappa, anti-[interleukina 13 de Homo sapiens (IL13, IL-13)], anticuerpo monoclonal humanizado; cadena pesada gamma4 [VH humanizada (Homo sapiens IGHV2-70*01 (82.80%) -(IGHD)-IGHJ6*01) [8.7.12] (1-118) -Homo sapiens IGHG4*01 bisagra S10>P (119-445)], (132-218')-disulfuro con la cadena ligera kappa (1’-218’) [V-KAPPA humanizada (Homo sapiens IGKV4-1*01 (79.20%) –IGKJ4*01) [10.3.9] (1'-111') -Homo sapiens IGKC*01 (112'-218')]; dímero (224-224":227-227")-bisdisulfuro

C6434H9972N1700O2034S50

Heavy chain / Chaîne lourde / Cadena pesadaQVTLRESGPA LVKPTQTLTL TCTVSGFSLS AYSVNWIRQP PGKALEWLAM 50IWGDGKIVYN SALKSRLTIS KDTSKNQVVL TMTNMDPVDT ATYYCAGDGY 100YPYAMDNWGQ GSLVTVSSAS TKGPSVFPLA PCSRSTSEST AALGCLVKDY 150FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTKTYT 200CNVDHKPSNT KVDKRVESKY GPPCPPCPAP EFLGGPSVFL FPPKPKDTLM 250ISRTPEVTCV VVDVSQEDPE VQFNWYVDGV EVHNAKTKPR EEQFNSTYRV 300VSVLTVLHQD WLNGKEYKCK VSNKGLPSSI EKTISKAKGQ PREPQVYTLP 350PSQEEMTKNQ VSLTCLVKGF YPSDIAVEWE SNGQPENNYK TTPPVLDSDG 400SFFLYSRLTV DKSRWQEGNV FSCSVMHEAL HNHYTQKSLS LSLGK 445

Light chain / Chaîne légère / Cadena ligeraDIVMTQSPDS LSVSLGERAT INCRASKSVD SYGNSFMHWY QQKPGQPPKL 50LIYLASNLES GVPDRFSGSG SGTDFTLTIS SLQAEDVAVY YCQQNNEDPR 100TFGGGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKV 150QWKVDNALQS GNSQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEV 200THQGLSSPVT KSFNRGEC 218



lersivirinum lersivirine 5-{[3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}benzene-

1,3-dicarbonitrile

lersivirine 5-{[3,5-diéthyl-1-(2-hydroxyéthyl)-1H-pyrazol-4-yl]oxy}benzène- 1,3-dicarbonitrile

lersivirina 5-{[3,5-dietil-1-(2-hidroxietil)-1H-pirazol-4-il]oxi}benceno- 1,3-dicarbonitrilo

C17H18N4O2

CN

CNO

NN

H3C

HO

H3C


65

levomequitazinum levomequitazine 10-{[(3S)-1-azabicyclo[2.2.2]octan-3-yl]methyl}-10H-phenothiazine

lévoméquitazine 10-[(3S)-1-azabicyclo[2.2.2]oct-3-ylméthyl]-10H-phénothiazine

levomequitazina 10-{[(3S)-1-azabiciclo[2.2.2]octan-3-il]metil}-10H-fenotiazina

C20H22N2S

S

NNH

litronesibum litronesib (-)-N-{4-(2,2-dimethylpropanoyl)-

5-{[2-(ethylamino)ethanesulfonamido]methyl}-5-phenyl-4,5-dihydro- 1,3,4-thiadiazol-2-yl}-2,2-dimethylpropanamide

litronésib (-)-N-{4-(2,2-diméthylpropanoyl)- 5-{[2-(éthylamino)éthanesulfonamido]méthyl}-5-phényl-4,5-dihydro- 1,3,4-thiadiazol-2-yl}-2,2-diméthylpropanamide

litronesib (-)-N-{4-(2,2-dimetilpropanoil)- 5-{[2-(etilamino)etanosulfonamido]metil}-5-fenil-4,5-dihidro- 1,3,4-tiadiazol-2-il}-2,2-dimetilpropanamida

C23H37N5O4S2

SN

NHN

H3C OHN

S

HN CH3O

CH3H3CH3C

CH3

CH3

O O

or enantiomer(-)-isomer

ou énantiomère(-)-isomère

o enantiómero(-)-isómero

lomitapidum lomitapide N-(2,2,2-trifluoroethyl)-9-(4-{4-[4'-(trifluoromethyl)[1,1'-biphenyl]-

2-carboxamido]piperidin-1-yl}butyl)-9H-fluorene-9-carboxamide

lomitapide N-(2,2,2-trifluoroéthyl)-9-(4-{4-[4'-(trifluorométhyl)[1,1'-biphényl]- 2-carboxamido]pipéridin-1-yl}butyl)-9H-fluorène-9-carboxamide

lomitapida N-(2,2,2-trifluoroetil)-9-(4-{4-[4'-(trifluorometil)[1,1'-bifenil]- 2-carboxamido]piperidin-1-il}butil)-9H-fluoreno-9-carboxamida

C39H37F6N3O2

HN CF3

N

NH

F3C

O

O


66

losmapimodum losmapimod 6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-

N-(2,2-dimethylpropyl)pyridine-3-carboxamide

losmapimod 6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-méthylphényl]- N-(2,2-diméthylpropyl)pyridine-3-carboxamide

losmapimod 6-[5-(ciclopropilcarbamoil)-3-fluoro-2-metilfenil]- N-(2,2-dimetilpropil)piridina-3-carboxamida

C22H26FN3O2

N NH

CH3

F

NH

O

O

CH3

H3C CH3

miravirsenum miravirsen all-P-ambo-5-methyl-2'-O,4'-C-methylene-P-thiocytidylyl-(3'→5')-2'-

deoxy-P-thiocytidylyl-(3'→5')-2'-O,4'-C-methylene-P-thioadenylyl-(3'→5')-P-thiothymidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-O,4'-C-methylene-P-thioguanylyl-(3'→5')-5-methyl-2'-O,4'-C-methylene- P-thiouridylyl-(3'→5')-2'-deoxy-P-thiocytidylyl-(3'→5')-2'-deoxy- P-thioadenylyl-(3'→5')-5-methyl-2'-O,4'-C-methylene-P-thiocytidylyl-(3'→5')-2'-deoxy-P-thioadenylyl-(3'→5')-5-methyl-2'-O,4'-C-methylene-P-thiocytidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-5-methyl-2'-O,4'-C-methylene-P-thiocytidylyl-(3'→5')-5-methyl-2'-O,4'-C-methylene-P-thiocytidine

miravirsen all-P-ambo-5-méthyl-2'-O,4'-C-méthylène-P-thiocytidylyl-(3'→5')-2'-déoxy-P-thiocytidylyl-(3'→5')-2'-O,4'-C-méthylène-P-thioadénylyl-(3'→5')-P-thiothymidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-O,4'-C-méthylène-P-thioguanylyl-(3'→5')-5-méthyl-2'-O,4'-C-méthylène- P-thiouridylyl-(3'→5')-2'-déoxy-P-thiocytidylyl-(3'→5')-2'-déoxy- P-thioadénylyl-(3'→5')-5-méthyl-2'-O,4'-C-méthylène-P-thiocytidylyl-(3'→5')-2'-déoxy-P-thioadénylyl-(3'→5')-5-méthyl-2'-O,4'-C-méthylène-P-thiocytidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-5-méthyl-2'-O,4'-C-méthylène-P-thiocytidylyl-(3'→5')-5-méthyl-2'-O,4'-C-méthylènecytidine

miravirsén todo-P-ambo-5-metil-2'-O,4'-C-metileno-P-tiocitidilil-(3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')-2'-O,4'-C-metileno-P-tioadenilil-(3'→5')-P-tiotimidilil-(3'→5')-P-tiotimidilil-(3'→5')-2'-O,4'-C-metileno- P-tioguanilil-(3'→5')-5-metil-2'-O,4'-C-metileno-P-tiouridilil-(3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')-2'-desoxi-P-tioadenilil-(3'→5')-5-metil-2'-O,4'-C-metileno-P-tiocitidilil-(3'→5')-2'-desoxi-P-tioadenilil-(3'→5')-5-metil-2'-O,4'-C-metileno-P-tioctidilil-(3'→5')-P-tiotimidilil-(3'→5')-5-metil-2'-O,4'-C-metileno-P-tiocitidilil-(3'→5')-5-metil-2'-O,4'-C-metileno-P-tiocitidina


67

C156H195N49O83P14S14

(3'-5')(P-thio)(mC-dC-A-dT-dT-G-T-dC-dA-mC-dA-mC-dT-mC-mC)

mC

H2C

O

N

NO NH2

O

HO

OH

CH3

H

H2C

O

O

HO

OH

H

N N

NN NH2

A

H2C

O

N

HNO O

O

HO

OH

CH3

T

H

H2C

O

O

HO

OH

H

N N

NHN O

H2NG

mocetinostatum mocetinostat N-(2-aminophenyl)-4-({[4-(pyridin-3-yl)pyrimidin-

2-yl]amino}methyl)benzamide

mocétinostat N-(2-aminophényl)-4-({[4-(pyridin-3-yl)pyrimidin- 2-yl]amino}méthyl)benzamide

mocetinostat N-(2-aminofenil)-4-({[4-(piridin-3-il)pirimidin- 2-il]amino}metil)benzamida

C23H20N6O

NH H

N NNH2

O

N

N

modithromycinum modithromycin N-[(1R,2R,3R,6R,8R,9R,10R,13E,16S,17E,18R)-3-ethyl-2-hydroxy-

2,6,8,10,16,18-hexamethyl-5,7-dioxo-13-{[6-(1H-pyrazol-1-yl)pyridin-3-yl]methoxyimino}-9-{[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy}-4,11,15-trioxabicyclo[8.5.4]nonadecane- 17-ylidene]acetamide

modithromycine N-[(1R,2R,3R,6R,8R,9R,10R,13E,16S,17E,18R)-3-éthyl-2-hydroxy-2,6,8,10,16,18-tétraméthyl-5,7-dioxo-13-({[6-(1H-pyrazol-1-yl)pyridin-3-yl]méthoxy}imino)-9-{[3,4,6-tridéoxy-3-(diméthylamino)-β-D-xylo-hexopyranosyl]oxy}-4,11,15-trioxabicyclo[8.5.4]nonadéc- 17-ylidène]acétamide

moditromicina N-[(1R,2R,3R,6R,8R,9R,10R,13E,16S,17E,18R)-3-etil-2-hidroxi-2,6,8,10,16,18-hexametil-5,7-dioxo-13-{[6-(1H-pirazol-1-il)piridin- 3-il]metoxiimino}-9-{[3,4,6-tridesoxi-3-(dimetilamino)-β-D-xilo-hexopiranosil]oxi}-4,11,15-trioxabiciclo[8.5.4]nonadecane- 17-ilidene]acetamido


68

C43H64N6O11

O

HCH3

CH3

OH

H CH3

N

OO

H

HH3C

CH3

CH3

H

O

H3C

OO

N

H

ON

N

N

HCH3

OH3C

N

O

OHCH3

H3C

naluzotanum naluzotan N-(3-{4-[4-(1-cyclohexylmethanesulfonamido)butyl]piperazin-

1-yl}phenyl)acetamide

naluzotan N-(3-{4-[4-(1-cyclohexylméthanesulfonamido)butyl]pipérazin- 1-yl}phényl)acétamide

naluzotán N-(3-{4-[4-(1-ciclohexilmetanosulfonamido)butil]piperazin- 1-il}fenil)acetamida

C23H38N4O3S

N

N

NH

S

NH

CH3

O

OO

nelotanserinum nelotanserin 1-[3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-methoxyphenyl]-

3-(2,4-difluorophenyl)urea

nélotansérine 1-[3-(4-bromo-1-méthyl-1H-pyrazol-5-yl)-4-méthoxyphényl]- 3-(2,4-difluorophényl)urée

nelotanserina 1-[3-(4-bromo-1-metil-1H-pirazol-5-il)-4-metoxifenil]- 3-(2,4-difluorofenil)urea

C18H15BrF2N4O2

HN

HN

FFO

OCH3

NNH3C

Br


69

ocriplasminum # ocriplasmin truncated human plasmin:

human plasmin heavy chain A-(543-561)-peptide (548-666;558-566)-bisdisulfide with human plasmin light chain B

ocriplasmine plasmine humaine tronquée : chaîne lourde A de la plasmine humaine-(543-561)-peptide (548-666;558-566)-bisdisulfure avec la chaîne légère B de la plasmine humaine

ocriplasmina plasmina humana truncada: cadena pesada A de la plasmina humana-(543-561)-péptido (548-666;558-566)-bisdisulfuro con la cadena ligera B de la plasmina humana

C1214H1890N338O348S14

Truncated heavy chain / Chaîne lourde tronquée/ Cadena pesada truncada APSFDCGK 550PQVEPKKCPG R 561

Light chain / Chaîne légère / Cadena ligera VVGGCVAHP HSWPWQVSLR TRFGMHFCGG TLISPEWVLT 600AAHCLEKSPR PSSYKVILGA HQEVNLEPHV QEIEVSRLFL EPTRKDIALL 650KLSSPAVITD KVIPACLPSP NYVVADRTEC FITGWGETQG TFGAGLLKEA 700QLPVIENKVC NRYEFLNGRV QSTELCAGHL AGGTDSCQGD SGGPLVCFEK 750DKYILQGVTS WGLGCARPNK PGVYVRVSRF VTWIEGVMRN N 791

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro548-666 558-566 588-604 680-747 710-726 737-765

olodaterolum olodaterol 6-hydroxy-8-[(1R)-1-hydroxy-2-{[1-(4-methoxyphenyl)-

1,1-diméthyléthyl]amino}ethyl]-2H-1,4-benzoxazin-3(4H)-one

olodatérol 6-hydroxy-8-[(1R)-1-hydroxy-2-{[2-(4-méthoxyphényl)- 1,1-diméthyléthyl]amino}éthyl]-2H-1,4-benzoxazin-3(4H)-one

olodaterol 6-hidroxi-8-[(1R)-1-hidroxi-2-{[1-(4-metoxifenil)-2-metilpropan- 2-il]amino}etil]-2H-1,4-benzoxazin-3(4H)-ona

C21H26N2O5

HN

OHH

HN

O

O

HO

OCH3

H3C CH3

razupenemum razupenem (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-({4-[(5S)-5-methyl-

2,5-dihydro-1H-pyrrol-3-yl]-1,3-thiazol-2-yl}sulfanyl)-7-oxo- 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

razupénem acide (4R,5S,6S)-6-[(1R)-1-hydroxyéthyl]-4-méthyl-3-({4-[(5S)- 5-méthyl-2,5-dihydro-1H-pyrrol-3-yl]thiazol-2-yl}sulfanyl)-7-oxo- 1-azabicyclo[3.2.0]hept-2-ène-2-carboxylique

razupenem ácido (4R,5S,6S)-6-[(1R)-1-hidroxietil]-4-metil-3-({4-[(5S)-5-metil- 2,5-dihidro-1H-pirrol-3-il]-1,3-tiazol-2-il}sulfanil)-7-oxo- 1-azabiciclo[3.2.0]hept-2-eno-2-carboxílico


70

C18H21N3O4S2

N

CO2HO

H H

H3C

HOH

S

SN

NHCH3

HCH3

H

ridaforolimusum ridaforolimus (1R,2R,4S)-4-[(2R)-2-

{(3S,6R,7E,9R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,27-dihydroxy-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-1,5,11,28,29-pentaoxo-1,4,5,6,9,10,11,12,13,14,21,22,23,24,25,26,27,28,29,31,32,33,34,34a-tetracosahydro-3H-23,27-epoxypyrido[2,1-c][1,4]oxaazacyclohentricosin-3-yl}propyl]-2-methoxycyclohexyl dimethylphosphinate

ridaforolimus (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-12-[(1R)-2-{(1S,3R,4R)-4-[(diméthylphosphinoyl)oxy]- 3-méthoxycyclohexyl}-1-méthyléthyl]-1,18-dihydroxy- 19,30-diméthoxy-15,17,21,23,29,35-hexaméthyl-11,36-dioxa- 4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tétraène-2,3,10,14,20-pentone

ridaforolimus (1R,2R,4S)-4-[(2R)-2-{(3S,6R,7E,9R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,27-dihidroxi-10,21-dimetoxi-6,8,12,14,20,26-hexametil-1,5,11,28,29-pentaoxo-1,4,5,6,9,10,11,12,13,14,21,22,23,24,25,26,27,28,29,31,32,33,34,34a-tetracosahidro-3H-23,27-epoxipirido[2,1-c][1,4]oxaazaciclohentricosin-3-il}propil]-2-metoxiciclohexil dimetilfosfinato

C53H84NO14P

N

OO

O

O

O

H3C

O

OCH3

OH

H

H3COH

H OCH3

H

H

OHH

H3C H

CH3

HH H

H

CH3CH3O

OH

HH3C

CH3

H

PO

CH3H3C


71

rilotumumabum # rilotumumab immunoglobulin G2-kappa, anti-[Homo sapiens hepatocyte growth

factor (HGF, scatter factor, SF, hepatopoeitin A)], Homo sapiens monoclonal antibody; gamma2 heavy chain (1-446) [Homo sapiens VH (IGHV4-59*01 (96.90%) -(IGHD)-IGHJ4*01) [8.7.14] (1-120) -IGHG2*01 (121-446)], (134-215')-disulfide with kappa light chain (1'-215') [Homo sapiens V-KAPPA (IGKV3-15*01 (96.80%) -IGKJ5*01) [6.3.10] (1'-108') -IGKC*01 (109'-215')]; (222-222'':223-223'':226-226'':229-229'')-tetradisulfide dimer

rilotumumab immunoglobuline G2-kappa, anti-[Homo sapiens facteur de croissance de l'hépatocyte (HGF, facteur dispersant, SF, hépatopoïétine A)], Homo sapiens anticorps monoclonal; chaîne lourde gamma2 (1-446) [Homo sapiens VH (IGHV4-59*01 (96.90%) -(IGHD)-IGHJ4*01) [8.7.14] (1-120) -IGHG2*01 (121-446)], (134-215')-disulfure avec la chaîne légère kappa (1'-215') [Homo sapiens V-KAPPA (IGKV3-15*01 (96.80%) -IGKJ5*01) [6.3.10] (1'-108') -IGKC*01 (109'-215')]; dimère (222-222'':223-223'':226-226'':229-229'')-tétradisulfure

rilotumumab inmunoglobulina G2-kappa, anti-[factor de crecimiento de hepatocitos de Homo sapiens (HGF, factor dispersante, SF, hepatopoyetina A)], anticuerpo monoclonal de Homo sapiens ; cadena pesada gamma2 (1-446) [Homo sapiens VH (IGHV4-59*01 (96.90%) -(IGHD)-IGHJ4*01) [8.7.14] (1-120) -IGHG2*01 (121-446)], (134-215')-disulfuro con la cadena ligera kappa (1'-215') [Homo sapiens V-KAPPA (IGKV3-15*01 (96.80%) -IGKJ5*01) [6.3.10] (1'-108') -IGKC*01 (109'-215')]; dímero (222-222'':223-223'':226-226'':229-229'')-tetradisulfuro

C6464H9932N1708O2010S46

Heavy chain / Chaîne lourde / Cadena pesadaQVQLQESGPG LVKPSETLSL TCTVSGGSIS IYYWSWIRQP PGKGLEWIGY 50VYYSGSTNYN PSLKSRVTIS VDTSKNQFSL KLNSVTAADT AVYYCARGGY 100DFWSGYFDYW GQGTLVTVSS ASTKGPSVFP LAPCSRSTSE STAALGCLVK 150DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSNFGTQT 200YTCNVDHKPS NTKVDKTVER KCCVECPPCP APPVAGPSVF LFPPKPKDTL 250MISRTPEVTC VVVDVSHEDP EVQFNWYVDG VEVHNAKTKP REEQFNSTFR 300VVSVLTVVHQ DWLNGKEYKC KVSNKGLPAP IEKTISKTKG QPREPQVYTL 350PPSREEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPMLDSD 400GSFFLYSKLT VDKSRWQQGN VFSCSVMHEA LHNHYTQKSL SLSPGK 446

Light chain / Chaîne légère / Cadena ligeraEIVMTQSPAT LSVSPGERAT LSCRASQSVD SNLAWYRQKP GQAPRLLIYG 50ASTRATGIPA RFSGSGSGTE FTLTISSLQS EDFAVYYCQQ YINWPPITFG 100QGTRLEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK 150VDNALQSGNS QESVTEQDSK DSTYSLSSTL TLSKADYEKH KVYACEVTHQ 200GLSSPVTKSF NRGEC 215

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuroIntra-H 22-95 147-203 260-320 366-424 22''-95'' 147''-203'' 260''-320'' 366''-424''Intra-L 23'-88' 135'-195' 23'''-88''' 135'''-195''' Inter-H-L 134-215' 134''-215''' Inter-H-H 222-222'' 223-223'' 226-226'' 229-229''



72

rontalizumabum # rontalizumab immunoglobulin G1-kappa, anti-[Homo sapiens interferon alpha

(IFN-alpha)], humanized monoclonal antibody; gamma1 heavy chain [humanized VH (Homo sapiens IGHV3-74*01 (76.30%) -(IGHD)-IGHJ4*01) [8.8.10] (1-117) -Homo sapiens IGHG1*03, CH1 R120>K (118-447)], (220-218')-disulfide with kappa light chain (1'-218') [humanized V-KAPPA (Homo sapiens IGKV1-39*01 (83.80%) -IGKJ1*01) [10.3.9] (1'-111') -Homo sapiens IGKC*01 (112'-218')]; (226-226":229-229")-bisdisulfide dimer

rontalizumab immunoglobuline G1-kappa, anti-[Homo sapiens interféron alpha (IFN-alpha)], anticorps monoclonal humanisé; chaîne lourde gamma1 [VH humanisé (Homo sapiens IGHV3-74*01 (76.30%) -(IGHD)-IGHJ4*01) [8.8.10] (1-117) -Homo sapiens IGHG1*03, CH1 R120>K (118-447)], (220-218')-disulfure avec la chaîne légère kappa (1'-218') [V-KAPPA humanisé (Homo sapiens IGKV1-39*01 (83.80%) -IGKJ1*01) [10.3.9] (1'-111') -Homo sapiens IGKC*01 (112'-218')]; dimère (226-226":229-229")-bisdisulfure

rontalizumab inmunoglobulina G1-kappa, anti-[interferón alfa de Homo sapiens (IFN-alpha)], anticuerpo monoclonal humanizado; cadena pesada gamma1 [VH humanizada (Homo sapiens IGHV3-74*01 (76.30%) -(IGHD)-IGHJ4*01) [8.8.10] (1-117) -Homo sapiens IGHG1*03, CH1 R120>K (118-447)], (220-218')-disulfuro con la cadena ligera kappa (1'-218') [V-KAPPA humanizada (Homo sapiens IGKV1-39*01 (83.80%) -IGKJ1*01) [10.3.9] (1'-111') -Homo sapiens IGKC*01 (112'-218')]; dímero (226-226":229-229")-bisdisulfuro

C6486H9990N1722O2026S44

Heavy chain / Chaîne lourde / Cadena pesadaEVQLVESGGG LVQPGGSLRL SCATSGYTFT EYIIHWVRQA PGKGLEWVAS 50INPDYDITNY NQRFKGRFTI SLDKSKRTAY LQMNSLRAED TAVYYCASWI 100SDFFDYWGQG TLVTVSSAST KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF 150PEPVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSVVTVPS SSLGTQTYIC 200NVNHKPSNTK VDKKVEPKSC DKTHTCPPCP APELLGGPSV FLFPPKPKDT 250LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY 300RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK GQPREPQVYT 350LPPSREEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS 400DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPGK 447

Light chain / Chaîne légère / Cadena ligeraDIQMTQSPSS LSASVGDRVT ITCRASQSVS TSSYSYMHWY QQKPGKAPKV 50LISYASNLES GVPSRFSGSG SGTDFTLTIS SLQPEDFATY YCQHSWGIPR 100TFGQGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKV 150QWKVDNALQS GNSQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEV 200THQGLSSPVT KSFNRGEC 218



semaglutidum semaglutide N6.26-{18-[N-(17-carboxyheptadecanoyl)-L-γ-glutamyl]-10-oxo-

3,6,12,15-tetraoxa-9,18-diazaoctadecanoyl}-[8-(2-amino-2-propanoic acid),34-L-arginine]human glucagon-like peptide 1(7-37)

sémaglutide N6.26-{18-[N-(17-carboxyheptadécanoyl)-L-γ-glutamyl]-10-oxo-3,6,12,15-tétraoxa-9,18-diazaoctadécanoyl}-[8-(acide 2-amino- 2-méthylpropanoïque),34-L-arginine]peptide 1(7-37) apparenté au glucagon humain (GLP-1(7-37))


73

semaglutida N6.26-{18-[N-(17-carboxiheptadecanoil)-L-γ-glutamil]-10-oxo-3,6,12,15-tetraoxa-9,18-diazaoctadecanoil}-[8-(ácido 2-amino- 2-metilpropanoico ),34-L-arginina]péptido 1(7-37) similar al glucagón tipo 1 humano

C187H291N45O59

Glu Gly Thr Phe Thr Ser Asp Val Ser

Leu Glu Gly Gln Ala Ala Lys Glu Phe

Ile Ala Trp Leu Val Arg Gly Arg Gly OH

Ser Tyr

Glu OH

O

7 10

20

30 37

N6

H His NH

CH3H3C

O

OO

O

HO2C

HNO

O

O

NH

serdemetanum serdemetan N-[2-(1H-indol-3-yl)ethyl]-N'-(pyridin-4-yl)benzene-1,4-diamine

serdémétan N-[2-(1H-indol-3-yl)éthyl]-N'-(pyridin-4-yl)benzène-1,4-diamine

serdemetán N-[2-(1H-indol-3-il)etil]-N'-(piridin-4-il)benceno-1,4-diamina

C21H20N4

H

N

NH

HN

N

setileutonum setileuton 4-(4-fluorophenyl)-7-[({5-[(2S)-1,1,1-trifluoro-2-hydroxybutan-2-yl]-

1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one

sétileuton 4-(4-fluorophényl)-7-[({5-[(2S)-1,1,1-trifluoro-2-hydroxybutan-2-yl]-1,3,4-oxadiazol-2-yl}amino)méthyl]-2H-chromèn-2-one

setileutón 4-(4-fluorofenil)-7-[({5-[(2S)-1,1,1-trifluoro-2-hidroxibutan-2-il]- 1,3,4-oxadiazol-2-il}amino)metil]-2H-cromen-2-ona

C22H17F4N3O4

O

O

FNH

NN

O CH3HO CF3


74

sifalimumabum # sifalimumab immunoglobulin G1-kappa, anti-[Homo sapiens interferon alpha

(IFN-alpha)], Homo sapiens monoclonal antibody; gamma1 heavy chain (1-446) [Homo sapiens VH (IGHV1-18*01 (95.90%) -(IGHD)-IGHJ4*01) [8.8.9] (1-116) -IGHG1*03 CH1 R120>K (117-446)], (219-213')-disulfide with kappa light chain (1'-213') [Homo sapiens V-KAPPA (IGKV3-20*01 (99.00%) -IGKJ1*01) [7.3.9] (1'-108') -IGKC*01 (109'-215')]; (225-225'':228-228'')-bisdisulfide dimer

sifalimumab immunoglobuline G1-kappa, anti-[Homo sapiens interféron alpha (IFN-alpha)], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-446) [Homo sapiens VH (IGHV1-18*01 (95.90%) -(IGHD)-IGHJ4*01) [8.8.9] (1-116) -IGHG1*03 CH1 R120>K (117-446)], (219-215')-disulfure avec la chaîne légère kappa (1'-215') [Homo sapiens V-KAPPA (IGKV3-20*01 (99.00%) -IGKJ1*01) [7.3.9] (1'-108') -IGKC*01 (109'-215')]; dimère (225-225'':228-228'')-bisdisulfure

sifalimumab inmunoglobulina G1-kappa, anti-[interferón alfa (IFN-alfa) de Homo sapiens], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma1 (1-446) [Homo sapiens VH (IGHV1-18*01 (95.90%) -(IGHD)-IGHJ4*01) [8.8.9] (1-116) -IGHG1*03 CH1 R120>K (117-446)], (219-215')-disulfuro con la cadena ligera kappa (1'-215') [Homo sapiens V-KAPPA (IGKV3-20*01 (99.00%) -IGKJ1*01) [7.3.9] (1'-108') -IGKC*01 (109'-215')]; dímero (225-225'':228-228'')-bisdisulfuro

C6396H9922N1714O2008S42

Heavy chain / Chaîne lourde / Cadena pesadaQVQLVQSGAE VKKPGASVKV SCKASGYTFT SYSISWVRQA PGQGLEWMGW 50ISVYNGNTNY AQKFQGRVTM TTDTSTSTAY LELRSLRSDD TAVYYCARDP 100IAAGYWGQGT LVTVSSASTK GPSVFPLAPS SKSTSGGTAA LGCLVKDYFP 150EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS SLGTQTYICN 200VNHKPSNTKV DKKVEPKSCD KTHTCPPCPA PELLGGPSVF LFPPKPKDTL 250MISRTPEVTC VVVDVSHEDP EVKFNWYVDG VEVHNAKTKP REEQYNSTYR 300VVSVLTVLHQ DWLNGKEYKC KVSNKALPAP IEKTISKAKG QPREPQVYTL 350PPSREEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPVLDSD 400GSFFLYSKLT VDKSRWQQGN VFSCSVMHEA LHNHYTQKSL SLSPGK 446

Light chain / Chaîne légère / Cadena ligeraEIVLTQSPGT LSLSPGERAT LSCRASQSVS STYLAWYQQK PGQAPRLLIY 50GASSRATGIP DRFSGSGSGT DFTLTISRLE PEDFAVYYCQ QYGSSPRTFG 100QGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK 150VDNALQSGNS QESVTEQDSK DSTYSLSSTL TLSKADYEKH KVYACEVTHQ 200GLSSPVTKSF NRGEC 215



sonedenosonum sonedenoson 2-[2-(4-chlorophenyl)ethoxy]adenosine

sonédénoson 2-[2-(4-chlorophényl)éthoxy]-9-β-D-ribofuranosyl-9H-purin-6-amine

sonedenosón 2-[2-(4-clorofenil)etoxi]adenosina


75

C18H20ClN5O5

OHO

N

N N

N

NH2

O

OH OH

Cl

sothrombomodulinum alfa # sothrombomodulin alfa soluble mutated human thrombomodulin

[388-leucine(M>L),456-glycine(R>G),457-glutamine(H>Q),474-alanine(S>A)]human thrombomodulin (fetomodulin, CD141)-(4-490)-peptide, glycosylated

sothrombomoduline alfa thrombomoduline humaine soluble mutée [388-leucine(M>L),456-glycine(R>G),457-glutamine(H>Q),474-alanine(S>A)]thrombomoduline humaine (fétomoduline, CD141)- (4-490)-peptide, glycosylée

sotrombomodulina alfa trombomodulina humana soluble mutada [388-leucina(M>L),456-glicina(R>G),457-glutamina(H>Q),474-alanina(S>A)]trombomodulina humana (fetomodulina, CD141)- (4-490)-péptido, glicosilado

C2181H3278N616O706S49

EPQPGGSQCV EHDCFALYPG PATFLNASQI CDGLRGHLMT VRSSVAADVI 50SLLLNGDGGV GRRRLWIGLQ LPPGCGDPKR LGPLRGFQWV TGDNNTSYSR 100WARLDLNGAP LCGPLCVAVS AAEATVPSEP IWEEQQCEVK ADGFLCEFHF 150PATCRPLAVE PGAAAAAVSI TYGTPFAARG ADFQALPVGS SAAVAPLGLQ 200LMCTAPPGAV QGHWAREAPG AWDCSVENGG CEHACNAIPG APRCQCPAGA 250ALQADGRSCT ASATQSCNDL CEHFCVPNPD QPGSYSCMCE TGYRLAADQH 300RCEDVDDCIL EPSPCPQRCV NTQGGFECHC YPNYDLVDGE CVEPVDPCFR 350ANCEYQCQPL NQTSYLCVCA EGFAPIPHEP HRCQLFCNQT ACPADCDPNT 400QASCECPEGY ILDDGFICTD IDECENGGFC SGVCHNLPGT FECICGPDSA 450LAGQIGTDCD SGKVDGGDSG AGEPPPSPTP GSTLTPP 487

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuroTotal 23 disulfide bridges in the molecule, so far only four disulfide bridge positions verified.23 ponts disulfure au total dans la molécule, pour le moment, seuls quatre ont été vérifiés.23 puentes disulfuro en el total en la molécula, por el momento, sólo cuatro han sido verificados.9-14 31-146 154-203 224-235

N-Glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación Asn-26 Asn-95 Asn-361 Asn-388

tafamidisum tafamidis 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid

tafamidis acide 2-(3,5-dichlorophényl)-1,3-benzoxazole-6-carboxylique

tafamidis ácido 2-(3,5-diclorofenil)-1,3-benzoxazol-6-carboxílico


76

C14H7Cl2NO3

N

O CO2HCl

Cl

taliglucerasum alfa # taliglucerase alfa L-glutamyl-L-phenylalanyl-[495(497)-L-histidine(R>H)]human

glucosylceramidase (beta-glucocerebrosidase) peptide with L-aspartyl-L-leucyl-L-leucyl-L-valyl-L-aspartyl-L-threonyl-L-methionine, glycosylated peptide 1-506

taliglucérase alfa L-glutamyl-L-phénylalanyl-[495(497)- L-histidine(R>H)]glucosylcéramidase humaine (bêta-glucocérébrosidase) peptide avec la L-aspartyl-L-leucyl-L-leucyl- L-valyl-L-aspartyl-L-thréonyl-L-méthionine, peptide 1-506 glycosylé

taliglucerasa alfa L-glutamil-L-fenilalanil-[495(497)-L-histidina(R>H)]glucosilceramidasa humana (beta-glucocerebrosidasa) péptido con la L-aspartil-L-leucil-L-leucil-L-valil-L-aspartil-L-treonil-L-metionina, péptido 1-506 glicosilado

C2580H3918N680O727S17

EFARPCIPKS FGYSSVVCVC NATYCDSFDP PTFPALGTFS RYESTRSGRR 50MELSMGPIQA NHTGTGLLLT LQPEQKFQKV KGFGGAMTDA AALNILALSP 100PAQNLLLKSY FSEEGIGYNI IRVPMASCDF SIRTYTYADT PDDFQLHNFS 150LPEEDTKLKI PLIHRALQLA QRPVSLLASP WTSPTWLKTN GAVNGKGSLK 200GQPGDIYHQT WARYFVKFLD AYAEHKLQFW AVTAENEPSA GLLSGYPFQC 250LGFTPEHQRD FIARDLGPTL ANSTHHNVRL LMLDDQRLLL PHWAKVVLTD 300PEAAKYVHGI AVHWYLDFLA PAKATLGETH RLFPNTMLFA SEACVGSKFW 350EQSVRLGSWD RGMQYSHSII TNLLYHVVGW TDWNLALNPE GGPNWVRNFV 400DSPIIVDITK DTFYKQPMFY HLGHFSKFIP EGSQRVGLVA SQKNDLDAVA 450LMHPDGSAVV VVLNRSSKDV PLTIKDPAVG FLETISPGYS IHTYLWHRQD 500LLVDTM 506

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro6-18 20-25

Glycosylation sites N / Sites de glycosylation N / Posiciones de glicosilación NAsn-21 Asn-61 Asn-148 Asn-272

Fuc = 6-deoxy-D-galactopyranosylGl-N = 2-(acetylamino)-2-deoxy-D-glucopyranosylMan = D-mannopyranosyl Xyl = D-xylopyranosyl

β-Man→4-β-Gl-N→4−

R→6−β-Gl-N→peptide

α-Man→3−

α-Man→6−

R'→2− R = α-Fuc or H ; R' = β-Xyl or H

tecarfarinum tecarfarin 1,1,1,3,3,3-hexafluoro-2-methylpropan-2-yl 4-[(4-hydroxy-2-oxo-

2H-chromen-3-yl)methyl]benzoate

técarfarine 4-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]benzoate de 1,1,1,3,3,3-hexafluoro-2-méthylpropan-2-yl

tecarfarina 4-[(4-hidroxi-2-oxo-2H-cromen-3-il)metil]benzoato de 1,1,1,3,3,3-hexafluoro-2-metilpropan-2-ilo


77

C21H14F6O5

O O

OH

O

O

CH3

CF3

CF3

teglarinadi chloridum teglarinad chloride 4-({N'-[6-(4-chlorophenoxy)hexyl]}-N''-cyanocarbamimidamido)-

1-(3-oxo-2,4,7,10,13,16-hexaoxaheptadecyl)pyridin-1-ium chloride

chlorure de téglarinad chlorure de 4-({N'-[6-(4-chlorophénoxy)hexyl]}- N''-cyanocarbamimidamido)-1-(3-oxo-2,4,7,10,13,16-hexaoxaheptadécyl)pyridin-1-ium

cloruro de teglarinad cloruro de 4-({N'-[6-(4-clorofenoxi)hexil]}-N''-cianocarbamimidamido)-1-(3-oxo-2,4,7,10,13,16-hexaoxaheptadecil)piridin-1-io

C30H43Cl2N5O8

N O O

O

NH

NH

NNC

O

Cl OO

OO

H3C

Cl

teprotumumabum # teprotumumab immunoglobulin G1-kappa, anti-[Homo sapiens insulin-like growth

factor 1 receptor (IGF1R, IGF-1R, IGF-1 receptor, CD221)], Homo sapiens monoclonal antibody; gamma1 heavy chain (1-448) [Homo sapiens VH (IGHV3-33*01 (91.80%) -(IGHD)-IGHJ2*01) [8.8.11] (1-118) -IGHG1*01 (119-448)], (221-215')-disulfide with kappa light chain (1'-215') [Homo sapiens V-KAPPA (IGKV3-11*01 (97.90%) -IGKJ1*01) [6.3.10] (1'-108') -IGKC*01 (109'-215')]; (227-227'':230-230'')-bisdisulfide dimer

téprotumumab immunoglobuline G1-kappa, anti-[Homo sapiens récepteur du facteur de croissance 1 analogue à l'insuline (IGF1R, IGF-1R, récepteur de l'IGF-1, CD221)], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-448) [Homo sapiens VH (IGHV3-33*01 (91.80%) -(IGHD)-IGHJ2*01) [8.8.11] (1-118) -IGHG1*01 (119-448)], (221-215')-disulfure avec la chaîne légère kappa (1'-215') [Homo sapiens V-KAPPA (IGKV3-11*01 (97.90%) -IGKJ1*01) [6.3.10] (1'-108') -IGKC*01 (109'-215')]; dimère (227-227'':230-230'')-bisdisulfure

teprotumumab inmunoglobulina G1-kappa, anti-[receptor del factor de crecimiento insulínico tipo 1 de Homo sapiens (IGF1R, IGF-1R, receptor deI GF-1, CD221)], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma1 (1-448) [Homo sapiens VH (IGHV3-33*01 (91.80%) -(IGHD)-IGHJ2*01) [8.8.11] (1-118) -IGHG1*01 (119-448)], (221-215')-disulfuro con la cadena ligera kappa (1'-215') [Homo sapiens V-KAPPA (IGKV3-11*01 (97.90%) -IGKJ1*01) [6.3.10] (1'-108') -IGKC*01 (109'-215')]; dímero (227-227'':230-230'')-bisdisulfuro


78

C6476H10012N1748O2000S40

Heavy chain / Chaîne lourde / Cadena pesadaQVELVESGGG VVQPGRSQRL SCAASGFTFS SYGMHWVRQA PGKGLEWVAI 50IWFDGSSTYY ADSVRGRFTI SRDNSKNTLY LQMNSLRAED TAVYFCAREL 100GRRYFDLWGR GTLVSVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY 150FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI 200CNVNHKPSNT KVDKKVEPKS CDKTHTCPPC PAPELLGGPS VFLFPPKPKD 250TLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST 300YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY 350TLPPSRDELT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD 400SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPGK 448

Light chain / Chaîne légère / Cadena ligeraEIVLTQSPAT LSLSPGERAT LSCRASQSVS SYLAWYQQKP GQAPRLLIYD 50ASKRATGIPA RFSGSGSGTD FTLTISSLEP EDFAVYYCQQ RSKWPPWTFG 100QGTKVESKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK 150VDNALQSGNS QESVTEQDSK DSTYSLSSTL TLSKADYEKH KVYACEVTHQ 200GLSSPVTKSF NRGEC 215



tipapkinogenum sovacivecum # tipapkinogene sovacivec an attenuated recombinant vaccinia viral vector (derived from the

Modified Virus Ankara clone 33.1, MVATG33.1) containing an approximately 168 kilobasepair DNA genome encoding itself, human interleukin-2 (IL-2) and mutated-forms of the Human Papilloma Virus 16 (HPV-16) E6 and E7 antigens

tipapkinogène sovacivec vecteur viral de la vaccine recombinant atténué (dérivé du virus modifié Ankara clone 33.1, MVATG33.1) contenant un génome ADN d'aproximativement 168 kilopaires de bases se codifiant lui-même, l'interleukine 2 humaine (IL-2) et des formes mutées du papillomavirus humain 16 (HPV-16) et les antigènes E6 et E7

tipapkinogén sovacivec vector viral vaccinia recombinante atenuado (derivado del Virus Modificado Ankara clon 33.1, MVATG33.1) contiene un DNA genómico de aproximadamente 168 kilopares de bases que codifican el propio virus, interleukina-2 (IL-2) humana y formas mutadas del Virus del papiloma humano 16 (HPV-16) y los antígenos E6 y E7

varfollitropinum alfa # varfollitropin alfa [alpha,83-L-asparagine;beta,55-L-asparagine,57-L-threonine]

follitropin alpha (human) modified human follicle-stimulating hormone: heterodimer of [83-L-asparagine(H>N)]human glycoprotein hormones alpha chain (FSH-alpha) and [55-L-asparagine(E>N), 57-L-threonine(V>T)]human follitropin subunit beta (FSH-beta), glycosylated

varfollitropine alfa [alpha,83-L-asparagine;bêta,55-L-asparagine,57-L-thréonine] follitropine alpha (humaine) hormone stimulante du follicule de De Graaf humaine modifiée : hétérodimère constitué de la [83-L-asparagine(H>N)]chaîne alpha de la glycoprotéine des hormones humaines (FSH-alpha) et de la [55-L-asparagine(E>N),57-L-thréonine(V>T)]sous-unité bêta de la follitropine humaine (FSH-bêta) glycosylées


79

varfolitropina alfa [alfa,83-L-asparagina;beta,55-L-asparagina,57-L-treonina] folitropina alfa (humana) hormona estimulante del folículo de De Graaf humana modificada : heterodímero constituido por la [83-L-asparagina(H>N)]cadena alfa de la glicoproteína de las hormonas humanas (FSH-alfa) y de la [55- L-asparagina(E>N),57-L-treonina(V>T)]subunidad beta de la folitropina humana (FSH-beta) glicosiladas

C971H1511N267O306S26

Alpha subunit / Sous-unité alpha / Subunidad alfaAPDVQDCPEC TLQENPFFSQ PGAPILQCMG CCFSRAYPTP LRSKKTMLVQ 50KNVTSESTCC VAKSYNRVTV MGGFKVENHT ACNCSTCYYH KS 92

Beta subunit / Sous-unité bêta / Subunidad betaNSCELTNITI AIEKEECRFC ISINTTWCAG YCYTRDLVYK DPARPKIQKT 50'CTFKNLTYET VRVPGCAHHA DSLYTYPVAT QCHCGKCDSD STDCTVRGLG 100'PSYCSFGEMK E 111'

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro7-31 10-60 28-82 32-84 59-87 3'-51' 17'-66' 20'-104' 28'-82' 32'-84' 87'-94'

N-Glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilaciónAsn-7' Asn-24' Asn-55' Asn-52 Asn-78

velusetragum velusetrag N-{(1R,3r,5S)-8-[(2R)-2-hydroxy-

3-(N-methylmethanesulfonamido)propyl]-8-azabicyclo[3.2.1]octan- 3-yl}-2-oxo-1-(propan-2-yl)-1,2-dihydroquinoline-3-carboxamide

vélusétrag N-{(1R,3r,5S)-8-[(2R)-2-hydroxy- 3-(N-méthylméthanesulfonamido)propyl]-8-azabicyclo[3.2.1]octan- 3-yl}-2-oxo-1-(propan-2-yl)-1,2-dihydroquinoline-3-carboxamide

velusetrag N-{(1R,3r,5S)-8-[(2R)-2-hidroxi-3-(N-metilmetanosulfonamido)propil]-8-azabiciclo[3.2.1]octan-3-il}-2-oxo-1-(propan-2-il)- 1,2-dihidroquinolina-3-carboxamida

C25H36N4O5S

N

HN

N

NS

CH3

H3C CH3

O

OOHH

O O

H

H

H

CH3

zaurategrastum zaurategrast (2S)-2-[(2-bromo-3-oxospiro[3.5]non-1-en-1-yl)amino]-

3-{4-[(2,7-naphthyridin-1-yl)amino]phenyl}propanoic acid

zauratégrast acide (2S)-2-[(2-bromo-3-oxospiro[3.5]non-1-én-1-yl)amino]- 3-[4-(2,7-naphtyridin-1-ylamino)phényl]propanoïque

zaurategrast ácido (2S)-2-[(2-bromo-3-oxospiro[3.5]non-1-en-1-il)amino]- 3-{4-[(2,7-naftiridin-1-il)amino]fenil}propanoico


80

C26H25BrN4O3

NH

O

OH

HN

H

N

N

Br

O

# Electronic structure available on Mednet: http://mednet.who.int/ # Structure électronique disponible sur Mednet: http://mednet.who.int/ # Estructura electrónica disponible en Mednet: http://mednet.who.int/

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.

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