WHO Drug Information Vol. 24, No. 2, 2010 World Health Organization
WHO Drug Information
Contents WHO Prequalification Regulatory Action and News Programmes Ceftobiprole medocaril: discontinuation WHO Prequalification of diagnostics, of sale 111 medicines and vaccines 83 Bufexamac : revocation of marketing WHO Prequalfication of Medicines authorization 111 Programme: Inspection of finished Rosiglitazone: authorization suspended 111 pharmaceutical product manufacturers 87 Sitimagene ceradenovec: withdrawal of marketing authorization application 112 Albinterferon alfa-2b: withdrawal of Regulatory Harmonization marketing authorization application 112 Optimization of medicines regulatory Docetaxel: withdrawal of marketing authority web sites 91 authorization application 112 Rotarix¨ oral vaccine: new information 113 Essential Medicines Paediatric Medicines Regulators Network113 Regulatory action needed to stop the sale of oral artemisinin-based Consultation Document monotherapy 98 The International Pharmacopoeia Emtricitabine and tenofovir tablets 115 Safety and Efficacy Issues Sulfadoxine and pyrimethamine Leflunomide and peripheral neuropathy 105 tablets 118 Saquinavir mesylate: prolongation of QT and PR intervals 106 Recent Publications, Human immune globulin: intravascular Information and Events haemolysis 106 Life-saving antivenoms: guidelines Irinotecan-induced severe neutropenia: and database 123 UGT1A1 variant alleles 107 Sources of paediatric medicines 123 Combination of niacin/laropiprant and Multidrug and drug-resistant tuberculosis123 simvastatin: myopathy 108 Guidelines for the treatment of malaria 124 Entacapone/carbidopa/levodopa: Where there are no pharmacists 124 prostate cancer 109 Becaplermin contraindicated in cancer patients 109 Proposed International Panitumumab: hypersensitivity reactions 110 Nonproprietary Names List 103 125
81 World Health Organization WHO Drug Information Vol. 24, No. 2, 2010
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
82 WHO Drug Information Vol. 24, No. 2, 2010
WHO Prequalification Programmes
WHO Prequalification of international, harmonized quality and safety standards and seeks to ensure that diagnostics, medicines other agencies and organizations pro- and vaccines mote and adhere to these standards. The Programme is also working with United World Health Organization (WHO) pre- Nations (UN) partners and procurement qualification is a highly visible service organizations to harmonize procurement having an immediate impact for countries. requirements for diagnostics. In areas WHO prequalification programmes for where no prequalified products yet exist, diagnostics, medicines and vaccines it advises on purchase of non-prequalified operate on similar principles and offer a products. valuable assurance of quality. Each programme regularly conducts technical Capacity building and performance reviews to identify The WHO Programme for Diagnostics potential gains in efficiency. Prequalification is working with Burkina Faso, Côte d’Ivoire, South Africa and Diagnostics Tanzania to strengthen implementation of regulations concerning registration and In recent years, the number of diagnostic licensing of diagnostics and to establish products for priority diseases such as systems for postmarketing surveillance. HIV, TB and malaria has increased. Of (Activities will be extended to China WHO’s 193 Member States, fewer than during 2010.) one-third have a regulatory system in place and even where regulations for Guidance documents highlighting require- diagnostics exist, they are often not ments for inspections and quality man- enforced. agement systems are being finalized for use by manufacturers seeking to obtain Approximately 85% of applications WHO prequalification. submitted to the WHO Programme for Diagnostics Prequalification are for Cost effectiveness products made in less stringently regu- Prequalification of diagnostics stimulates lated countries, particularly in Asia. innovation and helps create a secure Moreover, as the target markets for these market for good-quality, safe and appro- diagnostics are resource-limited coun- priate diagnostics that would otherwise tries, the manufacturers concerned do not not be accessible. For example, prequali- consider that they need to obtain licens- fication of diagnostics stimulates develop- ing from a stringent regulatory authority. ment of technologies such as rapid tests, The Programme targets its assessment appropriate for use at primary health care efforts at such products, paying particular level and by non-lab technicians (which attention to appropriateness for use in promotes task shifting). During the past resource-limited settings and advocating four years, the UN and Global Fund to for the development of innovative diag- Fight AIDS, Tuberculosis and Malaria nostics for such settings. (GFATM) procurement of HIV and malaria The WHO Programme for Diagnostics rapid tests has ranged between 10 and Prequalification bases its activities on 18 million tests annually.
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WHO facilitates access to safe, appropri- international, harmonized quality and ate diagnostics of good quality at reduced safety standards. This includes working cost, saving money that can be used to with the GFATM and procurement organi- purchase additional diagnostics or in- zations to harmonize procurement and vested in other health care interventions. quality assurance requirements. In areas In the USA, for example, a rapid HIV test for which no prequalified product yet costs around ten US dollars, while the exists, and on behalf of UN partners, the UN/WHO price is around one US dollar. WHO Prequalification of Medicines Savings are also generated since health Programme organizes, upon request, care costs associated with poor-quality expert assessment reviews to advise on diagnostics are reduced. Additionally, the levels of risk associated with purchase of value of laboratory services is increased non-prequalified products. It also advises through reliable accurate diagnosis and UNFPA and the WHO Department of the efficacy of treatment programmes is Reproductive Health and Research on improved. More patients can therefore be methods for prequalifying condoms and treated. intrauterine devices.
Information and guidance Concurrently, activities to prequalify Information on WHO’s procedure for quality control laboratories are also of prequalifying diagnostics, together with great value to agencies and organizations guidance and application forms, and a who provide or fund significant quantities wide range of technical documents and of medicines for disease treatment reports, can be found at: http://www.who. programmes. National prequalified int/diagnostics_laboratory/ evaluations/ laboratories enable rapid and reliable en/ and the WHO Programme for Diag- analysis of medicines quality analysis nostics Prequalification web site is at close to locations where the medicines http://diagnostics_ laboratory technology/ are in actual use. By 2009, 11 laborato- ries have been prequalified and a further Medicines 28, most of which are in Africa, have expressed interest in becoming prequali- WHO’s list of prequalified medicines is fied or are undergoing assessment. used by the GFATM, UNICEF, the World Bank, international nongovernmental The WHO Prequalification of Medicines organizations (NGOs) and, increasingly, Programme is closely linked to WHO’s by government procurement agencies as quality assurance normative work and a basis for many procurement decisions. provides “real life” feedback for develop- Similarly, the Model Quality Assurance ment of pharmaceutical norms and Guideline developed by the WHO Pre- standards. The Programme is further qualification of Medicines Programme is linked to WHO pharmacovigilance activi- used by the US President’s Emergency ties and monitoring of adverse drug Plan for AIDS Relief (PEPFAR) and the reactions (ADRs) provides follow-up on World Bank to guide organizations that the quality and safety of prequalified procure medicines in improving their medicines. Joint planning and implemen- quality systems. tation of prospective proactive safety monitoring for selected prequalified new More generally, the WHO Prequalification products (such as an amodiaquine + of Medicines Programme has done much artesunate fixed-dose combination to ensure that medicines procured by UN product for malaria) will be an important agencies and other organizations meet source of information.
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Capacity building The above activities contribute to: Unlike other regulatory options (such as product approvals/registration by a ¥ more effective regulation and production stringent regulatory authority, including of medicines of assured quality; US FDA tentative approval), the WHO ¥ more rapid development of new, quality Prequalification of Medicines Programme products; faster regulatory approval of is open to participation of regulators from products, and developing countries. For example, these regulators can actively participate in ¥ identification of norms and standards dossier assessments and inspections. needed for development by the WHO Expert Committee on Specifications for Additionally, the Programme undertakes Pharmaceutical Preparations. considerable capacity building through its provision of standards, guidance and Cost effectiveness training to assessors and inspectors WHO prequalification of medicines for regarding regulatory assessment of the HIV/AIDS, in particular, has stimulated quality, safety and efficacy of medicines. generic production of quality medicines Most of the training workshops organized and global competition, serving to lower in developing countries are also open to medicines prices and enabling more participants from local industry. Training patients to be treated. The prices negoti- to date has focused on pharmaceutical ated by the Clinton HIV/AIDS Initiative, development of quality products and on with the support of UNITAID and govern- quality of manufacture. In 2009, 12 ment partners, for fixed-dose combination training courses were organized for (FDC) paediatric antiretroviral treatment regulators and local industries and a are a case in point. further five training courses co-organized or supported for around 760 participants An external business plan completed for in total. the WHO Prequalification of Medicines Programme in August 2009 comments, On-the-job training is offered in the form “It is clear that in the context of today’s of a unique three-month rotational post at disease landscape the Programme has a WHO, Geneva, open to promising train- vital, pivotal and ongoing role”. It projects ees from developing country national an economic return on investment of medicines regulatory authorities (MRAs). 170:1 for the programme for the period Developing country manufacturers of 2009Ð2013. This estimate is based on: products of high public health value (such as second-line TB medicines and inject- ¥ projected availability of global funding able antimalarials) receive tailored for procuring medicines for treating HIV/ technical assistance to help them bring AIDS, TB and malaria; the quality of their medicines production up to international standards. In the case ¥ projected prequalification of 105 addi- of technically complex products, the tional medicines, around 90% of which Programme provides regulatory advice to will be generic medicines, and applicants, for example, on conducting bioequivalence studies. ¥ projected estimated impact on additional volume of medicines that can be pur- The WHO Prequalification of Medicines chased as a result of increased compe- Programme makes ample information tition among generics. about prequalified medicines (including evaluation/inspection outcomes) publicly Sampling and quality control testing available (http://www.who.int/prequal/). undertaken by the WHO Prequalification
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of Medicines Programme has demon- suitable for use by immunization pro- strated that the failure rate among WHO grammes covered within their jurisdiction. prequalified medicines is exceptionally low (<3%). To date, no critical failures Vaccines supplied to immunization have appeared among sampling and programmes supported by the UN must testing results. The results underscore be safe and effective in conditions that that, provided procurement and distribu- differ from those in developed countries. tion practices are sound, medicines Illustrative examples relate to: (i) the prequalified by WHO can be viewed with immunization schedule and (ii) the confidence, by health workers, patients temperature-controlled supply chain. For and donor agencies alike. UN supply, immunization is based on the Expanded Programme on Immunization Information and guidance (EPI) 2, 3, 4 months schedule which All documentation regarding the WHO includes oral poliovirus vaccine and Prequalification of Medicines Programme whole-cell pertussis. is posted at: http://www.who.int/prequal/ default.htm and is available in CD-ROM The temperature-controlled supply chain and DVD format. Programme procedures required for vaccines is more fragile in and technical guidelines have all been countries receiving vaccines through UN adopted by the WHO Expert Committee supply than in developed countries. WHO on Specifications for Pharmaceutical Vaccines Prequalification thus pays Products and are therefore available in special attention to the thermostability WHO’s Technical Report Series in hard profile of vaccines. For example, a copy and electronic versions. The WHO rotavirus vaccine product was originally Prequalification of Medicines Programme developed for the US market. Review by WHO Vaccines Prequalification discov- web site is at http://www.who.int/prequal/ ered that even brief heat exposure Vaccines resulted in destruction of one of the strains in the vaccine. WHO requested Vaccines prequalified by WHO are used the manufacturer to introduce additional in 112 countries to immunize 53% of the shipping precautions and stimulated the global birth cohort each year. By the end company to create a development pro- of 2009, 104 vaccines from 26 manufac- gramme for a more heat-resistant vac- turers had been prequalified by WHO. cine. In 2009, the manufacturer an- The starting point for WHO vaccines nounced the creation of a new vaccine prequalification is the licensing of a research institute in India to develop vaccine by a national regulatory authority vaccines that are optimized for use in (NRA) that has been audited by WHO developing countries. and shown to meet international stand- ards for regulatory oversight. Capacity building WHO Vaccines Prequalification conducts The added value of WHO prequalification an audit of NRA functionality before is that it provides objective and independ- accepting an application from a vaccine ent evidence to UN procurement agen- producer which includes identification of cies that the products concerned are regulatory gaps. Such audits enable suitable for use in immunization pro- NRAs to leverage increased human and grammes supported by UN supply. financial resources from their govern- National licensure, even by developed ments. WHO Vaccines Prequalification country regulators such as the US FDA has thus stimulated increased global and European Medicines Agency (EMA), capacity for adequate regulatory over- considers only whether vaccines are sight of vaccines in countries such as
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Brazil, Cuba, India, Indonesia, Senegal products. Evidence from UN procurement and Thailand. agencies, such as UNICEF, shows how the entry of WHO prequalified vaccines The audit process requires that WHO into the market serves to lower vaccine establish the first international bench- prices. Further, WHO Vaccines Prequalifi- marks of regulatory functions. These are cation contributes to global vaccine now being used by developed country security by expanding the number of authorities, such as EMA, for inter- quality-assured manufacturers per authority reviews within their jurisdictions. vaccine type. Furthermore, the WHO audit process provides countries with an objective Information and guidance institutional development plan for regula- The WHO procedure for prequalifying tory functionality that can be incorporated vaccines is published as: Assessment of in a strategy for health systems strength- the Acceptability, in Principle, of Vaccines ening. for Purchase by United Nations Agencies (WHO/IVB/05.19). A separate document Cost effectiveness provides guidance to manufacturers on Prequalification of vaccines gives manu- how to produce a good product summary facturers in emerging economies — file: Guideline for Preparation of Vaccine whose prices may be lower than those of Product Summary File for Vaccine Pre- manufactures in developed countries — qualification (WHO/IVB/06.16). Both access to international markets. This documents exist in hard copy and are occurs both directly, through UN procure- posted on the WHO vaccines web site ment, and indirectly when national pro- (www.who.int/immunization). Additional curement agencies in middle-income documents are being prepared: Guidance countries use the WHO list of prequalified for Master Formula; Guidance for Envi- vaccines to select vaccines for national ronmental Monitoring of Aseptic Areas; procurement. WHO Vaccines Prequalifi- Guidance for Clinical Trials. Each of these cation assists emerging economy manu- documents are or will be used principally facturers to attain international standards by manufacturers, but they are also of of quality. This facilitates entry into the relevance to governments and other global market and additionally acts as an interested parties. The WHO Vaccines incentive to developed country manufac- Prequalification web site is at http:// turers to lower the prices of their vaccine www.who.int/immunization
WHO Prequalfication of Medicines Programme
Inspection of finished sumed in developing countries are pharmaceutical product believed to be counterfeit. A WHO survey manufacturers of reports on counterfeit medicines from 20 countries in the period from January Substandard, counterfeit and adulterated 1999 to October 2000 found that 60% of medicines have far-reaching conse- cases occurred in poor countries and quences for patients and the quality of 40% in industrialized countries (1Ð2). The medicines remains a concern. Some Pharmaceutical Society of Nigeria reports estimates put counterfeits at more than that at around 70% of medicines circulat- 10% of the global medicines market and ing in that country may be counterfeit (3). an estimated 25% of medicines con- Many cases of substandard medicines
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Table 1. Manufacturing sites inspected by WHO in 2008Ð2009
China Egypt India Morocco South Total Africa
2008 3 1 16 1 1 22 2009 1 0 22 0 2 25
Total 4 1 38 1 3 47 could be prevented through effective country of the Pharmaceutical Inspection implementation and enforcement of Cooperation Scheme (PIC/S). During legislation requiring that medicines be inspections, manufacturers are assessed produced and controlled in compliance for compliance with WHO GMP. Inspec- with good manufacturing practices tors further verify the reliability of data (GMP). submitted in product dossiers against the original data on site (5). The World Health Organization (WHO) defines GMP as “that part of quality The first inspections were carried out in assurance that ensures that products are June 2001 and focused on manufacturers consistently produced and controlled to of HIV/AIDS medicines. Since then, the the quality standards appropriate to their Programme has expanded and now intended use and as required by the includes products used in the treatment of marketing authorization”. GMP comprises malaria, tuberculosis, influenza and the standards under which the production reproductive health products. During and control of pharmaceutical products 2008 and 2009, several site inspections should take place. Specific risks associ- were carried out in China, Egypt, India, ated with the manufacture and control of Morocco and South Africa. pharmaceutical products are essentially cross-contamination and mix-ups (4). The location of manufacturing sites inspected in 2008 and 2009 is set out in One component of the extensive evalua- Table 1, and the number of inspections by tion process of the United Nations Pre- product range (disease group) in Table 2. qualification of Medicines Programme In the majority of cases, inspections were managed by WHO focuses on the inspec- carried out in India focusing on dosage tion of finished pharmaceutical product forms used in the treatment of HIV/AIDS. manufacturing facilities. An inspection In 2009, four inspections were carried out team is made up of a WHO inspector plus at sites producing reproductive health an appointed inspector from a member products, and one each at sites produc-
Table 2. Product range by disease group
Product 2008 2009 Total
HIV/AIDS 10 9 19 Tuberculosis 6 5 11 Malaria 5 4 9 HIV/AIDS and malaria 1 0 1
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Figure 1. Number of observations by site Number of observations of Number
Number of sites ing HIV/AIDS and influenza products, possibility in mix-ups and a possibility of antituberculosis and HIV/AIDS products; cross contamination due to lack of appro- and HIV/AIDS, antituberculosis and priate cleaning. In some manufacturing malaria products. facilities, sampling and testing was deficient in ensuring the identity of mate- Co-inspectors were appointed from rial used in production (including active Australia (5), Denmark (2), Estonia (5), pharmaceutical ingredients). In the case France (12), Hungary (3), South Africa (2) of sterile products, the sterilization proc- Switzerland (4) and the United Kingdom ess was not validated in some cases and (7). In seven cases, sites were inspected the aseptic technique and media fill was by a team of inspectors from WHO inadequate. An unacceptable risk of without a co-inspector. These were product contamination was also identified. special inspections or investigations. Figure 1 shows the number of total and Examples of major non-compliance in major deficiencies (observations) re- manufacturing sites of antituberculosis corded in each of the sites inspected in products included inappropriate manage- 2008 and 2009. Overall, the trend shows ment of deviations and changes that may that the average number of observations have an impact on product quality. In one per site remains more or less the same site, all deviations inspected showed that over the last two years and that there was even as a deviation was initially reported a small amount of major non-compliance by an operator, the deviation was com- in almost all cases. This does not mean pleted prior to authorization by the pro- that there is no improvement in compli- duction supervisor, manager, director, and ance with GMP — since the same sites quality assurance. The company further were not necessarily inspected year to failed to appropriately implement the year. written programme for ongoing stability testing. Because there was a backlog in Examples of major non-compliance in testing stability samples — in some cases manufacturing sites of anti-malaria up to 90 days delay — the stability products included lack of validation, laboratory had to assist the quality control insufficient control over deviations, lack of laboratory to test finished products for in-line clearance procedures with a final release.
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During one inspection, in several identi- cases; room pressures measured were fied cases, there was no record of an out OOS and did not comply with the design of specification (OOS) result having been room pressures. In one case, batches of reported by the analysts and in several product that failed the sterility test were cases no investigation of reported OOS kept on hold for almost a year and were results was performed. not destroyed. Examples of major non-compliance in In several cases during site inspections of manufacturing sites of HIV/AIDS products reproductive health products, the obser- included insufficiently documented vations were so many that it was not evidence that appropriate process valida- possible to classify the observations. tion was carried out. This was due to inappropriate management and control of In conclusion, a higher number of non- quality control laboratory generated data. compliance events were observed at There was lack of traceability of data and manufacturing sites of reproductive health source data as the company failed to products than any other manufacturers. retain and maintain electronically gener- References ated data and results in an accessible form. In several cases, chromatograms 1. World Health Organization. Fact Sheet No. demonstrated peaks and baselines which 275, Counterfeit medicines. 2006. http:// were essentially similar if not identical, www.who.int/mediacentre/factsheets/fs275/en and retention times were identical. No 2. Van Zyl AJ, Zweygarth M, Summers RS. electronic source data had been retained Making medicines better. Medical University of in any way to enable verification of data. Southern Africa, September 2007. ISBN 978- 9-620-39472-7 Examples of major non-compliance at manufacturing sites of reproductive health 3. Raufu LA. India agrees to help Nigeria products included lack of control of tackle the import of fake drugs. British Medical changes. In one case, the change control Journal 2003;326:1234. http://www.bmj.com/ cgi/content/full/326/7401/1234-d?etoc procedure appropriately described the process to be followed. However, there 4. World Health Organization. Quality Assur- were approximately 200 open change ance of pharmaceuticals. A compendium of request forms corresponding to an guidelines and related materials. Volume 2, approximate five month period. In several Second updated edition. Good manufacturing cases, there was insufficient air filtration practices and inspection. 2007. http://www. (supply and exhaust) and pressure who.int/medicines/areas/quality_safety/ quality_assurance/production/en/index.html cascades, inappropriate gowning by operators and lack of containment to 5. World Health Organization Prequalification ensure safety of operators, products and of Medicines Programme. http://www.who.int/ protection of the environment. In several prequal Corrigendum The following correction refers to the article entitled “WHO Prequalification of Medicines Programme: facts and figures for 2009” found in the section “Inspections” on page 4 of WHO Drug Information, Volume 24, Number 1.
Prequalification of Medicines Programme inspectors carried out 52 inspections in nine coun- tries: 27 finished pharmaceutical product manufacturing sites, seven of API manufacturing sites, ten of contract research organizations (CROs) and eight of pharmaceutical quality con- trol laboratories (including two pre-audit inspections). The majority of inspections were carried out in India, followed by China, Singapore, South Africa, Ukraine and Viet Nam.
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Regulatory Harmonization
Optimization of medicines regulatory authority web sites
The objective of every medicines regulatory authority (MRA) is to ensure that all medicines marketed in the respective country are of assured quality, safety and efficacy, and are accompanied by appropriate information to promote their rational use. Therefore, the existence of a reliable and accessible web site plays a vital role in providing independent regulatory information. A study carried out by the World Health Organization in 2001 on the status of 51 MRA web sites operating nationally has now been updated and a report published which shows that the number of web sites has risen to 116 (1). Most criteria, such as frequency of updates, pharmacovigilance information and regulatory guidance for medicines marketing authorization have improved substantially, although navi- gability of web sites is still problematic. Overall, development of new MRA web sites over the past eight years is impressive and the number has more than dou- bled. It is remarkable how countries from all income categories have made efforts to launch and maintain web sites that provide the general public, health professionals and industry with good-quality regulatory information.
Review of web sites: Over 80% of web sites had inadequate 2001 and 2009 sections on medicines safety alerts and reporting of adverse drug reactions and The Internet is a tool used extensively by more than 50% of web sites did not patients, health professionals and phar- provide access to information on regis- maceutical companies to obtain informa- tered medicines. tion on pharmaceutical products. Through the Internet, medicines regulatory authori- The information gap about legitimately ties (MRAs) can provide access to regula- marketed medicines and restricted/ tions and requirements for ensuring the cancelled marketing authorizations is of quality, safety and efficacy of medicines, concern to many healthcare professionals regulatory guidance on marketing and and researchers. A number of publica- information on approved products. tions have expressed the need for trans- parency and the provision of good quality The present review updates a WHO study health information by medicines regula- undertaken in 2001 to assess the quality tory authorities [4Ð7]. of information available on 51 MRA web sites [2Ð3]. Since then, there has been a In 2008, a study of Australia, Canada, major increase in the number of countries European Medicines Agency, France, that maintain a web site. The 2001 study New Zealand, United Kingdom and USA demonstrated that many web sites web sites assessed the availability of provided limited information that was information [8]. It concluded that the type often not easy to access and almost 60% and amount of information varied widely, did not have an adequate search engine. with several MRAs not making basic
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information publicly available. The Euro- cine users evaluated the Internet as pean Medicines Agency alone published reliable. For example, in Singapore in complete information on cancelled 2009, 15% of consumers reported having marketing authorizations and the Health used the Internet as a medicines informa- Canada web site was the only site to offer tion source, with 34% having problems full access to pharmacovigilance data. No finding reliable and accurate information web site released the periodic safety [10]. Among physicians in Thailand, 29% update reports that companies have to of faculty and 25% of residents used the provide to MRAs. The study criticized the Internet as the first means through which lack of openness and called for increased they learnt of new medicines [11]. transparency and independence of regulatory authority activities [8]. As a consequence of increased demand, the amount and quality of information The general public is also a stakeholder available on the Internet has increased in the debate on the relative lack of enormously over the past eight years. certain types of information related to However, it is not clear which countries medicines. In 2007, it was reported that are leading and which subject areas still 20% of Finnish medicine users name the need strengthening on their web sites. Internet as a source of information, with up to 30% in the age group 15Ð34 years The objective of the present study (1) is of age [9]. Medical doctors, pharmacists to provide an update on the status of and patient information leaflets (PILs) MRA web sites, the number of MRAs that were reported as the most reliable have web sites, and show any associa- sources of medicines information, fol- tion with income group classification of lowed by MRAs, nurses, information the country. It reviews the accessibility, leaflets and medicine guides and text- completeness and quality of information books. However, only 24Ð43% of medi- on MRA web sites.
Table 1: Numbers and percentages of countries with identified MRA web site by WHO Region
Region Number of MRA % Number of MRA % web sites 2001* web sites 2009
AFR 4 of 46 9 16 of 46 35 AMR / PAHO 7 of 35 20 20 of 35 57 EMR 1 of 21 5 11 of 21 52 EUR 29 of 54 54 47 of 54 87 SEAR 3 of 11 27 8 of 11 73 WPR 9 of 29 31 14 of 29 48
Totals: 2001: 53 of 196 potential websites (27%) 2009: 116 of 196 potential websites (59%)
*The list of countries for 2001 has been adjusted to the 2009 list. Abbreviations: AFR: WHO Region for Africa; AMR / PAHO: Region for the Americas / Pan American Health Organization; EMR: Region for the Eastern Mediterranean EUR: Region for Europe; SEAR: Region for South-East Asia; WPR: Region for the Western Pacific
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Identification of available web sites Many researchers have argued that the In 2009, 116 MRA web sites were identi- provision of information by MRAs is fied. The percentage of countries with inadequate [3Ð4, 6, 11, 14]. However, the web sites has more than doubled from situation has improved significantly over 27% in 2001 to 59% in 2009. Table 1 the past eight years, especially on poten- shows the increase in numbers and tially confidential and controversial percentage of countries with identified subjects such as clinical trial data and MRA web sites by WHO Region. medicines safety information. However, although this is a positive development Scores there is still room for improvement as only Table 2 shows scoring for 51 countries 43% of web sites provide at least satis- assessed in 2001 together with results factory information on pharmacovigilance. from 2009 for the same countries. In addition, improvement could be made
Table 2: results of scoring for 51 countries assessed in 2001 and 2009
2001 in % 2009 in %
Criteria Inadequate Inter- good Inadequate Inter- good mediate mediate
user-friendliness 22 49 29 10 47 43 site map 61 12 28 20 10 71 navigability 10 31 59 12 53 35 speed* 18 26 57 37 31 33 search 57 18 26 14 73 14 update 55 8 37 16 14 71 mission statement 18 51 31 24 14 63 contact information 29 33 37 10 57 33 organizational structure 31 28 41 18 55 27 services 71 10 20 12 29 59 news, events & meetings 53 20 28 29 45 25 pharmacovigilance 80 8 12 18 39 43 feedback form 57 14 29 51 8 41 regulatory guidance, 33 39 28 10 45 45 legislation & regulation instructions for marketing 28 26 47 22 29 49 applicants medicinal products 53 33 14 35 27 37 licensed manufacturers 84 10 6 59 4 37 import & export 80 12 8 35 47 18 approved wholesalers 75 20 6 75 8 18 distributors, pharmacies statistics: medicines 88 4 8 78 8 14 consumption statistics on country profile 88 0 12 82 14 4 statistics on MRA activities 75 4 22 59 10 31 links 51 18 31 25 25 49 publications 59 20 22 37 25 37 languages 33 28 39
* The speed of the MRA web sites of Morocco and Thailand could not be assessed using the web site optimization tool.
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by the online publication of data that is Updating of web sites has improved being provided on paper. PILs and SPCs significantly. Fifty-five per cent of web were only available on a third of reviewed sites reviewed in 2001 were not updated web sites whereas this information could during the previous year but this percent- be very valuable for consumers and age has declined to 16% in 2009. Cur- health care professionals alike [9Ð11]. rently, 71% of web sites studied are being updated monthly. In assessing the World Bank income group classification of the country, it The greatest improvement has been became clear that national income has a made in the section on pharmacovigi- strong association with the existence of lance. Over 80% of web sites assessed in MRA web sites. However, a number of 2001 did not provide adequate informa- low income countries also have web sites tion on how to report adverse drug and the improvement in content of web reactions nor publish safety alerts. In sites is striking. Whereas many web sites 2009, only 18% of web sites scored provided no more than contact informa- inadequately on this item and 41% of web tion and an organigram in 2001, current sites had good sections on pharmacovigi- web sites include comprehensive pages lance. As an example, the United States on legislation and regulatory guidance, Food and Drug Administration web site information on medicinal products and gives very comprehensive pharmacovigi- pharmacovigilance. User-friendliness of lance data. the regulatory web sites has improved Overall, web sites that were already considerably, although many could still online in the earlier survey are more likely profit from some improvement in attrac- to have improved both in terms of quality tiveness, site mapping and navigation. and content. In addition, the countries that had web sites in 2001 were mainly Efficient search engines and subject high income countries and score better in indexes are often missing. Although the general. On the other hand, a number of percentage of countries with intermediate new web sites have been identified that search engines increased from 18% to exceed some of the older web sites. 73%, only 14% of countries really allow Particularly good examples of new MRA thorough searching of the web site. web sites are those of Sudan and Argen- tina. Good examples of user-friendly web sites that were easy to navigate include the In countries where ministries of health United Kingdom and Denmark [12] and have regulatory functions, specific web Ireland and India web sites scored pages for regulatory activities should be intermediate on navigability which is launched. Web sites should endeavour to reflected in difficulties users had when improve their accessibility by establishing searching web sites for more specific links from other sites, such as the rele- information. It is not always certain that vant governmental authorities and institu- users will have the persistence needed to tions (ministries of health, commerce and find information being sought. Many trade, customs authorities, etc.), general MRAs provide enormous amounts of health information sites and regional information and documents on their web medicines regulatory authority sites. sites but navigability is often poor. The importance of a good infrastructure, the In conclusion, the 51 countries that have availability of a site map and efficient maintained web sites over the past eight search engines should not be underesti- years show considerable improvement in mated. the content and comprehensiveness of
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information provided. Such subjects as 5. Abraham J, Lewis G. Secrecy and transpar- site maps, updates and mission state- ency of medicines licensing in the EU. Lancet. ments that were missing in 2001 are now 1998;352(9126):480Ð2. almost fully covered. On the other hand, 6. Garattini S, Chalmers I. Patients and the there is still room for improvement on all public deserve big changes in evaluation of topics, including key subjects such as drugs. BMJ. 2009;338:b1025. regulatory guidance, pharmacovigilance and registries of medicinal products. 7. Lexchin J, Mintzes B. Transparency in drug regulation: mirage or oasis? CMAJ. 2004 23;171(11):1363Ð5. References 8. Vitry A, Lexchin J, Sasich L et al. Provision 1. World Health Organization. Medicines of information on regulatory authorities web Regulatory Authority web sites: review of sites. Intern Med J. 2008;38(7):559-67. progress made since 2001. http://www.who. int/medicines 9. Narhi U. Sources of medicine information and their reliability evaluated by medicine 2. Improving the quality and usefulness of users. Pharm World Sci. 2007;29(6):688-94. drug regulatory authority web sites. WHO Drug Information. 2001;15(3Ð4):163Ð8. 10. Ho CH, Ko Y, Tan ML. Patient needs and sources of drug information in Singapore: is 3. World Health Organization. Jambert E. the Internet replacing former sources? Ann Pilot study on drug regulatory web sites: Pharmacother. 2009;43(4):732-9. Current status and future challenges. Joint NLN Ð WHO Workshop 2001, Pharmaceuti- 11. Layton MR, Sritanyarat W, Chadbuncha- cals and the Internet. Drug Regulatory chai S et al. Sources of information for new Authorities Perspective; 2001, drugs among physicians in Thailand. Pharm World Sci. 2007;29(6):619-27. 4. Abraham J. The science and politics of 12. Alexa Internet. Traffic Stats Ð Time on Site. medicines control. Drug Saf. 2003;26(3): [cited 2009 22 September]; Available from: 135Ð43. http://www.alexa.com/siteinfo/fda.gov.
Medicines regulatory authority web sites
WHO Region for Africa Algeria http://www.ands.dz Botswana http://www.moh.gov.bw Burkina Faso http://www.sante.gov.bf Ethiopia http://www.daca.gov.et Ghana http://www.fdbghana.gov.gh Kenya http://www.pharmacyboardkenya.org Mali http://www.dirpharma.org Mauritius http://www.gov.mu Namibia http://www.nmrc.com.na Nigeria http://www.nafdacnigeria.org Rwanda http://www.moh.gov.rw Senegal http://www.sante.gouv.sn South Africa http://www.mccza.com Swaziland http://www.gov.sz Uganda http://www.nda.or.ug United Republic of Tanzania http://www.tfda.or.tz Zimbabwe http://www.mcaz.co.zw
,../
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Medicines regulatory authority web sites (continued)
WHO Region for the Americas Argentina http://www.anmat.gov.ar Bahamas http://www.phabahamas.org Bolivia http://www.sns.gov.bo Brazil http://www.anvisa.gov.br Canada http://www.hc-sc.gc.ca Chile http://www.ispch.cl Colombia http://www.invima.gov.co Costa Rica http://www.ministeriodesalud.go.cr Cuba http://www.cecmed.sld.cu Dominican Republic http://www.drogasyfarmacias.gov.do Guatemala http://portal.mspas.gob.gt Guyana http://www.health.gov.gy Honduras http://www.dgrs.gob.hn Jamaica http://www.pcoj.org Mexico http://www.cofepris.gob.mx Panama http://www.minsa.gob.pa Paraguay http://www.mspbs.gov.py Peru http://www.digemid.minsa.gob.pe Trinidad and Tobago http://www.health.gov.tt United States of America http://www.fda.gov Uruguay http://www.msp.gub.uy Venezuela http://www.inhrr.gov.ve WHO Region for the Eastern Mediterranean Egypt http://www.eda.mohp.gov.eg Jordan http://www.jfda.jo Lebanon http://cms1.omsar.gov.lb Morocco http://srvweb.sante.gov.ma Oman http://www.moh.gov.om Pakistan http://www.dcomoh.gov.pk Qatar http://www.nha.org.qa Saudi Arabia http://www.sfda.gov.sa Sudan http://www.nmpb.gov.sd Tunisia http://www.dpm.tn United Arab Emirates http://www.moh.gov.ae Yemen http://www.sbd-ye.org WHO Region for Europe Albania http://www.qkkb.gov.al Andorra http://www.salutibenestar.ad Armenia http://www.pharm.am Austria http://www.ages.at Azerbaijan http://www.pharm.az Belarus http://www.rceth.by Belgium http://www.fagg-afmps.be Bosnia and Herzegovina http://www.alims.gov.ba Bulgaria http://www.bda.bg Croatia http://www.almp.hr Cyprus http://www.moh.gov.cy Czech Republic http://www.sukl.cz Denmark http://www.dkma.dk European Medicines Agency http://www.ema.europa.eu Estonia http://www.sam.ee Finland http://www.nam.fi France http://www.afssaps.fr Georgia http://gdna.georgia.gov Germany http://www.bfarm.de ,../
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Medicines regulatory authority web sites (continued)
Greece http://www.eof.gr Hungary http://www.ogyi.hu Iceland http://www.imca.is Ireland http://www.imb.ie Israel http://www.health.gov.il Italy http://www.aifa.gov.it & http://www.agenziafarmaco.it Kazakhstan http://www.dari.kz Kyrgyzstan http://pharm.med.kg Latvia http://www.vza.gov.lv Lithuania http://www.vvkt.lt Luxembourg http://www.ms.public.lu Malta http://www.medicinesauthority.gov.mt Montenegro http://sntcg.com Netherlands http://www.cbg-meb.nl Norway http://www.legemiddelverket.no Poland http://www.bip.urpl.gov.pl Portugal http://www.infarmed.pt Republic of Moldova http://www.amed.md Romania http://www.anm.ro Russian Federation http://www.roszdravnadzor.ru Serbia http://www.alims.gov.rs Slovakia http://www.sukl.sk Slovenia http://www.jazmp.si Spain http://www.agemed.es Sweden http://www.lakemedelsverket.se Switzerland http://www.swissmedic.ch Tajikistan http://health.tj Turkey http://www.iegm.gov.tr Ukraine http://www.pharma-center.kiev.ua United Kingdom http://www.mhra.gov.uk/index.htm WHO Region for South-East Asia Bangladesh http://www.ddabd.org Bhutan http://www.health.gov.bt/dra.php India http://cdsco.nic.in Indonesia http://www.pom.go.id Maldives http://www.mfda.gov.mv Nepal http://www.dda.gov.np Sri Lanka http://www.health.gov.lk Thailand http://www.fda.moph.go.th WHO Region for the Western Pacific Australia http://www.tga.gov.au Brunei Darussalam http://www.moh.gov.bn China http://www.sfda.gov.cn Fiji http://www.health.gov.fj Hong Kong SAR China http://www.psdh.gov.hk Japan http://www.pmda.go.jp Malaysia http://www.pharmacy.gov.my Mongolia http://www.moh.mn New Zealand http://www.medsafe.govt.nz Philippines http://www.bfad.gov.ph Republic of Korea http://ezdrug.kfda.go.kr Singapore http://www.hsa.gov.sg Vietnam http://www.dav.gov.vn
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Essential Medicines
Regulatory action needed to stop the sale of oral artemisinin-based monotherapy
Continued use of oral artemisinin-based monotherapy is widely considered as one of the main contributing factors to the development and spread of resistance to artemisinin and its derivatives. Few patients take the full sevenÐday course of mono- therapy required to achieve high cure rates — most patients tend to discontinue treatment after two or three days due to the rapid resolution of symptoms provided by artemisinin. This results in persistent parasitaemia exposed to sub-therapeutic drug levels. In 2007, the World Health Assembly adopted a resolution to progres- sively remove oral artemisinin-based monotherapy from the market and instead deploy artemisinin-based combination therapies (ACTs) for the treatment of un- complicated falciparum malaria. While 34 countries have withdrawn marketing au- thorization for oral artemisinin-based monotherapy, 29 countries have not yet taken regulatory action. Out of 73 companies involved in the production and marketing of these medicines, a total of 36 companies have de-listed oral artemisinin-based mono- therapy from their product catalogues but 37 companies — mainly those targeting the private sector markets of malaria-endemic countries — are still actively provid- ing monotherapy in this sector. Progress made by regulatory authorities at country level shows that phasing out oral artemisinin-based monotherapy from the market is possible through a range of interventions as long as government commitment and strong stewardship of the national regulatory authorities is maintained.
Artemisinin-based derivative with a second longer acting monotherapy and risk of antimalarial partner — killing the parasite Plasmodium falciparum using two different modes of action — is to delay the development of resistance. drug resistance Prevention of artemisinin resistance is Malaria causes an estimated 243 million particularly important as there are no clinical attacks every year with 863 000 alternative antimalarial medicines under deaths, mostly in children under 5 years development with equivalent levels of of age, due to Plasmodium falciparum (1). efficacy expected to become available WHO recommends artemisinin-based over the next 7Ð8 years (3). combination therapies (ACTs) as the mainstay of treatment of uncomplicated Artemisinin and its derivatives are highly P. falciparum malaria (2). The rationale of efficacious. They rapidly eliminate combining a rapidly acting artemisinin asexual parasite stages and early sexual forms of falciparum malaria, producing a rapid clinical and parasitological response *Authors: S. Schwarte, P. Ringwald, (4). When used as monotherapy, artem- K. Mendis, A. Bosman. Global Malaria isinin derivatives need to be given for Programme, World Health Organization, seven days to achieve high cure rates, Geneva, Switzerland. while three-day monotherapy treatment
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results in unacceptably high (48Ð54%) parasites to give rise to a pool of mutated recrudescence rates (5). Consequently, and recombined parasites. Antimalarial there are two main product presentations immunity in patients, which increases in which promote artemisinin resistance: proportion to the intensity of malaria transmission, might conceal the effects of ¥ Medicinal products with 5Ð7 day admin- drug resistance and delay the detection istration of artemisinin-based mono- of drug resistant infections (6). therapy. Plasmodium falciparum has thus far ¥ ACTs which are co-blistered rather than developed resistance to all classes of co-formulated. antimalarial medicines used in its treat- ment (6). While quinine remained effec- Full seven-day treatment is impractical tive for decades after its large-scale and most patients tend to discontinue introduction in the early 20th century, the treatment early due to the rapid clinical development of resistance to the other resolution provided by artemisinin. With antimalarial compounds emerged rela- co-blistered ACTs many patients tend to tively faster, varying from 12 years for take the three-day treatment of the chloroquine to five years for mefloquine, artemisinin derivative and discard the to approximately one year for proguanil, partner medicine (e.g. amodiaquine or sulfadoxine-pyrimethamine and mefloquine) due to the poor tolerability of atovaquone. In the 1950s and 1960s, the latter medicines. Both products, which P. falciparum resistance to chloroquine lead to inadequately dosed artemisinin and sulfadoxine-pyrimethamine was first monotherapy, leave the parasite exposed detected in the Pailin province, Western to sub-therapeutic blood levels of the Cambodia (4), from where it subsequently medicine which promotes the develop- spread to the Indian subcontinent in the ment of parasite resistance by eliminating 1970s and then to East African countries the most sensitive parasite strains and in the 1980s. leaving the more resistant ones to multi- ply unrestrained. More recently in 2009, scientists con- firmed the first cases of falciparum Emergence and selection of drug resistance to artemisinin derivatives in the resistant parasites same province of Pailin (8). In this area The emergence of resistance to antima- artemisinins have been extensively used larial medicines is initiated by rare spon- as monotherapy over the past decade, taneous mutations which provide survival and this may have contributed to the advantages to the parasite while exposed development of resistance together with to a specific antimalarial compound. other unidentified factors (4, 8). There is When exposed to the medicine in ques- major concern that artemisinin resistance tion (drug pressure), the mutant parasite in P. falciparum malaria parasites may strains which have a survival advantage increase and spread to other areas of the get selected in favour of the sensitive world. ones. Mutations can originate in the population of parasites from the same The loss of artemisinin derivatives will geographical area or in parasites from have devastating consequences on different areas. Migrating populations people’s health in malaria-endemic contribute to the development and spread countries and threaten recent malaria of resistance by importing mutated control progress achieved in many parasites from other geographical areas countries. which then recombine with the local
99 Essential Medicines WHO Drug Information Vol. 24, No. 2, 2010
Drug pressure and its impact on recommendations were endorsed by all antimalarial drug resistance WHO Member States in May 2007. Since Past experience shows that once resist- 2006, the WHO Global Malaria Pro- ance has arisen the removal of drug gramme has contacted the major pro- pressure can prolong the useful thera- curement and funding agencies in rela- peutic life of the corresponding medicine tion to these recommendations and, as a (9). Mutations associated with drug result, all major agencies have progres- resistance in P. falciparum generally sively discontinued funding or procure- affect the parasite’s fitness. Studies ment of these medicines. undertaken with chloroquine and meflo- quine showed that parasite susceptibility Monitoring the phasing out of to the corresponding active pharmaceuti- artemisinin-based monotherapy cal ingredient was restored after discon- Until all ACTs become available as fixed- tinuing use of the medicines. dose combinations, oral artemisinin- based monotherapies will need to be In China, in vivo resistance to chloroquine manufactured for co-blistering with decreased over a 5Ð8 year period from partner medicines; the call is against the more than 84% to 40%. In certain regions sale and use of oral artemisinin-based of Malawi — the first African country to monotherapy. To track compliance with discontinue chloroquine use in 1993 in Resolution WHA60.18 by pharmaceutical favour of sulfadoxine-pyrimethamine — companies marketing these medicines molecular markers of chloroquine resist- and progress in implementation of regula- ant parasites decreased in prevalence tory action by national drug regulatory over time (9). For other antimalarial authorities, WHO has established a web- medicines, such as sulfadoxine-pyrimeth- based monitoring system. Regularly amine, drug resistant mutations may updated information can be accessed persist after drug pressure is removed if through the following links: http:// they do not affect the parasite’s fitness or www.who.int/malaria/monotherapy_ if secondary mutations occur, providing manufacturers.pdf (pharmaceutical compensatory mechanisms to strengthen companies) and http://www.who.int/ parasite fitness. malaria/monotherapy_NDRAs.pdf (na- tional drug regulatory authorities). Phasing out oral artemisinin-based monotherapy Since 2005, WHO has identified a total of Based on the biological mechanisms of 73 pharmaceutical companies involved in resistance observed with the other the production and marketing of oral antimalarial compounds, it is expected artemisinin-based monotherapy medi- that with removal of oral artemisinin- cines. On a regular basis, WHO contacts based monotherapy the resistance of these companies in order to update their P. falciparum to artemisinins will either positions with regard to WHO recommen- reduce or stabilize at prevailing levels dations. All but one of the 36 companies rather than get worse. Both mechanisms which have ceased marketing so far have will result in extending the useful thera- been identified in the period from 2005Ð peutic life of artemisinin derivatives. WHO 2007; action was taken following re- therefore urges Member States to cease peated requests from WHO. Companies the marketing and use of oral artemisinin- identified more recently are less prone to based monotherapy in both the public withdraw their products from the market. and private sectors and to promote the By April 2010, an additional six compa- use of artemisinin-based combination nies had declared their intentions to therapies. As part of World Health Assem- comply, but have not taken action so far bly Resolution WHA60.18 (10), these and a total of 30 companies have not
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Figure 1. Companies marketing oral artemisinin-based monotherapies by year of identification by WHO updated on a regular basis (last update 13 April 2010)
Not yet contacted Monotherapies withdrawn Intention to comply No intention disclosed
disclosed their position (Figure 1). Nearly based monotherapy is the poor regulation all companies which have a consistent of pharmaceutical markets in malaria- market share in public sector procure- endemic countries. In February 2010, out ment funded by international agencies of the 78 national regulatory authorities have de-listed oral artemisinin-based (NRAs) of falciparum-endemic countries, monotherapy medicines from their prod- 49 have either never registered or have uct catalogues. However, smaller compa- taken regulatory measures to withdraw nies mainly targeting private sector marketing authorizations of oral artemisi- markets are more prone to ignore the nin-based monotherapy and 29 still do WHO appeal. When responsible compa- not yet comply with WHO recommenda- nies comply with WHO recommendations tions. Most of the countries which have and withdraw their monotherapy prod- not yet taken regulatory steps are located ucts, they leave ‘niche markets’ which are in the WHO African Region (16 NRAs) rapidly exploited by opportunistic compa- followed by the South-East Asia Region nies manufacturing monotherapy and (6 NRAs) and the Western Pacific Region substandard products. Most of the com- (3 NRAs). panies still involved in the marketing of oral artemisinin-based monotherapy The regulation of pharmaceutical markets medicines are located in India (21), in malaria-endemic countries is a com- followed by Nigeria (5), Kenya (2) and plex process. A number of successful Viet Nam (2), as well as the Democratic examples show that phasing out oral Republic of Congo, Dubai (United Arab artemisinin-based monotherapy can Emirates), Ghana, Greece, Netherlands, succeed. Countries are adopting WHO Pakistan and Switzerland (1 company recommendations to progressively phase each). out artemisinin-based monotherapies and adapt them to their national context. In One of the main reasons for the limited some countries, like Cameroon and Côte success in phasing out oral artemisinin- d’Ivoire, the new regulations aim to align
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the availability of products for sale in the affecting both international and domestic private sector with those listed in the markets, and targeting both APIs and national treatment guidelines and avail- FPPs can be applied to phase out oral able in the public sector. Other countries artemisinin-based monotherapy medi- like Benin have used this opportunity not cines from the markets. only to remove oral artemisinin-based monotherapy but also all formulations of Export markets can be influenced by chloroquine, which is no longer effective regulatory actions targeting those coun- due to high levels of P. falciparum resist- tries which are the major exporters of ance. The critical step in Benin was to these medicines. In particular, withdraw- ensure large-scale availability of ACTs. ing manufacturing and export licenses for For some countries, e.g. China and Viet FPPs can prevent pharmaceutical com- Nam, the main target of decisions of the panies from exporting their monotherapy national health authorities has been the products to malaria-endemic countries. To removal of oral artemisinin-based mono- protect domestic markets, the most therapy from the public sector, following effective strategy is to stop import li- change of the national treatment guide- cences and not to grant marketing au- lines. The examples of India and Pakistan thorizations for such products. Domestic show the importance of national regula- manufacturers should be regulated more tory authorities in coordinating this stringently with regard to import licenses initiative and support provided by the for APIs, e.g., not granting API import national Malaria Control Programme and licenses to companies exclusively manu- WHO in both countries to accelerate the facturing oral artemisinin-based mono- process. The active recall of existing therapies. In addition, to regulate domes- stocks of chloroquine and sulfadoxine- tic companies involved in the re-packag- pyrimethamine in Burundi has proven to ing or re-branding of artemisinin-based be highly effective. FPPs produced in other countries, FPP import licenses should be suspended for The way forward: targets companies exclusively marketing oral and timelines for action artemisinin-based monotherapies. The active withdrawal of a medicine from It is crucial to ensure large-scale availabil- the market in the interest of public health ity of ACTs in both the public and private through a regulatory approach — in this sectors, before oral artemisinin-based particular case to limit the risk of develop- monotherapies can effectively be re- ment of resistance — is unprecedented. moved from the market. Based on the Many steps are involved in the manufac- initial experiences of successful coun- ture of artemisinin-based medicines, from tries, Table 1 overleaf offers generic the planting of the seeds to extraction of timelines for progressively removing the active pharmaceutical ingredient (API) these medicines from the market which and subsequent manufacture of the can be adapted to specific situations. finished pharmaceutical products (FPPs). Thereafter the sale of oral artemisinin- Conclusion based monotherapy takes place in the Progress made by several pharmaceuti- context of domestic and international cal companies and regulatory authorities market dynamics. A variety of interven- at country level show that phasing out tions can and have successfully been oral artemisinin-based monotherapy applied at these various steps in order to medicines from the markets is possible interrupt both the manufacture and sale of through a range of interventions. How- these monotherapies. Thus, measures ever, the problem is still rife and is cur-
102 WHO Drug Information Vol. 24, No. 2, 2010 Essential Medicines
Table 1. Generic guide with timelines to phase out oral artemisinin-based monotherapy medicines from the market
Action Task Timeline
Step 1 Agreement on timeframe of phasing out oral artemisinin-based monotherapies in synchrony with Immediate large-scale implementation of artemisinin-based combination therapies (ACTs)
Step 2 Suspension of new approvals of marketing authoriza- Immediate tions for oral artemisinin-based monotherapies
Step 3 Suspension of import licences for artemisinin or its derivatives (as API or FPP) to domestic companies 3Ð4 months exclusively marketing oral artemisinin-based mono- therapies
Step 4 Large-scale deployment of ACTs in the public sector and communication to prescribers and consumers Time X* to move away from monotherapies
Step 5 Widespread availability and affordability of ACTs in Time Z** the private sector
Step 6 Withdrawal of marketing authorization and of manu- 6 months facturing licences for oral artemisinin-based mono- after time X therapies as FPPs
Step 7 Suspension of export licence for oral artemisinin- 6 months based monotherapies as FPPs after time X
Step 8 Complete elimination of oral artemisinin-based 10Ð12 months monotherapy medicines as FPPs from the market after time X
Step 9 Active recall of oral artemisinin-monotherapies 3 months from the market after time Z
* X refers to the time at which a country will deploy on a large scale artemisinin-based combination therapies in the public sector, generally associated with external funding for procurement (e.g. from GFATM or other sources). All subsequent timelines are conditioned on this. ** Z requires distribution of quality ACTs at subsidized prices in the private sector, as expected in countries participating in the Affordable Medicines Facility Ð malaria (Global Fund to Fight AIDS, Tuberculosis and Malaria [GFATM]).
rently one of the major threats for devel- accessing international funds for public opment of drug resistance. The response sector procurement. Smaller companies of pharmaceutical companies to stop which mainly target the pharmaceutical marketing oral artemisinin-based private sector in developing countries monotherapies has been successful in have largely compromised the success of those with a consistent market share in this approach. Thus, ultimate success in
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phasing out oral artemisinin-based 2. World Health Organization. Guidelines for monotherapy depends on effective drug the treatment of malaria, 2nd Edition, 2010. regulation at country level. Only the http://www.who.int/malaria/publications/atoz/ removal of marketing authorizations for 9789241547925/en/index.html oral artemisinin-based monotherapies will make them unavailable in the public and 3. Olliaro P, Wells TNC. The Global Portfolio of New antimalarial medicines under develop- formal private sectors. A flourishing ment. Clinical Pharmacology & Therapeutics. informal private sector, which is common Nature publishing Group. Advance online in many malaria-endemic countries, will publication April 2009. still continue to provide oral monotherapy to potential users and can be overcome 4. White N. Qinghaosu (artemisinin): The by the provision of good access to quality Price of Success. Science. 2008;320. www. medicines through a national drug supply schiencemag.org management system. 5. Li GQ et al. Clinical trials of artemisinin and Experience shows that a number of its derivatives in the treatment of malaria in critical steps should be taken in the China. Trans R Soc Trop Med Hyg. 1994;88 process of phasing out oral artemisinin- Suppl 1:S5Ð6. based monotherapy from the market. It is essential to synchronize these with the 6. White N. Antimalarial drug resistance. Journal of Clinical Investigation. 2004;113, large-scale deployment of ACTs in the Number 8. public sector and the provision of reason- able timelines allowing the progressive 7. World Health Organization. Epidemiological adaptation and response of the private approach to malaria control. WHO Reference sector to new health directives. Code 98121. http://www.who.int/malaria
Enhanced action to phase out oral 8. Dondorp AM, Nosten F, Yi P et al. Artemisi- artemisinin-based monotherapy medi- nin resistance in Plasmodium falciparum cines in the remaining malaria-endemic malaria. N Engl J Med. 2009;361:455Ð67. countries is urgently required. Govern- ment commitment and strong stewardship 9. Laufer M. K., Plowe C. V. Withdrawing of national regulatory authorities is antimalarial drugs: impact on parasite resist- required to achieve this. Artemisinin ance and implications for malaria treatment resistance — which is being accelerated policies. Drug Resistance Updates. 2004;7 (4Ð5):279Ð88. by the use of oral artemisinin-based monotherapy — is too grave a public 10. World Health Organization. World Health health risk to continue deployment of Assembly Resolution 60.18 (WHA60.18) these medicines.. http://apps.who.int/gb/ebwha/pdf_files/ WHA60/A60_R18-en.pdf References 1. World Health Organization. World Malaria Report 2009. http://www.who.int/malaria/ world_malaria_report_2009/en/index.html
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Safety and Efficacy Issues
Leflunomide and peripheral Extracted from Canadian Adverse Reac- neuropathy tion Newsletter, Volume 20, Number 2, 2010 at http://www.hc-sc.gc.ca/dhp-mps/ Canada — Neuropathy has been re- medeff/bulletin/carn-bcei_v20n2-eng.php ported in association with several dis- ease-modifying antirheumatic drugs. References During the past seven years, additional data regarding the suspected association 1. Arava (leflunomide) [product monograph]. Laval (QC): Sanofi-Aventis Canada Inc.; 2006. between peripheral neuropathy and leflunomide have emerged in the medical 2. Council for International Organizations of literature. Medical Sciences (CIOMS). Reporting adverse drug reactions: definitions of terms, Leflunomide is a disease-modifying and criteria for their use. Geneva: 1999. antirheumatic drug (DMARD) indicated 3. Parker D Jr. Peripheral neuropathy. In: for use in adults with active rheumatoid Tisdale JE, Miller DA, editors. Drug-induced arthritis (1). It has been marketed in diseases: prevention, detection, and manage- Canada since 2000 under the brand ment. Bethesda (MD): American Society of name Arava¨ and is also available in Health-System Pharmacists; 2005. generic form. 4. Argov Z, Mastaglia FL. Drug-induced Peripheral neuropathy is an impairment of peripheral neuropathies. BMJ 1979;1:663Ð6. the peripheral motor, sensory or auto- 5. Bharadwaj A, Haroon N. Peripheral neu- nomic nervous system (2). Signs and ropathy in patients on leflunomide. Rheuma- symptoms include muscular weakness or tology (Oxford) 2004;43: 934. flaccid paralysis and sensory distur- bances, including pain (2). Neuropathy 6. Richards BL, Spies J, McGill N, et al. Effect of leflunomide on the peripheral nerves in has been reported in association with rheumatoid arthritis. Intern Med J 2007; several DMARDs, including sulfasalazine, 37:101Ð7. chloroquine and penicillamine (3, 4). Over the last seven years, several cases 7. Metzler C, Arlt AC, Gross WL, et al. Periph- of peripheral neuropathy suspected of eral neuropathy in patients with systemic being associated with leflunomide have rheumatic diseases treated with leflunomide. been published (5Ð15). Patients had Ann Rheum Dis 2005;64:1798Ð800. paraesthesia or weakness, or both, in the upper or lower extremities, or both. In a 8. Martin K, Bentaberry F, Dumoulin C, et al. few cases the symptoms were severe or Peripheral neuropathy associated with leflunomide: Is there a risk patient profile? debilitating (12Ð16). The incidence of Pharmacoepidemiol Drug Saf, 2007;16:74Ð8. peripheral neuropathy has ranged from 1.4% to 10% in open studies to assess 9. Bonnel RA, Graham DJ. Peripheral neu- leflunomide neurotoxicity (5Ð8). In these ropathy in patients treated with leflunomide. studies, the proportion of patients for Clin Pharmacol Ther 2004;75:580Ð5. whom this adverse reaction (AR) im- proved after discontinuation of the drug or 10. Adverse Drug Reactions Advisory Commit- reduction of the dosage ranged from 37% tee. Leflunomide and peripheral neuropathy. to 100%. Aust Adv Drug Reactions Bull 2006;25:18Ð9.
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11. Martin K, Bentaberry F, Dumoulin C, et al. Saquinavir/ritonavir should not be used in Neuropathy associated with leflunomide: a patients already taking medications case series. Ann Rheum Dis 2005;64:649Ð50. known to cause QT interval prolongation or in patients with a history of QT interval 12. Gabelle A, Antoine JC, Hillaire-Buys D, et prolongation. al. [Leflunomide-related severe axonal neuro- pathy]. Rev Neurol (Paris) 2005;161:1106Ð9. Caution is warranted when administering 13. Carulli MT, Davies UM. Peripheral neu- ritonavir-boosted saquinavir to patients ropathy: An unwanted effect of leflunomide? with pre-existing conduction system Rheumatology (Oxford) 2002;41:952Ð3. disease.
14. Hill CL. Leflunomide-induced peripheral Reference: Communication dated 14 April neuropathy: rapid resolution with cholestyr- 2010 from Hoffmann-La Roche Limited at amine wash-out. Rheumatology 2004;43:809. http://www.hc-sc.gc.ca.
15. Lormeau C, Vandecandelaere M, Gasseu N, et al. Neuropathies périphériques au cours Human immune globulin: d’un traitement par léflunomide: deux intravascular haemolysis nouvelles observations. Revue Rhu 2003;70: 1001. Canada — Healthcare professionals have been informed of changes to the 16. Lipsky PE. Rheumatoid arthritis. In: Fauci prescribing information, including new AS, Braunwald E, Hauser SL, et al, editors. contraindications and conditions for use, Harrison’s principles of internal medicine. 17th for the treatment of immune thrombocyto- ed. New York (NY): McGraw-Hill; 2008. pp. penic purpura (ITP) with human Rho(D) e2083Ðe2091. immune globulin (WinRho¨ SDF). There have been rare serious (sometimes fatal) Saquinavir mesylate: adverse events of intravascular haemoly- prolongation of QT sis (IVH) and its complications which and PR intervals have been reported following ITP treat- ment with WinRho¨ SDF. Canada — Healthcare professionals have been informed of important new WinRho¨ SDF should not be adminis- safety information regarding the use of tered to patients: saquinavir mesylate (Invirase¨) and significant dose-dependent prolongation ¥ with ITP secondary to other conditions of QT and PR intervals in healthy volun- including leukaemia, lymphoma, or teers. active viral infections with EBV (Epstein- Barr virus) or HCV (hepatitis C) Saquinavir is authorized for the treatment of HIV-1 infected adult patients and ¥ who are elderly with co-morbidity should only be given in combination with predisposing to acute haemolytic ritonavir and other antiretroviral medicinal reaction (AHR) or its complications products. ¥ with evidence of autoimmune haemo- Based on the findings of a dedicated lytic anaemia (Evan Syndrome), or electrocardiogram study with saquinavir/ Systemic Lupus Erythematosus (SLE) ritonavir in healthy volunteers, dose- or anti phospholipid antibody syndrome dependent prolongation of QT and PR (APS) intervals have been observed in healthy volunteers receiving ritonavir-boosted ¥ who are IgA deficient. saquinavir.
106 WHO Drug Information Vol. 24, No. 2, 2010 Safety and Efficacy Issues
Patients treated with WinRho¨ SDF for Polymorphisms in other UGT genes as ITP should be closely monitored in a well as ABCB1, ABCG2, ABCC2 and healthcare setting for at least eight hours SLCO1B1 genes which encode proteins after administration. Urine dipstick testing involved in irinotecan transport, may also for blood should be conducted before contribute to variation in irinotecan and dosing and at 2, 4 and 8 hours after SN-38 pharmacokinetics and severity of receiving the dose. neutropenia, but the evidence is consider- ably less well developed than for In post-marketing surveillance from UGT1A1*6 and *28. No definitive clinical March 1995 to March 2009 the manufac- studies have been published yet on the turer reported a total of 180 serious case impact of irinotecan dosage adjustment reports of suspected and/or confirmed on response rate based on a patient’s cases of IVH worldwide. A disproportion- genotype. This is an active area of clinical ate number of IVH cases have been research internationally. reported in patients with ITP secondary to haematological malignancies such as In 2005, the United States Food and Drug leukaemia or lymphoma, or active viral Administration (FDA) amended the infections with HCV and EBV. product label for Camptosar¨, a brand of irinotecan used in the US, to warn of an Reference: Communication dated 22 March increased risk of severe neutropenia 2010 from Cangene Corporation at http:// among patients who are homozygous for www.hc-sc.gc.ca/. UGT1A1*28. This decision was reached after reviewing data from several clinical Irinotecan-induced severe trials that supported the conclusion of a neutropenia: UGT1A1 variant greater risk of Grade 3 or 4 neutropenia alleles in patients homozygous for UGT1A1*28. Another meta-analysis of nine studies Singapore — Irinotecan is converted in (821 subjects) from North America and the body to a metabolite called SN-38, Europe, published in 2007, confirmed a which is 100 to 1000 times more potent significant association between than irinotecan itself. SN-38 is inactivated UGT1A1*28 genotype and severe neutro- primarily by UGT1A1 which glucuro- penia at doses greater than 150 mg/m2, nidates SN-38 to an inactive metabolite, but no association was seen at lower SN-38G. UGT1A1 is the same enzyme doses (100Ð125 mg/m2). In 2008, a that mediates bilirubin conjugation. clinical study from Taiwan demonstrated Glucuronidating activity is reduced when that patients who were either heterozy- variants of the UGT1A1 gene, gous or homozygous for UGT1A1*28 had UGT1A1*28 or UGT1A1*6 are present. a higher rate of neutropenic fever and UGT1A1*28 contains seven, rather than grade 3 or 4 neutropenia. six, thymine-adenine (TA) repeats in the UGT1A1 promoter region and reduces In Japan, the Pharmaceutical and Medi- enzyme expression; UGT1A1*6 repre- cal Devices Agency (PMDA) also exam- sents a nucleotide change from guanine ined the evidence for an association (G) to adenine (A) that causes an amino between UGT1A1 variants and neutrope- acid change from glycine to arginine and nia. The UGT1A1*28 variant is much less lowers the enzyme’s activity. As a result, common in Japanese compared to patients with these variants have higher Caucasians. On the other hand, blood levels of SN-38 after receiving the UGT1A1*6 is not uncommon in Japa- same dose of irinotecan. nese, yet is absent in Caucasians. In
107 Safety and Efficacy Issues WHO Drug Information Vol. 24, No. 2, 2010
2008, PMDA updated its product label for Combination of niacin/ irinotecan to alert prescribers of the laropiprant and simvastatin: association between increased risk of myopathy serious adverse events and UGT1A1*6 and *28 variants. Singapore — The Health Sciences Authority (HSA) has recently been in- Local Context formed of the results of an interim analy- The Health Sciences Authority (HSA) has sis from an ongoing study, HPS2- reviewed the distribution of UGT1A1 THRIVE, which suggest a higher inci- variants in the three major ethnic groups dence of myopathy observed in Chinese of Singapore — Chinese, Malay, and patients on concomitant extended release Indian using data from the National (ER) niacin/laropiprant 2 g/40 mg Cancer Centre (16,17), the National (Tredaptive¨) and simvastatin 40 mg University Hospital (18), and the Singa- (with or without ezetimibe). pore Genome Variation Project (19). Among Singapore Indians, the genotype ER niacin/laropiprant is a lipid-lowering distribution of the UGT1A1*28 variant is agent indicated for the treatment of comparable to Caucasians, while among dyslipidaemia. It contains a combination Singapore Chinese, the genotype distri- of ER niacin, a lipid-modifying agent and bution of the UGT1A1*6 variant is similar laropiprant, a potent, selective antagonist to Japanese. The prevalence of double of the prostaglandin D2 (PGD2) receptor heterozygotes (*6/*28) in Singapore is subtype 1 (DP1). Laropiprant is a novel 6.9%, 1.2% and 2.9% in Chinese, Malays agent that is added to the combination to and Indians, respectively. suppress the PGD2 mediated flushing that is associated with the use of niacin. In view of the available evidence of Tredaptive¨ has been licensed for use in greater risk of irinotecan toxicity associ- Singapore since March 2009. ated with UGT1A1*6 and UGT1A1*28 variants and its potential impact on our Myopathy and rhabdomyolysis are known local population, the HSA Pharmaco- adverse effects of HMG-CoA reductase genetics Advisory Committee has advised inhibitors (statins), and the risk increases that the package inserts for irinotecan be with higher doses and concomitant use of updated. A genotyping test for UGT1A1*6 certain CYP3A4 inhibitors such as gemfi- and UGT1A1*28 variants is available at brozil and ciclosporin (1). the National Cancer Centre. HPS2-THRIVE is a double blind, rand- The era of genomics is producing an omized placebo controlled study to abundance of information about genetic assess the long term clinical effects of variation within and across populations. increasing HDL-cholesterol with ER As studies gradually dissect the informa- niacin/laropiprant in 25 000 patients with tion and establish linkages between pre-existing atherosclerotic vascular genetic variations and response to drugs, disease who were receiving simvastatin they add to a body of knowledge that will 40 mg daily (plus ezetimibe 10 mg daily, help physicians tailor therapies for the where indicated). This study, sponsored individual characteristics of their patients. by Oxford University, is currently con- ducted in China, Scandinavia and United Reference: Health Sciences Authority, 19 Kingdom. The study is currently in April 2010 at http://www.hsa.gov.sg progress and is expected to be completed in 2012.
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HSA has not received any local reports of pared to those taking carbidopa/levo- rhabdomyolysis or myopathy associated dopa. with Tredaptive¨ or in combination with statins to date. Physicians prescribing the Reference: FDA Safety Announcement dated 31 March 2010 at http://www.fda.gov combined therapy of Tredaptive¨ with statins are advised to carefully monitor patients for any signs and symptoms of Becaplermin contraindicated muscle pain, tenderness, or weakness, in cancer patients particularly during the initial months of therapy and when dosage of either drug European Union — Following a review is increased. of the available data on a possible risk of cancer in patients using becaplermin Reference: Health Sciences Authority, 19 April (Regranex¨), the European Medicines 2010 at http://www.hsa.gov.sg Agency has concluded that the medicine must not be used in patients who have Entacapone/carbidopa/ any form of cancer. A similar restriction previously applied but only for patients levodopa: prostate cancer who had a skin cancer close to the area United States of America —The Food where the gel was to be applied. and Drug Administration (FDA) is evaluat- ing clinical trial data that may suggest that Regranex¨ is a gel that is used together patients taking Entacapone/carbidopa/ with other wound care measures to treat levodopa (Stalevo¨), a Parkinson dis- long-term skin ulcers in people with ease medication, may be at increased diabetes. risk for developing prostate cancer. At this time, FDA’s review of Stalevo¨ is ongoing The review, conducted by the Agency’s and no new conclusions or recommenda- Committee for Medicinal Products for tions about the use of this drug have Human Use (CHMP), was initiated at the been made. request of the European Commission because of reports of cancer developing Entacapone is also available as a single- in a small number of patients using the ingredient product sold under the brand gel. The Committee noted that while there name Comtan¨. Both Stalevo¨ and was no firm evidence of a link between Comtan¨ are used to treat symptoms of Regranex¨ and cancer there was also Parkinson disease. not enough evidence to rule out such a link. The data being reviewed are from a long- References: term clinical trial called Stalevo¨ Reduc- tion in Dyskinesia Evaluation Ð Parkin- 1. Press Release at http://www.ema. son’s Disease (STRIDE-PD). STRIDE-PD europa.eu. evaluated the time to onset of dyskinesia 2. Question and Answer document at http:// (difficulty controlling voluntary movement) www.ema.europa.eu/humandocs/PDFs/ in patients with Parkinson disease taking EPAR/Regranex/31245209en.pdf. Stalevo compared to those taking only carbidopa/levodopa. An unexpected 3. European Public Assessment Report finding in the trial was that a greater (EPAR) at http://www.emea.europa.eu/ number of patients taking Stalevo¨ were humandocs/Humans/EPAR/regranex/ observed to have prostate cancer com- regranex.htm
109 Safety and Efficacy Issues WHO Drug Information Vol. 24, No. 2, 2010
Panitumumab: ¥ Serious infusion-related reactions are hypersensitivity reactions unpredictable and can occur suddenly. Panitumumab should be permanently United Kingdom — Healthcare profes- discontinued if a severe or life threaten- sionals have been informed of new ing reaction occurs. reports of serious hypersensitivity reac- tions, including anaphylaxis, in patients ¥ In patients experiencing a mild or receiving panitumumab (Vectibix¨), some moderate infusion-related reaction, the of which have been fatal. Panitumumab is infusion rate should be reduced for the associated with mild to moderate infu- duration of that infusion. It is recom- sion-related reactions, including chills, mended to maintain this lower rate in all dyspnoea, flushing, hypertension, hypo- subsequent infusions. tension, pyrexia, tachycardia and vomit- ing in about 3% of patients. However, Hypersensitivity reactions occurring more severe infusion reactions, including than 24 hours after infusion have also anaphylaxis, angioedema, bronchos- been reported. Patients should be pasm, cardio-respiratory arrest and warned of the possibility of a late onset hypotension requiring treatment may reaction and instructed to contact their occur and are potentially life-threatening. physician if symptoms of a hypersensitiv- ity reaction occur. The product Information has been up- dated to highlight the following: Reference: Communication from the manu- facturer dated 16 April 2010. Healthcare ¥ Panitumumab is contraindicated in Products Regulatory Agency (MHRA) at http:// patients with a history of severe or life www.mhra.gov.uk threatening hypersensitivity reactions to panitumumab;
110 WHO Drug Information Vol. 24, No. 2, 2010
Regulatory Action and News
Ceftobiprole medocaril: ing authorizations for bufexamac-contain- discontinuation of sale ing medicines be revoked. Canada — The manufacturer of cefto- The CHMP recommendations follow a biprole medocaril for injection (Zeftera¨) scientific review which identified a high is discontinuing sale as of 16 April 2010. risk of sometimes serious contact allergic reactions with bufexamac. The risk was Ceftobiprole medocaril is currently ap- even higher in patients with pre-disposing proved for the treatment of complicated conditions such as certain forms of skin and skin structure infections includ- eczema for which bufexamac is fre- ing non-limb-threatening diabetic foot quently prescribed. Furthermore, the infections without concomitant osteomy- allergic reactions caused by bufexamac elitis caused by Enterobacter cloacae, are very similar to the disease being Escherichia coli, Klebsiella pneumoniae, treated which may lead to a potential Proteus mirabilis, Staphylococcus aureus delay in the correct diagnosis and treat- (including methicillin-resistant isolates) ment of patients. It is also likely that the and Streptococcus pyogenes. difficulty to differentiate between a treat- ment failure and an allergic reaction has This action is being taken by the manu- led to the cases of contact allergic reac- facturer in response to recent regulatory tion being underreported. In addition to recommendations in the United States this, the data to support the effectiveness and European Union to not approve of bufexamac are very limited. Zeftera¨ for this indication due to con- cerns regarding the conduct of clinical Bufexamac is a nonsteroidal anti- trials. inflammatory drug (NSAID) used in topical formulations to treat dermatologi- Prescribers are advised: cal diseases (eczema and dermatitis) and proctological conditions (haemorrhoids ¥ To allow all patients on the product to and anal fissure). Bufexamac-containing complete their course of therapy. medicines have been available in EU Member States since the 1970s. ¥ Not to initiate treatment of new patients. Reference: Press Release dated 22 April Reference: Communication dated 9 April 2010. EMA/246395/2010 at http:// 2010 from Janssen-Ortho Inc. at http:// www.ema.europa.eu www.hc-sc.gc.ca Rosiglitazone: authorization Bufexamac : revocation of suspended marketing authorization Saudi Arabia — The Saudi Food and European Union — The European Drug Authority (SFDA) has reviewed the Medicines Agency’s Committee for safety of rosiglitazone (Avandia¨) which Medicinal Products for Human Use is used in the treatment of type 2 diabetes (CHMP) has recommended that market- mellitus. Based on growing evidence from
111 Regulatory Action and News WHO Drug Information Vol. 24, No. 2, 2010
clinical trial meta-analyses and observa- operable glioma. The company has been tional studies indicating serious cardio- unable to demonstrate to the Committee vascular adverse events associated with that its main study provides clear evi- the use of rosiglitazone, the Advisory dence of a clinically meaningful benefit in Committee for Pharmacovigilance in relation to risk. Saudi Arabia has concluded that: Reference: Press Release dated 11 March 2010. EMA/151854/2010 at http://www.ema. ¥ The risk of using rosiglitazone out- europa.eu weighs its benefit, in particular with regard to cardiovascular events includ- ing myocardial infarction and congestive Albinterferon alfa-2b: heart failure, and increased risk of withdrawal of marketing fractures. authorization application ¥ Safer alternatives which could be used European Union — The European for treatment of diabetes mellitus are Medicines Agency has been formally available in Saudi Arabia. notified by the manufacturer of its deci- sion to withdraw its application for a Consequently, the Committee for Medici- centralized marketing authorization for nal Products Registration decided to the medicine albinterferon alfa-2b suspend marketing authorization for a (Joulferon¨), 900 mg powder and solvent period of six months during which the for solution for injection in pre-filled pen manufacturer has the opportunity to and vials. provide the SFDA with evidence as to why rosiglitazone and combination This medicine was intended to be used in products containing rosiglitazone should combination with ribavirin for the treat- not be permanently removed from the ment of adults with chronic hepatitis C Saudi Arabian market. Rosiglitazone virus infection who have compensated containing products marketed in Saudi liver disease and have not been previ- Arabia include Avandia¨, Avandamet¨ ously treated with interferon alfa. and Avandaryl¨ The decision to withdraw the application was based on preliminary comments of Reference: Saudi Food and Drug Authority Committee for Medicinal Products for Advisory, 17 March 2010 http://dpic.sfda. gov.sa Human Use (CHMP) that additional new data would be requested for a favourable opinion. These could not be generated Sitimagene ceradenovec: within the timeframe allowed in the withdrawal of marketing centralized procedure. authorization application Reference: Press Release dated 19 April European Union — The European 2010. EMA/249301/2010 at http:// Medicines Agency has been formally www.ema.europa.eu notified by the manufacturer of its deci- sion to withdraw its application for a Docetaxel: withdrawal of centralized marketing authorization for marketing authorization the advanced therapy medicinal product application sitimagene ceradenovec (Cerepro¨). European Union — The European Cerepro received an orphan designation Medicines Agency has been formally on 6 February 2002 and was intended for notified by the manufacturer of its deci- the treatment of patients with high-grade sion to withdraw its application for a
112 WHO Drug Information Vol. 24, No. 2, 2010 Regulatory Action and News
centralized marketing authorization for that its source is unclear. The Committee the medicinal product docetaxel (do- has therefore requested the manufacturer cetaxel Mylan¨), 10 mg/ml powder and to provide further information as a matter solvent for solution for infusion. of urgency. The medicine was developed as a ge- Reference: Press Release dated 22 March neric to be used for breast cancer, non 2010. EMA/189350/2010 at http://www.ema. small cell lung cancer, prostate cancer, europa.eu gastric adenocarcinoma and head and neck cancer. Paediatric Medicines Regulators Network The application was withdrawn because the Committee for Medicinal Products for World Health Organization — Only a Human Use (CHMP) considers that the limited number of medicines that are data provided do not allow it to conclude currently available have been clinically on a positive benefit-risk balance. evaluated for their safety and efficacy in the paediatric population. The lack of Reference: Press Release dated 15 March suitable paediatric medicines, combined 2010. EMA/164498/2010 at http://www.ema. with an inconsistent regulatory frame- europa.eu works poses significant challenges in ensuring access to medicines for a Rotarix® oral vaccine: particularly vulnerable patient population. new information There is thus a significant need for research and development on paediatric European Union — The European medicines, biological products and Medicines Agency is aware of new vaccines. information reported by the manufacturer of Rotarix¨ relating to the unexpected Following recommendations made at the presence of DNA of a non-disease 13th International Conference of Drug causing viral strain in batches of the oral Regulatory Authorities (ICDRA) in 2008, vaccine. Through its own tests, the and as part of the World Health Organiza- company has confirmed the finding of tion’s Better Medicines for Children DNA originating from porcine circovirus initiative, a Paediatric Medicines Regula- type 1. This virus is commonly found in tors Network (PMRN) has been estab- certain meat and other food products, and lished by national medicines regulatory is not known to cause disease in either authorities. The first meeting of the animals or humans. PMRN was held at WHO, Geneva, in February 2010. An initial review by the Agency’s Commit- tee for Medicinal Products for Human Use The objectives of the meeting were to: (CHMP) considered these findings on 17 March 2010 and concluded that no action ¥ Define PMRN structure, aims and was necessary at this point. The Commit- potential role in the development of tee stresses that the findings do not international recommendations on present a public health threat. It also paediatric medicines. noted that there have been no safety signals reported with the vaccine that ¥ To review the current regulatory, scien- suggest otherwise. tific and ethical standards for paediatric medicines and to determine their It is nonetheless clear that viral DNA applicability to developing country should not be present in the vaccine and settings.
113 Regulatory Action and News WHO Drug Information Vol. 24, No. 2, 2010
Background documents concerning The objectives of the PMRN are to: clinical trials, ethics and international guidelines on research in the paediatric ¥ Provide a forum for discussion. population formed the basis for discus- sion. During the meeting, the following ¥ Build awareness on paediatric medi- topics were considered: cines regulatory considerations and work towards consensus on regulatory ¥ Common standards for registration of standards for paediatric medicines. paediatric medicines. ¥ Promote capacity for development and ¥ Mechanisms for information sharing formulation of paediatric medicines. between national medicines regulatory authorities. ¥ Support appropriate conduct of paediat- ric clinical trials, including establishing ¥ Training and capacity development in links with existing networks. Facilitate developing countries (e.g., IT infrastruc- scientific and ethical review of clinical ture, expertise in the review of clinical trials for the development of paediatric trials and marketing applications). medicines.
As a first step, participants agreed to: ¥ Strengthen licensing (approval) systems for paediatric medicines. 1. Support establishment of the PMRN. ¥ Promote evidence-based recommenda- 2. Promote effective communication tions and advice on all aspects of mechanisms. medicines for children, including dosage forms, excipients and delivery devices. 3. Work with WHO in assisting national medicines regulatory authorities world- ¥ Provide a forum for promoting paediatric wide on matters concerning regulation of pharmacovigilance. paediatric medicines. ¥ Collaborate with other networks and In addition, there was agreement on the nongovernmental organizations. need for capacity building for effective regulation of medicines for children. WHO References: http://www.who.int/childmedi- will provide the PMRN Secretariat. cines/paediatric_regulators/meetings/en/ Interested national medicines regulatory index.html authorities are welcome to participate in the PMRN.
114 WHO Drug Information Vol. 24, No. 2, 2010
Consultation Document
The International Pharmacopoeia
Emtricitabini et tenofoviri compressi Emtricitabine and tenofovir tablets
Draft proposal for The International Pharmacopoeia (March 2010). Please address any comments to Quality Assurance and Safety: Medicines, World Health Organization, 1211 Geneva 27, Switzer- land. Fax +41227914730 or e-mail to mendyc©who.int. A sub- scriber mailing list is now available to speed up consultation. For more information please contact bonnyw©who.int.
Category. Antiretroviral (Nucleoside/Nucleotide Reverse Transcriptase Inhibitor).
Storage. Emtricitabine and tenofovir tablets should be kept in a tightly closed con- tainer.
Additional information. Strength in the current WHO Model list of essential medi- cines: 200 mg Emtricitabine and 300 mg Tenofovir disoproxil fumarate.
REQUIREMENTS
Comply with the monograph for ‘Tablets’.
Definition. Emtricitabine and tenofovir tablets contain Emtricitabine and Tenofovir disoproxil fumarate. They contain not less than 90.0% and not more than 110.0% of the amounts of emtricitabine (C8H10FN3O3S) and tenofovir disoproxil fumarate (C19H30N5O10P,C 4H4O4) stated on the label. Manufacture. The manufacturing process and the product packaging are designed and controlled so as to minimize the moisture content of the tablets. They ensure that, if tested, the tablets would comply with a water content limit of not more than 60 mg/g when determined as described under 2.8 Determination of water by the Karl Fischer method, Method A, using about 0.5 g of the powdered tablets.
Identity tests
Either tests A and B or test C may be applied.
A. Carry out test A.1 or, where UV detection is not available, test A.2.
A.1 Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R6 as the coating substance and a mixture of 90 volumes of dichloromethane
115 Consultation Document WHO Drug Information Vol. 24, No. 2, 2010
R, 10 volumes of methanol R and 3 volumes of glacial acetic acid R as the mobile phase. Apply separately to the plate 5 l of each of the following solutions. For solution (A) disperse a quantity of powdered tablets in methanol R to obtain 5 mg of Emtricitabine per ml, filter and use the filtrate. For solution (B) use 5 mg of emtricitabine RS per ml in methanol R. For solution (C) use 7.5 mg of tenofovir diso- proxil fumarate RS per ml in methanol R. After removing the plate from the chromato- graphic chamber, allow it to dry exhaustively in air or in a current of air. Examine the chromatogram in ultraviolet light (254 nm).
One of the two principal spots obtained with solution A corresponds in position, ap- pearance and intensity with that obtained with solution B and the other one corre- sponds with that obtained with solution C.
A.2 Carry out the test as described under 1.14.1 Thin-layer chromatography, using the conditions described above under test A.1 but using silica gel R5 as the coating substance. Stain the plate with iodine vapour and examine the chromatogram in daylight.
One of the two principal spots obtained with solution A corresponds in position, ap- pearance and intensity with that obtained with solution B and the other one corre- sponds with that obtained with solution C.
B. Carry out test B.1. or, where UV detection is not available, test B.2.
B.1 Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R6 as the coating substance and a mixture of 50 volumes of heptane R, 30 volumes of glacial acetic acid R and 20 volumes of dichloromethane R as the mobile phase. Apply separately to the plate 5 l of each of the following solutions. For solution (A) disperse a quantity of powdered tablets in ethanol R to obtain 10 mg of Tenofovir disoproxil fumarate per ml, filter and use the filtrate. For solution (B) use 2 mg of fumaric acid R per ml of ethanol R. Develop the plate in an unsaturated tank over a path of 10 cm. After removing the plate from the chromatographic chamber, allow it to dry exhaustively in air or in a current of air. Examine the chromatogram in ultraviolet light (254 nm).
One of the spots obtained with solution A corresponds in position, appearance and intensity with that obtained with solution B.
B.2 Carry out the test as described under 1.14.1 Thin-layer chromatography, using the conditions described above under test B.1 but using silica gel R5 as the coating substance. Spray lightly with a 16 g/l solution of potassium permanganate R and examine the chromatogram in daylight.
One of the spots obtained with solution A corresponds in position, appearance and intensity with that obtained with solution B.
C. See the test described under Assay. The retention times of the principal peaks in the chromatogram obtained with the test solution are similar to those due to emtricitabine, tenofovir disoproxil and to fumarate in the chromatogram obtained with the reference solution.
116 WHO Drug Information Vol. 24, No. 2, 2010 Consultation Document
Dissolution
Carry out the test as described under 5.5 Dissolution test for solid oral dosage forms, using as the dissolution medium, 900 ml of 0.01 M hydrochloric acid, and rotating the paddle at 50 revolutions per minute. At 45 minutes withdraw a sample of 10 ml of the medium and filter. Allow the filtered sample to cool to room temperature and dilute if necessary [solution (1)]. Prepare solution (2) containing 0.22 mg/ml of emtricitabine RS and 0.33 mg/ml of tenofovir disoproxil fumarate RS in the dissolution medium.
Determine the content of emtricitabine (C8H10FN3O3S) and tenofovir disoproxil fuma- rate (C19H30N5O10P,C 4H4O4) as described under Assay using solution (1) and solution (2).
For each of the six tablets tested, calculate the total amount of emtricitabine
(C8H10FN3O3S) and tenofovir disoproxil fumarate (C19H30N5O10P,C 4H4O4) in the medium from the results obtained. The amount in solution for each tablet is not less than 75% of the amount stated on the label. If the amount obtained for one of the six tablets is less than 75%, repeat the test using a further six tablets; the average amount for all 12 tablets tested is not less than 70% and the amount obtained for no tablet is less than 55%.
Assay
Carry out the test as described under 1.14.4 High-performance liquid chromatography, using a stainless steel column (25 cm x 4.6 mm) packed with base-deactivated parti- cles of silica gel the surface of which has been modified with chemically bonded octadecylsilyl groups (5 µm). (Hypersil BDS column).
The mobile phases for gradient elution consist of a mixture of Mobile phase A and Mobile phase B, using the following conditions:
Mobile phase A: 5 volumes of phosphate solution and 95 volumes of water R.
Mobile phase B: 70 volumes of acetonitrile R, 5 volumes of phosphate solution and 25 volumes of water R.
Prepare the phosphate solution by dissolving 27.22 g of potassium dihydrogen phos- phate R in 1000 ml of water R.
Time Mobile phase A Mobile phase B Comments (min) (% v/v) (% v/v)
0 Ð 9 93 7 Isocratic 9 Ð 15 93 to 0 7 to 100 Linear gradient 15 Ð 19 0 100 Isocratic 19 Ð 19.1 0 to 93 100 to 7 Return to initial composition 19.1Ð30 93 7 Re-equilibration
After preparation, keep the solutions at about 6 °C, or use an injector with cooling. Prepare the following solutions using a mixture of 20 volumes of acetonitrile R and 80
117 Consultation Document WHO Drug Information Vol. 24, No. 2, 2010
volumes of water R as a diluent. For solution (1) weigh and powder 20 tablets. Dis- perse a quantity of the powder containing about 10 mg of Tenofovir disoproxil fuma- rate, accurately weighed in 100 ml of the diluent and filter. For solution (2) dissolve quantities of tenofovir disoproxil fumarate RS and emtricitabine RS in the diluent to obtain a concentration of 0.1 mg/ml and 66.7 µg/ml of tenofovir disoproxil fumarate and emtricitabine, respectively. If necessary, adapt the concentration of solution (2) according to the ratio of Emtricitabine and Tenofovir disoproxil fumarate in the tablets. For solution (3) use 0.02 mg of fumaric acid R per ml of water R.
Operate with a flow rate of 1.0 ml per minute. As a detector use an ultraviolet spectro- photometer set at a wavelength of 280 nm.
Maintain the column temperature at 35 °C.
Inject alternatively 20 µl each of solutions (1), (2) and (3).
The test is not valid unless in the chromatograms obtained with solutions (1) and (2) three well-separated peaks are shown.
Measure the areas of the peak responses obtained in the chromatograms from solu- tions (1) and (2), and calculate the content of emtricitabine (C8H10FN3O3S) and tenofo- vir disoproxil fumarate (C19H30N5O10P,C 4H4O4) in the tablets.
Sulfadoxine and pyrimethamine tablets
Revised draft proposal for The International Pharmacopoeia (March 2010). Please address any comments to Quality Assur- ance and Safety: Medicines, World Health Organization, 1211 Ge- neva 27, Switzerland. Fax +41227914730 or e-mail to mendyc©who.int. A subscriber mailing list is now available to speed up consultation. For more information please contact bonnyw©who.int.
Category. Antimalarial.
Storage. Sulfadoxine and pyrimethamine tablets should be kept in a well-closed container, protected from light.
Additional information. Strength in the current WHO Model list of essential medi- cines: 500 mg sulfadoxine and 25 mg pyrimethamine.
Strength in the current WHO Model list of essential medicines for children: 500 mg sulfadoxine and 25 mg pyrimethamine.
REQUIREMENTS
Comply with the monograph for ‘Tablets’.
118 WHO Drug Information Vol. 24, No. 2, 2010 Consultation Document
Definition. Sulfadoxine and pyrimethamine tablets contain Sulfadoxine and Pyrimeth- amine. They contain not less than 90.0% and not more than 110.0% of the amounts of sulfadoxine (C12H14N4O4S) and pyrimethamine (C12H13ClN4) stated on the label. Identity tests
A. Carry out test A.1 or, where UV detection is not available, test A.2. A.1 Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R6 as the coating substance and a mixture of 75 volumes of ethylacetate R, 25 volumes of methanol R and 1 volume of glacial acetic acid R as the mobile phase. Apply separately to the plate 10 µl of each of the following two solutions in methanol R. For solution (A) shake a quantity of the powdered tablets containing about 100 mg of sulfadoxine for 5 minutes with 20 ml, filter, and use the filtrate. For solution (B) use 5 mg of sulfadoxine RS and 0.25 mg of pyrimethamine RS per ml. After removing the plate from the chromatographic chamber, allow it to dry in a current of air and examine the chromatogram in ultraviolet light (254 nm). The two principal spots obtained with solution A correspond in position, appearance and intensity to those obtained with solution B. A.2 Carry out the test as described under 1.14.1 Thin-layer chromatography, using the conditions described above under test A.1 but using silica gel R5 as the coating substance. Dip the plate in modified Dragendorff reagent TS. Examine the chromato- gram in daylight.
The two principal spots obtained with solution A correspond in position, appearance, and intensity to those obtained with solution B (the spot for pyrimethamine is faintly visible).
B. See the test described under Assay. The retention times of the two principal peaks in the chromatogram obtained with solution (1) are similar to those in the chromato- gram obtained with solution (4).
Dissolution
Carry out the test as described under 5.5 Dissolution test for solid oral dosage forms, using as the dissolution medium 1000 ml of hydrochloric acid (0.1 mol/l) VS and rotating the paddle at 75 revolutions per minute. At 30 minutes withdraw a sample of about 5 ml of the medium through an in-line filter and use the filtrate. Determine the content of sulfadoxine (C12H14N4O4S) and pyrimethamine (C12H13ClN4) in the filtrate according to the method as described under Assay and preparing solution (4) under Assay as follows: transfer 10 ml of solution (2) and 2 ml of solution (3) to a 20-ml volumetric flask and make up to volume with hydrochloric acid (0.1 mol/l) VS.
For each of the six tablets, calculate the total amount of sulfadoxine (C12H14N4O4S) and pyrimethamine (C12H13ClN4) in the medium from the results obtained. For both substances, the amount in solution for each tablet is not less than 80% of the amount declared on the label. For either substance, if the amount obtained for one of the six tablets is less than 80%, repeat the test using a further six tablets; the average amount for all 12 tablets tested is not less than 75% and the amount obtained for no tablet is less than 60%.
119 Consultation Document WHO Drug Information Vol. 24, No. 2, 2010
Sulfadoxine-related substances
Carry out the test as described under 1.14.4 High-performance liquid chromatography, using a stainless steel column (25 cm x 4.6 mm) packed with particles of silica gel, the surface of which has been modified with chemically bonded octadecylsilyl groups (5 µm). (Phenomenex Luna¨ is suitable.)
As the mobile phase, use a solution prepared as follows: dissolve 10 ml of glacial acetic acid R and 0.5 ml of triethylamine R in about 800 ml of water R, dilute to 1000 ml and adjust the pH to 4.2 by adding sodium hydroxide (~400 g/l) TS. Mix 850 ml of this solution with 120 ml of acetonitrile R and 30 ml of methanol R.
Use solutions (1) and (2) as described under Assay. For solution (3) transfer 1 ml of solution (1) as prepared for the assay, to a 200-ml volumetric flask and make up to volume with the mobile phase.
For solution (4) prepare a solution of sulfamethoxazole RS in a mixture of equal volumes of acetonitrile R and the mobile phase to obtain a concentration of approxi- mately 0.5 mg/ml. Transfer 2 ml of this solution and 2 ml of solution (2) to a 20-ml volumetric flask and make up to volume with the mobile phase.
Operate with a flow rate of 2 ml per minute. As a detector use an ultraviolet spectro- photometer set at a wavelength of about 270 nm.
Inject separately 20 µl each of solutions (1), (3) and (4). Record the chromatograms for about 3 times the retention time of sulfadoxine (to ensure that pyrimethamine is eluted).
In the chromatogram obtained with solution (1), the following impurity peaks, if present, are eluted at the following relative retention with reference to sulfadoxine (retention time about 18 minutes): impurity A (sulfanilamide) about 0.1, impurity B about 0.2, impurity D about 0.3, impurity C about 1.4 and pyrimethamine about 2.7. The test is not valid unless in the chromatogram obtained with solution (4), the re- solution between the peaks due to sulfadoxine and to sulfamethoxazole (with relative retention about 1.1 with reference to sulfadoxine) is at least 2.
In the chromatogram obtained with solution (1) the area of any peak, other than the peaks due to sulfadoxine and to pyrimethamine, is not greater than the area of the peak due to sulfadoxine in the chromatogram obtained with solution (3) (0.5%). The sum of the areas of all peaks, other than the peaks due to sulfadoxine and pyrimeth- amine, is not greater than twice the area of the principal peak in the chromatogram obtained with solution (3) (1.0%). Disregard any peak with an area less than 0.1 times the area of the principal peak in the chromatogram obtained with solution (3) (0.05%).
Assay
Carry out the test as described under 1.14.4 High-performance liquid chromatography, using a stainless steel column (25 cm x 4.6 mm) packed with particles of silica gel, the surface of which has been modified with chemically bonded octadecylsilyl groups (5 µm). (Phenomenex Luna¨ is suitable.)
120 WHO Drug Information Vol. 24, No. 2, 2010 Consultation Document
As the mobile phase, use a solution prepared as follows: dissolve 10 ml of glacial acetic acid R and 0.5 ml of triethylamine R in about 800 ml of water R, dilute to 1000 ml and adjust the pH to 4.2 by adding sodium hydroxide (~400 g/l) TS. Mix 800 ml of this solution with 200 ml of acetonitrile R.
For solution (1) weigh and powder 20 tablets, and transfer a quantity of the powder containing about 0.50 g of Sulfadoxine, accurately weighed, into a 200-ml volumetric flask. Add about 70 ml of acetonitrile R and sonicate for 10 minutes. Allow to cool to room temperature, make up to volume using the mobile phase and sonicate for 10 minutes. Dilute 5 ml of this solution to 25 ml with mobile phase and filter a portion of this solution through a 0.45-m filter, discarding the first few ml of the filtered solution. For solution (2), transfer 25 mg of sulfadoxine RS, accurately weighed, to a 25-ml volumetric flask, add about 10 ml of acetonitrile R, sonicate until dissolved and dilute to volume with the mobile phase. For solution (3), transfer 25 mg of pyrimethamine RS, accurately weighed, to a 100-ml volumetric flask, add about 35 ml of acetonitrile R, sonicate until dissolved and dilute to volume with the mobile phase. For solution (4) transfer 10 ml of solution (2) and 2 ml of solution (3) to a 20-ml volumetric flask and make up to volume with the mobile phase.
Operate with a flow rate of 2 ml per minute. As a detector use an ultraviolet spectro- photometer set at a wavelength of about 227 nm.
Inject 20 µl of solution (4). The assay is not valid unless the resolution between the peaks due to sulfadoxine and to pyrimethamine, eluting in this order, is at least 5. The run time for the analyses is not less than 25 minutes.
Inject alternately 20 µl each of solutions (1) and (4).
Measure the areas of the peak responses obtained in the chromatograms from solutions (1) and (4), and calculate the content of sulfadoxine, C12H14N4O4S, and pyrimethamine, C12H13ClN4, in the tablets. Impurities
The following list of known and potential impurities that have been shown to be controlled by the tests in this monograph is given for information.
A. sulfanilamide
121 Consultation Document WHO Drug Information Vol. 24, No. 2, 2010
B. N1-(6-hydroxy-5-methoxy-4-pyrimidinyl) sulfanilamide
C. 4-(p-acetamido-benzolsulfonamido)-5,6-dimethoxy-pyrimidine
D. 4-Amino-5,6-dimethoxy-pyrimidine.
[Note from the Secretariat: structures and chemical names for related substances to be confirmed]
122 WHO Drug Information Vol. 24, No. 2, 2010 Recent Publications, Information and Events
Life-saving antivenoms: current details on 612 different paediatric guidelines and database formulations of 240 medicines selected from the WHO Model List of Essential World Health Organizaton — Snake Medicines for Children, as well as thera- bites kill at least 100 000 people a year peutic food, vitamin and mineral supple- and for countries facing a shortage of ments to treat major childhood illnesses appropriate antivenoms, access to and and diseases. information about available antivenoms is WHO recommends that medicines for increasingly important. WHO has pub- children should be provided as flexible, lished new guidelines for the production, solid, oral dosage forms that can be regulation and control of snake anti- administered in a liquid when given to a venoms and a provides a dedicated web sick child. Liquid formulations are more site with details on where the venomous expensive to buy compared with snakes are located, what they look like, dispersible tablets and are also more which antivenoms are appropriate, and costly to store, package, and transport where they can be obtained. safely. The guidelines provide details for the Reference: World Health Organizaton. http:// production, regulation and control of www.who.int/medicines snake antivenoms while the online database identifies venomous snake species (including information and colour Multidrug and drug- photographs) for which availability of resistant tuberculosis appropriate antivenoms should be World Health Organization — A new, prioritized. global WHO report on extensively drug- Reference: World Health Organizaton. http:// resistant (M/XDR-TB) tuberculosis www.who.int/bloodproducts/snakeantivenoms examines the trends, progress and challenges in treating these forms of Sources of paediatric tuberculosis. In some parts of the world, medicines one in four people with tuberculosis becomes ill with a form of the disease World Health Organizaton — To ad- that can no longer be treated with stand- dress problems associated with produc- ard drugs. Drug-resistant tuberculosis is tion and provision of paediatric medi- now at record levels. cines, especially in the developing world, the United Nations Children’s Fund In Multidrug and Extensively Drug- (UNICEF) and WHO have released a new Resistant Tuberculosis: 2010 Global publication that lists medicines formulated Report on Surveillance and Response, it for children to help doctors and organiza- is estimated that 440 000 people had tions obtain some of the 240 essential MDR-TB worldwide in 2008 and that a medicines that can save the lives of third of them died. Tuberculosis pro- children. grammes face tremendous challenges in reducing MDR-TB rates. The report The second edition of Sources and Prices presents drug resistance data from 114 of Selected Medicines for Children offers countries and updated information from
123 Recent Publications, Information and Events WHO Drug Information Vol. 24, No. 2, 2010
35 of them. Despite the growing under- regions) and in epidemics and complex standing of the magnitude and trends in emergency situations. drug-resistant TB, major gaps remain in geographical areas covered. Since 1994, This second edition introduces a fifth only 59% of all countries globally have artemisinin combination therapy (ACT) to been able to collect high quality repre- the four already recommended. Further- sentative data on drug resistance. There more, the guidelines recommend is an urgent need to obtain information, parasitological confirmation of diagnosis particularly from Africa and those high in all patients suspected of having malaria MDR-TB burden countries where data before treatment.The move towards have never been reported: Bangladesh, universal diagnostic testing of malaria is a Belarus, Kyrgyzstan, Nigeria and Paki- critical step forward in the fight against stan. Moreover, countries need to expand malaria as it will allow for the targeted use the scope of their surveys to cover entire of ACTs for those who actually have populations, repeat surveys are needed malaria. to better understand trends in drug resistance and countries need to move Reference: Guidelines for the Treatment of towards adopting systematic continuous Malaria. Second Edition. at http://www.who.int/ surveillance. publications/en Reference: Multidrug and Extensively Drug- Where there are no Resistant Tuberculosis: 2010 Global Report on Surveillance and Response. March 2010 pharmacists at http://www.who.int//publications/en A new Book, Where There Are No Phar- Guidelines for the treatment macists, has recently been launched by Health Action International Asia-Pacific of malaria (HAIAP). World Health Organization — Guide- lines for the treatment of malaria provides Where There Are No Pharmacists is evidence-based and up-to-date recom- about managing medicines. It explains mendations for countries on malaria in easy English how to order, store, diagnosis and treatment. prepare, dispense and use medicines safely and effectively. This book provides The guidelines cover the diagnosis and advice on all these aspects for people treatment of uncomplicated and severe working with medicines as well as infor- malaria caused by all types of malaria, mation to help communities benefit from including in special groups (young chil- the use of medicines. dren, pregnant women, HIV /AIDS), in travellers (from non-malaria endemic Reference: Health Action International Asia- Pacific at http://www.twnside.org.sg/
124 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103
International Nonproprietary Names for Pharmaceutical Substances (INN)
Notice is hereby given that, in accordance with article 3 of the Procedure for the Selection of Recommended International Nonproprietary Names for Pharmaceutical Substances, the names given in the list on the following pages are under consideration by the World Health Organization as Proposed International Nonproprietary Names. The inclusion of a name in the lists of Proposed 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). The statements indicating action and use are based largely on information supplied by the manufacturer. This information is merely meant to provide an indication of the potential use of new substances at the time they are accorded Proposed International Nonproprietary Names. WHO is not in a position either to uphold these statements or to comment on the efficacy of the action claimed. Because of their provisional nature, these descriptors will neither be revised nor included in the Cumulative Lists of INNs.
Dénominations communes internationales des Substances pharmaceutiques (DCI) Il est notifié que, conformément aux dispositions de l'article 3 de la Procédure à suivre en vue du choix de Dénominations communes internationales recommandées pour les Substances pharmaceutiques les dénominations ci-dessous sont mises à l'étude par l'Organisation mondiale de la Santé en tant que dénominations communes internationales proposées. L'inclusion d'une dénomination dans les listes de DCI proposées n'implique aucune recommandation en vue de l'utilisation de la substance correspondante en médecine ou en pharmacie.
On trouvera d'autres listes de Dénominations communes internationales proposées (1–101) et recommandées (1–62) dans la Liste récapitulative No. 13, 2009 (disponible sur CD-ROM seulement). Les mentions indiquant les propriétés et les indications des substances sont fondées sur les renseignements communiqués par le fabricant. Elles ne visent qu'à donner une idée de l'utilisation potentielle des nouvelles substances au moment où elles sont l'objet de propositions de DCI. L'OMS n'est pas en mesure de confirmer ces déclarations ni de faire de commentaires sur l'efficacité du mode d'action ainsi décrit. En raison de leur caractère provisoire, ces informations ne figureront pas dans les listes récapitulatives de DCI.
Denominaciones Comunes Internacionales para las Sustancias Farmacéuticas (DCI) De conformidad con lo que dispone el párrafo 3 del "Procedimiento de Selección de Denominaciones Comunes Internacionales Recomendadas para las Sustancias Farmacéuticas", se comunica por el presente anuncio que las denominaciones detalladas en las páginas siguientes están sometidas a estudio por la Organización Mundial de La Salud como Denominaciones Comunes Internacionales Propuestas. La inclusión de una denominación en las listas de las DCI Propuestas 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). Las indicaciones sobre acción y uso que aparecen se basan principalmente en la información facilitada por los fabricantes. Esta información tiene por objeto dar una idea únicamente de las posibilidades de aplicación de las nuevas sustancias a las que se asigna una DCI Propuesta. La OMS no está facultada para respaldar esas indicaciones ni para formular comentarios sobre la eficacia de la acción que se atribuye al producto. Debido a su carácter provisional, esos datos descriptivos no deben incluirse en las listas recapitulativas de DCI.
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Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010
Proposed International Nonproprietary Names: List 103 Comments on, or formal objections to, the proposed names may be forwarded by any person to the INN Programme of the World Health Organization within four months of the date of their publication in WHO Drug Information, i.e., for List 103 Proposed INN not later than 31 October 2010. Publication date: 30 June 2010
Dénominations communes internationales proposées: Liste 103 Des observations ou des objections formelles à l'égard des dénominations proposées peuvent être adressées par toute personne au Programme des Dénominations communes internationales de l'Organisation mondiale de la Santé dans un délai de quatre mois à compter de la date de leur publication dans WHO Drug Information, c'est à dire pour la Liste 103 de DCI Proposées le 31 octobre 2010 au plus tard. Date de publication: 30 juin 2010
Denominaciones Comunes Internacionales Propuestas: Lista 103 Cualquier persona puede dirigir observaciones u objeciones respecto de las denominaciones propuestas, al Programa de Denominaciones Comunes Internacionales de la Organización Mundial de la Salud, en un plazo de cuatro meses, contados desde la fecha de su publicación en WHO Drug Information, es decir, para la Lista 103 de DCI Propuestas el 31 de octubre de 2010 a más tardar. Fecha de publicación: 30 de junio de 2010
Proposed INN Chemical name or description: Action and use: Molecular formula (Latin, English, French, Spanish) Chemical Abstracts Service (CAS) registry number: Graphic formula
DCI Proposée Nom chimique ou description: Propriétés et indications: Formule brute Numéro dans le registre du CAS: Formule développée
DCI Propuesta Nombre químico o descripción: Acción y uso: Fórmula molecular Número de registro del CAS: Fórmula desarrollada
amuvatinibum amuvatinib N-[(1,3-benzodioxol-5-yl)methyl]-4-([1]benzofuro[3,2-d]pyrimidin- 4-yl)piperazine-1-carbothioamide antineoplastic
amuvatinib N-[(1,3-benzodioxol-5-yl)méthyl]-4-([1]benzofuro[3,2-d]pyrimidin- 4-yl)pipérazine-1-carbothioamide antinéoplasique
amuvatinib N-[(1,3-benzodioxol-5-il)metil]-4-([1]benzofuro[3,2-d]pirimidin- 4-il)piperazina-1-carbotioamida antineoplásico
C23H21N5O3S 850879-09-3
N N
O N H O N N O
S
126 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103
anagliptinum anagliptin N-[2-({2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl}amino)- 2-methylpropyl]-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide antidiabetic
anagliptine N-[2-({2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoéthyl}amino)- 2-méthylpropyl]-2-méthylpyrazolo[1,5-a]pyrimidine-6-carboxamide antidiabétique
anagliptina N-[2-({2-[(2S)-2-cianopirrolidin-1-il]-2-oxoetil}amino)-2-metilpropil]- 2-metilpirazolo[1,5-a]pirimidina-6-carboxamida hipoglucemiante
C19H25N7O2 739366-20-2
O O H H CN N N N N H H3CCH3 N N H C 3
atecegatranum atecegatran (2S)-N-[(4-carbamimidoylphenyl)methyl]-1-{(2R)-2-[3-chloro- 5-(difluoromethoxy)phenyl]-2-hydroxyacetyl}azetidine-2-carboxamide thrombin inhibitor
atécégatran (2S)-N-[(4-carbamimidoylphényl)méthyl]-1-{(2R)-2-[3-chloro- 5-(difluorométhoxy)phényl]-2-hydroxyacétyl}azétidine-2-carboxamide inhibiteur de la thrombine
atecegatrán (2S)-N-[(4-carbamimidoilfenil)metil]-1-{(2R)-2-[3-cloro- 5-(difluorometoxi)fenil]-2-hidroxiacetil}azetidina-2-carboxamida inhibidor de la trombina
C21H21ClF2N4O4 917904-13-3
NH
H2N H OH H N N Cl H O O
O F
F
atecegatranum fexenetilum atecegatran fexenetil (2S)-1-{(2R)-2-[3-chloro-5-(difluoromethoxy)phenyl]- 2-hydroxyacetyl}-N-({4-[(Z)-N'- methoxycarbamimidoyl]phenyl}methyl)azetidine-2-carboxamide thrombin inhibitor
127 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010
atécégatran fexénétil (2S)-1-{(2R)-2-[3-chloro-5-(difluorométhoxy)phényl]- 2-hydroxyacétyl}-N-({4-[(Z)-N'- méthoxycarbamimidoyl]phényl}méthyl)azétidine-2-carboxamide inhibiteur de la thrombine
atecegatrán fexenetilo (2S)-1-{(2R)-2-[3-cloro-5-(difluorometoxi)fenil]-2-hidroxiacetil}- N-({4-[(Z)-N'-metoxicarbamimidoil]fenil}metil)azetidina- 2-carboxamida inhibidor de la trombina
C22H23ClF2N4O5 433937-93-0
H3CO N
H2N H OH H N N Cl H O O
O F
F
avibactamum avibactam (1R,2S,5R)-7-oxo-6-sulfooxy-1,6-diazabicyclo[3.2.1]octane- 2-carboxamide beta-lactamase inhibitor
avibactam (1R,2S,5R)-7-oxo-6-sulfooxy-1,6-diazabicyclo[3.2.1]octane- 2-carboxamide inhibiteur de bêta-lactamase
avibactam (1R,2S,5R)-7-oxo-6-sulfooxi-1,6-diazabiciclo[3.2.1]octano- 2-carboxamida inhibidor de la beta-lactamasa
C7H11N3O6S 1192500-31-4
O H O N NH2 O O N S O HO H
bavisantum bavisant (4-cyclopropylpiperazin-1-yl}){4-[(morpholin- 4-yl)methyl]phenyl}methanone histamine H3 receptor antagonist
bavisant (4-cyclopropylpipérazin-1-yl){4-[(morpholin- 4-yl)méthyl]phényl}méthanone antagoniste du récepteur H3 de l'histamine
128 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103
bavisant (4-ciclopropilpiperazin-1-il){4-[(morfolin-4-il)metil]fenil}metanona antagonista del receptor H3 de la histamina
C19H27N3O2 929622-08-2
O
O N N N
bedaquilinum bedaquiline (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)- 2-(naphthalen-1-yl)-1-phenylbutan-2-ol antibacterial
bédaquiline (1R,2S)-1-(6-bromo-2-méthoxyquinoléin-3-yl)-4-(diméthylamino)- 2-(naphtalén-1-yl)-1-phénylbutan-2-ol antibactérien
bedaquilina (1R,2S)-1-(6-bromo-2-metoxiquinolein-3-il)-4-(dimetilamino)- 2-(naftalen-1-il)-1-fenilbutan-2-ol antibacteriano
C32H31BrN2O2 843663-66-1
N OCH3 H Br HO
CH3 N
CH3
brentuximabum vedotinum # brentuximab vedotin immunoglobulin G1-kappa auristatin E conjugate, anti-[Homo sapiens TNFRSF8 (tumor necrosis factor receptor superfamily member 8, KI-1, CD30)], chimeric monoclonal antibody conjugated to auristatin E; gamma1 heavy chain (1-446) [Mus musculus VH (IGHV1-84*02 - (IGHD)-IGHJ3*01) [8.8.10] (1-117) -Homo sapiens IGHG1*01 CH3 K130>del (118-446)], (220-218')-disulfide (if not conjugated) with kappa light chain (1'-218') [Mus musculus V-KAPPA (IGKV3-4*01 - IGKJ1*01) [10.3.9] (1'-111') -Homo sapiens IGKC*01 (112'-218')]; (226-226'')-disulfide dimer; conjugated, on an average of 3 to 5 cysteinyl, to monomethylauristatin E (MMAE), via a maleimidecaproyl-valyl-citrullinyl-p-aminobenzylcarbamate (mc-val- cit-PABC) linker For the vedotin part, please refer to the document "INN for pharmaceutical substances: Names for radicals, groups & others"*. antineoplastic
129 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010
brentuximab védotine immunoglobuline G1-kappa conjuguée à l’auristatine E, anti-[Homo sapiens TNFRSF8 (membre 8 de la superfamille des récepteurs du facteur de nécrose tumorale, KI-1, CD30)], anticorps monoclonal chimérique conjugué à l’auristatine E; chaîne lourde gamma1 (1-446) [Mus musculus VH (IGHV1-84*02 - (IGHD)-IGHJ3*01) [8.8.10] (1-117) -Homo sapiens IGHG1*01 CH3 K130>del (118-446)], (220-218')-disulfure (si non conjugué) avec la chaîne légère kappa (1'-218') [Mus musculus V-KAPPA (IGKV3-4*01 -IGKJ1*01) [10.3.9] (1'-111') -Homo sapiens IGKC*01 (112'-218')]; dimère (226-226'')-disulfure; conjugué, sur 3 à 5 cystéinyl en moyenne, au monométhylauristatine E (MMAE), via un linker maléimidécaproyl-valyl-citrullinyl-p-aminobenzylcarbamate (mc-val- cit-PABC) Pour la partie védotine, veuillez vous référer au document "INN for pharmaceutical substances: Names for radicals, groups & others"*. antinéoplasique
brentuximab vedotina inmunoglobulina G1-kappa conjugada con auristatina E, anti-[Homo sapiens TNFRSF8 (miembro 8 de la superfamilia de los receptores del factor de necrosis tumoral, KI-1, CD30)], anticuerpo monoclonal quimérico conjugado con auristatina E; cadena pesada gamma1 (1-446) [Mus musculus VH (IGHV1-84*02 - (IGHD)-IGHJ3*01) [8.8.10] (1-117) -Homo sapiens IGHG1*01 CH3 K130>del (118-446)], (220-218')-disulfuro (si non está conjugado) con la cadena ligera kappa (1'-218') [Mus musculus V-KAPPA (IGKV3-4*01 -IGKJ1*01) [10.3.9] (1'-111') -Homo sapiens IGKC*01 (112'-218')]; dimero (226-226'')-disulfuro; conjugado, en 3 a 5 residuos cisteinil en término medio, con monometilauristatina E (MMAE), mediante un conector maleimidecaproil-valil-citrulinil- p-aminobenzilcarbamato (mc-val-cit-PABC) Por la parte vedotina, por favor, vaya al documento "INN for pharmaceutical substances: Names for radicals, groups & others"*. antineoplásico
914088-09-08
Heavy chain / Chaîne lourde / Cadena pesada QIQLQQSGPE VVKPGASVKI SCKASGYTFT DYYITWVKQK PGQGLEWIGW 50 IYPGSGNTKY NEKFKGKATL TVDTSSSTAF MQLSSLTSED TAVYFCANYG 100 NYWFAYWGQG TQVTVSAAST KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF 150 PEPVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSVVTVPS SSLGTQTYIC 200 NVNHKPSNTK VDKKVEPKSC DKTHTCPPCP APELLGGPSV FLFPPKPKDT 250 LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY 300 RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK GQPREPQVYT 350 LPPSRDELTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS 400 DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPG 446 Light chain / Chaîne légère / Cadena ligera DIVLTQSPAS LAVSLGQRAT ISCKASQSVD FDGDSYMNWY QQKPGQPPKV 50 LIYAASNLES GIPARFSGSG SGTDFTLNIH PVEEEDAATY YCQQSNEDPW 100 TFGGGTKLEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKV 150 QWKVDNALQS GNSQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEV 200 THQGLSSPVT KSFNRGEC 218 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 144-200 261-321 367-425 22''-96'' 144''-200'' 261''-321'' 367''-425'' Intra-L 23'-92' 138'-198' 23'''-92''' 138'''-198''' Inter-H-L * 220-218' 220''-218''' Inter-H-H * 226-226'' 229-229'' *Two or three of the inter-chain disulfide bridges are not present, the antibody being conjugated to an average of 3 to 5 drug linkers each via a thioether bond. * Deux ou trois des ponts disulfure ne sont pas présents, l'anticorps étant conjugué à une moyenne de 3 à 5 linker-principe actif chacun via une liaison thioéther. * Faltan dos o tres puentes disulfuro inter-catenarios por estar el anticuerpo conjugado, con sendos enlaces tioéter, a una media de 3 a 5 conectores de principio activo
N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 297, 297''
130 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103
cenicrivirocum cenicriviroc 8-{4-[2-(butoxy)ethoxy]phenyl}-1-(2-methylpropyl)-N-(4-{(S)-[(1- propyl-1H-imidazol-5-yl)methyl]sulfinyl}phenyl)-1,2,3,4-tetrahydro- 1-benzazocine-5-carboxamide antiviral
cénicriviroc 8-{4-[2-(butoxy)éthoxy]phényl}-1-(2-méthylpropyl)-N-(4-{(S)-[(1- propyl-1H-imidazol-5-yl)méthyl]sulfinyl}phényl)-1,2,3,4-tétrahydro- 1-benzazocine-5-carboxamide antiviral
cenicriviroc 8-{4-[2-(butoxi)etoxi]fenil}-1-(2-metilpropil)-N-(4-{(S)-[(1-propil- 1H-imidazol-5-il)metil]sulfinil}fenil)-1,2,3,4-tetrahidro-1-benzazocina- 5-carboxamida antiviral
C41H52N4O4S 497223-25-3
H C 3 H3C
H3C N CH3 O N N S
O N O H O
cobicistatum cobicistat (1,3-thiazol-5-yl)methyl (5S,8R,11R)-8,11-dibenzyl-2-methyl- 5-[2-(morpholin-4-yl)ethyl]-1-[2-(propan-2-yl)-1,3-thiazol-4-yl]- 3,6-dioxo-2,4,7,12-tetraazatridecan-13-oate cytochrome P450 3A4 (CYP3A4) inhibitor
cobicistat (5S,8R,11R)-8,11-dibenzyl-2-méthyl-5-[2-(morpholin-4-yl)éthyl]- 1-[2-(propan-2-yl)-1,3-thiazol-4-yl]-3,6-dioxo-2,4,7,12- tétraazatridécan-13-oate de (1,3-thiazol-5-yl)méthyle cytochrome P450 3A4 inhibitor
cobicistat (5S,8R,11R)-8,11-dibencil-2-metil-5-[2-(morfolin-4-il)etil]- 1-[2-(propan-2-il)-1,3-tiazol-4-il]-3,6-dioxo-2,4,7,12-tetraazatridecan- 13-oato de (1,3-tiazol-5-il)metilo inhibidor del citocromo P450 3A4
C40H53N7O5S2 1004316-88-4
O
N
O H H O H H C N N S 3 N N N O H H H CH3 O N H3C S
131 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010
crizotinibum crizotinib 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)- 1H-pyrazol-4-yl]pyridin-2-amine antineoplastic
crizotinib 3-[(1R)-1-(2,6-dichloro-3-fluorophényl)éthoxy]-5-[1-(pipéridin-4-yl)- 1H-pyrazol-4-yl]pyridin-2-amine antinéoplasique
crizotinib 3-[(1R)-1-(2,6-dicloro-3-fluorofenil)etoxi]-5-[1-(piperidin-4-il)- 1H-pirazol-4-il]piridin-2-amina antineoplásico
C21H22Cl2FN5O 877399-52-5
N NH2 Cl H CH3 F O N N Cl
HN
dacomitinibum dacomitinib (2E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin- 6-yl}-4-(piperidin-1-yl)but-2-enamide antineoplastic
dacomitinib (2E)-N-{4-[(3-chloro-4-fluorophényl)amino]-7-méthoxyquinazolin- 6-yl}-4-(pipéridin-1-yl)but-2-énamide antinéoplasique
dacomitinib (2E)-N-{4-[(3-cloro-4-fluorofenil)amino]-7-metoxiquinazolin-6-il}- 4-(piperidin-1-il)but-2-enamida antineoplásico
C24H25ClFN5O2 1110813-31-4
H3CO N
N HN N HN Cl O
F
132 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103
dexpramipexolum dexpramipexole (6R)-N6-propyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine antioxidant
dexpramipexole (6R)-N6-propyl-4,5,6,7-tétrahydro-1,3-benzothiazole-2,6-diamine antioxydant
dexpramipexol (6R)-N6-propil-4,5,6,7-tetrahidro-1,3-benzotiazol-2,6-diamina antioxidante
C10H17N3S 104632-28-2
H S HN NH2 N H3C
drozitumabum # drozitumab immunoglobulin G1-lambda, anti-[Homo sapiens TNFRSF10B (tumor necrosis factor receptor superfamily member 10B, DR5, death receptor 5, TRAIL-R2, TNF-related apoptosis-inducing ligand receptor 2, TR-2, CD262)], Homo sapiens monoclonal antibody; gamma1 heavy chain (1-451) [Homo sapiens VH (IGHV3-20*01 (91.80%) -(IGHD)-IGHJ2*01 R120>K, L123>T) [8.8.14] (1-121) - IGHG1*03 CH1 R120>K (122-451)], (224-212')-disulfide with lambda light chain (1'-213') [Homo sapiens V-LAMBDA (IGLV3-19*01 (96.80%) -IGLJ3*01) [6.3.11] (1'-107') -IGLC3*03 (108'-213')]; (230- 230'':233-233'')-bisdisulfide dimer antineoplastic
drozitumab immunoglobuline G1-lambda, anti-[Homo sapiens TNFRSF10B (membre 10B de la superfamille des récepteurs du facteur de nécrose tumorale, DR5, death receptor 5, TRAIL-R2, récepteur 2 du ligand inducteur d'une apoptose liée au TNF, TR-2, CD262)], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-451) [Homo sapiens VH (IGHV3-20*01 (91.80%) -(IGHD)-IGHJ2*01 R120>K, L123>T) [8.8.14] (1-121) - IGHG1*03 CH1 R120>K (122-451)], (224-212')-disulfure avec la chaîne légère lambda (1'-213') [Homo sapiens V-LAMBDA (IGLV3- 19*01 (96.80%) -IGLJ3*01) [6.3.11] (1'-107') -IGLC3*03 (108'-213')]; dimère (230-230'':233-233'')-bisdisulfure antinéoplasique
drozitumab inmunoglobulina G1-lambda, anti-[Homo sapiens TNFRSF10B (miembro 10B de la superfamilia de receptores del factor de necrosis tumoral, DR5, receptor de muerte 5, TRAIL-R2, receptor 2 del ligando inductor de la apoptosis de la familiaTNF, TR-2, CD262)], anticuerpo monoclonal de Homo sapiens ; cadena pesada gamma1 (1-451) [Homo sapiens VH (IGHV3-20*01 (91.80%) -(IGHD)-IGHJ2*01 R120>K, L123>T) [8.8.14] (1-121) - IGHG1*03 CH1 R120>K (122-451)], (224-212')-disulfuro con la cadena ligera lambda (1'-213') [Homo sapiens V-LAMBDA (IGLV3- 19*01 (96.80%) -IGLJ3*01) [6.3.11] (1'-107') -IGLC3*03 (108'-213')]; dímero (230-230'':233-233'')-bisdisulfuro antineoplásico
133 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010
912628-39-8
Heavy chain / Chaîne lourde / Cadena pesada EVQLVQSGGG VERPGGSLRL SCAASGFTFD DYAMSWVRQA PGKGLEWVSG 50 INWQGGSTGY ADSVKGRVTI SRDNAKNSLY LQMNSLRAED TAVYYCAKIL 100 GAGRGWYFDY WGKGTTVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV 150 KDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTQ 200 TYICNVNHKP SNTKVDKKVE PKSCDKTHTC PPCPAPELLG GPSVFLFPPK 250 PKDTLMISRT PEVTCVVVDV SHEDPEVKFN WYVDGVEVHN AKTKPREEQY 300 NSTYRVVSVL TVLHQDWLNG KEYKCKVSNK ALPAPIEKTI SKAKGQPREP 350 QVYTLPPSRE EMTKNQVSLT CLVKGFYPSD IAVEWESNGQ PENNYKTTPP 400 VLDSDGSFFL YSKLTVDKSR WQQGNVFSCS VMHEALHNHY TQKSLSLSPG 450 K 451 Light chain / Chaîne légère / Cadena ligera SELTQDPAVS VALGQTVRIT CSGDSLRSYY ASWYQQKPGQ APVLVIYGAN 50 NRPSGIPDRF SGSSSGNTAS LTITGAQAED EADYYCNSAD SSGNHVVFGG 100 GTKLTVLGQP KAAPSVTLFP PSSEELQANK ATLVCLISDF YPGAVTVAWK 150 ADSSPVKAGV ETTTPSKQSN NKYAASSYLS LTPEQWKSHK SYSCQVTHEG 200 STVEKTVAPT ECS 213 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 148-204 265-325 371-429 22''-96'' 148''-204'' 265''-325'' 371''-429'' Intra-L 21'-86' 135'-194' 21'''-86''' 135'''-194''' Inter-H-L 224-212' 224''-212''' Inter-H-H 230-230'' 233-233''
N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 301, 301''
dulaglutidum # dulaglutide glucagon-like peptide-1-immunoglobulin G4 fusion protein, [2-glycyl,16-L-glutamyl,30-glycyl][human glucagon-like peptide 1-(7- 37)-peptide] {(8-A>G,22-G>E,36-R>G)-GLP-1(7-37)} fusion protein with tris(tetraglycyl-L-seryl)-L-alanine (linker) fusion protein with des- 276-lysine-[57-L-proline,63-L-alanine,64-L-alanine]human immunoglobulin G4 Fc region {(10-S>P)-H-(4-F>A,5-L>A)-CH2-(107- K>-)-CH3 of IGHG4*01}, dimer (55-55':58-58')-bisdisulfide antidiabetic
dulaglutide protéine de fusion entre le peptide 1 semblable au glucagon et l'immunoglobuline G4, [2-glycyl,16-L-glutamyl,30-glycyl][peptide 1 semblable au glucagon humain-(7-37)-peptide] {(8-A>G,22-G>E,36-R>G)GLP-1(7-37)} protéine de fusion avec le tris(tétraglycyl-L-séryl)-L-alanine (lien) protéine de fusion avec la dès-276-lysine-[57-L-proline, 63-L-alanine,64-L-alanine]région Fc de l'immunoglobuline G4 humaine {(10-S>P)H-(4-F>A,5-L>A)CH2-(107-K>-)CH3 du IGHG4*01}, (55-55':58-58')-bisdisulfure du dimère antidiabétique
dulaglutida proteína de fusión entre el péptido similar al glucagón 1 y la inmunoglobulina G4, [2-glicil,16-L-glutamil,30-glicil][péptido similar al glucagón humano 1- (7-37)-péptido] {(8-A>G,22-G>E,36-R>G)GLP-1(7-37)} proteína de fusión con el tris(tetraglicil-L-seril)-L-alanina (vínculo) proteína de fusión con la des-276-lisina-[57-L-prolina,63-L-alanina, 64-L-alanina]región Fc de la inmunoglobulina G4 humana {(10- S>P)H-(4-F>A,5-L>A)CH2-(107-K>-)CH3 del IGHG4*01}, (55-55':58- 58')-bisdisulfuro del dímero hipoglucemiante
134 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103
C2646H4044N704O836S18 923950-08-7
Monomer / Monomère / Monomero HGEGTFTSDV SSYLEEQAAK EFIAWLVKGG GGGGGSGGGG SGGGGSAESK 50 YGPPCPPCPA PEAAGGPSVF LFPPKPKDTL MISRTPEVTC VVVDVSQEDP 100 EVQFNWYVDG VEVHNAKTKP REEQFNSTYR VVSVLTVLHQ DWLNGKEYKC 150 KVSNKGLPSS IEKTISKAKG QPREPQVYTL PPSQEEMTKN QVSLTCLVKG 200 FYPSDIAVEW ESNGQPENNY KTTPPVLDSD GSFFLYSRLT VDKSRWQEGN 250 VFSCSVMHEA LHNHYTQKSL SLSLG 275 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro 55-55' 58-58' 90-150 90'-150' 196-254 196'-254'
eliglustatum eliglustat N-{(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy- 3-(pyrrolidin-1-yl)propan-2-yl}octanamide glucosylceramide synthase inhibitor
éliglustat N-{(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy- 3-(pyrrolidin-1-yl)propan-2-yl}octanamide inhibiteur de la glucosylcéramide synthétase
eliglustat N-{(1R,2R)-1-(2,3-dihidro-1,4-benzodioxin-6-il)-1-hidroxi-3-(pirrolidin- 1-il)propan-2-il}octanamida inhibidor de la glucosilceramida
C23H36N2O4 491833-29-5
N O O H
H3C N O H HOH
elpamotidum elpamotide L-arginyl-L-phenylalanyl-L-valyl-L-prolyl-L-α-aspartylglycyl- L-asparaginyl-L-arginyl-L-isoleucine human soluble (Vascular Endothelial Growth Factor Receptor) VEGFR2-(169-177)-peptide immunological agent for active immunization
elpamotide L-arginyl-L-phénylalanyl-L-valyl-L-prolyl-L-α-aspartylglycyl- L-asparaginyl-L-arginyl-L-isoleucine (récepteur du facteur de croissance de l'endothélium vasculaire) RFCEV2 soluble humain-(169-177)-peptide agent immunologique d'immunisation active
elpamotida L-arginil-L-fenilalanil-L-valil-L-prolil-L-α-aspartilglicil-L-asparaginil- L-arginil-L-isoleucina (receptor del factor de crecimiento endotelial vascular) RFCEV2 soluble humano-(169-177)-péptido agente inmunológico para inmuzación activa
C47H76N16O13 673478-49-4
HArg Phe Val Pro Asp Gly Asn Arg Ile OH 9
135 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010
ensituximabum # ensituximab immunoglobulin G1-kappa, anti-[Homo sapiens MUC5AC (mucin 5AC, mucin 5 subtypes A and C tracheobronchial/gastric)], chimeric monoclonal antibody; gamma1 heavy chain (1-443) [Mus musculus VH (IGHV2-3*01 - (IGHD)-IGHJ4*01) [8.7.7] (1-113) -Homo sapiens IGHG1*01 CH1 L85.3>P, CH3 T81>M (114-443)], (216-213')-disulfide with kappa light chain (1'-213') [Mus musculus V-KAPPA (IGKV4-70*01 - IGKJ1*01) [5.3.9] (1'-106') -Homo sapiens IGKC*01 (107'-213')]; (222-222'':225-225'')-bisdisulfide dimer antineoplastic
ensituximab immunoglobuline G1-kappa, anti-[Homo sapiens MUC5AC (mucine 5AC, mucine 5 de sous-types A et C trachéo-bronchique/gastrique)], anticorps monoclonal chimérique; chaîne lourde gamma1 (1-443) [Mus musculus VH (IGHV2-3*01 - (IGHD)-IGHJ4*01) [8.7.7] (1-113) -Homo sapiens IGHG1*01 CH1 L85.3>P, CH3 T81>M (114-443)], (216-213')-disulfure avec la chaîne légère kappa (1'-213') [Mus musculus V-KAPPA (IGKV4-70*01 - IGKJ1*01) [5.3.9] (1'-106') -Homo sapiens IGKC*01 (107'-213')]; dimère (222-222'':225-225'')-bisdisulfure antinéoplasique
ensituximab inmunoglobulina G1-kappa, anti-[Homo sapiens MUC5AC (mucina 5AC, mucina 5 de subtipos A y C traqueo-bronquial/gástrico], anticuerpo monoclonal quimérico; cadena pesada gamma1 (1-443) [Mus musculus VH (IGHV2-3*01 - (IGHD)-IGHJ4*01) [8.7.7] (1-113) -Homo sapiens IGHG1*01 CH1 L85.3>P, CH3 T81>M (114-443)], (216-213')-disulfuro con la cadena ligera kappa (1'-213') [Mus musculus V-KAPPA (IGKV4-70*01 - IGKJ1*01) [5.3.9] (1'-106') -Homo sapiens IGKC*01 (107'-213')]; dímero (222-222'':225-225'')-bisdisulfuro antineoplásico
1092658-06-4
Heavy chain / Chaîne lourde / Cadena pesada QVQLKESGPD LVAPSQSLSI TCTVSGFSLS KFGVNWVRQP PGKGLEWLGV 50 IWGDGSTSYN SGLISRLSIS KENSKSQVFL KLNSLQADDT ATYYCVKPGG 100 DYWGHGTSVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV 150 TVSWNSGALT SGVHTFPAVL QSSGPYSLSS VVTVPSSSLG TQTYICNVNH 200 KPSNTKVDKK VEPKSCDKTH TCPPCPAPEL LGGPSVFLFP PKPKDTLMIS 250 RTPEVTCVVV DVSHEDPEVK FNWYVDGVEV HNAKTKPREE QYNSTYRVVS 300 VLTVLHQDWL NGKEYKCKVS NKALPAPIEK TISKAKGQPR EPQVYTLPPS 350 RDELTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTM PPVLDSDGSF 400 FLYSKLTVDK SRWQQGNVFS CSVMHEALHN HYTQKSLSLS PGK 443 Light chain / Chaîne légère / Cadena ligera QVVLTQSPVI MSASPGEKVT MTCSASSSIS YMYWYQQKPG TSPKRWIYDT 50 SKLASGVPAR FSGSGSGTSY SLTISNMEAG DAATYYCHQR DSYPWTFGGG 100 TNLEIKRTVA APSVFIFPPS DEQLKSGTAS VVCLLNNFYP REAKVQWKVD 150 NALQSGNSQE SVTEQDSKDS TYSLSSTLTL SKADYEKHKV YACEVTHQGL 200 SSPVTKSFNR GEC 213 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-95 140-196 257-317 363-421 22''-95'' 140''-196'' 257''-317'' 363''-421'' Intra-L 23'-87' 133'-193' 23'''-87''' 133'''-193''' Inter-H-L 216-213' 216''-213''' Inter-H-H 222-222'' 225-225''
N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 293, 293''
136 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103
eteplirsenum eteplirsen all-P-ambo-5'-{P-[4-({2-[2-(2- hydroxyethoxy)ethoxy]ethoxy}carbonyl)piperazin-1-yl]-N,N- dimethylphosphonamidate}-P,2',3'-trideoxy-P-dimethylamino-2',3'- imino-2',3'-secocytidylyl-(2'a→5')-P,3'-dideoxy-P-dimethylamino- 2',3'-imino-2',3'-secothymidylyl-(2'a→5')-P,2',3'-trideoxy-P- dimethylamino-2',3'-imino-2',3'-secocytidylyl-(2'a→5')-P,2',3'- trideoxy-P-dimethylamino-2',3'-imino-2',3'-secocytidylyl-(2'a→5')- P,2',3'-trideoxy-P-dimethylamino-2',3'-imino-2',3'-secoadenylyl- (2'a→5')-P,2',3'-trideoxy-P-dimethylamino-2',3'-imino-2',3'- secoadenylyl-(2'a→5')-P,2',3'-trideoxy-P-dimethylamino-2',3'-imino- 2',3'-secocytidylyl-(2'a→5')-P,2',3'-trideoxy-P-dimethylamino-2',3'- imino-2',3'-secoadenylyl-(2'a→5')-P,3'-dideoxy-P-dimethylamino- 2',3'-imino-2',3'-secothymidylyl-(2'a→5')-P,2',3'-trideoxy-P- dimethylamino-2',3'-imino-2',3'-secocytidylyl-(2'a→5')-P,2',3'- trideoxy-P-dimethylamino-2',3'-imino-2',3'-secoadenylyl-(2'a→5')- P,2',3'-trideoxy-P-dimethylamino-2',3'-imino-2',3'-secoadenylyl- (2'a→5')-P,2',3'-trideoxy-P-dimethylamino-2',3'-imino-2',3'- secoguanylyl-(2'a→5')-P,2',3'-trideoxy-P-dimethylamino-2',3'-imino- 2',3'-secoguanylyl-(2'a→5')-P,2',3'-trideoxy-P-dimethylamino-2',3'- imino-2',3'-secoadenylyl-(2'a→5')-P,2',3'-trideoxy-P-dimethylamino- 2',3'-imino-2',3'-secoadenylyl-(2'a→5')-P,2',3'-trideoxy-P- dimethylamino-2',3'-imino-2',3'-secoguanylyl-(2'a→5')-P,2',3'- trideoxy-P-dimethylamino-2',3'-imino-2',3'-secoadenylyl-(2'a→5')- P,3'-dideoxy-P-dimethylamino-2',3'-imino-2',3'-secothymidylyl- (2'a→5')-P,2',3'-trideoxy-P-dimethylamino-2',3'-imino-2',3'- secoguanylyl-(2'a→5')-P,2',3'-trideoxy-P-dimethylamino-2',3'-imino- 2',3'-secoguanylyl-(2'a→5')-P,2',3'-trideoxy-P-dimethylamino-2',3'- imino-2',3'-secocytidylyl-(2'a→5')-P,2',3'-trideoxy-P-dimethylamino- 2',3'-imino-2',3'-secoadenylyl-(2'a→5')-P,3'-dideoxy-P- dimethylamino-2',3'-imino-2',3'-secothymidylyl-(2'a→5')-P,3'-dideoxy- P-dimethylamino-2',3'-imino-2',3'-secothymidylyl-(2'a→5')-P,3'- dideoxy-P-dimethylamino-2',3'-imino-2',3'-secothymidylyl-(2'a→5')- P,2',3'-trideoxy-P-dimethylamino-2',3'-imino-2',3'-secocytidylyl- (2'a→5')-P,3'-dideoxy-P-dimethylamino-2',3'-imino-2',3'- secothymidylyl-(2'a→5')-P,2',3'-trideoxy-P-dimethylamino-2',3'-imino- 2',3'-secoadenylyl-(2'a→5')-2',3'-dideoxy-2',3'-imino-2',3'- secoguanosine treatment of Duchenne muscular distrophy
137 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010
étéplirsen tout-P-ambo-5'-{P-[4-({2-[2-(2- hydroxyéthoxy)éthoxy]éthoxy}carbonyl)pipérazin-1-yl]-N,N- diméthylphosphonamidate}-P,2',3'-déoxy-P-diméthylamino-2',3'- imino-2',3'-sécocytidylyl-(2'a→5')-P,3'-didéoxy-P-diméthylamino- 2',3'-imino-2',3'-sécothymidylyl-(2'a→5')-P,2',3'-déoxy-P- diméthylamino-2',3'-imino-2',3'-sécocytidylyl-(2'a→5')-P,2',3'-déoxy- P-diméthylamino-2',3'-imino-2',3'-sécocytidylyl-(2'a→5')-P,2',3'- déoxy-P-diméthylamino-2',3'-imino-2',3'-sécoadénylyl-(2'a→5')- P,2',3'-déoxy-P-diméthylamino-2',3'-imino-2',3'-sécoadénylyl- (2'a→5')-P,2',3'-déoxy-P-diméthylamino-2',3'-imino-2',3'- sécocytidylyl-(2'a→5')-P,2',3'-déoxy-P-diméthylamino-2',3'-imino- 2',3'-sécoadénylyl-(2'a→5')-P,3'-didéoxy-P-diméthylamino-2',3'- imino-2',3'-sécothymidylyl-(2'a→5')-P,2',3'-déoxy-P-diméthylamino- 2',3'-imino-2',3'-sécocytidylyl-(2'a→5')-P,2',3'-déoxy-P- diméthylamino-2',3'-imino-2',3'-sécoadénylyl-(2'a→5')-P,2',3'-déoxy- P-diméthylamino-2',3'-imino-2',3'-sécoadénylyl-(2'a→5')-P,2',3'- déoxy-P-diméthylamino-2',3'-imino-2',3'-sécoguanylyl-(2'a→5')- P,2',3'-déoxy-P-diméthylamino-2',3'-imino-2',3'-sécoguanylyl- (2'a→5')-P,2',3'-déoxy-P-diméthylamino-2',3'-imino-2',3'- sécoadénylyl-(2'a→5')-P,2',3'-déoxy-P-diméthylamino-2',3'-imino- 2',3'-sécoadénylyl-(2'a→5')-P,2',3'-déoxy-P-diméthylamino-2',3'- imino-2',3'-sécoguanylyl-(2'a→5')-P,2',3'-déoxy-P-diméthylamino- 2',3'-imino-2',3'-sécoadénylyl-(2'a→5')-P,3'-didéoxy-P- diméthylamino-2',3'-imino-2',3'-sécothymidylyl-(2'a→5')-P,2',3'- tridéoxy-P-diméthylamino-2',3'-imino-2',3'-sécoguanylyl-(2'a→5')- P,2',3'-tridéoxy-P-diméthylamino-2',3'-imino-2',3'-sécoguanylyl- (2'a→5')-P,2',3'-tridéoxy-P-diméthylamino-2',3'-imino-2',3'- sécocytidylyl-(2'a→5')-P,2',3'-tridéoxy-P-diméthylamino-2',3'-imino- 2',3'-sécoadénylyl-(2'a→5')-P,3'-didéoxy-P-diméthylamino-2',3'- imino-2',3'-sécothymidylyl-(2'a→5')-P,3'-didéoxy-P-diméthylamino- 2',3'-imino-2',3'-sécothymidylyl-(2'a→5')-P,3'-didéoxy-P- diméthylamino-2',3'-imino-2',3'-sécothymidylyl-(2'a→5')-P,2',3'- tridéoxy-P-diméthylamino-2',3'-imino-2',3'-sécocytidylyl-(2'a→5')- P,3'-didéoxy-P-diméthylamino-2',3'-imino-2',3'-sécothymidylyl- (2'a→5')-P,2',3'-tridéoxy-P-diméthylamino-2',3'-imino-2',3'- sécoadenylyl-(2'a→5')-2',3'-didéoxy-2',3'-imino-2',3'-sécoguanosine traitement de la myopathie de Duchenne
138 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103
eteplirsén todo-P-ambo-5'-{P-[4-({2-[2-(2- hidroxietoxi)etoxi]etoxi}carbonl)piperazin-1-il]-N,N- dimetilfosfonamidato}-P,2',3'-tridesoxi-P-dimetilamino-2',3'-imino- 2',3'-secocitidilil-(2'a→5')-P,3'-didesoxi-P-dimetilamino-2',3'-imino- 2',3'-secotimidilil-(2'a→5')-P,2',3'-tridesoxi-P-dimetilamino-2',3'- imino-2',3'-secocitidilil-(2'a→5')-P,2',3'-tridesoxi-P-dimetilamino-2',3'- imino-2',3'-secocitidilil-(2'a→5')-P,2',3'-tridesoxi-P-dimetilamino-2',3'- imino-2',3'-secoadenilil-(2'a→5')-P,2',3'-tridesoxi-P-dimetilamino- 2',3'-imino-2',3'-secoadenilil-(2'a→5')-P,2',3'-tridesoxi-P- dimetilamino-2',3'-imino-2',3'-secocitidilil-(2'a→5')-P,2',3'-tridesoxi-P- dimetilamino-2',3'-imino-2',3'-secoadenilil-(2'a→5')-P,3'-didesoxi-P- dimetilamino-2',3'-imino-2',3'-secotimidilil-(2'a→5')-P,2',3'-tridesoxi- P-dimetilamino-2',3'-imino-2',3'-secocitidilil-(2'a→5')-P,2',3'-tridesoxi- P-dimetilamino-2',3'-imino-2',3'-secoadenilil-(2'a→5')-P,2',3'- tridesoxi-P-dimetilamino-2',3'-imino-2',3'-secoadenil-(2'a→5')-P,2',3'- tridesoxi-P-dimetilamino-2',3'-imino-2',3'-secoguanilil-(2'a→5')- P,2',3'-tridesoxi-P-dimetilamino-2',3'-imino-2',3'-secoguanilil- (2'a→5')-P,2',3'-tridesoxi-P-dimetilamino-2',3'-imino-2',3'- secoadenilil-(2'a→5')-P,2',3'-tridesoxi-P-dimetilamino-2',3'-imino- 2',3'-secoadenilil-(2'a→5')-P,2',3'-tridesoxi-P-dimetilamino-2',3'- imino-2',3'-secoguanilil-(2'a→5')-P,2',3'-tridesoxi-P-dimetilamino- 2',3'-imino-2',3'-secoadenilil-(2'a→5')-P,3'-didesoxi-P-dimetilamino- 2',3'-imino-2',3'-secotimidilil-(2'a→5')-P,2',3'-tridesoxi-P- dimetilamino-2',3'-imino-2',3'-secoguanilil-(2'a→5')-P,2',3'-tridesoxi- P-dimetilamino-2',3'-imino-2',3'-secoguanilil-(2'a→5')-P,2',3'- tridesoxi-P-dimetilamino-2',3'-imino-2',3'-secocitidilil-(2'a→5')-P,2',3'- tridesoxi-P-dimetilamino-2',3'-imino-2',3'-secoadenill-(2'a→5')-P,3'- didesoxi-P-dimetilamino-2',3'-imino-2',3'-secotimidilil-(2'a→5')-P,3'- didesoxi-P-dimetilamino-2',3'-imino-2',3'-secotimidilil-(2'a→5')-P,3'- didesoxi-P-dimetilamino-2',3'-imino-2',3'-secotimidilil-(2'a→5')-P,2',3'- tridesoxi-P-dimetilamino-2',3'-imino-2',3'-secocitidilil-(2'a→5')-P,3'- didesoxi-P-dimetilamino-2',3'-imino-2',3'-secotimidilil-(2'a→5')-P,2',3'- tridesoxi-P-dimetilamino-2',3'-imino-2',3'-secoadenilil-(2'a→5')-2',3'- didesoxi-2',3'-imino-2',3'-secoguanosina tratamiento de la distrofia muscular de Duchenne
C364H569N177O122P30 1173755-55-9
O B(n) B(30)
O N O 1' O 2'a HO N O N O NH 3 P P 5' H3C NO H3C NO CH3 CH3 n = 1 - 29 29 B(1-30): C-T-C-C-A-A-C-A-T-C-A-A-G-G-A-A-G-A-T-G-G-C-A-T-T-T-C-T-A-G
139 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010
fasitibanti chloridum fasitibant chloride (4S)-4-amino-5-{4-[4-(2,4-dichloro-3-{[(2,4-dimethylquinolin- 8-yl)oxy]methyl}benzenesulfonamido)oxane-4-carbonyl]piperazin- 1-yl}-N,N,N-trimethyl-5-oxopentan-1-aminium chloride bradykinin B2 receptor antagonist
chlorure de fasitibant chlorure de (4S)-4-amino-5-{4-[4-(2,4-dichloro-3-{[(2,4- diméthylquinoléin-8-yl)oxy]méthyl}benzènesulfonamido)oxane- 4-carbonyl]pipérazin-1-yl}-N,N,N-triméthyl-5-oxopentan-1-aminium antagoniste des récepteurs B2 de la bradykinine
cloruro de fasitibant cloruro de (4S)-4-amino-5-{4-[4-(2,4-dicloro-3-{[(2,4-dimetilquinolein- 8-il)oxi]metil}bencenosulfonamido)oxano-4-carbonil]piperazin-1-il}- N,N,N-trimetil-5-oxopentan-1-aminio antagonista del receptor B2 de la bradiquinina
C36H49Cl3N6O6S 1157852-02-2
Cl O H Cl O N S N CH H NH2 3 OO Cl N N CH3 N O CH3 O H3C CH3
fedovapagonum fedovapagon (2S)-N2,N2-dimethyl-N1-{[2-methyl-4-(2,3,4,5-tetrahydro- 1H-1-benzazepine-1-carbonyl)phenyl]methyl}pyrrolidine- 1,2-dicarboxamide vasopressine V2 receptor agonist
fédovapagon (2S)-N2,N2-diméthyl-N1-{[2-méthyl-4-(2,3,4,5-tétrahydro- 1H-1-benzazépine-1-carbonyl)phényl]méthyl}pyrrolidine- 1,2-dicarboxamide agoniste des récepteurs V2 de la vasopressine
fedovapagón (2S)-N2,N2-dimetil-N1-{[2-metil-4-(2,3,4,5-tetrahidro- 1H-1-benzazepina-1-carbonil)fenil]metil}pirrolidina- 1,2-dicarboxamida agonista del receptor V2 de vasopresina
C27H34N4O3 347887-36-9
O CH O H 3 N
N N CH3 H N CH3 O
140 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103
florbetapirum (18F) florbetapir (18F) 4-[(1E)-2-(6-{2-[2-(2-[18F]fluoroethoxy)ethoxy]ethoxy}pyridine- 3-yl)ethen-1-yl]-N-methylaniline diagnostic agent
florbétapir (18F) 4-[(1E)-2-(6-{2-[2-(2-[18F]fluoroéthoxy)éthoxy]éthoxy}pyridin- 3-yl)éthén-1-yl]-N-méthylaniline produit à usage diagnostique
florbetapir (18F) 4-[(1E)-2-(6-{2-[2-(2-[18F]fluoroetoxi)etoxi]etoxi}piridin-3-il)eten-1-il]- N-metilanilina agente de diagnóstico
18 C20H25 FN2O3 956103-76-7
H N H3C
O [18F] N O O
fluciclatidum (18F) fluciclatide (18F) N6-[(28E)-29-(4-[18F]fluorophenyl)-5,25-dioxo-3,9,12,15,18,21,27- heptaoxa-6,24,28-triazanonacos-28-enoyl]-N2-(sulfanylacetyl)- L-lysyl-L-cysteinyl-L-arginylglycyl-L-α-aspartyl-L-cysteinyl- L-phenylalanyl-N-(17-amino-13,17-dioxo-3,6,9,15-tetraoxa- 12-azaheptadecyl)-L-cysteinamide cyclic (2→6)-disulfide cyclic (1→8)-thioether radiodiagnostic agent
fluciclatide (18F) (2→6)-disulfure cyclique et (1→8)-thioéther cyclique du N6-[(28E)- 29-(4-[18F]fluorophényl)-5,25-dioxo-3,9,12,15,18,21,27-heptaoxa- 2 6,24,28-triazanonacos-28-énoyl]-N -(2-sulfanylacétyl)-L-lysyl- L-cystéinyl-L-arginylglycyl-L-α-aspartyl-L-cystéinyl-L-phénylalanyl- 1-N-(17-amino-13,17-dioxo-3,6,9,15-tétraoxa-12-azaheptadécyl)- L-cystéinamide radiodiagnostique
fluciclatida (18F) (2→6)-disulfuro cíclico y (1→8)-tioéter cíclico del N6-[(28E)-29- (4-[18F]fluorofenil)-5,25-dioxo-3,9,12,15,18,21,27-heptaoxa-6,24,28- 2 triazanonacos-28-enoil]-N -(2-sulfanilacetil)-L-lisil- L-cisteinil-L-arginilglicil-L-α-aspartil-L-cisteinil-L-fenilalanil- 1-N-(17-amino-13,17-dioxo-3,6,9,15-tetraoxa-12-azaheptadecil)- L-cisteinamida agente de radiodiagnóstico
18 C75H115 FN18O27S3 879894-01-6
O O O O H2N N O H O S H
Lys Cys Arg Gly Asp Cys Phe N N 6 H H O N O O O O O O N O H O O O O N N H 18 [ F]
141 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010
fluciclovinum (18F) fluciclovine (18F) (1r,3r)-1-amino-3[18F]fluorocyclobutane-1-carboxylic acid radiodiagnostic agent
fluciclovine (18F) acide trans-1-amino-3-[18F]fluorocyclobutane-1-carboxylique radiodiagnostique
fluciclovina (18F) ácido (1r,3r)-1-amino-3-[18F]fluorociclobutano-1-carboxílico agente de radiodiagnóstico
18 C5H8 FNO2 222727-39-1
H NH2 18 [ F] CO2H
flurpiridazum (18F) flurpiridaz (18F) 2-tert-butyl-4-chloro-5-({4-[(2- [18F]fluoroethoxy)methyl]phenyl}methoxy)pyridazin-3(2H)-one radiodiagnostic agent
flurpiridaz (18F) 2-tert-butyl-4-chloro-5-({4-[(2- [18F]fluoroéthoxy)méthyl]phényl}méthoxy)pyridazin-3(2H)-one radiodiagnostique
flurpiridaz (18F) 2-terc-butil-4-cloro-5-({4-[(2- [18F]fluoroetoxi)metil]fenil}metoxi)piridazin-3(2H)-ona agente de radiodiagnóstico
18 C18H22Cl FN2O3 863887-89-2
O H3C CH3 Cl H3C N N O
O 18 [ F]
foralumabum # foralumab immunoglobulin G1-kappa, anti-[Homo sapiens CD3E (CD3 epsilon)], Homo sapiens monoclonal antibody; gamma1 heavy chain (1-448) [Homo sapiens VH (IGHV3-33*01 (95.90%) -(IGHD)-IGHJ2*01) [8.8.11] (1-118) -IGHG1*03 CH2 L1.3(235)>A, L1.2(236)>E (119-448)], (221-215')-disulfide with kappa light chain (1'-215') [Homo sapiens V-KAPPA (IGKV3-11*01 (100.00%) -IGKJ4*01) [6.3.10] (1'-108') -IGKC*01 (109'-215')]; (227- 227'':230-230'')-bisdisulfide dimer immunomodulator
142 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103
foralumab immunoglobuline G1 -kappa, anti-[Homo sapiens CD3E (CD3 epsilon)], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-448) [Homo sapiens (IGHV3-33*01 (95.90%) -(IGHD)-IGHJ2*01) [8.8.11] (1-118) -IGHG1*03 CH2 L1.3(235)>A, L1.2(236)>E (119-448)], (221-215')-disulfure avec la chaîne légère kappa (1'-215') [Homo sapiens V-KAPPA (IGKV3- 11*01 (100.00%) -IGKJ4*01) [6.3.10] (1'-108') -IGKC*01 (109'-215')]; dimère (227-227'':230-230'')-bisdisulfure immunomodulateur
foralumab inmunoglobulina G1-kappa, anti-[Homo sapiens CD3E (CD3 epsilon)], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma1 (1-448) [Homo sapiens (IGHV3-33*01 (95.90%) -(IGHD)-IGHJ2*01) [8.8.11] (1-118) -IGHG1*03 CH2 L1.3(235)>A, L1.2(236)>E (119-448)], (221-215')-disulfuro con la cadena ligera kappa (1'-215') [Homo sapiens V-KAPPA (IGKV3- 11*01 (100.00%) -IGKJ4*01) [6.3.10] (1'-108') -IGKC*01 (109'-215')]; dímero (227-227'':230-230'')-bisdisulfuro inmunomodulador
946415-64-1
Heavy chain / Chaîne lourde / Cadena pesada QVQLVESGGG VVQPGRSLRL SCAASGFKFS GYGMHWVRQA PGKGLEWVAV 50 IWYDGSKKYY VDSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARQM 100 GYWHFDLWGR GTLVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY 150 FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI 200 CNVNHKPSNT KVDKRVEPKS CDKTHTCPPC PAPEAEGGPS VFLFPPKPKD 250 TLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST 300 YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY 350 TLPPSREEMT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD 400 SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPGK 448 Light chain / Chaîne légère / Cadena ligera EIVLTQSPAT LSLSPGERAT LSCRASQSVS SYLAWYQQKP GQAPRLLIYD 50 ASNRATGIPA RFSGSGSGTD FTLTISSLEP EDFAVYYCQQ RSNWPPLTFG 100 GGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK 150 VDNALQSGNS QESVTEQDSK DSTYSLSSTL TLSKADYEKH KVYACEVTHQ 200 GLSSPVTKSF NRGEC 215 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 145-201 262-322 368-426 22''-96'' 145''-201'' 262''-322'' 368''-426'' Intra-L 23'-88' 135'-195' 23'''-88''' 135'''-195''' Inter-H-L 221-215' 221''-215''' Inter-H-H 227-227'' 230-230''
N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 298, 298''
fosdevirinum fosdevirine methyl (R)-(2-carbamoyl-5-chloro-1H-indol-3-yl){3-[(1E)-2- cyanoethen-1-yl]-5-methylphenyl}phosphinate antiviral
fosdévirine (R)-(2-carbamoyl-5-chloro-1H-indol-3-yl){3-[(1E)-2-cyanoéthén-1-yl]- 5-méthylphényl}phosphinate de méthyle antiviral
fosdevirina (R)-(2-carbamoil-5-cloro-1H-indol-3-il){3-[(1E)-2-cianoeten-1-il]- 5-metilfenil}fosfinato de metilo antiviral
143 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010
C20H17ClN3O3P 1018450-26-4
NH O 2 O O CH3 P CN HN
CH3 Cl
ganitumabum # ganitumab immunoglobulin G1-kappa, anti-[Homo sapiens IGF1R (insulin-like growth factor 1 receptor, IGF1-R, IGF-1R, CD221)], Homo sapiens monoclonal antibody; gamma1 heavy chain (1-449) [Homo sapiens VH (IGHV4-4*02 (100.00%) -(IGHD)-IGHJ3*02) [9.7.12] (1-119) -IGHG1*01 (120- 449)], (222-219')-disulfide with kappa light chain (1'-219') [Homo sapiens V-KAPPA (IGKV2-28*01 (95.00%) -IGKJ1*01) [11.3.9] (1'- 112') -IGKC*01 (113'-219')]; (228-228'':231-231'')-bisdisulfide dimer antineoplastic
ganitumab immunoglobuline G1-kappa, anti-[Homo sapiens IGF1R (récepteur du facteur de croissance 1 analogue à l'insuline, IGF1-R, IGF-1R, CD221)], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-449) [Homo sapiens VH (IGHV4-4*02 (100.00%) -(IGHD)-IGHJ3*02) [9.7.12] (1-119) -IGHG1*01 (120- 449)], (222-219')-disulfure avec la chaîne légère kappa (1'-219') [Homo sapiens V-KAPPA (IGKV2-28*01 (95.00%) -IGKJ1*01) [11.3.9] (1'-112') -IGKC*01 (113'-219')]; dimère (228-228'':231-231'')- bisdisulfure antinéoplasique
ganitumab inmunoglobulina G1-kappa, anti-[Homo sapiens IGF1R (receptor del factor de crecimiento 1 análogo a la insulina, IGF1-R, IGF-1R, CD221)], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma1 (1-449) [Homo sapiens VH (IGHV4-4*02 (100.00%) -(IGHD)-IGHJ3*02) [9.7.12] (1-119) -IGHG1*01 (120- 449)], (222-219')-disulfuro con la cadena ligera kappa (1'-219') [Homo sapiens V-KAPPA (IGKV2-28*01 (95.00%) -IGKJ1*01) [11.3.9] (1'-112') -IGKC*01 (113'-219')]; dímero (228-228'':231-231'')- bisdisulfuro antineoplásico
144 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103
905703-97-1
Heavy chain / Chaîne lourde / Cadena pesada QVQLQESGPG LVKPSGTLSL TCAVSGGSIS SSNWWSWVRQ PPGKGLEWIG 50 EIYHSGSTNY NPSLKSRVTI SVDKSKNQFS LKLSSVTAAD TAVYYCARWT 100 GRTDAFDIWG QGTMVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD 150 YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY 200 ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK 250 DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS 300 TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV 350 YTLPPSRDEL TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL 400 DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK 449 Light chain / Chaîne légère / Cadena ligera DVVMTQSPLS LPVTPGEPAS ISCRSSQSLL HSNGYNYLDW YLQKPGQSPQ 50 LLIYLGSNRA SGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCMQGTHWP 100 LTFGQGTKVE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK 150 VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE 200 VTHQGLSSPV TKSFNRGEC 219 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 146-202 263-323 369-427 22''-96'' 146''-202'' 263''-323'' 369''-427'' Intra-L 23'-93' 139'-199' 23'''-93''' 139'''-199''' Inter-H-L 222-219' 222''-219''' Inter-H-H 228-228'' 231-231''
N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 299, 299''
gataparsenum gataparsen all-P-ambo-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'- O-(2-methoxyethyl)-P-thioguanylyl-(3'→5')-2'-O-(2-methoxyethyl)- 5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioguanylyl- (3'→5')-2'-deoxy-5-methyl-P-thiocytidylyl-(3'→5')-P-thiothymidylyl- (3'→5')-2'-deoxy-P-thioadenylyl-(3'→5')-P-thiothymidylyl-(3'→5')-P- thiothymidylyl-(3'→5')-2'-deoxy-5-methyl-P-thioucytidylyl-(3'→5')-P- thiothymidylyl-(3'→5')-2'-deoxy-P-thioguanylyl-(3'→5')-P- thiothymidylyl-(3'→5')-2'-deoxy-P-thioguanylyl-(3'→5')-2'-O- (2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-P- thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl- (3'→5')-2'-O-(2-methoxyethyl)-5-methyluridine antineoplastic
gataparsen tout-P-ambo-2'-O-(2-méthoxyéthyl)-5-méthyl-P-thiouridylyl-(3'→5')- 2'-O-(2-méthoxyéthyl)-P-thioguanylyl-(3'→5')-2'-O-(2-méthoxyéthyl)- 5-méthyl-P-thiouridylyl-(3'→5')-2'-O-(2-méthoxyéthyl)-P-thioguanylyl- (3'→5')-2'-déoxy-5-méthyl-P-thiocytidylyl-(3'→5')-P-thiothymidylyl- (3'→5')-2'-déoxy-P-thioadénylyl-(3'→5')-P-thiothymidylyl-(3'→5')-P- thiothymidylyl-(3'→5')-2'-déoxy-5-méthyl-P-thiocytidylyl-(3'→5')-P- thiothymidylyl-(3'→5')-2'-déoxy-P-thioguanylyl-(3'→5')-P- thiothymidylyl-(3'→5')-2'-déoxy-P-thioguanylyl-(3'→5')-2'-O- (2-méthoxyéthyl)-P-thioadénylyl-(3'→5')-2'-O-(2-méthoxyéthyl)- P-thioadénylyl-(3'→5')-2'-O-(2-méthoxyéthyl)-5-méthyl-P-thiouridylyl- (3'→5')-2'-O-(2-méthoxyéthyl)-5-méthyluridine antinéoplasique
145 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010
gataparsén todo-P-ambo-2'-O-(2-metoxietil)-5-metil-P-tiouridilil-(3'→5')-2'-O- (2-metoxietil)-P-tioguanilil-(3'→5')-2'-O-(2-metoxietil)-5-metil- P-tiouridilil-(3'→5')-2'-O-(2-metoxietil)-P-tioguanilil-(3'→5')-2'-desoxi- 5-metil-P-tiocitidilil-(3'→5')-P-tiotimidilil-(3'→5')-2'-desoxi- P-tioadenilil-(3'→5')-P-tiotimidilil-(3'→5')-P-tiotimidilil-(3'→5')-2'- desoxi-5-metil-P-tiocitidilil-(3'→5')-P-tiotimidilil-(3'→5')-2'-desoxi- P-tioguanilil-(3'→5')-P-tiotimidilil-(3'→5')-2'-desoxi-P-tioguanilil- (3'→5')-2'-O-(2-metoxietil)-P-tioadenilil-(3'→5')-2'-O-(2-metoxietil)- P-tioadenilil-(3'→5')-2'-O-(2-metoxietil)-5-metil-P-tiouridilil-(3'→5')- 2'-O-(2-metoxietil)-5-metiluridina antineoplásico
C204H278N59O111P17S17 1065019-70-6
(3'→5')d(P-thio)(rU-rG-rU-rG-C-T-A-T-T-C-T-G-T-G-rA-rA-rU-rU)
Modified nucleosides / Nucléosides modifiés / Nucleosidos modificados:
A N G H2N N NH2 NH OH N O O NN OH O NN OCH3
HO O OCH3 HO O U H O N O C O N NH2 OH OH O N O N CH3 CH3
OCH3 HO O HO OH
gemigliptinum gemigliptin 1-{(2S)-2-amino-4-[2,4-bis(trifluoromethyl)-5,8-dihydropyrido[3,4- d]pyrimidin-7(6H)-yl]-4-oxobutyl}-5,5-difluoropiperidin-2-one antidiabetic
gémigliptine 1-{(2S)-2-amino-4-[2,4-bis(trifluorométhyl)-5,8-dihydropyrido[3,4- d]pyrimidin-7(6H)-yl]-4-oxobutyl}-5,5-difluoropipéridin-2-one antidiabétique
gemigliptina 1-{(2S)-2-amino-4-[2,4-bis(trifluorometil)-5,8-dihidropirido[3,4- d]pirimidin-7(6H)-il]-4-oxobutil}-5,5-difluoropiperidin-2-ona hipoglucemiante
C18H19F8N5O2 911637-19-9
CF3
N O N F3C N N O HNH2
FF
146 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103
iniparibum iniparib 4-iodo-3-nitrobenzamide antineoplastic
iniparib 4-iodo-3-nitrobenzamide antinéoplasique
iniparib 4-iodo-3-nitrobenzamida antineoplásico
C7H5IN2O3 160003-66-7
I
NH2 O2N O
insulinum tregopilum insulin tregopil N6,29B-(4,7,10,13-tetraoxatetradecanoyl)human insulin antidiabetic
insuline trégopil N6,29B-(4,7,10,13-tétraoxatétradécanoyl)insuline humaine antidiabétique
insulina tregopilo N6,29B-(4,7,10,13-tetraoxatetradecanoil)insulina humana hipoglucemiante
C267H401N65O82S6 874442-57-6
HGly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Gln Leu 10 Glu Asn Tyr Cys Asn OH 20
HPhe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr 10 Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys Thr OH 20 N6 30 O O H3C O O O
ioflubenzamidum (131I) ioflubenzamide (131I) N-[2-(diethylamino)ethyl]-4-(4-fluorobenzamido)-5-[131I]iodo- 2-methoxybenzamide radiopharmaceutical
ioflubenzamide (131I) N-[2-(diéthylamino)éthyl]-4-(4-fluorobenzamido)-5-[131I]iodo- 2-méthoxybenzamide radiopharmaceutique
ioflubenzamida (131I) N-[2-(dietilamino)etil]-4-(4-fluorobenzamido)-5-[131I]iodo- 2-metoxibenzamida radiofármaco
147 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010
131 C21H25F IN3O3 1214283-52-9
CH3 O 131 [ I] N CH3 N O H
N OCH3 H F
ioforminolum ioforminol all-ambo-5,5'-[2-hydroxypropane- 1,3-diylbis(formylazanediyl)]bis[N,N'-bis(2,3-dihydroxypropyl)- 2,4,6-triiodobenzene-1,3-dicarboxamide] radiodiagnostic agent
ioforminol tout-ambo-5,5'-[2-hydroxypropane- 1,3-diylbis(formylazanediyl)]bis[N,N'-bis(2,3-dihydroxypropyl)- 2,4,6-triiodobenzène-1,3-dicarboxamide] radiodiagnostique
ioforminol todo-ambo-5,5'-[2-hidroxipropano- 1,3-diilbis(formilazanodiil)]bis[N,N'-bis (2,3-dihidroxipropil)-2,4,6-triiodobenceno-1,3-dicarboxamida] agente de radiodiagnóstico
C33H40I6N6O15 1095110-48-7
OH OH H H HO N O O N OH
I I I I OH OH H H HO N N OH N N O I OH I O O O
ipragliflozinum ipragliflozin (1S)-1,5-anhydro-1-C-{3-[(1-benzothiophen-2-yl)methyl]- 4-fluorophenyl}-D-glucitol antidiabetic
ipragliflozine (1S)-1,5-anhydro-1-C-{3-[(1-benzothiophén-2-yl)méthyl]- 4-fluorophényl}-D-glucitol antidiabétique
ipragliflozina (1S)-1,5-anhidro-1-C-{3-[(1-benzotiofen-2-il)metil]-4-fluorofenil}- D-glucitol hipoglucemiante
148 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103
C21H21FO5S 761423-87-4
S F
HO
O OH HO OH
itolizumabum # itolizumab immunoglobulin G1-kappa, anti-[Homo sapiens CD6 (Tp120, T12)], humanized monoclonal antibody; gamma1 heavy chain (1-449) [humanized VH (Homo sapiens IGHV3-21*08 (83.70%) -(IGHD)-IGHJ5*01) [8.8.12] (1-119) -Homo sapiens IGHG1*01 (120-449)], (222-214')-disulfide with kappa light chain (1'-214') [humanized V-KAPPA (Homo sapiens IGKV1-17*01 (76.80%) -IGKJ2*01 F118>L, Q120>S) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; (228-228":231-231")-bisdisulfide dimer immunomodulator
itolizumab immunoglobuline G1-kappa, anti-[Homo sapiens CD6 (Tp120, T12)], anticorps monoclonal humanisé; chaîne lourde gamma1 (1-449) [VH humanisé (Homo sapiens IGHV3-21*08 (83.70%) -(IGHD)-IGHJ5*01) [8.8.12] (1-119) -Homo sapiens IGHG1*01 (120-449)], (222-214')-disulfure avec la chaîne légère kappa (1'-214') [V-KAPPA humanisé (Homo sapiens IGKV1- 17*01 (76.80%) -IGKJ2*01 F118>L, Q120>S) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dimère (228-228":231-231")- bisdisulfure immunomodulateur
itolizumab inmunoglobulina G1-kappa, anti-[Homo sapiens CD6 (Tp120, T12)], anticuerpo monoclonal humanizado; cadena pesada gamma1 (1-449) [VH humanizado (Homo sapiens IGHV3-21*08 (83.70%) -(IGHD)-IGHJ5*01) [8.8.12] (1-119) -Homo sapiens IGHG1*01 (120-449)], (222-214')-disulfuro con la cadena ligera kappa (1'-214') [V-KAPPA humanizado (Homo sapiens IGKV1- 17*01 (76.80%) -IGKJ2*01 F118>L, Q120>S) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dímero (228-228":231-231")- bisdisulfuro inmunomodulador
149 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010
1116433-11-4
Heavy chain / Chaîne lourde / Cadena pesada EVQLVESGGG LVKPGGSLKL SCAASGFKFS RYAMSWVRQA PGKRLEWVAT 50 ISSGGSYIYY PDSVKGRFTI SRDNVKNTLY LQMSSLRSED TAMYYCARRD 100 YDLDYFDSWG QGTLVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD 150 YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY 200 ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK 250 DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS 300 TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV 350 YTLPPSRDEL TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL 400 DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK 449 Light chain / Chaîne légère / Cadena ligera DIQMTQSPSS LSASVGDRVT ITCKASRDIR SYLTWYQQKP GKAPKTLIYY 50 ATSLADGVPS RFSGSGSGQD YSLTISSLES DDTATYYCLQ HGESPFTLGS 100 GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150 DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200 LSSPVTKSFN RGEC 214 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 146-202 263-323 369-427 22''-96'' 146''-202'' 263''-323'' 369''-427'' Intra-L 23'-88' 134'-194' 23'''-88''' 134'''-194''' Inter-H-L 222-214' 222''-214''' Inter-H-H 228-228'' 231-231''
N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 299, 299''
lorvotuzumabum mertansinum # lorvotuzumab mertansine immunoglobulin G1-kappa, anti-[Homo sapiens NCAM1 (neural cell adhesion molecule 1, CD56, NCAM-1)], humanized monoclonal antibody conjugated to maytansinoid DM1; gamma1 heavy chain (1-448) [humanized VH (Homo sapiens IGHV3-30*03 (91.80%) -(IGHD)-IGHJ4*01) [8.8.11] (1-118) -Homo sapiens IGHG1*01 (119-448)], (221-219')-disulfide with kappa light chain (1’-219’) [humanized V-KAPPA (Homo sapiens IGKV2-30*02 (92.00%) -IGKJ1*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; (227-227":230-230")-bisdisulfide dimer; conjugated, on an average of 3 to 4 lysyl, to maytansinoid DM1 via a thiopentanoate linker For the mertansine part, please refer to the document "INN for pharmaceutical substances: Names for radicals, groups & others"*. antineoplastic
lorvotuzumab mertansine immunoglobuline G1-kappa, anti-[Homo sapiens NCAM1 (molécule d’adhésion 1 de cellule neurale, CD56, NCAM-1)], anticorps monoclonal humanisé conjugué au maytansinoïde DM1; chaîne lourde gamma1 (1-448) [VH humanisé (Homo sapiens IGHV3-30*03 (91.80%) -(IGHD)-IGHJ4*01) [8.8.11] (1-118) -Homo sapiens IGHG1*01 (119-448)], (221-219')-disulfure avec la chaîne légère kappa (1’-219’) [V-KAPPA humanisé (Homo sapiens IGKV2- 30*02 (92.00%) -IGKJ1*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; dimère (227-227":230-230")-bisdisulfure; conjugué, sur 3 à 4 lysyl en moyenne, au maytansinoïde DM1 via un linker thiopentanoate Pour la partie mertansine, veuillez vous référer au document "INN for pharmaceutical substances: Names for radicals, groups & others"*. antinéoplasique
150 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103
lorvotuzumab mertansina inmunoglobulina G1-kappa, anti-[Homo sapiens NCAM1 (molécula de adhesión 1 de celula neural, CD56, NCAM-1)], anticuerpo monoclonal humanizado conjugado con maitansinoide DM1; cadena pesada gamma1 (1-448) [VH humanizado (Homo sapiens IGHV3-30*03 (91.80%) -(IGHD)-IGHJ4*01) [8.8.11] (1-118) -Homo sapiens IGHG1*01 (119-448)], (221-219')-disulfuro con la cadena ligera kappa (1’-219’) [V-KAPPA humanizado (Homo sapiens IGKV2-30*02 (92.00%) -IGKJ1*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; dimero (227-227":230-230")-bisdisulfuro; conjugado, en 3 a 4 residuos lisil por término medio, con maitansinoide DM1 con un conector tiopentanoato Por la parte mertansina, por favor, vaya al documento "INN for pharmaceutical substances: Names for radicals, groups & others"*. antineoplásico
1008106-64-6
Heavy chain / Chaîne lourde / Cadena pesada QVQLVESGGG VVQPGRSLRL SCAASGFTFS SFGMHWVRQA PGKGLEWVAY 50 ISSGSFTIYY ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARMR 100 KGYAMDYWGQ GTLVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY 150 FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI 200 CNVNHKPSNT KVDKKVEPKS CDKTHTCPPC PAPELLGGPS VFLFPPKPKD 250 TLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST 300 YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY 350 TLPPSRDELT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD 400 SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPGK 448 Light chain / Chaîne légère / Cadena ligera DVVMTQSPLS LPVTLGQPAS ISCRSSQIII HSDGNTYLEW FQQRPGQSPR 50 RLIYKVSNRF SGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCFQGSHVP 100 HTFGQGTKVE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK 150 VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE 200 VTHQGLSSPV TKSFNRGEC 219 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 145-201 262-322 368-426 22''-96'' 145''-201'' 262''-322'' 368''-426'' Intra-L 23'-93' 139'-199' 23'''-93''' 139'''-199''' Inter-H-L 221-219' 221''-219''' Inter-H-H 227-227'' 230-230''
N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 298, 298''
maraciclatidum maraciclatide N6-(5-{[5-{[3-(hydroxyimino)-2-methylbutan-2-yl]amino}-3-(2-{[3- (hydroxyimino)-2-methylbutan-2-yl]amino}ethyl)pentyl]amino}- 2 5-oxopentanoyl)-N -(2-sulfanylacetyl)-L-lysyl-L-cysteinyl- L-arginylglycyl-L-α-aspartyl-L-cysteinyl-L-phenylalanyl-N-(17-amino- 13,17-dioxo-3,6,9,15-tetraoxa-12-azaheptadecyl)-L-cysteinamide cyclic (2→6)-disulfide cyclic (1→8)-thioether diagnostic agent
maraciclatide (2→6)-disulfure cyclique et (1→8)-thioéther cyclique du N6-(5-{[5-{[3- (hydroxyimino)-2-méthylbutan-2-yl]amino}-3-(2-{[3-(hydroxyimino)-2- méthylbutan-2-yl]amino}éthyl)pentyl]amino}-5-oxopentanoyl)- 2 N -(2-sulfanylacétyl)-L-lysyl-L-cystéinyl-L-arginylglycyl-L-α-aspartyl- L-cystéinyl-L-phénylalanyl-N-(17-amino-13,17-dioxo-3,6,9,15- tétraoxa-12-azaheptadécyl)-L-cystéinamide produit à usage diagnostique
151 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010
maraciclatida (2→6)- disulfuro ciclíco y (1→8)-tioéter cíclico del N6-(5-{[5-{[3- (hidroxiimino)-2-metilbutan-2-il]amino}-3-(2-{[3-(hidroxiimino)- 2-metilbutan-2-il]amino}etil)pentil]amino}-5-oxopentanoil)- 2 N -(2-sulfanilacetil)-L-lisil-L-cisteinil-L-arginilglicil-L-α-aspartil- L-cisteinil-L-fenilalanil-N-(17-amino-13,17-dioxo-3,6,9,15-tetraoxa- 12-azaheptadecil)-L-cisteinamida agente de diagnóstico
C72H120N20O21S3 489427-17-0
O O O O H2N N O H O S H
Lys Cys Arg Gly Asp Cys Phe N N O 6 H H N O O
O NH
H C CH H C CH HO 3 3 3 3 OH N N N N H H CH3 CH3
metformini glycinas metformin glycinate N,N-dimethyl-1,2,3-triimidodicarbonic diamide glycinate (1:1) antidiabetic
glycinate de metformine glycinate du diamide N,N-diméthyl-1,2,3-triimidodicarbonique (1:1) antidiabétique
glicinato de metformina glicinato de la diamida N,N-dimetil-1,2,3-triimidodicarbóníco (1:1) hipoglucemiante
C4H11N5 . C2H5NO2 121369-64-0
NH NH CH3 . H2N N N H2N CO2H H CH3
mibampatorum mibampator N-[(2R)-2-{4'-[2-(methanesulfonamido)ethyl][1,1'-biphenyl]- 4-yl}propyl]propane-2-sulfonamide antipsychotic
mibampator N-[(2R)-2-{4'-[2-(méthanesulfonamido)éthyl][1,1'-biphényl]- 4-yl}propyl]propane-2-sulfonamide antipsychotique
mibampator N-[(2R)-2-{4'-[2-(metanosulfonamido)etil][1,1'-bifenil]- 4-il}propil]propano-2-sulfonamida antisicótico
152 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103
C21H30N2O4S2 375345-95-2
H N CH3 S OO O O
H3C S N H HCH CH3 3
navitoclaxum navitoclax 4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en- 1-yl]methyl}piperazin-1-yl)-N-(4-{[(2R)-4-(morpholin-4-yl)- 1-(phenylsulfanyl)butan-2-yl]amino}- 3-(trifluoromethanesulfonyl)benzenesulfonyl]benzamide antineoplastic
navitoclax 4-(4-{[2-(4-chlorophényl)-5,5-diméthylcyclohex-1-én- 1-yl]méthyl}pipérazin-1-yl)-N-(4-{[(2R)-4-(morpholin-4-yl)- 1-(phénylsulfanyl)butan-2-yl]amino}- 3-(trifluorométhanesulfonyl)benzènesulfonyl]benzamide antinéoplasique
navitoclax 4-(4-{[2-(4- clorofenil)-5,5- dimetilciclohex -1-en-1-il]metil}piperazin- 1-il)-N-(4-{[(2R)-1-(fenilsulfanil)-4-(morfolin-4-il)-butan-2-il]amino}- 3-(trifluorometanosulfonil)bencenosulfonil]benzamida antineoplásico
C47H55ClF3N5O6S3 923564-51-6
O O O O O S S H C CH N CF3 3 3 H N NH N H S N O
Cl
nonacogum beta pegolum # nonacog beta pegol pegylated human blood coagulation factor IX; human blood-coagulation factor IX (EC 3.4.21.22, Christmas factor, plasma thromboplastin component), on average of one sialyl unit of the N-linked carbohydrates are 5-N-[N-({2,3-bis[ω- methoxypoly(oxyethane-1,2-diyl)]propoxy}carbonyl)glycyl]- 5-N-deacetyl blood coagulation factor
153 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010
nonacog bêta pegol facteur IX humain de coagulation sanguine, pégylé facteur IX humain de coagulation (EC 3.4.21.22, facteur Christmas, facteur antihémophile B) dont quelques unités sialyl, en moyenne une par molécule d’enzyme, de la partie N-glycosyl sont 5-N-[N- ({2,3-bis[ω-méthoxypoly(oxyéthylène)]propoxy}carbonyl)glycyl]- 5-N-désacétyl facteur de coagulation sanguine
nonacog beta pegol factor IX humano de coagulación sanguínea, pegilado factor IX humano de coagulación (EC 3.4.21.22, factor Christmas, factor antihemofilico B) algunas de cuyas unidades sialil, una por molécula de enzima, por término medio, de la fracción N-glicosil son 5-N-[N-({2,3-bis[ω-metoxipoli(oxietilen)]propoxi}carbonil)glicil]- 5-N-desacetil factor de coagulación de la sangre
1175512-71-6
YNSGKLEEFV QGNLERECME EKCSFEEARE VFENTERTTE FWKQYVDGDQ 50 CESNPCLNGG SCKDDINSYE CWCPFGFEGK NCELDVTCNI KNGRCEQFCK 100 NSADNKVVCS CTEGYRLAEN QKSCEPAVPF PCGRVSVSQT SKLTRAEAVF 150 PDVDYVNSTE AETILDNITQ STQSFNDFTR VVGGEDAKPG QFPWQVVLNG 200 KVDAFCGGSI VNEKWIVTAA HCVETGVKIT VVAGEHNIEE TEHTEQKRNV 250 IRIIPHHNYN AAINKYNHDI ALLELDEPLV LNSYVTPICI ADKEYTNIFL 300 KFGSGYVSGW GRVFHKGRSA LVLQYLRVPL VDRATCLRST KFTIYNNMFC 350 AGFHEGGRDS CQGDSGGPHV TEVEGTSFLT GIISWGEECA MKGKYGIYTK 400 VSRYVNWIKE KTKLT 415 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro 18-23 51-62 56-71 73-82 88-99 95-109 111-124 132-289 206-222 336-350 361-389 Modified residues / Résidus modifiés / Residuos modifícados HO C E 2 H NH2 7-8-15-17-20-21-26-27-30-33-36-40 4-carboxyGlu HO C CO H 2 2 Glycosylation sites (N) / Sites de glycosylation (N) / Posiciones de glicosilación (N) Asn-157 Asn-167 R→3-β-Gal→3-β-Gl-N→2-α-Man→6- β-Man→4-β-Gl-N→4-β-Gl-N→N 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 Gal = D-galactopyranosyl Gl-N = 2-(acetylamino)-2-deoxy-D-glucopyranosyl Man = D-mannopyranosyl PEG- = O-[α-methylpoly(oxyethylene) hydrogen phosphate] Sia = 5-N-acetyl-α-neuramin-2-yl
Other positions of post-translational modifications: partial-hydroxylation of Asp64; O-linked glycosylation on positions Ser53 and Ser61, partially O-linked glycosylation on positions Thr159 and Thr169
Autres positions de modifications post-traductionelles: hydroxylation partielle de Asp64; glycosylation O-liée sur les positions Sér53 et Sér61, glycosylation partielle O-liée sur les positions Thr159 et Thr169
Otras posiciones de modificaciones post-traducción hidroxilación parcial de Asp64; glicosilación O-ligada en las posiciones Ser53 y Ser61, glicosilación parcial O-ligada en las posiciones Thr159 y Thr169
154 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103
obenoxazinum obenoxazine 5-ethoxy-2-{[2-(morpholin-4-yl)ethyl]sulfanyl}-1H-benzimidazole anxiolytic
obenoxazine 5-éthoxy-2-{[2-(morpholin-4-yl)éthyl]sulfanyl}-1H-benzimidazole anxiolytique
obenoxazina 5-etoxi-2-{[2-(morfolin-4-il)etil]sulfanil}-1H-benzoimidazol ansiolítico
C15H21N3O2S 173352-21-1
O NH O H C 3 N N S
olaratumabum # olaratumab immunoglobulin G1-kappa, anti-[Homo sapiens PDGFRA (platelet- derived growth factor receptor alpha subunit, CD140a, PDGFR2)], Homo sapiens monoclonal antibody; gamma1 heavy chain (1-457) [Homo sapiens VH (IGHV4-39*01 (90.90%) -(IGHD)-IGHJ5*01 G119>D) [10.7.19] (1-127) -IGHG1*03 (128-457)], (230-214')-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')]; (236-236'':239-239'')- bisdisulfide dimer antineoplastic
olaratumab immunoglobuline G1-kappa, anti-[Homo sapiens PDGFRA (sous- unité alpha du récepteur du facteur de croissance dérivé des plaquettes, CD140a, PDGFR2)], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-457) [Homo sapiens VH (IGHV4-39*01 (90.90%) -(IGHD)-IGHJ5*01 G119>D) [10.7.19] (1-127) -IGHG1*03 (128-457)], (230-214')-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 (236-236'':239-239'')- bisdisulfure antinéoplasique
olaratumab inmunoglobulina G1-kappa, anti-[Homo sapiens PDGFRA (subunidad alfa del receptor del factor de crecimiento derivado de las plaquetas, CD140a, PDGFR2)], Homo sapiens anticuerpo monoclonal; cadena pesada gamma1 (1-457) [Homo sapiens VH (IGHV4-39*01 (90.90%) -(IGHD)-IGHJ5*01 G119>D) [10.7.19] (1-127) -IGHG1*03 (128-457)], (230-214')-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')]; dimero (236-236'':239-239'')- bisdisulfuro antineoplásico
155 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010
1024603-93-7
Heavy chain / Chaîne lourde / Cadena pesada QLQLQESGPG LVKPSETLSL TCTVSGGSIN SSSYYWGWLR QSPGKGLEWI 50 GSFFYTGSTY YNPSLRSRLT ISVDTSKNQF SLMLSSVTAA DTAVYYCARQ 100 STYYYGSGNY YGWFDRWDQG TLVTVSSAST KGPSVFPLAP SSKSTSGGTA 150 ALGCLVKDYF PEPVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSVVTVPS 200 SSLGTQTYIC NVNHKPSNTK VDKRVEPKSC DKTHTCPPCP APELLGGPSV 250 FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK 300 PREEQYNSTY RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK 350 GQPREPQVYT LPPSREEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN 400 YKTTPPVLDS DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS 450 LSLSPGK 457 Light chain / Chaîne légère / Cadena ligera EIVLTQSPAT LSLSPGERAT LSCRASQSVS SYLAWYQQKP GQAPRLLIYD 50 ASNRATGIPA RFSGSGSGTD FTLTISSLEP EDFAVYYCQQ RSNWPPAFGQ 100 GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150 DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200 LSSPVTKSFN RGEC 214 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-97 154-210 271-331 377-435 22''-97'' 154''-210'' 271''-331'' 377''-435'' Intra-L 23'-88' 134'-194' 23'''-88''' 134'''-194''' Inter-H-L 230-214' 230''-214''' Inter-H-H 236-236'' 239-239''
N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 30, 30'', 307, 307''
olokizumabum # olokizumab immunoglobulin G4-kappa, anti-[Homo sapiens IL6 (interleukin 6; IL-6)], humanized monoclonal antibody; gamma4 heavy chain (1-447) [humanized VH (Homo sapiens IGHV3-72*01 (84.00%) -(IGHD)-IGHJ4*01) [8.10.11] (1-120) -Homo sapiens IGHG4*01 hinge S10(228)>P (121-447)], (134-214')- disulfide with kappa light chain (1'-214') [humanized V-KAPPA (Homo sapiens IGKV1-33*01 (84.20%) -IGKJ2*01) [6.3.9] (1'-107') - Homo sapiens IGKC*01 (108'-214')]; (226-226":229-229")- bisdisulfide dimer immunomodulator
olokizumab immunoglobuline G4-kappa, anti-[Homo sapiens Homo sapiens IL6 (interleukine 6; IL-6)], anticorps monoclonal humanisé; chaîne lourde gamma4 (1-447) [VH humanisé (Homo sapiens IGHV3-72*01 (84.00%) -(IGHD)-IGHJ4*01) [8.10.11] (1-120) -Homo sapiens IGHG4*01 charnière S10(228)>P (121-447)], (134-214')- disulfure avec la chaîne légère kappa (1'-214') [V-KAPPA humanisé (Homo sapiens IGKV1-33*01 (84.20%) -IGKJ2*01) [6.3.9] (1'-107') - Homo sapiens IGKC*01 (108'-214')]; dimère (226-226":229-229")- bisdisulfure immunomodulateur
olokizumab inmunoglobulina G4-kappa, anti-[Homo sapiens Homo sapiens IL6 (interleukina 6; IL-6)], anticuerpo monoclonal humanizado; cadena pesada gamma4 (1-447) [VH humanizado (Homo sapiens IGHV3-72*01 (84.00%) -(IGHD)-IGHJ4*01) [8.10.11] (1-120) -Homo sapiens IGHG4*01 bisagra S10(228)>P (121-447)], (134-214')- disulfuro con la cadena ligera kappa (1'-214') [V-KAPPA humanizado (Homo sapiens IGKV1-33*01 (84.20%) -IGKJ2*01) [6.3.9] (1'-107') - Homo sapiens IGKC*01 (108'-214')]; dímero (226-226":229-229")- bisdisulfuro inmunomodulador
156 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103
1007223-17-7
Heavy chain / Chaîne lourde / Cadena pesada EVQLVESGGG LVQPGGSLRL SCAASGFNFN DYFMNWVRQA PGKGLEWVAQ 50 MRNKNYQYGT YYAESLEGRF TISRDDSKNS LYLQMNSLKT EDTAVYYCAR 100 ESYYGFTSYW GQGTLVTVSS ASTKGPSVFP LAPCSRSTSE STAALGCLVK 150 DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTKT 200 YTCNVDHKPS NTKVDKRVES KYGPPCPPCP APEFLGGPSV FLFPPKPKDT 250 LMISRTPEVT CVVVDVSQED PEVQFNWYVD GVEVHNAKTK PREEQFNSTY 300 RVVSVLTVLH QDWLNGKEYK CKVSNKGLPS SIEKTISKAK GQPREPQVYT 350 LPPSQEEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS 400 DGSFFLYSRL TVDKSRWQEG NVFSCSVMHE ALHNHYTQKS LSLSLGK 447 Light chain / Chaîne légère / Cadena ligera DIQMTQSPSS LSASVGDRVT ITCQASQDIG ISLSWYQQKP GKAPKLLIYN 50 ANNLADGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCLQ HNSAPYTFGQ 100 GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150 DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200 LSSPVTKSFN RGEC 214 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfur Intra-H 22-98 147-203 261-321 367-425 22''-98'' 147''-203'' 261''-321'' 367''-425'' Intra-L 23'-88' 134'-194' 23'''-88''' 134'''-194''' Inter-H-L 134-214' 134''-214''' Inter-H-H 226-226'' 229-229''
N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 297, 297''
opicaponum opicapone 2,5-dichloro-3-[5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl]- 4,6-dimethylpyridine N-oxide antiparkinsonian
opicapone N-oxyde de 2,5-dichloro-3-[5-(3,4-dihydroxy-5-nitrophényl)- 1,2,4-oxadiazol-3-yl]-4,6-diméthylpyridine antiparkinsonien
opicapona N-óxido de 2,5-dicloro-3-[5-(3,4-dihidroxi-5-nitrofenil)- 1,2,4-oxadiazol-3-il]-4,6-dimetilpiridina antiparkinsoniano
C15H10Cl2N4O6 923287-50-7
H3C Cl N O CH3 O N 2 N N Cl O HO OH
orantinibum orantinib 3-(2,4-dimethyl-5-{[(3Z)-2-oxo-1,2-dihydro-3H-indol- 3-ylidene]methyl}-1H-pyrrol-3-yl)propanoic acid antineoplastic
orantinib acide 3-(2,4-diméthyl-5-{[(3Z)-2-oxo-1,2-dihydro-3H-indol- 3-ylidène]méhyl}-1H-pyrrol-3-yl)propanoïque antinéoplasique
157 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010
orantinib ácido 3-(2,4-dimetil-5-{[(3Z)-2-oxo-1,2-dihidro-3H-indol- 3-ilideno]metil}-1H-pirrol-3-il)propanoico antineoplásico
C18H18N2O3 252916-29-3
H N O H N CH3
CO2H H3C
oxelumabum # oxelumab immunoglobulin G1-kappa, anti-[Homo sapiens TNFSF4 (Tumor necrosis factor ligand superfamily member 4, OX40 ligand, OX-40L, TAX transcriptionally-activated glycoprotein 1, TXGP1, gp34, CD252], Homo sapiens monoclonal antibody; gamma1 heavy chain (1-449) [Homo sapiens VH (IGHV3-23*01 (94.90%) -(IGHD)-IGHJ4*01 T122>A) [8.8.13] (1-120) -IGHG1*01 K130>del (121-449)], (223-214')-disulfide with kappa light chain (1'- 214') [Homo sapiens V-KAPPA (IGKV1D-16*01 (100.00%) - IGKJ2*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; (229-229'':232- 232'')-bisdisulfide dimer immunomodulator
oxélumab immunoglobuline G1-kappa, anti-[Homo sapiens TNFSF4 (membre 4 de la superfamille des ligands du facteur de nécrose tumorale, ligand de OX40, OX40L, glycoprotéine 1 activée transcriptionellement par TAX, TXGP1, CD252], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-449) [Homo sapiens VH (IGHV3-23*01 (94.90%) -(IGHD)-IGHJ4*01 T122>A) [8.8.13] (1-120) -IGHG1*01 K130>del (121-449)], (223-214')-disulfure avec la chaîne légère kappa (1'-214') [Homo sapiens V-KAPPA (IGKV1D-16*01 (100.00%) -IGKJ2*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dimère (229- 229'':232-232'')-bisdisulfure immunomodulateur
oxelumab inmunoglobulina G1-kappa, anti-[Homo sapiens TNFSF4 (miembro 4 de la superfamilia de ligandos del factor de necrosis tumoral, ligando de OX40, OX40L, glicoproteína 1 activada por transcripción por TAX, TXGP1, CD252 ], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma1 (1-449) [Homo sapiens VH (IGHV3-23*01 (94.90%) -(IGHD)-IGHJ4*01 T122>A) [8.8.13] (1-120) -IGHG1*01 K130>del (121-449)], (223-214')-disulfuro con la cadena ligera kappa (1'-214') [Homo sapiens V-KAPPA (IGKV1D-16*01 (100.00%) -IGKJ2*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dimero (229- 229'':232-232'')-bisdisulfuro inmunomodulador
158 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103
89957-37-9
Heavy chain / Chaîne lourde / Cadena pesada EVQLLESGGG LVQPGGSLRL SCAASGFTFN SYAMSWVRQA PGKGLEWVSI 50 ISGSGGFTYY ADSVKGRFTI SRDNSRTTLY LQMNSLRAED TAVYYCAKDR 100 LVAPGTFDYW GQGALVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK 150 DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT 200 YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP 250 KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 300 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ 350 VYTLPPSRDE LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV 400 LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPG 449 Light chain / Chaîne légère / Cadena ligera DIQMTQSPSS LSASVGDRVT ITCRASQGIS SWLAWYQQKP EKAPKSLIYA 50 ASSLQSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQQ YNSYPYTFGQ 100 GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150 DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200 LSSPVTKSFN RGEC 214 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 147-203 264-324 370-428 22''-96'' 147''-203'' 264''-324'' 370''-428'' Intra-L 23'-88' 134'-194' 23'''-88''' 134'''-194''' Inter-H-L 223-214' 223''-214''' Inter-H-H 229-229'' 232-232''
N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 300, 300''
paliflutinum paliflutine {4-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}[5- (methanesulfonyl)-2-{[(2S)-1,1,1-trifluoropropan- 2-yl]oxy}phenyl]methanone neuroleptic
paliflutine {4-[3-fluoro-5-(trifluorométhyl)pyridin-2-yl]pipérazin-1-yl}[5- (méthanesulfonyl)-2-{[(2S)-1,1,1-trifluoropropan- 2-yl]oxy}phényl]méthanone neuroleptique
paliflutina {4-[3-fluoro-5-(trifluorometil)piridin-2-il]piperazin-1-il}[5- (metanosulfonil)-2-{[(2S)-1,1,1-trifluoropropan- 2-il]oxy}fenil]metanona neuroléptico
C21H20F7N3O4S 845614-11-1
O O O S H3C N F N O H N CF3 CF3 H3C
159 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010
pegdinetanibum pegdinetanib pegylated 94 residues protein derived from human fibronectin 10th type III domain: glycyl[1438-L-arginine(D>R),1439-L-histidine(A>H),1441-L- histidine(A>H),1442-L-phenylalanine(V>F),1443-L- proline(T>P),1444-L-threonine(V>T),1467-L-leucine(G>L),1468-L- glutamine(S>Q),1469-L-proline(K>P),1470-L-proline(S>P),1492-L- aspartic acid(G>D),1493-glycine(R>G),1494-L-arginine(G>R),1495- L-asparagine(D>N),1496-glycine(S>G),1497-L-arginine(P>R),1498-L- leucine(A>L),1499-L-leucine(S>L),1501-L-isoleucine(K>I),1515-S- [(3RS)-1-(1-{[α-methylpoly(oxyethylene)]carbamoyl}-3-[({[α- methylpoly(oxyethylene)]carbamoyl}oxy)methyl]-8,13-dioxo- 1,4-dioxa-9,12-diazapentadecan-15-yl)-2,5-dioxopyrrolidin-3-yl]- L-cysteine(S>C)]human fibronectin-(1424-1516)-peptide antineoplastic
pegdinétanib protéine de 94 résidus derivée du 10ème domaine de type III de la fibronectine humaine pégylée : glycyl[1438-L-arginine(D>R),1439-L-histidine(A>H),1441-L- histidine(A>H),1442-L-phénylalanine(V>F),1443-L- proline(T>P),1444-L-thréonine(V>T),1467-L-leucine(G>L),1468-L- glutamine(S>Q),1469-L-proline(K>P),1470-L-proline(S>P),1492- acide L-aspartique(G>D),1493-glycine(R>G),1494-L- arginine(G>R),1495-L-asparagine(D>N),1496-glycine(S>G),1497-L- arginine(P>R),1498-L-leucine(A>L),1499-L-leucine(S>L),1501-L- isoleucine(K>I),1515-S-[(3RS)-1-(1-{[α- méthylpoly(oxyéthylène)]carbamoyl}-3-[({[α- méthylpoly(oxyéthylène)]carbamoyl}oxy)méthyl]-8,13-dioxo- 1,4-dioxa-9,12-diazapentadécan-15-yl)-2,5-dioxopyrrolidin-3-yl]- L-cysteine(S>C)]fibronectine humaine-(1424-1516)-peptide antinéoplasique
pegdinetanib proteína de 94 residuos derivada del décimo dominio de tipo III de la fibronectina humana pegilada : glicil[1438-L-arginina(D>R),1439-L-histidina(A>H), 1441-L-histidina(A>H),1442-L-fenilalanina(V>F),1443-L- prolina(T>P),1444-L-treonina(V>T),1467-L-leucina(G>L),1468-L- glutamina(S>Q),1469-L-prolina(K>P),1470-L-prolina(S>P),1492- ácido L-aspártico(G>D),1493-glicina(R>G),1494-L- arginina(G>R),1495-L-asparagina(D>N),1496-glicina(S>G),1497-L- arginina(P>R),1498-L-leucina(A>L),1499-L-leucina(S>L), 1501-L-isoleucina(K>I),1515-S-[(3RS)-1-(1-{[α- metilpoli(oxietileno)]carbamoil}-3-[({[α- metilpoli(oxietileno)]carbamoil}oxi)metil]-8,13-dioxo-1,4-dioxa- 9,12-diazapentadecan-15-il)-2,5-dioxopirrolidin-3-il]- L-cisteína(S>C)]fibronectina humana-(1424-1516)-péptido antineoplásico
160 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103
906450-24-6
GEVVAATP TSLLISWRHP HFPTRYYRIT 1450 YGETGGNSPV QEFTVPLQPP TATISGLKPG VDYTITVYAV TDGRNGRLLS 1500 IPISINYRTE IDKPCQ 1516
Modified residue / Résidu modifié / Residuo modificado H C O N 1515 pegylated cystein H cystéine pégylée H3C N O cisteína pegilada O NH n O O H O O N H S H3C N O H O n O O n # 450 N H O
peginesatidum peginesatide pegylated erythropoietin receptor agonist, N6.21,N6.21'-{[(N2,N6-bis{[ω-methoxypoly(oxyethylene)]carbonyl}- L-lysyl-β-alanyl)imino]bis(methylenecarbonyl)}bis[acetylglycylglycyl- L-leucyl-L-tyrosyl-L-alanyl-L-cysteinyl-L-histidyl-L-methionylglycyl- L-prolyl-L-isoleucyl-L-threonyl-3-(naphtalen-1-yl)-L-alanyl-L-valyl- L-cysteinyl-L-glutaminyl-L-prolyl-L-leucyl-L-arginyl-N-methylglycyl- L-lysinamide] (6→15:6'→15')-bisdisulfure cyclic antianaemic
péginésatide agoniste du récepteur de l'érythropoïétine, pégylé (6→15:6'→15')-bisdisulfure cyclique du N6.21,N6.21'- 2 6 {[(N ,N -bis{[ω-méthoxypoly(oxyéthylène)]carbonyl}-L-lysyl- β-alanyl)imino]bis(méthylènecarbonyl)}bis[acétylglycylglycyl-L-leucyl- L-tyrosyl-L-alanyl-L-cystéinyl-L-histidyl-L-méthionylglycyl-L-prolyl- L-isoleucyl-L-thréonyl-3-(naphtalén-1-yl)-L-alanyl-L-valyl-L-cystéinyl- L-glutaminyl-L-prolyl-L-leucyl-L-arginyl-N-méthylglycyl-L-lysinamide] antianémique
peginesatida agonista del receptor de la eritropoyetina, pegilado (6→15:6'→15')-bisdisulfuro cíclico del N6.21,N6.21'- 2 6 {[(N ,N -bis{[ω-metoxipoly(oxietileno)]carbonil}-L-lisil- β-alanil)imino]bis(metilenocarbonil)}bis[acetilglicilglicil-L-leucil- L-tirosil-L-alanil-L-cisteinil-L-histidil-L-metionilglicil-L-prolil- L-isoleucil-L-treonil-3-(naftalen-1-il)-L-alanil-L-valil-L-cisteinil- L-glutaminil-L-prolil-L-leucil-L-arginil-N-metilglicil-L-lisinamida] antianémico
161 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010
913976-27-9
O Gly Gly Leu Tyr Ala Cys His Met Gly
H3C Pro Ile Thr Nal Val Cys Gln Pro Leu Arg Sar Lys NH2 10 20 6 O N O H3C O N O a H N n = a + b # 900 O H O O NH O H3C O N b H O O Gly Gly Leu Tyr Ala Cys His Met Gly
H3C N6 Pro Ile Thr Nal Val Cys Gln Pro Leu Arg Sar Lys NH2 10' 20'
3-(naphthalen-1- yl)-L-alanyl Sar = N H N-methylglycyl CH3 O Nal = N H O
pegsiticasum # pegsiticase pegylated Urate Oxidase from Candida utilis, [198-threonine(S>T)]uricase (EC 1.7.3.3, urate oxidase) Pichia jadinii (Yeast) (Candida utilis) tetramer, 6-amino group of an average of 3 lysine residues, mostly in position 16, 19, and 85 of each monomer, are amidified with α-(3-carboxypropanoyl)- ω-methoxypoly(oxyethylene) enzyme
pegsiticase urate oxidase de Candida utilis pégylée, [198-thréonine(S>T)]uricase (EC 1.7.3.3, urate oxydase) Pichia jadinii (levure) (Candida utilis), tétramère, la fonction amine en 6 de certaines lysines, en moyenne 3, principalement en positions 16, 19, and 85 de chaque monomère, sont amidifiées par le α-(3-carboxypropanoyl)-ω-méthoxypoly(oxyéthylène) enzyme
pegsiticasa urato oxidasa de Candida utilis pegilada, [198-treonina(S>T)]uricasa (EC 1.7.3.3, urato oxidasa) Pichia jadinii (levadura) (Candida utilis), tetrámero, la función amina en 6 de ciertas lisinas, 3 por término medio, principalmente en las posiciones 16, 19, and 85 de cada monómero, está amidificada con α-(3-carboxipropanoil)-ω-metoxipoli(oxietileno) enzima
162 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103
1040753-26-1
Monomer / Monomère / Monómero MSTTLSSSTY GKDNVKFLKV KKDPQNPKKQ EVMEATVTCL LEGGFDTSYT 50 EADNSSIVPT DTVKNTILVL AKTTEIWPIE RFAAKLATHF VEKYSHVSGV 100 SVKIVQDRWV KYAVDGKPHD HSFIHEGGEK RITDLYYKRS GDYKLSSAIK 150 DLTVLKSTGS MFYGYNKCDF TTLQPTTDRI LSTDVDATWV WDNKKIGTVY 200 DIAKAADKGI FDNVYNQARE ITLTTFALEN SPSVQATMFN MATQILEKAC 250 SVYSVSYALP NKHYFLIDLK WKGLENDNEL FYPSPHPNGL IKCTVVRKEK 300 TKL 303 Modified residues / Résidus modifiés / Residuos modificados O K H3C O 16, 19, 85 O NH main pegylation sites n principaux sites pégylés O principios sitios pegilado H
N H O
ponesimodum ponesimod (2Z,5Z)-5-{3-chloro-4-[(2R)-2,3- dihydroxypropoxy]phenylmethylidene}-3-(2-methylphenyl)- 2-(propylimino)-1,3-thiazolidin-4-one immunomodulator
ponésimod (2Z,5Z)-5-{3-chloro-4-[(2R)-2,3- dihydroxypropoxy]phénylméthylidène}-3-(2-méthylphényl)- 2-(propylimino)-1,3-thiazolidin-4-one immunomodulateur
ponesimod (2Z,5Z)-5-{3-cloro-4-[(2R)-2,3-dihidroxipropoxi]fenilmetilideno}- 3-(2-metilfenil)-2-(propilimino)-1,3-tiazolidin-4-ona inmunomodulador
C23H25CIN2O4S 854107-55-4
O Cl N
CH3 S O OH N HOH
CH3
rezatomidinum rezatomidine 4-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1,3-dihydro-2H-imidazol- 2-thione α2-adrenoreceptor antagonist
rézatomidine 4-[(1S)-1-(2,3-diméthylphényl)éthyl]-1,3-dihydro-2H-imidazole- 2-thione antagoniste des récepteurs α2-adrénergiques
rezatomidina 4-[(1S)-1-(2,3-dimetilfenil)etil]-1,3-dihidro-2H-imidazol-2-tiona antagonista del receptor α2-adrenérgico
163 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010
C13H16N2S 847829-38-3
H N S N H3C H HCH CH3 3
roledumabum # roledumab immunoglobulin G1-kappa, anti-[Homo sapiens RHD (Rhesus blood group D antigen, RhD, CD240D)], Homo sapiens monoclonal antibody; gamma1 heavy chain (1-456) [Homo sapiens VH (IGHV3-30*01 (86.70%) -(IGHD)-IGHJ3*02) [8.8.19] (1-126) -IGHG1*01 (127-456)], (229-214')-disulfide with kappa light chain (1'-214') [Homo sapiens V- KAPPA (IGKV1-8*01 (89.50%) -IGKJ1*01 K123>R, K127>T) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; (235-235'':238-238'')-bisdisulfide dimer inmunomodulador
rolédumab immunoglobuline G1-kappa, anti-[Homo sapiens RHD (antigène groupe sanguin Rhésus D, RhD, CD240D)], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-456) [Homo sapiens VH (IGHV3-30*01 (86.70%) -(IGHD)-IGHJ3*02) [8.8.19] (1-126) -IGHG1*01 (127-456)], (229-214')-disulfure avec la chaîne légère kappa (1'-214') [Homo sapiens V-KAPPA (IGKV1-8*01 (89.50%) -IGKJ1*01 K123>R, K127>T) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dimère (235- 235'':238-238'')-bisdisulfure immunomodulateur
roledumab inmunoglobulina G1-kappa, anti-[Homo sapiens RHD (antígeno sanguíneo D Rhesus, RhD, CD240D)], anticuerpo monoclonal de Homo sapiens ; cadena pesada gamma1 (1-456) [Homo sapiens VH (IGHV3-30*01 (86.70%) -(IGHD)-IGHJ3*02) [8.8.19] (1-126) -IGHG1*01 (127-456)], (229-214')-disulfuro con la cadena ligera kappa (1'-214') [Homo sapiens V-KAPPA (IGKV1-8*01 (89.50%) -IGKJ1*01 K123>R, K127>T) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dímero (235- 235'':238-238'')-bisdisulfuro inmunomodulador
164 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103
1174008-79-7
Heavy chain / Chaîne lourde / Cadena pesada QVQLVESGGG VVQPGRSLRL SCTASGFTFK NYAMHWVRQA PAKGLEWVAT 50 ISYDGRNIQY ADSVKGRFTF SRDNSQDTLY LQLNSLRPED TAVYYCARPV 100 RSRWLQLGLE DAFHIWGQGT MVTVSSASTK GPSVFPLAPS SKSTSGGTAA 150 LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS 200 SLGTQTYICN VNHKPSNTKV DKKVEPKSCD KTHTCPPCPA PELLGGPSVF 250 LFPPKPKDTL MISRTPEVTC VVVDVSHEDP EVKFNWYVDG VEVHNAKTKP 300 REEQYNSTYR VVSVLTVLHQ DWLNGKEYKC KVSNKALPAP IEKTISKAKG 350 QPREPQVYTL PPSRDELTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY 400 KTTPPVLDSD GSFFLYSKLT VDKSRWQQGN VFSCSVMHEA LHNHYTQKSL 450 SLSPGK 456 Light chain / Chaîne légère / Cadena ligera AIRMTQSPSS FSASTGDRVT ITCRASQDIR NYVAWYQQKS GKAPKFLIYA 50 ASTLQSGVPS RFSGSGSGTD FTLTINSLQS EDFATYYCQQ YYNSPPTFGQ 100 GTRVEITRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150 DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200 LSSPVTKSFN RGEC 214 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 153-209 270-330 376-434 22''-96'' 153''-209'' 270''-330'' 376''-434'' Intra-L 23'-88' 134'-194' 23'''-88''' 134'''-194''' Inter-H-L 229-214' 229''-214''' Inter-H-H 235-235'' 238-238''
N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 306, 306''
ruxolitinibum ruxolitinib (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol- 1-yl]propanenitrile antineoplastic
ruxolitinib (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol- 1-yl]propanenitrile antinéoplasique
ruxolitinib (3R)-3-ciclopentil-3-[4-(7H-pirrolo[2,3-d]pirimidin-4-il)-1H-pirazol- 1-il]propanonitrilo antineoplásico
C17H18N6 941678-49-5
H N CN N N N HN
samalizumabum # samalizumab immunoglobulin G2-kappa, anti-[Homo sapiens CD200 (OX-2)], humanized monoclonal antibody; gamma2 heavy chain (1-442) [humanized VH (Homo sapiens IGHV1-69*01 (73.50%) -(IGHD)-IGHJ4*01 L123>T, V124>L) [8.8.10] (1-117) -Homo sapiens IGHG2*01 CH1-hinge-CH2 1.6-1.1 (118- 232)- IGHG4*01 CH2 1-125, CH3 1-129 K130>del (233-442)], (131- 214')-disulfide with kappa light chain (1'-214') [humanized V-KAPPA (Homo sapiens IGKV1-33*01 (81.10%) -IGKJ2*01 Q120>G) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; (219-219":220- 220":223-223":226-226")-tetrakisdisulfide dimer antineoplastic
165 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010
samalizumab immunoglobuline G2-kappa, anti-[Homo sapiens CD200 (OX-2)], anticorps monoclonal humanisé; chaîne lourde gamma2 (1-442) [humanized VH (Homo sapiens IGHV1-69*01 (73.50%) -(IGHD)-IGHJ4*01 L123>T, V124>L) [8.8.10] (1-117) -Homo sapiens IGHG2*01 CH1-charnière-CH2 1.6-1.1 (118- 232)- IGHG4*01 CH2 1-125, CH3 1-129 K130>del (233-442)], (131- 214')-disulfure avec la chaîne légère kappa (1'-214') [V-KAPPA humanisé (Homo sapiens IGKV1-33*01 (81.10%) -IGKJ2*01 Q120>G) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dimère (219-219":220-220":223-223":226-226")-tétrakisdisulfure antinéoplasique
samalizumab inmunoglobulina G2-kappa, anti-[Homo sapiens CD200 (OX-2)], anticuerpo monoclonal humanizado; cadena pesado gamma2 (1- 442) [humanizado VH (Homo sapiens IGHV1-69*01 (73.50%) - (IGHD)-IGHJ4*01 L123>T, V124>L) [8.8.10] (1-117) -Homo sapiens IGHG2*01 CH1-bisagra-CH2 1.6-1.1 (118-232)- IGHG4*01 CH2 1- 125, CH3 1-129 K130>del (233-442)], (131-214')-disulfuro con la cadena ligera kappa (1'-214') [V-KAPPA humanizada(Homo sapiens IGKV1-33*01 (81.10%) -IGKJ2*01 Q120>G) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dímero (219-219":220-220":223- 223":226-226")-tetrakisdisulfuro antineoplásico
1073059-33-2
Heavy chain / Chaîne lourde / Cadena pesada QVQLQQSGSE LKKPGASVKI SCKASGYSFT DYIILWVRQN PGKGLEWIGH 50 IDPYYGSSNY NLKFKGRVTI TADQSTTTAY MELSSLRSED TAVYYCGRSK 100 RDYFDYWGQG TTLTVSSAST KGPSVFPLAP CSRSTSESTA ALGCLVKDYF 150 PEPVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSVVTVPS SNFGTQTYTC 200 NVDHKPSNTK VDKTVERKCC VECPPCPAPP VAGPSVFLFP PKPKDTLMIS 250 RTPEVTCVVV DVSQEDPEVQ FNWYVDGVEV HNAKTKPREE QFNSTYRVVS 300 VLTVLHQDWL NGKEYKCKVS NKGLPSSIEK TISKAKGQPR EPQVYTLPPS 350 QEEMTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT PPVLDSDGSF 400 FLYSRLTVDK SRWQEGNVFS CSVMHEALHN HYTQKSLSLS LG 442 Light chain / Chaîne légère / Cadena ligera DIQMTQSPSS LSASIGDRVT ITCKASQDIN SYLSWFQQKP GKAPKLLIYR 50 ANRLVDGVPS RFSGSGSGTD YTLTISSLQP EDFAVYYCLQ YDEFPYTFGG 100 GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150 DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200 LSSPVTKSFN RGEC 214 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 144-200 257-317 363-421 22''-96'' 144''-200'' 257''-317'' 363''-421'' Intra-L 23'-88' 134'-194' 23'''-88''' 134'''-194''' Inter-H-L 131-214' 131''-214''' Inter-H-H 219-219'' 220-220'' 223-223'' 226-226''
N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 293, 293''
silmitasertibum silmitasertib 5-[(3-chlorophenyl)amino]benzo[c][2,6]naphthyridine-8-carboxylic acid antineoplastic
silmitasertib acide 5-[(3-chlorophényl)amino]benzo[c][2,6]naphtyridine- 8-carboxylique antinéoplasique
166 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103
silmitasertib ácido 5-[(3-clorofenil)amino]benzo[c][2,6]naftiridina-8-carboxílico antineoplásico
C19H12ClN3O2 1009820-21-6
H N N CO2H
Cl N
simenepagum simenepag 5-({[(2R)-1-{4-[(1S)-1-hydroxyhexyl]phenyl}-5-oxopyrrolidin- 2-yl]methoxy}methyl)thiophene-2-carboxylic acid prostaglandin E2 receptor agonist
siménépag acide 5-({[(2R)-1-{4-[(1S)-1-hydroxyhexyl]phényl}-5-oxopyrrolidin- 2-yl]méthoxy}méthyl)thiophène-2-carboxylique agoniste du récepteur de la prostaglandine E2
simenepag ácido 5-({[(2R)-1-{4-[(1S)-1-hidroxihexil]fenil}-5-oxopirrolidin- 2-il]metoxi}metil)tiofeno-2- carboxílico agonista del receptor de prostaglandina E2
C23H29NO5S 910562-15-1
H S CO2H O N
O CH3
HOH
somatropinum pegolum # somatropin pegol N5.141-[(2E)-({2-[({2,3-bis[ω-methoxypoly(oxyethylene)]propoxy}= carbonyl)amino]ethoxy}imino)ethyl]human somatotropin (growth hormone) growth hormone derivative
somatropine pegol N5.141-[(2E)-({2-[({2,3-bis[ω-méthoxypoly(oxyéthylène)]propoxy}= carbonyl)amino]éthoxy}imino)éthyl]somatotropine humaine (hormone de croissance) dérivé d'hormone de croissance
somatropina pegol N5.141-[(2E)-({2-[({2,3-bis[ω-metoxipoli(oxietileno)]propoxi}= carbonil)amino]etoxi}imino)etil]somatotropina humana (hormona de crecimiento) derivativo de la hormona de crecimiento
167 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010
1088845-67-3
FPTIPLSRLF DNAMLRAHRL HQLAFDTYQE FEEAYIPKEQ KYSFLQNPQT 50 SLCFSESIPT PSNREETQQK SNLELLRISL LLIQSWLEPV QFLRSVFANS 100 LVYGASDSNV YDLLKDLEEG IQTLMGRLED GSPRTGQIFK QTYSKFDTNS 150 HNDDALLKNY GLLYCFRKDM DKVETFLRIV QCRSVEGSCG F 191
Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro 53-165 182-189
Modified residue / Résidu modifié / Residuo modificado H H3C O O N N O n O NH Q O O O Gln(141) H3C O n H n # 480 N H O
taprenepagum taprenepag 2-{3-[(N-{[4-(1H-pyrazol-1-yl)phenyl]methyl}pyridine- 3-sulfonamido)methyl]phenoxy}acetic acid prostaglandin E2 receptor agonist
taprénépag acide 2-{3-[(N-{[4-(1H-pyrazol-1-yl)phényl]méthyl}pyridine- 3-sulfonamido)méthyl]phénoxy}acétique agoniste des récepteurs E2 de la prostaglandine
taprenepag ácido 2-{3-[(N-{[4-(1H-pirazol-1-il)fenil]metil}piridina- 3-sulfonamido)metil]fenoxi}acético agonista del receptor E2 de prostaglandina
C24H22N4O5S 752187-80-7
O CO2H
N S O N N N O
tasocitinibum tasocitinib 3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile anti-inflammatory
tasocitinib 3-{(3R,4R)-4-méthyl-3-[méthyl(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino]pipéridin-1-yl}-3-oxopropanenitrile anti-inflammatoire
tasocitinib 3-{(3R,4R)-4-metil-3-[metil(7H-pirrolo[2,3-d]pirimidin- 4-il)amino]piperidin-1-il}-3-oxopropanonitrilo anti-inflamatorio
168 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103
C16H20N6O 477600-75-2
H3C N N H N HN N CN H CH3 O
tedalinabum tedalinab (4S,7R)-N-tert-butyl-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro- 1H-4,7-methanoindazole-3-carboxamide cannabinoid CB2 receptor agonist
tédalinab (4S,7R)-N-tert-butyl-1-(2,4-difluorophényl)-4,5,6,7-tétrahydro- 1H-4,7-méthanoindazole-3-carboxamide antagoniste des récepteurs CB2 aux cannabinoïdes
tedalinab (4S,7R)-N-terc-butil-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro- 1H-4,7-metanoindazol-3-carboxamida agonista del receptor CB2 de cannabinoides
C19H21F2N3O 916591-01-0
F O H3C CH3 N N N CH3 H F H H
tegobuvirum tegobuvir 5-({6-[2,4-bis(trifluoromethyl)phenyl]pyridazin-3-yl}methyl)- 2-(2-fluorophenyl)-5H-imidazo[4,5-c]pyridine antiviral
tégobuvir 5-({6-[2,4-bis(trifluorométhyl)phényl]pyridazin-3-yl}méthyl)- 2-(2-fluorophényl)-5H-imidazo[4,5-c]pyridine antiviral
tegobuvir 5-({6-[2,4-bis(trifluorometil)fenil]piridazin-3-il}metil)-2-(2-fluorofenil)- 5H-imidazo[4,5-c]piridina antiviral
C25H14F7N5 1000787-75-6
F3C F N N N CF N 3 N
169 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010
telapristonum telapristone 11β-[4-(dimethylamino)phenyl]-17-hydroxy-21-methoxy- 19-norpregna-4,9-diene-3,20-dione progesterone receptor antagonist
télapristone 11β-[4-(diméthylamino)phényl]-17-hydroxy-21-méthoxy- 19-norprégna-4,9-diène-3,20-dione antagoniste des récepteurs de la progestérone
telapristona 11β-[4-(dimetilamino)fenil]-17-hidroxi-21-metoxi-19-norpregna- 4,9-dieno-3,20-diona antagonista del receptor de progesterona
C29H37NO4 198414-30-1
CH3 O CH3 N O H3C H CH3 OH H
H O
temanogrelum temanogrel 3-methoxy-N-{3-(1-methyl-1H-pyrazol-5-yl)-4-[2-(morpholin- 4-yl)ethoxy]phenyl}benzamide platelet aggregation inhibitor
témanogrel 3-méthoxy-N-{3-(1-méthyl-1H-pyrazol-5-yl)-4-[2-(morpholin- 4-yl)éthoxy]phényl}benzamide antiagrégant plaquettaire
temanogrel N-{3-(1-metil-1H-pirazol-5-il)-4-[2-(morfolin-4-il)etoxi]fenil}- 3-metoxibenzamida inhibidor de la agregación plaquetaria
C24H28N4O4 887936-68-7
H3C N N H N H3CO O O N O
tiprelestatum tiprelestat human elafin (elastase-specific inhibitor, skin-derived antileukoproteinase, peptidase inhibitor 3) elastase inhibitor
tiprélestat élafine humaine (inhibiteur spécifique de l'élastase, antileukoprotéinase dérivé de la peau, inhibiteur 3 de peptidase) inhibiteur de l'élastase
170 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103
tiprelestat elafina humana (inhibidor específico de la elastasa, antileukoproteinasa derivada de la piel, inhibidor 3 de peptidasa) inhibidor de la elastasa
C254H416N72O75S10 820211-82-3
AQEPVKGPVS TKPGSCPIIL IRCAMLNPPN RCLKDTDCPG IKKCCEGSCG 50 MACFVPQ 57 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro 16-45 23-49 32-44 38-53
tivantinibum tivantinib (3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol- 3-yl)pyrrolidine-2,5-dione antineoplastic
tivantinib (3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoléin-1-yl)-4-(1H-indol- 3-yl)pyrrolidine-2,5-dione antinéoplasique
tivantinib (3R,4R)-3-(5,6-dihidro-4H-pirrolo[3,2,1-ij]quinolein-1-il)-4-(1H-indol- 3-il)pirrolidina-2,5-diona antineoplásico
C23H19N3O2 905854-02-6
H O N O
HN H H N
tofogliflozinum tofogliflozin (1S,3'R,4'S,5'S,6'R)-6-[(4-ethylphenyl)methyl]-6'-(hydroxymethyl)- 3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyran]-3',4',5'-triol antidiabetic
tofogliflozine (1S,3'R,4'S,5'S,6'R)-6-[(4-éthylphényl)méthyl]-6'-(hydroxyméthyl)- 3',4',5',6'-tétrahydro-3H-spiro[2-benzofuran-1,2'-pyran]-3',4',5'-triol antidiabétique
tofogliflozina (1S,3'R,4'S,5'S,6'R)-6-[(4-etilfenil)metil]-6'-(hidroximetil)- 3',4',5',6'-tetrahidro-3H-espiro[2-benzofurano-1,2'-pirano]-3',4',5'-triol hipoglucemiante
171 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010
C22H26O6 903565-83-3
HO
O O OH HO OH
CH3
trastuzumabum emtansinum # trastuzumab emtansine immunoglobulin G1-kappa, anti-[Homo sapiens ERBB2 (epidermal growth factor receptor 2, HER-2, p185c-erbB2, NEU, EGFR2)], humanized monoclonal antibody conjugated to maytansinoid DM1; gamma1 heavy chain (1-449) [humanized VH (Homo sapiens IGHV3-66*01 (81.60%) -(IGHD)-IGHJ6*01 T123>L) [8.8.13] (1-120) - Homo sapiens IGHG1*03 (121-449) CH1 R120>K], (223-214')- disulfide with kappa light chain (1’-214’) [humanized V-KAPPA (Homo sapiens IGKV1-39*01 (86.30%) -IGKJ1*01) [6.3.9] (1'-107') - Homo sapiens IGKC*01 (108'-214')]; (229-229":232-232")- bisdisulfide dimer; conjugated, on an average of 3 to 4 lysyl, to maytansinoid DM1 via a succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) linker For the emtansine part, please refer to the document "INN for pharmaceutical substances: Names for radicals, groups & others"*. antineoplastic
trastuzumab emtansine immunoglobuline G1-kappa, anti-[Homo sapiens ERBB2 (récepteur 2 du facteur de croissance épidermique, HER-2, p185c-erbB2, NEU, EGFR2)]], anticorps monoclonal humanisé conjugué au maytansinoïde DM1; chaîne lourde gamma1 (1-449) [VH humanisé (Homo sapiens IGHV3-66*01 (81.60%) -(IGHD)-IGHJ6*01 T123>L) [8.8.13] (1-120) - Homo sapiens IGHG1*03 (121-449) CH1 R120>K], (223-214')- disulfure avec la chaîne légère kappa (1’-214’) [V-KAPPA humanisé (Homo sapiens IGKV1-39*01 (86.30%) -IGKJ1*01) [6.3.9] (1'-107') - Homo sapiens IGKC*01 (108'-214')]; dimère (229-229":232-232")- bisdisulfure; conjugué, sur 3 à 4 lysyl en moyenne, au maytansinoïde DM1 via un linker succinimidyl-4-(N- maléimidométhyl) cyclohexane-1-carboxylate (SMCC) Pour la partie emtasine, veuillez vous référer au document "INN for pharmaceutical substances: Names for radicals, groups & others"*. antinéoplasique
172 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103
trastuzumab emtansina inmunoglobulina G1-kappa, anti-[Homo sapiens ERBB2 (receptor 2 del factor de crecimiento epidérmico, HER-2, p185c-erbB2, NEU, EGFR2)]], anticuerpo monoclonal humanizado conjugado con maitansinoide DM1; cadena pesada gamma1 (1-449) [VH humanizado (Homo sapiens IGHV3-66*01 (81.60%) -(IGHD)-IGHJ6*01 T123>L) [8.8.13] (1-120) - Homo sapiens IGHG1*03 (121-449) CH1 R120>K], (223-214')- disulfuro con la cadena ligera kappa (1’-214’) [V-KAPPA humanizado (Homo sapiens IGKV1-39*01 (86.30%) -IGKJ1*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dimero (229- 229":232-232")-bisdisulfuro; conjugado, en 3 a 4 residuos lisil por término medio, con el maitansinoide DM1 mediante un conector succinimidil-4-(N-maleimidometil) ciclohexano-1-carboxilato (SMCC) Por la parte emtansina, por favor, vaya al documento "INN for pharmaceutical substances: Names for radicals, groups & others"*. antineoplásico
1018448-65-1
Heavy chain / Chaîne lourde / Cadena pesada EVQLVESGGG LVQPGGSLRL SCAASGFNIK DTYIHWVRQA PGKGLEWVAR 50 IYPTNGYTRY ADSVKGRFTI SADTSKNTAY LQMNSLRAED TAVYYCSRWG 100 GDGFYAMDYW GQGTLVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK 150 DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT 200 YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP 250 KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 300 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ 350 VYTLPPSREE MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV 400 LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPG 449 Light chain / Chaîne légère / Cadena ligera DIQMTQSPSS LSASVGDRVT ITCRASQDVN TAVAWYQQKP GKAPKLLIYS 50 ASFLYSGVPS RFSGSRSGTD FTLTISSLQP EDFATYYCQQ HYTTPPTFGQ 100 GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150 DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200 LSSPVTKSFN RGEC 214 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 147-203 264-324 370-428 22''-96'' 147''-203'' 264''-324'' 370''-428'' Intra-L 23'-88' 134'-194' 23'''-88''' 134'''-194''' Inter-H-L 223-214' 223''-214''' Inter-H-H 229-229'' 232-232''
N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 300, 300''
ulimorelinum ulimorelin (2R,5S,8R,11R)-5-cyclopropyl-11-[(4-fluorophenyl)methyl]- 2,7,8-trimethyl-2,3,4,5,7,8,10,11,13,14,15,16-dodecahydro- 6H-1,4,7,10,13-benzoxatetraazacyclooctadecine-6,9,12-trione growth hormone release stimulating peptide
ulimoréline (2R,5S,8R,11R)-5-cyclopropyl-11-[(4-fluorophényl)méthyl]- 2,7,8-triméthyl-2,3,4,5,7,8,10,11,13,14,15,16-dodécahydro- 6H-1,4,7,10,13-benzoxatétraazacyclooctadécine-6,9,12-trione peptide stimulant la libération de l'hormone de croissance
ulimorelina (2R,5S,8R,11R)-5-ciclopropil-11-[(4-fluorofenil)metil]-2,7,8-trimetil- 2,3,4,5,7,8,10,11,13,14,15,16-dodecahidro-6H-1,4,7,10,13- benzoxatetraazaciclooctadecino-6,9,12(5H)-triona péptido estimulador de la liberación de hormona del crecimiento
173 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010
C30H39FN4O4 842131-33-3
H H C 3 O H N H H O N H3C CH3
HN O H N H F O
umifenovirum umifenovir ethyl 6-bromo-4-[(dimethylamino)methyl]-5-hydroxy-1-methyl- 2-[(phenylsulfanyl)methyl]-1H-indole-3-carboxylate antiviral
umifénovir 6-bromo-4-[(diméthylamino)méthyl]-5-hydroxy-1-méthyl- 2-[(phénylsulfanyl)méthyl]-1H-indole-3-carboxylate d'éthyle antiviral
umifenovir 6-bromo-4-[(dimetilamino)metil]-5-hidroxi-1-metil- 2-[(fenilsulfanil)metil]-1H-indol-3-carboxilato de etilo antiviral
C22H25BrN2O3S 131707-25-0
Br
CH3 HO N H C 3 S N H C 3 O O CH3
umirolimusum umirolimus (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)- 3-{(1R)-2-[(1S,3R,4R)-4-(2-ethoxyethoxy)-3-méthoxycyclohexyl]- 1-methylehyl}-9,27-dihydroxy-10,21-dimethoxy-6,8,12,14,20,26- hexamethyl-3,4,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a- octadecahydro-23,27-epoxy-5H-pyrido[2,1- c][1,4]oxazacyclohentriacontine-1,5,11,28,29(6H,31H)-pentone immunosuppressant
umirolimus (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)- 3-{(1R)-2-[(1S,3R,4R)-4-(2-éthoxyéthoxy)-3-méthoxycyclohexyl]- 1-méthyléthyl}-9,27-dihydroxy-10,21-diméthoxy-6,8,12,14,20,26- hexaméthyl-3,4,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a- octadécahydro-23,27-époxy-5H-pyrido[2,1- c][1,4]oxazacyclohentriacontine-1,5,11,28,29(6H,31H)-pentone immunosuppresseur
174 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103
umirolimús (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)- 3-{(1R)-2-[(1S,3R,4R)-4-(2-etoxietoxi)-3-metoxiciclohexil]-1-metiletil}- 9,27-dihidroxi-10,21-dimetoxi-6,8,12,14,20,26-hexametil- 3,4,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a- octadecahidro-23,27-epoxi-5H-pirido[2,1- c][1,4]oxazaciclohentriacontina-1,5,11,28,29(6H,31H)-pentona inmunosupresor
C55H87NO14 851536-75-9
O CH3 O H H
H3CO H CH3 O O H OH H H H O O H H CH N O 3 CH3 OCH3 CH3 OH H H3C H O H O CH3 H HOCH3 H3C
uridini triacetas uridine triacetate 2',3',5'-tri-O-acetyluridine antidote
triacétate d'uridine 2',3',5'-tri-O-acétyluridine antidote
triacetato de uridina 2',3',5'-tri-O-acetiluridina antídoto
C15H18N2O9 4105-38-8
O
HN O CH3
O O N O
H3C O O CH3
O O
vaniprevirum vaniprevir (5R,7S,10S)-10-tert-butyl-N-{(1R,2R)-1-[N- (cyclopropanesulfonyl)carbamoyl]-2-ethylcyclopropyl}- 15,15-dimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17,18,19- dodecahydro-1H,3H,5H-2,23:5,8-dimethano-4,13,2,8,11- benzodioxatriazacyclohenicosine-7-carboxamide antiviral
175 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010
vaniprévir (5R,7S,10S)-10-tert-butyl-N-{(1R,2R)-1-[N- (cyclopropanesulfonyl)carbamoyl]-2-éthylcyclopropyl}- 15,15-diméthyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17,18,19- dodécahydro-1H,3H,5H-2,23:5,8-diméthano-4,13,2,8,11- benzodioxatriazacyclohénicosine-7-carboxamide antiviral
vaniprevir (5R,7S,10S)-10-terc-butil-N-{(1R,2R)-1-[N- (ciclopropanosulfonil)carbamoil]-2-etilciclopropil} -15,15-dimetil- 3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17,18,19-dodecahidro- 1H,3H,5H-2,23:5,8-dimetano-4,13,2,8,11- benzodioxatriazaciclohenicosina-7-carboxamida antiviral
C38H55N5O9S 923590-37-8
N O H H3C O H3C CH3 H3C H C O O O 3 O H N H N S NH N O H H O O HCH3
vemurafenibum vemurafenib N-{3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl]- 2,4-difluorophenyl}propane-1-sulfonamide antineoplastic
vémurafénib N-{3-[5-(4-chlorophényl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl]- 2,4-difluorophényl}propane-1-sulfonamide antinéoplasique
vemurafenib N-{3-[5-(4-clorofenil)-1H-pirrolo[2,3-b]piridin-3-carbonil]- 2,4-difluorofenil}propano-1-sulfonamida antineoplásico
C23H18ClF2N3O3S 918504-65-1
F HN O O N S N CH3 H O F
Cl
176 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103
verubulinum verubulin N-(4-methoxyphenyl)-N,2-dimethylquinazolin-4-amine antineoplastic
vérubuline N-(4-méthoxyphényl)-N,2-diméthylquinazolin-4-amine antinéoplasique
verubulina N,2-dimetil-N-(4-metoxifenil)quinazolin-4-amina antineoplásico
C17H17N3O 827031-83-4
CH3
OCH3 N N
N CH 3
vidofludimusum vidofludimus 2-[N-(3-fluoro-3'-methoxy[1,1'-biphenyl]-4-yl)carbamoyl]cyclopent- 1-ene-1-carboxylic acid immunosuppressant
vidofludimus acide 2-[N-(3-fluoro-3'-méthoxy[1,1'-biphényl]- 4-yl)carbamoyl]cyclopent-1-ène-1-carboxylique immunosuppresseur
vidofludimús ácido 2-[N-(3-fluoro-3'-metoxi[1,1'-bifenil]-4-il)carbamoil]ciclopent- 1-eno-1-carboxílico inmunosupresor
C20H18FNO4 717824-30-1
F H N CO2H O
OCH3
vilanterolum vilanterol 4-{(1R)-2-[(6-{2-[(2,6-dichlorophenyl)methoxy]ethoxy}hexyl)amino]- 1-hydroxyethyl}-2-(hydroxymethyl)phenol β2-adrenoreceptor agonist
vilantérol 4-{(1R)-2-[(6-{2-[(2,6-dichlorophényl)méthoxy]éthoxy}hexyl)amino]- 1-hydroxyéthyl}-2-(hydroxyméthyl)phénol agoniste des récepteurs β2-adrénergiques
vilanterol 4-{(1R)-2-[(6-{2-[(2,6-diclorofenil)metoxi]etoxi}hexil)amino]- 1-hidroxietil}-2-(hidroximetil)fenol agonista del receptor β2-adrenérgico
177 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010
C24H33Cl2NO5 503068-34-6
Cl H OH H N O O Cl HO
OH
vipadenantum vipadenant 3-[(4-amino-3-methylphenyl)methyl]-7-(furan-2-yl)- 3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine adenosine receptor antagonist
vipadénant 3-[(4-amino-3-méthylphényl)méthyl]-7-(furan-2-yl)- 3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine antagoniste des récepteurs de l'adénosine
vipadenant 3-[(4-amino-3-metilfenil)metil]-7-(furan-2-l)-3H-[1,2,3]triazolo[4,5- d]pirimidin-5-amina antagonista del receptor de adenosina
C16H15N7O 442908-10-3
CH3 O NH2 N N N N N
H2N
vismodegibum vismodegib 2-chloro-N-[4-chloro-3-(pyridin-2-yl)phenyl]- 4-(methanesulfonyl)benzamide antineoplastic
vismodégib 2-chloro-N-[4-chloro-3-(pyridin-2-yl)phényl]- 4-(méthylsulfonyl)benzamide antinéoplasique
vismodegib 2-cloro-N-[4-cloro-3-(piridin-2-il)fenil]-4-(metanosulfonil)benzamida antineoplásico
C19H14Cl2N2O3S 879085-55-9
O O S H3C H N N Cl O Cl
178 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103
vorapaxarum vorapaxar ethyl [(1R,3aR,4aR,6R,8aR,9S,9aS)-9-{(1E)-2-[5-(3- fluorophenyl)pyridine-2-yl]ethen-1-yl}-1-methyl- 3-oxododecahydronaphtho[2,3-c]furan-6-yl]carbamate platelet aggregation inhibitor
vorapaxar [(1R,3aR,4aR,6R,8aR,9S,9aS)-9-{(1E)-2-[5-(3-fluorophényl)pyridin- 2-yl]éthén-1-yl}-1-méthyl-3-oxododécahydronaphto[2,3-c]furan- 6-yl]carbamate d'éthyle antiagrégant plaquettaire
vorapaxar [(1R,3aR,4aR,6R,8aR,9S,9aS)-9-{(1E)-2-[5-(3-fluorofenil)piridin- 2-il]eten-1-il}-1-metil-3-oxododecahidronafto[2,3-c]furan- 6-il]carbamato de etilo inhibidor de la agregación plaquetaria
C29H33FN2O4 618385-01-6
O O H3C H H H H H N O H H
N O CH3 H
F
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Names for Radicals and Groups Some substances for which a proposed international nonproprietary name has been established may be used in the form of salts or esters. The radicals or groups involved may be of complex composition and it is then inconvenient to refer to them in a systematic chemical nomenclature. Consequently, shorter nonproprietary names for some radicals and groups have been devised or selected, and they are suggested for use with the proposed international nonproprietary names.
Dénominations applicables aux radicaux et groupes Certaines substances pour lesquelles une dénomination commune internationale proposée a été établie sont parfois utilisées sous forme de sels ou d'esters. Les radicaux ou groupes correspondants sont alors quelques fois si complexes qu'il est malcommode de les désigner conformément à la nomenclature chimique systématique. Des dénominations communes abrégées ont donc été formées ou choisies pour certains d'entre eux et il est suggéré de les employer avec les dénominations communes internationales proposées.
Denominaciones para Radicales y Grupos Ciertas sustancias para las cuales hay establecidas una denominación común internacional pueden usarse en forma de sales o de ésteres. Los radicales o grupos correspondientes pueden llegar a tener una composición tan compleja que resulte incómodo referirse a ellos mediante la nomenclatura química sistemática. Las siguientes denominaciones comunes abreviadas han sido ideadas o elegidas para algunos de estos radicales y grupos y se sugiere que se empleen con las denominaciones comunes internacionales propuestas.
trifenas trifenate triphenylacetate trifénate triphénylacétate trifenato trifenilacetato
C20H16O2 (acid) 595-91-5 (acid)
CO2
180 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103
AMENDMENTS TO PREVIOUS LISTS MODIFICATIONS APPORTÉES AUX LISTES ANTÉRIEURES MODIFICACIONES A LAS LISTAS ANTERIORES
Proposed International Non Proprietary Names (Prop. INN): List 66 Denominations communes internationales proposées (DCI Prop.): Liste 66 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 66 (WHO Drug Information, Vol. 5, No. 4, 1991) p. 6 gadobutrolum gadobutrol replace the CAS RN by the following gadobutrol remplacer le numéro de reigistre du CAS par le suivant gadobutrol sustitúyase el número de registro del CAS por el siguiente
770691-21-9
Proposed International Non Proprietary Names (Prop. INN): List 88 Denominations communes internationales proposées (DCI Prop.): Liste 88 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 88 (WHO Drug Information, Vol. 17, No. 1, 2003) p. 138 alvocidibum alvocidib replace the chemical name and structure by the following alvocidib remplacer le nom chimique et la structure par les suivants alvocidib sustitúyase el nombre químico et la estructura por los siguientes
(-)-2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin- 4-yl]-4H-1-benzopyran-4-one
(-)-2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin- 4-yl]-4H-1-benzopyran-4-one
(-)-2-(2-chlorofenil)-5,7-dihidroxi-8-[(3S,4R)-3-hidroxi-1-metilpiperidin-4-il]- 4H-1-benzopiran-4-ona
H3C N H OHCl H HO O
OH O
181 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010
Proposed International Non Proprietary Names (Prop. INN): List 89 Denominations communes internationales proposées (DCI Prop.): Liste 89 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 89 (WHO Drug Information, Vol. 17, No. 3, 2003) p. 209 delete/supprimer/suprimáse insert/insérer/insertese ralfinamidum priralfinamidum ralfinamide priralfinamide ralfinamide priralfinamide ralfinamida priralfinamida
Proposed International Non Proprietary Names (Prop. INN): List 98 Denominations communes internationales proposées (DCI Prop.): Liste 98 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 98 (WHO Drug Information, Vol. 21, No. 4, 2007) p. 345 delete/supprimer/suprimáse insert/insérer/insertese quarfloxinum itarnafloxinum quarfloxin itarnafloxin quarfloxine itarnafloxine quarfloxina itarnafloxina
Proposed International Non Proprietary Names (Prop. INN): List 101 Denominations communes internationales proposées (DCI Prop.): Liste 101 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 101 (WHO Drug Information, Vol. 23, No. 2, 2009) p. 132 aganirsenum aganirsen replace the chemical name by the following aganirsén sustitúyase el nombre químico por el siguiente all-P-ambo-P-thiothymidylyl-(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')-thymidine
todo-P-ambo-P-tiotimidilil-(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′)- timidina
182 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103
p. 133 albitiazolii bromidum albitiazolium bromide replace the action and use by the following antimalarial p. 136 bixalomerum bixalomer replace the chemical name by the following bixalomère remplacer le nom chimique par le suivant bixalómero sustitúyase el nombre químico por el siguiente
cross linked polymer made of N,N,N',N'-tetrakis(3-aminopropyl)butane- 1,4-diamine N substituted by bivalent substituent groups 2-hydroxypropane- 1,3-diyl and 1-(hydroxymethyl)ethane-1,2-diyl (x = 20, 45 N,N,N',N'-tétrakis(3-aminopropyl)butane-1,4-diamine N substituée par les groupes substituants divalents 2-hydroxypropane-1,3-diyle et 1-(hydroxyméthyl)éthane-1,2-diyle pour former un polymère réticulé (x = 20, 45 N,N,N',N'-tétrakis(3-aminopropil)butano-1,4-diamina N sustituida por los grupos sustituyentes divalentes 2-hidroxipropano-1,3-diilo y 1-(hidroximetil)etileno para formar un polímero reticulado (x=20, 45 p. 153 supprimer insérer isopropylis turofexoras turofexoras isopropylis isopropyl de turofexorate turofexorate d’isopropyle Proposed International Non Proprietary Names (Prop. INN): List 102 Denominations communes internationales proposees (DCI Prop.): Liste 102 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 102 (WHO Drug Information, Vol. 23, No. 4, 2009) p. 323 cabiotraxetanum cabiotraxetan replace the chemical name by the following cabiotraxétan remplacer le nom chimique par le suivant cabiotraxetán sustitúyase el nombre químico por el siguiente 2,2',2''-[10-(2-{[6-({5-[(3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol- 4-yl]pentyl}amino)hexyl]amino}-2-oxoethyl)-1,4,7,10-tetraazacyclododecane- 1,4,7-triyl]triacetic acid acide 2,2',2''-[10-(2-{[6-({5-[(3aS,4S,6aR)-2-oxohexahydro-1H-thiéno[3,4- d]imidazol-4-yl]pentyl}amino)hexyl]amino}-2-oxoéthyl)-1,4,7,10- tétraazacyclododécane-1,4,7-triyl]triacétique ácido [10-(2-{[6-({5-[(3aS,4S,6aR)-2-oxohexahidro-1H-tieno[3,4-d]imidazol- 4-il]pentil}amino)hexil]amino}-2-oxoetil)-1,4,7,10-tetraazaciclododecano- 1,4,7-triilo]triacético 183 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010 p. 325 dalotuzumabum dalotuzumab remplacer la description par la suivante immunoglobuline G1-kappa, anti-[Homo sapiens IGF1R (récepteur du facteur de croissance 1 analogue à l'insuline (IGF1-R, IGF-1R, CD221)], anticorps monoclonal humanisé; chaîne lourde gamma1 (1-447) [VH humanisé (Homo sapiens IGHV4-61*08 (79.80%) -(IGHD)-IGHJ4*01) [9.7.10] (1-117) -Homo sapiens IGHG1*03 (118-447)], (220-219')-disulfure avec la chaîne légère kappa (1'-219') [V-KAPPA humanisé (Homo sapiens IGKV2-29*02 (78.00%) - IGKJ1*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; dimère (226- 226":229-229")-bisdisulfure p. 338 suprimáse insertese omecantiv mecarbilo omecamtiv mecarbilo * "INN for pharmaceutical substances: Names for radicals, groups & others" document available at / document disponible à / documento disponible en : http://www.who.int/medicines/services/inn/publication/en/index.html # Electronic structure available on Mednet: http://mednet.who.int/ # Structure electronique disponible sur Mednet: http://mednet.who.int/ # Estructura electrónica disponible en Mednet: http://mednet.who.int/ 184 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103 ANNEX 1 PROCEDURE FOR THE SELECTION OF RECOMMENDED INTERNATIONAL NONPROPRIETARY NAMES FOR PHARMACEUTICAL SUBSTANCES1 The following procedure shall be followed by the World Health Organization (hereinafter also referred to as “WHO”) in the selection of recommended international nonproprietary names for pharmaceutical substances, in accordance with resolution WHA3.11 of the World Health Assembly, and in the substitution of such names. Article 1 - Proposals for recommended international nonproprietary names and proposals for substitution of such names shall be submitted to WHO on the form provided therefore. The consideration of such proposals shall be subject to the payment of an administrative fee designed only to cover the corresponding costs of the Secretariat of WHO (“the Secretariat”). The amount of this fee shall be determined by the Secretariat and may, from time to time, be adjusted. Article 2 - Such proposals shall be submitted by the Secretariat to the members of the Expert Advisory Panel on the International Pharmacopoeia and Pharmaceutical Preparations designated for this purpose, such designated members hereinafter referred to as “the INN Expert Group”, for consideration in accordance with the “General principles for guidance in devising International Nonproprietary Names for Pharmaceutical Substances”, annexed to this procedure2. The name used by the person discovering or first developing and marketing a pharmaceutical substance shall be accepted, unless there are compelling reasons to the contrary. Article 3 - Subsequent to the examination provided for in article 2, the Secretariat shall give notice that a proposed international nonproprietary name is being considered. a) Such notice shall be given by publication in WHO Drug Information3 and by letter to Member States and to national and regional pharmacopoeia commissions or other bodies designated by Member States. i) Notice shall also be sent to the person who submitted the proposal (“the original applicant”) and other persons known to be concerned with a name under consideration. b) Such notice shall: i) set forth the name under consideration; ii) identify the person who submitted the proposal for naming the substance, if so requested by such person; iii) identify the substance for which a name is being considered; iv) set forth the time within which comments and objections will be received and the person and place to whom they should be directed; v) state the authority under which WHO is acting and refer to these rules of procedure. c) In forwarding the notice, the Secretariat shall request that Member States take such steps as are necessary to prevent the acquisition of proprietary rights in the proposed name during the period it is under consideration by WHO. Article 4 - Comments on the proposed name may be forwarded by any person to WHO within four months of the date of publication, under article 3, of the name in WHO Drug Information. 1 See Annex 1 in WHO Technical Report Series, No. 581, 1975. The original text was adopted by the Executive Board in resolution EB15.R7 and amended in resolutions EB43.R9 and EB115.R4. 2 See Annex 2. 3 Before 1987, lists of international nonproprietary names were published in the Chronicle of the World Health Organization. 185 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010 Article 5 - A formal objection to a proposed name may be filed by any interested person within four months of the date of publication, under article 3, of the name in WHO Drug Information. Such objection shall: i) identify the person objecting; ii) state his or her interest in the name; iii) set forth the reasons for his or her objection to the name proposed. Article 6 - Where there is a formal objection under article 5, WHO may either reconsider the proposed name or use its good offices to attempt to obtain withdrawal of the objection. Without prejudice to the consideration by WHO of a substitute name or names, a name shall not be selected by WHO as a recommended international nonproprietary name while there exists a formal objection thereto filed under article 5 which has not been withdrawn. Article 7 - Where no objection has been filed under article 5, or all objections previously filed have been withdrawn, the Secretariat shall give notice in accordance with subsection (a) of article 3 that the name has been selected by WHO as a recommended international nonproprietary name. Article 8 - In forwarding a recommended international nonproprietary name to Member States under article 7, the Secretariat shall: a) request that it be recognized as the nonproprietary name for the substance; and b) request that Member States take such steps as are necessary to prevent the acquisition of proprietary rights in the name and to prohibit registration of the name as a trademark or trade name. Article 9 a) In the extraordinary circumstance that a previously recommended international nonproprietary name gives rise to errors in medication, prescription or distribution, or a demonstrable risk thereof, because of similarity with another name in pharmaceutical and/or prescription practices, and it appears that such errors or potential errors cannot readily be resolved through other interventions than a possible substitution of a previously recommended international nonproprietary name, or in the event that a previously recommended international nonproprietary name differs substantially from the nonproprietary name approved in a significant number of Member States, or in other such extraordinary circumstances that justify a substitution of a recommended international nonproprietary name, proposals to that effect may be filed by any interested person. Such proposals shall be submitted on the form provided therefore and shall: i) identify the person making the proposal; ii) state his or her interest in the proposed substitution; and iii) set forth the reasons for the proposal; and iv) describe, and provide documentary evidence regarding the other interventions undertaken in an effort to resolve the situation, and the reasons why these other interventions were inadequate. Such proposals may include a proposal for a new substitute international nonproprietary name, devised in accordance with the General principles, which takes into account the pharmaceutical substance for which the new substitute international nonproprietary name is being proposed. The Secretariat shall forward a copy of the proposal, for consideration in accordance with the procedure described in subsection (b) below, to the INN Expert Group and the original applicant or its successor (if different from the person bringing the proposal for substitution and provided that the original applicant or its successor is known or can be found through diligent effort, including contacts with industry associations). In addition, the Secretariat shall request comments on the proposal from: i) Member States and national and regional pharmacopoeia commissions or other bodies designated by Member States (by including a notice to that effect in the letter referred to in article 3(a), and 186 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103 ii) any other persons known to be concerned by the proposed substitution. The request for comments shall: i) state the recommended international nonproprietary name that is being proposed for substitution (and the proposed substitute name, if provided); ii) identify the person who submitted the proposal for substitution (if so requested by such person); iii) identify the substance to which the proposed substitution relates and reasons put forward for substitution; iv) set forth the time within which comments will be received and the person and place to whom they should be directed; and v) state the authority under which WHO is acting and refer to these rules of procedure. Comments on the proposed substitution may be forwarded by any person to WHO within four months of the date of the request for comments. b) After the time period for comments referred to above has elapsed, the Secretariat shall forward any comments received to the INN Expert Group, the original applicant or its successor and the person bringing the proposal for substitution. If, after consideration of the proposal for substitution and the comments received, the INN Expert Group, the person bringing the proposal for substitution and the original applicant or its successor all agree that there is a need to substitute the previously recommended international nonproprietary name, the Secretariat shall submit the proposal for substitution to the INN Expert Group for further processing. Notwithstanding the foregoing, the original applicant or its successor shall not be entitled to withhold agreement to a proposal for substitution in the event the original applicant or its successor has no demonstrable continuing interest in the recommended international nonproprietary name proposed for substitution. In the event that a proposal for substitution shall be submitted to the INN Expert Group for further processing, the INN Expert Group will select a new international nonproprietary name in accordance with the General principles referred to in article 2 and the procedure set forth in articles 3 to 8 inclusive. The notices to be given by the Secretariat under article 3 and article 7, respectively, including to the original applicant or its successor (if not the same as the person proposing the substitution, and provided that the original applicant or its successor is known or can be found through diligent effort, including contacts with industry associations), shall in such event indicate that the new name is a substitute for a previously recommended international nonproprietary name and that Member States may wish to make transitional arrangements in order to accommodate existing products that use the previously recommended international nonproprietary name on their label in accordance with national legislation. If, after consideration of the proposal for substitution and the comments received in accordance with the procedure described above, the INN Expert Group, the original applicant or its successor and the person bringing the proposal for substitution do not agree that there are compelling reasons for substitution of a previously recommended international nonproprietary name, this name shall be retained (provided always that the original applicant or its successor shall not be entitled to withhold agreement to a proposal for substitution in the event that the original applicant or its successor has no demonstrable continuing interest in the recommended international nonproprietary name proposed to be substituted). In such an event, the Secretariat shall advise the person having proposed the substitution, as well as the original applicant or its successor (if not the same as the person proposing the substitution, and provided that the original applicant or its successor is known or can be found through diligent effort, including contacts with industry associations), Member States, national and regional pharmacopoeia commissions, other bodies designated by Member States, and any other persons known to be concerned by the proposed substitution that, despite a proposal for substitution, it has been decided to retain the previously recommended international nonproprietary name (with a description of the reason(s) why the proposal for substitution was not considered sufficiently compelling). 187 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010 ANNEX 2 GENERAL PRINCIPLES FOR GUIDANCE IN DEVISING INTERNATIONAL NONPROPRIETARY NAMES FOR PHARMACEUTICAL SUBSTANCES1 1. International Nonproprietary Names (INN) should be distinctive in sound and spelling. They should not be inconveniently long and should not be liable to confusion with names in common use. 2. The INN for a substance belonging to a group of pharmacologically related substances should, where appropriate, show this relationship. Names that are likely to convey to a patient an anatomical, physiological, pathological or therapeutic suggestion should be avoided. These primary principles are to be implemented by using the following secondary principles: 3. In devising the INN of the first substance in a new pharmacological group, consideration should be given to the possibility of devising suitable INN for related substances, belonging to the new group. 4. In devising INN for acids, one-word names are preferred; their salts should be named without modifying the acid name, e.g. “oxacillin” and “oxacillin sodium”, “ibufenac” and “ibufenac sodium”. 5. INN for substances which are used as salts should in general apply to the active base or the active acid. Names for different salts or esters of the same active substance should differ only in respect of the name of the inactive acid or the inactive base. For quaternary ammonium substances, the cation and anion should be named appropriately as separate components of a quaternary substance and not in the amine-salt style. 6. The use of an isolated letter or number should be avoided; hyphenated construction is also undesirable. 7. To facilitate the translation and pronunciation of INN, “f” should be used instead of “ph”, “t” instead of “th”, “e” instead of “ae” or “oe”, and “i” instead of “y”; the use of the letters “h” and “k” should be avoided. 8. Provided that the names suggested are in accordance with these principles, names proposed by the person discovering or first developing and marketing a pharmaceutical preparation, or names already officially in use in any country, should receive preferential consideration. 9. Group relationship in INN (see General principle 2) should if possible be shown by using a common stem. The following list contains examples of stems for groups of substances, particularly for new groups. There are many other stems in active use.2 Where a stem is shown without any hyphens it may be used anywhere in the name. Latin English -acum -ac anti-inflammatory agents, ibufenac derivatives -adolum -adol } analgesics -adol- -adol-} -astum -ast antiasthmatic, antiallergic substances not acting primarily as antihistaminics -astinum -astine antihistaminics -azepamum -azepam diazepam derivatives bol bol steroids, anabolic -cain- -cain- class I antiarrhythmics, procainamide and lidocaine derivatives -cainum -caine local anaesthetics 1 In its Twentieth report (WHO Technical Report Series, No. 581, 1975), the WHO Expert committee on Nonproprietary Names for Pharmaceutical Substances reviewed the general principles for devising, and the procedures for selecting, INN in the light of developments in pharmaceutical compounds in recent years. The most significant change has been the extension to the naming of synthetic chemical substances of the practice previously used for substances originating in or derived from natural products. This practice involves the use of a characteristic “stem” indicative of a common property of the members of a group. The reason for, and the implications of, the change are fully discussed. The guiding principles were updated during the 13th consultation on nonproprietary names for pharmaceutical substances (Geneva, 27-29 April 1983) (PHARM S/NOM 928 13 May 1983, revised 18 August 1983). 2 A more extensive listing of stems is contained in the working document WHO/EMP/QSM/2009.3 which is regularly updated and can be requested from the INN Programme, WHO, Geneva. 188 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103 cef- cef- antibiotics, cefalosporanic acid derivatives -cillinum -cillin antibiotics, 6-aminopenicillanic acid derivatives -conazolum -conazole systemic antifungal agents, miconazole derivatives cort cort corticosteroids, except prednisolone derivatives -coxibum -coxib selective cyclo-oxygenase inhibitors -entanum -entan endothelin receptor antagonists gab gab gabamimetic agents gado- gado- diagnostic agents, gadolinium derivatives -gatranum -gatran thrombin inhibitors, antithrombotic agents gest gest steroids, progestogens gli gli antihyperglycaemics io- io- iodine-containing contrast media -metacinum -metacin anti-inflammatory, indometacin derivatives -mycinum -mycin antibiotics, produced by Streptomyces strains -nidazolum -nidazole antiprotozoal substances, metronidazole derivatives -ololum -olol β-adrenoreceptor antagonists -oxacinum -oxacin antibacterial agents, nalidixic acid derivatives -platinum -platin antineoplastic agents, platinum derivatives -poetinum -poetin erythropoietin type blood factors -pril(at)um -pril(at) angiotensin-converting enzyme inhibitors -profenum -profen anti-inflammatory substances, ibuprofen derivatives prost prost prostaglandins -relinum -relin pituitary hormone release-stimulating peptides -sartanum -sartan angiotensin II receptor antagonists, antihypertensive (non-peptidic) -vaptanum -vaptan vasopressin receptor antagonists vin- vin- } vinca-type alkaloids -vin- -vin-} ANNEXE 1 PROCEDURE A SUIVRE EN VUE DU CHOIX DE DENOMINATIONS COMMUNES INTERNATIONALES RECOMMANDEES POUR LES SUBSTANCES PHARMACEUTIQUES1 L’Organisation mondiale de la Santé (également désignée ci-après sous l’appellation « OMS ») observe la procédure exposée ci-dessous pour l’attribution de dénominations communes internationales recommandées pour les substances pharmaceutiques, conformément à la résolution WHA3.11 de l’Assemblée mondiale de la Santé, et pour le remplacement de telles dénominations. Article 1 - Les propositions de dénominations communes internationales recommandées et les propositions de remplacement de telles dénominations sont soumises à l’OMS sur la formule prévue à cet effet. L’examen de telles propositions est soumis au paiement d’une taxe administrative destinée uniquement à couvrir les coûts correspondants assumés par le Secrétariat de l’OMS (« le Secrétariat »). Le montant de cette taxe est déterminé par le Secrétariat et peut être modifié de temps à autre. Article 2 - Ces propositions sont soumises par le Secrétariat aux experts désignés à cette fin parmi les personnalités inscrites au Tableau d’experts de la Pharmacopée internationale et des Préparations pharmaceutiques, ci-après désignés sous l’appellation « le Groupe d’experts des DCI » ; elles sont examinées par les experts conformément aux « Directives générales pour la formation de dénominations communes internationales pour les substances pharmaceutiques » reproduites ci-après2. La dénomination acceptée est la dénomination employée par la personne qui découvre ou qui, la première, fabrique et lance sur le marché une substance pharmaceutique, à moins que des raisons majeures n’obligent à s’écarter de cette règle. 1 Voir annexe 1 dans OMS, Série de Rapports techniques, N° 581, 1975. Le texte original a été adopté par le Conseil exécutif dans sa résolution EB15.R7 et amendé dans ses résolutions EB43.R9 et EB115.R4. 2 Voir annexe 2. 189 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010 Article 3 - Après l’examen prévu à l’article 2, le Secrétariat notifie qu’un projet de dénomination commune internationale est à l’étude. a) Cette notification est faite par une insertion dans WHO Drug Information1 et par l’envoi d’une lettre aux Etats Membres et aux commissions nationales et régionales de pharmacopée ou autres organismes désignés par les Etats Membres. i) Notification est également faite à la personne qui a soumis la proposition (« le demandeur initial ») et à d’autres personnes portant à la dénomination mise à l’étude un intérêt notoire. b) Cette notification contient les indications suivantes : i) dénomination mise à l’étude; ii) nom de l’auteur de la proposition tendant à attribuer une dénomination à la substance, si cette personne le demande ; iii) définition de la substance dont la dénomination est mise à l’étude ; iv) délai pendant lequel seront reçues les observations et les objections à l’égard de cette dénomination ; nom et adresse de la personne habilitée à recevoir ces observations et objections ; v) mention des pouvoirs en vertu desquels agit l’OMS et référence au présent règlement. c) En envoyant cette notification, le Secrétariat demande aux Etats Membres de prendre les mesures nécessaires pour prévenir l’acquisition de droits de propriété sur la dénomination proposée pendant la période au cours de laquelle cette dénomination est mise à l’étude par l’OMS. Article 4 - Des observations sur la dénomination proposée peuvent être adressées à l’OMS par toute personne, dans les quatre mois qui suivent la date de publication de la dénomination dans WHO Drug Information (voir l’article 3). Article 5 - Toute personne intéressée peut formuler une objection formelle contre la dénomination proposée dans les quatre mois qui suivent la date de publication de la dénomination dans WHO Drug Information (voir l’article 3). Cette objection doit s’accompagner des indications suivantes : i) nom de l’auteur de l’objection ; ii) intérêt qu’il ou elle porte à la dénomination en cause ; iii) raisons motivant l’objection contre la dénomination proposée. Article 6 - Lorsqu’une objection formelle est formulée en vertu de l’article 5, l’OMS peut soit soumettre la dénomination proposée à un nouvel examen, soit intervenir pour tenter d’obtenir le retrait de l’objection. Sans préjudice de l’examen par l’OMS d’une ou de plusieurs appellations de remplacement, l’OMS n’adopte pas d’appellation comme dénomination commune internationale recommandée tant qu’une objection formelle présentée conformément à l’article 5 n’est pas levée. Article 7 - Lorsqu’il n’est formulé aucune objection en vertu de l’article 5, ou que toutes les objections présentées ont été levées, le Secrétariat fait une notification conformément aux dispositions du paragraphe a) de l’article 3, en indiquant que la dénomination a été choisie par l’OMS en tant que dénomination commune internationale recommandée. Article 8 - En communiquant aux Etats Membres, conformément à l’article 7, une dénomination commune internationale recommandée, le Secrétariat : a) demande que cette dénomination soit reconnue comme dénomination commune de la substance considérée ; et b) demande aux Etats Membres de prendre les mesures nécessaires pour prévenir l’acquisition de droits de propriété sur cette dénomination et interdire le dépôt de cette dénomination comme marque ou appellation commerciale. 1 Avant 1987, les listes de dénominations communes internationales étaient publiées dans la Chronique de l’Organisation mondiale de la Santé. 190 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103 Article 9 - a) Dans le cas exceptionnel où une dénomination commune internationale déjà recommandée donne lieu à des erreurs de médication, de prescription ou de distribution ou en comporte un risque démontrable, en raison d’une similitude avec une autre appellation dans la pratique pharmaceutique et/ou de prescription, et où il apparaît que ces erreurs ou ces risques d’erreur ne peuvent être facilement évités par d’autres interventions que le remplacement éventuel d’une dénomination commune internationale déjà recommandée, ou dans le cas où une dénomination commune internationale déjà recommandée diffère sensiblement de la dénomination commune approuvée dans un nombre important d’Etats Membres, ou dans d’autres circonstances exceptionnelles qui justifient le remplacement d’une dénomination commune internationale recommandée, toute personne intéressée peut formuler une proposition dans ce sens. Cette proposition est présentée sur la formule prévue à cet effet et doit s’accompagner des indications suivantes : i) nom de l’auteur de la proposition ; ii) intérêt qu’il ou elle porte au remplacement proposé ; iii) raisons motivant la proposition ; et iv) description, faits à l’appui, des autres interventions entreprises pour tenter de régler le problème et exposé des raisons pour lesquelles ces interventions ont échoué. Les propositions peuvent comprendre une proposition de nouvelle dénomination commune internationale de remplacement, établie conformément aux Directives générales, compte tenu de la substance pharmaceutique pour laquelle la nouvelle dénomination commune internationale de remplacement est proposée. Le Secrétariat transmet une copie de la proposition pour examen, conformément à la procédure exposée plus loin au paragraphe b), au Groupe d’experts des DCI et au demandeur initial ou à son successeur (s’il s’agit d’une personne différente de celle qui a formulé la proposition de remplacement et pour autant que le demandeur initial ou son successeur soit connu ou puisse être retrouvé moyennant des efforts diligents, notamment des contacts avec les associations industrielles). De plus, le Secrétariat demande aux entités et personnes ci-après de formuler des observations sur la proposition : i) les Etats Membres et les commissions nationales et régionales de pharmacopée ou d’autres organismes désignés par les Etats Membres (en insérant une note à cet effet dans la lettre mentionnée à l’article 3.a), et ii) toutes autres personnes portant au remplacement proposé un intérêt notoire. La demande d’observations contient les indications suivantes : i) dénomination commune internationale recommandée pour laquelle un remplacement est proposé (et la dénomination de remplacement proposée, si elle est fournie) ; ii) nom de l’auteur de la proposition de remplacement (si cette personne le demande) ; iii) définition de la substance faisant l’objet du remplacement proposé et raisons avancées pour le remplacement ; iv) délai pendant lequel seront reçus les commentaires et nom et adresse de la personne habilitée à recevoir ces commentaires ; et v) mention des pouvoirs en vertu desquels agit l’OMS et référence au présent règlement. Des observations sur la proposition de remplacement peuvent être communiquées par toute personne à l’OMS dans les quatre mois qui suivent la date de la demande d’observations. b) Une fois échu le délai prévu ci-dessus pour la communication d’observations, le Secrétariat transmet les observations reçues au Groupe d’experts des DCI, au demandeur initial ou à son successeur et à l’auteur de la proposition de remplacement. Si, après avoir examiné la proposition de remplacement et les observations reçues, le Groupe d’experts des DCI, l’auteur de la proposition de remplacement et le demandeur initial ou son successeur reconnaissent tous qu’il est nécessaire de remplacer la dénomination commune internationale déjà recommandée, le Secrétariat soumet la proposition de remplacement au Groupe d’experts des DCI pour qu’il y donne suite. 191 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010 Nonobstant ce qui précède, le demandeur initial ou son successeur n’est pas habilité à refuser son accord à une proposition de remplacement au cas où il ne peut être démontré qu’il porte un intérêt durable à la dénomination commune internationale recommandée qu’il est proposé de remplacer. Dans le cas où une proposition de remplacement est soumise au Groupe d’experts des DCI pour qu’il y donne suite, le Groupe choisit une nouvelle dénomination commune internationale conformément aux Directives générales mentionnées à l’article 2 et selon la procédure décrite dans les articles 3 à 8 inclus. La notification faite par le Secrétariat en vertu de l’article 3 et de l’article 7, respectivement, y compris au demandeur initial ou à son successeur (si ce n’est pas la même personne que celle qui a proposé le remplacement et pour autant que le demandeur initial ou son successeur soit connu ou puisse être retrouvé moyennant des efforts diligents, notamment des contacts avec les associations industrielles), doit dans un tel cas indiquer que la nouvelle dénomination remplace une dénomination commune internationale déjà recommandée et que les Etats Membres peuvent souhaiter prendre des mesures transitoires pour les produits existants qui utilisent la dénomination commune internationale déjà recommandée sur leur étiquette conformément à la législation nationale. Si, après examen de la proposition de remplacement et des observations communiquées conformément à la procédure exposée plus haut, le Groupe d’experts des DCI, le demandeur initial ou son successeur et l’auteur de la proposition de remplacement ne s’accordent pas sur le fait qu’il y a des raisons impératives de remplacer une dénomination commune internationale déjà recommandée, cette dernière est conservée (étant entendu toujours que le demandeur initial ou son successeur n’est pas habilité à refuser son accord à une proposition de remplacement au cas où il ne peut être démontré qu’il porte un intérêt durable à la dénomination commune internationale recommandée qu’il est proposé de remplacer). Dans un tel cas, le Secrétariat informe l’auteur de la proposition de remplacement, ainsi que le demandeur initial ou son successeur (s’il s’agit d’une personne différente de celle qui a formulé la proposition de remplacement et pour autant que le demandeur initial ou son successeur soit connu ou puisse être retrouvé moyennant des efforts diligents, notamment des contacts avec les associations industrielles), les Etats Membres, les commissions nationales et régionales de pharmacopée, les autres organismes désignés par les Etats Membres et toutes autres personnes portant un intérêt notoire au remplacement proposé que, malgré une proposition de remplacement, il a été décidé de conserver la dénomination commune internationale déjà recommandée (avec une brève description de la ou des raisons pour lesquelles la proposition de remplacement n’a pas été jugée suffisamment impérative). ANNEXE 2 DIRECTIVES GENERALES POUR LA FORMATION DE DENOMINATIONS COMMUNES INTERNATIONALES APPLICABLES AUX SUBSTANCES PHARMACEUTIQUES1 1. Les dénominations communes internationales (DCI) devront se distinguer les unes des autres par leur consonance et leur orthographe. Elles ne devront pas être d’une longueur excessive, ni prêter à confusion avec des appellations déjà couramment employées. 2. La DCI de chaque substance devra, si possible, indiquer sa parenté pharmacologique. Les dénominations susceptibles d’évoquer pour les malades des considérations anatomiques, physiologiques, pathologiques ou thérapeutiques devront être évitées dans la mesure du possible. Outre ces deux principes fondamentaux, on respectera les principes secondaires suivants : Lorsqu’on formera la DCI de la première substance d’un nouveau groupe pharmacologique, on tiendra compte de la possibilité de former ultérieurement d’autres DCI appropriées pour les substances apparentées du même groupe. 1 Dans son vingtième rapport (OMS, Série de Rapports techniques, N° 581, 1975), le Comité OMS d’experts des Dénominations communes pour les Substances pharmaceutiques a examiné les directives générales pour la formation des dénominations communes internationales et la procédure à suivre en vue de leur choix, compte tenu de l’évolution du secteur pharmaceutique au cours des dernières années. La modification la plus importante a été l’extension aux substances de synthèse de la pratique normalement suivie pour désigner les substances tirées ou dérivées de produits naturels. Cette pratique consiste à employer des syllabes communes ou groupes de syllabes communes (segments-clés) qui sont caractéristiques et indiquent une propriété commune aux membres du groupe des substances pour lequel ces segments-clés ont été retenus. Les raisons et les conséquences de cette modification ont fait l’objet de discussions approfondies. Les directives ont été mises à jour lors de la treizième consultation sur les dénominations communes pour les substances pharmaceutiques (Genève, 27-29 avril 1983) (PHARM S/NOM 928, 13 mai 1983, révision en date du 18 août 1983). 192 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103 4. Pour former des DCI des acides, on utilisera de préférence un seul mot. Leurs sels devront être désignés par un terme qui ne modifie pas le nom de l’acide d’origine : par exemple «oxacilline» et «oxacilline sodique», «ibufénac» et «ibufénac sodique». 5. Les DCI pour les substances utilisées sous forme de sels devront en général s’appliquer à la base active (ou à l’acide actif). Les dénominations pour différents sels ou esters d’une même substance active ne différeront que par le nom de l’acide inactif (ou de la base inactive). En ce qui concerne les substances à base d’ammonium quaternaire, la dénomination s’appliquera de façon appropriée au cation et à l’anion en tant qu’éléments distincts d’une substance quaternaire. On évitera de choisir une désignation évoquant un sel aminé. 6. On évitera d’ajouter une lettre ou un chiffre isolé ; en outre, on renoncera de préférence au trait d’union. 7. Pour simplifier la traduction et la prononciation des DCI, la lettre « f » sera utilisée à la place de « ph », « t » à la place de « th », « e » à la place de « ae » ou « oe », et « i » à la place de « y » ; l’usage des lettres « h » et « k » sera aussi évité. 8. On retiendra de préférence, pour autant qu’elles respectent les principes énoncés ici, les dénominations proposées par les personnes qui ont découvert ou qui, les premières, ont fabriqué et lancé sur le marché les préparations pharmaceutiques considérées, ou les dénominations déjà officiellement adoptées par un pays. 9. La parenté entre substances d’un même groupe (voir Directive générale 2) sera si possible indiquée dans les DCI par l’emploi de segments-clés communs. La liste ci-après contient des exemples de segments-clés pour des groupes de substances, surtout pour des groupes récents. Il y a beaucoup d’autres segments-clés en utilisation active. 1 Les segments- clés indiqués sans trait d’union pourront être insérés n’importe où dans une dénomination. Latin Français -acum -ac substances anti-inflammatoires du groupe de l’ibufénac -adolum -adol } analgésiques -adol- -adol- } -astum -ast antiasthmatiques, antiallergiques n’agissant pas principalement en tant qu’antihistaminiques -astinum -astine antihistaminiques -azepamum -azépam substances du groupe du diazépam bol bol stéroïdes anabolisants -cain- -caïn- antiarythmiques de classe I, dérivés du procaïnamide et de la lidocaïne -cainum -caïne anesthésiques locaux cef- céf- antibiotiques, dérivés de l’acide céphalosporanique -cillinum -cilline antibiotiques, dérivés de l’acide 6-aminopénicillanique -conazolum -conazole agents antifongiques systémiques du groupe du miconazole cort cort corticostéroïdes, autres que les dérivés de la prednisolone -coxibum -coxib inhibiteurs sélectifs de la cyclo-oxygénase -entanum -entan antagonistes du récepteur de l’endothéline gab gab gabamimétiques gado- gado- agents diagnostiques, dérivés du gadolinium -gatranum -gatran antithrombines, antithrombotiques gest gest stéroïdes progestogènes gli gli antihyperglycémiants io- io- produits de contraste iodés -metacinum -métacine substances anti-inflammatoires du groupe de l’indométacine -mycinum -mycine antibiotiques produits par des souches de Streptomyces -nidazolum -nidazole substances antiprotozoaires du groupe du métronidazole -ololum -olol antagonistes des récepteurs β-adrénergiques -oxacinum -oxacine substances antibactériennes du groupe de l’acide nalidixique -platinum -platine antinéoplasiques, dérivés du platine -poetinum -poétine facteurs sanguins de type érythropoïétine -pril(at)um -pril(ate) inhibiteurs de l’enzyme de conversion de l’angiotensine -profenum -profène substances anti-inflammatoires du groupe de l’ibuprofène prost prost prostaglandines 1 Une liste plus complète de segments-clés est contenue dans le document de travail WHO/EMP/QSM/2009.3 qui est régulièrement mis à jour et qui peut être demandé auprès du programme des DCI, OMS, Genève. 193 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010 -relinum -réline peptides stimulant la libération d’hormones hypophysaires -sartanum -sartan antagonistes d’un récepteur de l’angiotensine II, antihypertenseurs (non peptidiques) -vaptanum -vaptan antagonistes du récepteur de la vasopressine vin- vin- } alcaloïdes du type vinca -vin- -vin- } ANEXO 1 PROCEDIMIENTO DE SELECCIÓN DE DENOMINACIONES COMUNES INTERNACIONALES RECOMENDADAS PARA SUSTANCIAS FARMACÉUTICAS1 La Organización Mundial de la Salud (OMS) seguirá el procedimiento que se expone a continuación tanto para seleccionar denominaciones comunes internacionales recomendadas para las sustancias farmacéuticas, de conformidad con lo dispuesto en la resolución WHA3.11, como para sustituir esas denominaciones. Artículo 1 - Las propuestas de denominaciones comunes internacionales recomendadas y las propuestas de sustitución de esas denominaciones se presentarán a la OMS en los formularios que se proporcionen a estos efectos. El estudio de estas propuestas estará sujeto al pago de una tasa destinada a sufragar los costos de administración que ello suponga para la Secretaría de la OMS («la Secretaría»). La Secretaría establecerá la cuantía de esa tasa y podrá ajustarla periódicamente. Artículo 2 - Estas propuestas serán sometidas por la Secretaría a los miembros del Cuadro de Expertos en Farmacopea Internacional y Preparaciones Farmacéuticas encargados de su estudio, en adelante designados como «el Grupo de Expertos en DCI», para que las examinen de conformidad con los «Principios generales de orientación para formar denominaciones comunes internacionales para sustancias farmacéuticas», anexos a este procedimiento.2 A menos que haya poderosas razones en contra, la denominación aceptada será la empleada por la persona que haya descubierto o fabricado y comercializado por primera vez esa sustancia farmacéutica. Artículo 3 - Tras el examen al que se refiere el artículo 2, la Secretaría notificará que está en estudio un proyecto de denominación internacional. a) Esa notificación se hará mediante una publicación en Información Farmacéutica OMS3 y el envío de una carta a los Estados Miembros y a las comisiones nacionales y regionales de las farmacopeas u otros organismos designados por los Estados Miembros. i) La notificación será enviada también a la persona que haya presentado la propuesta («el solicitante inicial») y a otras personas que tengan un interés especial en una denominación objeto de estudio. b) En esa notificación se incluirán los siguientes datos: i) la denominación sometida a estudio; ii) la identidad de la persona que ha presentado la propuesta de denominación de la sustancia, si lo pide esa persona; iii) la identidad de la sustancia cuya denominación está en estudio; iv) el plazo fijado para recibir observaciones y objeciones, así como el nombre y la dirección de la persona a quien deban dirigirse; y v) los poderes conferidos para el caso a la OMS y una referencia al presente procedimiento. 1 Véase el anexo 1 en OMS, Serie de Informes Técnicos, Nº 581, 1975. El texto vigente fue adoptado por el Consejo Ejecutivo en su resolución EB15.R7 y modificado en las resoluciónes EB43.R9 y EB115.R4.. 2 Véase el anexo 2. 3 Hasta 1987 las listas de DCI se publicaban en la Crónica de la Organización Mundial de la Salud. 194 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103 c) Al enviar esa notificación, la Secretaría solicitará de los Estados Miembros la adopción de todas las medidas necesarias para impedir la adquisición de derechos de patente sobre la denominación propuesta, durante el periodo en que la OMS la tenga en estudio. Artículo 4 - Toda persona puede formular a la OMS observaciones sobre la denominación propuesta dentro de los cuatro meses siguientes a su publicación en Información Farmacéutica OMS, conforme a lo dispuesto en el artículo 3. Artículo 5 - Toda persona interesada puede presentar una objeción formal a una denominación propuesta dentro de los cuatro meses siguientes a su publicación en Información Farmacéutica OMS, conforme a lo dispuesto en el artículo 3. Esa objeción deberá acompañarse de los siguientes datos: i) la identidad de la persona que formula la objeción; ii) las causas que motivan su interés por la denominación; y iii) las causas que motivan su objeción a la denominación propuesta. Artículo 6 - Cuando se haya presentado una objeción formal en la forma prevista en el artículo 5, la OMS podrá reconsiderar el nombre propuesto o utilizar sus buenos oficios para intentar lograr que se retire la objeción. La OMS no seleccionará como denominación común internacional una denominación a la que se haya hecho una objeción formal, presentada según lo previsto en el artículo 5, que no haya sido retirada, todo ello sin perjuicio de que la Organización examine otra denominación o denominaciones sustitutivas. Artículo 7 - Cuando no se haya formulado ninguna objeción en la forma prevista en el artículo 5, o cuando todas las objeciones presentadas hayan sido retiradas, la Secretaría notificará, conforme a lo dispuesto en el párrafo a) del artículo 3, que la denominación ha sido seleccionada por la OMS como denominación común internacional recomendada. Artículo 8 - Al comunicar a los Estados Miembros una denominación común internacional, conforme a lo previsto en el artículo 7, la Secretaría: a) solicitará que esta denominación sea reconocida como denominación común para la sustancia de que se trate; y b) solicitará a los Estados Miembros que adopten todas las medidas necesarias para impedir la adquisición de derechos de patente sobre la denominación, y prohíban que sea registrada como marca de fábrica o como nombre comercial. Artículo 9 a) En el caso excepcional de que, debido a su semejanza con otra denominación utilizada en las prácticas farmacéuticas y/o de prescripción, una denominación común internacional recomendada anteriormente ocasione errores de medicación, prescripción o distribución, o suponga un riesgo manifiesto de que esto ocurra, y parezca que tales errores o potenciales errores no sean fácilmente subsanables con otras medidas que no sean la posible sustitución de esa denominación común internacional recomendada anteriormente; en el caso de que una denominación común internacional recomendada anteriormente difiera considerablemente de la denominación común aprobada en un número importante de Estados Miembros, o en otras circunstancias excepcionales que justifiquen el cambio de una denominación común internacional recomendada, cualquier persona interesada puede presentar propuestas en este sentido. Esas propuestas se presentarán en los formularios que se proporcionen a estos efectos e incluirán los siguientes datos: i) la identidad de la persona que presenta la propuesta; ii) las causas que motivan su interés en la sustitución propuesta; iii) las causas que motivan la propuesta; y iv) una descripción, acompañada de pruebas documentales, de las otras medidas que se hayan adoptado con el fin de resolver la situación y de los motivos por los cuales dichas medidas no han sido suficientes. Entre esas propuestas podrá figurar una relativa a una nueva denominación común internacional sustitutiva, formulada con arreglo a los Principios generales y que tenga en cuenta la sustancia farmacéutica para la que se proponga la nueva denominación común internacional sustitutiva. La Secretaría enviará al Grupo de Expertos en DCI y al solicitante inicial o a su sucesor (en el caso de que sea una persona diferente de la que ha presentado la propuesta de sustitución y siempre que el solicitante inicial o su sucesor sean conocidos o puedan ser encontrados mediante esfuerzos diligentes, como el contacto con las asociaciones 195 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010 industriales) una copia de la propuesta, para que sea examinada de conformidad con el procedimiento descrito en el párrafo b) infra. Además, la Secretaría solicitará observaciones sobre la propuesta: i) a los Estados Miembros y a las comisiones nacionales y regionales de las farmacopeas u otros organismos designados por los Estados Miembros (ello se hará incluyendo una notificación a tal efecto en la carta a la que se refiere el párrafo a) del artículo 3), y ii) a cualquier persona que tenga un interés especial en la sustitución propuesta. Al solicitar que se formulen estas observaciones se facilitarán los siguientes datos: i) la denominación común internacional recomendada que se propone sustituir (y la denominación sustitutiva propuesta, si se ha facilitado); ii) la identidad de la persona que ha presentado la propuesta de sustitución (si lo pide esa persona); iii) la identidad de la sustancia a la que se refiere la sustitución propuesta y las razones para presentar la propuesta de sustitución; iv) el plazo fijado para recibir observaciones, así como el nombre y la dirección de la persona a quien deban dirigirse; y v) los poderes conferidos para el caso a la OMS y una referencia al presente procedimiento. Toda persona puede formular a la OMS observaciones sobre la sustitución propuesta dentro de los cuatro meses siguientes a la fecha en que se realizó la solicitud de observaciones. b) Una vez agotado el mencionado plazo para la formulación de observaciones, la Secretaría enviará todos los comentarios recibidos al Grupo de Expertos en DCI, al solicitante inicial o a su sucesor, y a la persona que haya presentado la propuesta de sustitución. Si después de examinar la propuesta de sustitución y las observaciones recibidas, el Grupo de Expertos en DCI, la persona que haya presentado la propuesta de sustitución y el solicitante inicial, o su sucesor, están de acuerdo en la necesidad de sustituir la denominación común internacional recomendada anteriormente, la Secretaría remitirá la propuesta de sustitución al Grupo de Expertos en DCI para que la tramite. No obstante lo anterior, el solicitante inicial o su sucesor no tendrán derecho a impedir el acuerdo sobre una propuesta de sustitución en el caso de que hayan dejado de tener un interés demostrable en la denominación común internacional cuya sustitución se propone. En caso de que la propuesta de sustitución sea presentada al Grupo de Expertos en DCI para que la tramite, este grupo seleccionará una nueva denominación común internacional de conformidad con los Principios generales a los que se refiere el artículo 2 y al procedimiento establecido en los artículos 3 a 8 inclusive. En ese caso, en las notificaciones que la Secretaría ha de enviar con arreglo a los artículos 3 y 7, respectivamente, incluida la notificación al solicitante inicial o a su sucesor (en el caso de que no sea la misma persona que propuso la sustitución y siempre que el solicitante inicial o su sucesor sean conocidos o puedan ser encontrados mediante esfuerzos diligentes, como el contacto con las asociaciones industriales), se indicará que la nueva denominación sustituye a una denominación común internacional recomendada anteriormente y que los Estados Miembros podrán, si lo estiman oportuno, adoptar disposiciones transitorias aplicables a los productos existentes en cuya etiqueta se utilice, con arreglo a la legislación nacional, la denominación común internacional recomendada anteriormente que se haya sustituido. En caso de que, después de haber estudiado la propuesta de sustitución y los comentarios recibidos de conformidad con el procedimiento descrito anteriormente, el Grupo de Expertos en DCI, el solicitante inicial o su sucesor y la persona que haya presentado la propuesta de sustitución no lleguen a un acuerdo sobre la existencia de razones poderosas para sustituir una denominación común internacional recomendada anteriormente, esta denominación se mantendrá (siempre en el entendimiento de que el solicitante inicial o su sucesor no tendrán derecho a impedir el acuerdo sobre una propuesta de sustitución en el caso de que hayan dejado de tener un interés demostrable en la denominación común internacional cuya sustitución se propone). En ese caso, la Secretaría comunicará a la persona que haya propuesto la sustitución, así como al solicitante inicial o a su sucesor (en el caso de que no sea la misma persona que propuso la sustitución y siempre que el solicitante inicial o su sucesor sean conocidos o puedan ser encontrados mediante esfuerzos diligentes, como el contacto con las asociaciones industriales), a los Estados Miembros, a las comisiones nacionales y regionales de las farmacopeas o a otros organismos designados por los Estados Miembros y a cualquier otra persona que tenga interés en la sustitución 196 WHO Drug Information Vol. 24, No. 2, 2010 Proposed INN: List 103 propuesta, que, pese a la presentación de una propuesta de sustitución, se ha decidido mantener la denominación común internacional recomendada anteriormente (con una descripción de la o las razones por las que se ha considerado que la propuesta de sustitución no estaba respaldada por razones suficientemente poderosas). ANEXO 2 PRINCIPIOS GENERALES DE ORIENTACIÓN PARA FORMAR DENOMINACIONES 1 COMUNES INTERNACIONALES PARA SUSTANCIAS FARMACÉUTICAS 1. Las denominaciones comunes internacionales (DCI) deberán diferenciarse tanto fonética como ortográficamente. No deberán ser incómodamente largas, ni dar lugar a confusión con denominaciones de uso común. 2. La DCI de una sustancia que pertenezca a un grupo de sustancias farmacológicamente emparentadas deberá mostrar apropiadamente este parentesco. Deberán evitarse las denominaciones que puedan tener connotaciones anatómicas, fisiológicas, patológicas o terapéuticas para el paciente. Estos principios primarios se pondrán en práctica utilizando los siguientes principios secundarios: 3. Al idear la DCI de la primera sustancia de un nuevo grupo farmacológico, deberá tenerse en cuenta la posibilidad de poder formar DCI convenientes para las sustancias emparentadas que se agreguen al nuevo grupo. 4. Al idear DCI para ácidos, se preferirán las de una sola palabra; sus sales deberán denominarse sin modificar el nombre del ácido: p. ej. «oxacilina» y «oxacilina sódica», «ibufenaco» y «ibufenaco sódico». 5. Las DCI para las sustancias que se usan en forma de sal deberán en general aplicarse a la base activa o al ácido activo. Las denominaciones para diferentes sales o esteres de la misma sustancia activa solamente deberán diferir en el nombre del ácido o de la base inactivos. En los compuestos de amonio cuaternario, el catión y el anión deberán denominarse adecuadamente por separado, como componentes independientes de una sustancia cuaternaria y no como sales de una amina. 6. Deberá evitarse el empleo de letras o números aislados; también es indeseable el empleo de guiones. 7. Para facilitar la traducción y la pronunciación, se emplearán de preferencia las letras «f» en lugar de «ph», «t» en lugar de «th», «e» en lugar de «ae» u «oe», e «i» en lugar de «y»; se deberá evitar el empleo de las letras «h» y «k». 8. Siempre que las denominaciones propuestas estén de acuerdo con estos principios, recibirán una consideración preferente las denominaciones propuestas por la persona que haya descubierto las sustancias, o que fabrique y comercialice por primera vez una sustancia farmacéutica, así como las denominaciones ya adoptadas oficialmente en cualquier país. 9. El parentesco entre sustancias del mismo grupo se pondrá de manifiesto en las DCI (véase el Principio 2) utilizando una partícula común. En la lista que figura a continuación se indican ejemplos de partículas para grupos de sustancias, en particular para grupos nuevos. Existen muchas otras partículas que se usan habitualmente.2 Cuando una partícula aparece sin guión alguno, puede utilizarse en cualquier lugar de la palabra. 1 En su 20º informe (OMS, Serie de Informes Técnicos, Nº 581, 1975), el Comité de Expertos de la OMS en Denominaciones Comunes para las Sustancias Farmacéuticas revisó los Principios generales para formar denominaciones comunes internacionales (DCI), y su procedimiento de selección, a la luz de las novedades registradas en los últimos años en materia de compuestos farmacéuticos. El cambio más importante había consistido en hacer extensivo a la denominación de sustancias químicas sintéticas el método utilizado hasta entonces para las sustancias originadas en productos naturales o derivadas de éstos. Dicho método conlleva la utilización de una «partícula» característica que indica una propiedad común a los miembros de un grupo. En el citado informe se examinan en detalle las razones y consecuencias de este cambio. Los Principios generales de orientación se actualizaron durante la 13ª consulta sobre denominaciones comunes para sustancias farmacéuticas (Ginebra, 27 a 29 de abril de 1983) (PHARM S/NOM 928, 13 de mayo de 1983, revisado el 18 de agosto de 1983). 2 En el documento de trabajo WHO/EMP/QSM/2009.3, que se actualiza periódicamente y puede solicitarse al Programa sobre Denominaciones Comunes Internacionales, OMS, Ginebra, figura una lista más amplia de partículas. 197 Proposed INN: List 103 WHO Drug Information Vol. 24, No. 2, 2010 Latin Español -acum -aco antiinflamatorios derivados del ibufenaco -adolum -adol ) analgésicos -adol- -adol- ) -astum -ast antiasmáticos, sustancias antialérgicas cuya acción principal no es la antihistamínica -astinum -astina antihistamínicos -azepamum -azepam derivados del diazepam bol bol esteroides anabolizantes -cain- -caína- antiarrítmicos de clase I, derivados de procainamida y lidocaína -cainum -caína- anestésicos locales cef- cef- antibióticos, derivados del ácido cefalosporánico -cillinum - cilina antibióticos derivados del ácido 6-aminopenicilánico -conazolum -conazol antifúngicos sistémicos derivados del miconazol cort cort corticosteroides, excepto derivados de prednisolona -coxibum -coxib inhibidores selectivos de ciclooxigenasa -entanum -entán antagonistas del receptor de endotelina gab gab gabamiméticos gado- gado- agentes para diagnóstico derivados de gadolinio -gartranum -gatrán inhibidores de la trombina antitrombóticos gest gest esteroides progestágenos gli gli hipoglucemiantes, antihiperglucémicos io- io- medios de contraste iodados -metacinum -metacina antiinflamatorios derivados de indometacina -mycinum -micina antibióticos producidos por cepas de Streptomyces -nidazolum -nidazol antiprotozoarios derivados de metronidazol -ololum -olol antagonistas de receptores β-adrenérgicos -oxacinum -oxacino antibacterianos derivados del ácido nalidíxico -platinum -platino antineoplásicos derivados del platino -poetinum -poetina factores sanguíneos similares a la eritropoyetina -pril(at)um -pril(at) inhibidores de la enzima conversora de la angiotensina -profenum -profeno antiinflamatorios derivados del ibuprofeno prost prost prostaglandinas -relinum -relina péptidos estimulantes de la liberación de hormonas hipofisarias -sartanum -sartán antihipertensivos (no peptídicos) antagonistas del receptorde angiotensina II -vaptanum -vaptán antagonistas del receptor de vasopresina vin- vin- ) alcaloides de la vinca -vin- -vin- ) 198